@article {284, title = {Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability.}, journal = {Mol Cell}, volume = {61}, year = {2016}, month = {2016 Feb 18}, pages = {535-46}, abstract = {

XPG is a structure-specific endonuclease required for nucleotide excision repair, and incision-defective XPG mutations cause the skin cancer-prone syndrome xeroderma pigmentosum. Truncating mutations instead cause the neurodevelopmental progeroid disorder Cockayne syndrome, but little is known about how XPG loss results in this devastating disease. We identify XPG as a partner of BRCA1 and BRCA2 in maintaining genomic stability through homologous recombination (HRR). XPG depletion causes DNA double-strand breaks, chromosomal abnormalities, cell-cycle delays, defective HRR, inability to overcome replication fork stalling, and replication stress. XPG directly interacts with BRCA2, RAD51, and PALB2, and XPG depletion reduces their chromatin binding and subsequent RAD51 foci formation. Upstream in HRR, XPG interacts directly with BRCA1. Its depletion causes BRCA1 hyper-phosphorylation and persistent chromatin binding. These unexpected findings establish XPG as an HRR protein with important roles in genome stability and suggest how XPG defects produce severe clinical consequences including cancer and accelerated aging.

}, keywords = {Animals, BRCA1 Protein, BRCA2 Protein, Cell Line, Tumor, Cockayne Syndrome, DNA Repair, DNA-Binding Proteins, Endonucleases, Genome, Human, Genomic Instability, HeLa Cells, Homologous Recombination, Humans, Mice, Nuclear Proteins, Phosphorylation, Rad51 Recombinase, Transcription Factors, Tumor Suppressor Proteins}, issn = {1097-4164}, doi = {10.1016/j.molcel.2015.12.026}, author = {Trego, Kelly S and Groesser, Torsten and Davalos, Albert R and Parplys, Ann C and Zhao, Weixing and Nelson, Michael R and Hlaing, Ayesu and Shih, Brian and Rydberg, Bjorn and Pluth, Janice M and Tsai, Miaw-Sheue and Hoeijmakers, Jan H J and Sung, Patrick and Wiese, Claudia and Campisi, Judith and Cooper, Priscilla K} } @article {227, title = {Cul4A overexpression associated with Gli1 expression in malignant pleural mesothelioma.}, journal = {J Cell Mol Med}, volume = {19}, year = {2015}, month = {2015 Oct}, pages = {2385-96}, abstract = {

Malignant pleural mesothelioma (mesothelioma) is a highly aggressive cancer without an effective treatment. Cul4A, a scaffold protein that recruits substrates for degradation, is amplified in several human cancers, including mesothelioma. We have recently shown that Cul4A plays an oncogenic role in vitro and in a mouse model. In this study, we analysed clinical mesothelioma tumours and found moderate to strong expression of Cul4A in 70.9\% (51/72) of these tumours, as shown by immunohistochemistry. In 72.2\% mesothelioma tumours with increased Cul4A copy number identified by fluorescence in situ hybridization analysis, Cul4A protein expression was moderate to strong. Similarly, Cul4A was overexpressed and Cul4A copy number was increased in human mesothelioma cell lines. Because Gli1 is highly expressed in human mesothelioma cells, we compared Cul4A and Gli1 expression in mesothelioma tumours and found their expression associated (P < 0.05, chi-square). In mesothelioma cell lines, inhibiting Cul4A by siRNA decreased Gli1 expression, suggesting that Gli1 expression is, at least in part, regulated by Cul4A in mesothelioma cells. Our results suggest a linkage between Cul4A and Gli1 expression in human mesothelioma.

}, keywords = {Case-Control Studies, Cell Line, Tumor, Chi-Square Distribution, Cullin Proteins, Gene Dosage, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Lung Neoplasms, Mesothelioma, Pleural Neoplasms, Real-Time Polymerase Chain Reaction, RNA, Messenger, Transcription Factors}, issn = {1582-4934}, doi = {10.1111/jcmm.12620}, author = {Yang, Yi-Lin and Ni, Jian and Hsu, Ping-Chih and Jiang-Hua Mao and Hsieh, David and Xu, Angela and Chan, Geraldine and Au, Alfred and Xu, Zhidong and Jablons, David M and You, Liang} } @article {226, title = {Elevated expression of UBE2T exhibits oncogenic properties in human prostate cancer.}, journal = {Oncotarget}, volume = {6}, year = {2015}, month = {2015 Sep 22}, pages = {25226-39}, abstract = {

Increased expression of ubiquitin-conjugating enzyme E2T (UBE2T) is reported in human prostate cancer. However, whether UBE2T plays any functional role in prostate cancer development remains unknown. We here report the first functional characterization of UBE2T in prostate carcinogenesis. Prostate cancer tissue array analysis confirmed upregulation of UBE2T in prostate cancer, especially these with distant metastasis. Moreover, higher level of UBE2T expression is associated with poorer prognosis of prostate cancer patients. Ectopic expression of UBE2T significantly promotes prostate cancer cell proliferation, motility and invasion, while UBE2T depletion by shRNA significantly inhibits these abilities of prostate cancer cells. Xenograft mouse model studies showed that overexpression of UBE2T promotes whereas UBE2T depletion inhibits tumor formation and metastasis significantly. Collectively, we identify critical roles of UBE2T in prostate cancer development and progression. These findings may serve as a framework for future investigations designed to more comprehensive determination of UBE2T as a potential therapeutic target.

}, keywords = {Cell Line, Tumor, Cell Movement, Cell Proliferation, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Heterografts, Humans, Kaplan-Meier Estimate, Male, Neoplasm Invasiveness, Neoplasm Transplantation, Prognosis, Prostatic Neoplasms, RNA Interference, Signal Transduction, Time Factors, Transfection, Ubiquitin-Conjugating Enzymes, Up-Regulation}, issn = {1949-2553}, doi = {10.18632/oncotarget.4712}, author = {Wen, Mingxin and Kwon, Yongwon and Wang, Yongsheng and Jiang-Hua Mao and Wei, Guangwei} } @article {219, title = {Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment.}, journal = {Sci Rep}, volume = {5}, year = {2015}, month = {2015}, pages = {8919}, abstract = {

The interplay between host genetics, tumor microenvironment and environmental exposure in cancer susceptibility remains poorly understood. Here we assessed the genetic control of stromal mediation of mammary tumor susceptibility to low dose ionizing radiation (LDIR) using backcrossed F1 into BALB/c (F1Bx) between cancer susceptible (BALB/c) and resistant (SPRET/EiJ) mouse strains. Tumor formation was evaluated after transplantation of non-irradiated Trp53-/- BALB/c mammary gland fragments into cleared fat pads of F1Bx hosts. Genome-wide linkage analysis revealed 2 genetic loci that constitute the baseline susceptibility via host microenvironment. However, once challenged with LDIR, we discovered 13 additional loci that were enriched for genes involved in cytokines, including TGFβ1 signaling. Surprisingly, LDIR-treated F1Bx cohort significantly reduced incidence of mammary tumors from Trp53-/- fragments as well as prolonged tumor latency, compared to sham-treated controls. We demonstrated further that plasma levels of specific cytokines were significantly correlated with tumor latency. Using an ex vivo 3-D assay, we confirmed TGFβ1 as a strong candidate for reduced mammary invasion in SPRET/EiJ, which could explain resistance of this strain to mammary cancer risk following LDIR. Our results open possible new avenues to understand mechanisms of genes operating via the stroma that affect cancer risk from external environmental exposures.

}, keywords = {Animals, Breast Neoplasms, Cell Line, Tumor, Cytokines, Female, Genetic Predisposition to Disease, Mice, Mice, Inbred BALB C, Neoplasms, Radiation-Induced, Quantitative Trait Loci, Risk Factors, Transforming Growth Factor beta1, Tumor Microenvironment}, issn = {2045-2322}, doi = {10.1038/srep08919}, author = {Zhang, Pengju and Lo, Alvin and Huang, Yurong and Huang, Ge and Liang, Guozhou and Mott, Joni and Karpen, Gary H and Blakely, Eleanor A and Bissell, Mina J and Barcellos-Hoff, Mary Helen and A Snijders and Jiang-Hua Mao} } @article {218, title = {Inhibition of ERK1/2 down-regulates the Hippo/YAP signaling pathway in human NSCLC cells.}, journal = {Oncotarget}, volume = {6}, year = {2015}, month = {2015 Feb 28}, pages = {4357-68}, abstract = {

Alterations of the EGFR/ERK and Hippo/YAP pathway have been found in non-small cell lung cancer (NSCLC). Herein, we show that ERK1 and ERK2 have an effect on the Hippo/YAP pathway in human NSCLC cells. Firstly, inhibition of ERK1/2 by siRNA or small-molecular inhibitors decreased the YAP protein level, the reporter activity of the Hippo pathway, and the mRNA levels of the Hippo downstream genes, CTGF, Gli2, and BIRC5. Secondly, degradation of YAP protein was accelerated after ERK1/2 depletion in NSCLC cell lines, in which YAP mRNA level was not decreased. Thirdly, forced over-expression of the ERK2 gene rescued the YAP protein level and Hippo reporter activity after siRNA knockdown targeting 3{\textquoteright}UTR of the ERK2 gene in NSCLC cells. Fourthly, depletion of ERK1/2 reduced the migration and invasion of NSCLC cells. Combined depletion of ERK1/2 had a greater effect on cell migration than depletion of either one separately. Finally, the MEK1/2 inhibitor Trametinib decreased YAP protein level and transcriptional activity of the Hippo pathway in NSCLC cell lines. Our results suggest that ERK1/2 inhibition participates in reducing YAP protein level, which in turn down-regulates expression of the downstream genes of the Hippo pathway to suppress migration and invasion of NSCLC cells.

}, keywords = {Adaptor Proteins, Signal Transducing, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Movement, Down-Regulation, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Lung Neoplasms, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Neoplasm Invasiveness, Phosphoproteins, Protein-Serine-Threonine Kinases, Real-Time Polymerase Chain Reaction, RNA, Small Interfering, Signal Transduction, Transfection}, issn = {1949-2553}, doi = {10.18632/oncotarget.2974}, author = {You, Bin and Yang, Yi-Lin and Xu, Zhidong and Dai, Yuyuan and Liu, Shu and Jiang-Hua Mao and Tetsu, Osamu and Li, Hui and Jablons, David M and You, Liang} } @article {230, title = {Knockdown of Cul4A increases chemosensitivity to gemcitabine through upregulation of TGFBI in lung cancer cells.}, journal = {Oncol Rep}, volume = {34}, year = {2015}, month = {2015 Dec}, pages = {3187-95}, abstract = {

Cullin 4A (Cul4A) promotes oncogenesis through overexpression and then ubiquitination-mediated proteolysis of tumor suppressors in various types of cancers. Transforming growth factor β-induced (TGFBI) has been implicated as a tumor suppressor, which enhances gemcitabine chemosensitivity in lung cancer cells. The present study aimed to investigate the association of TGFBI and Cul4A and the mechanism by which Cul4A regulates TGFBI. In addition, we also evaluated the therapeutic value of Cul4A RNAi using adenoviral transfection of Cul4A RNAi in nude mouse xenograft models. We observed that knockdown of Cul4A was associated with increased sensitivity to gemcitabine through upregulation of TGFBI in lung cancer cells. Cul4A regulated TGFBI through direct interaction and then ubiquitin-mediated protein degradation. In the nude mouse xenograft models, adenoviral transfection of Cul4A RNAi in combination with gemcitabine chemotherapy inhibited lung cancer tumor growth. As the result, combination of Cul4A RNAi with chemotherapy may provide a new approach to lung cancer treatment.

}, keywords = {Animals, Cell Line, Tumor, Cell Transformation, Neoplastic, Cullin Proteins, Deoxycytidine, Drug Resistance, Neoplasm, Extracellular Matrix Proteins, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Lung Neoplasms, Mice, Transforming Growth Factor beta, Xenograft Model Antitumor Assays}, issn = {1791-2431}, doi = {10.3892/or.2015.4324}, author = {Hung, Ming-Szu and Chen, I-Chuan and You, Liang and Jablons, David M and Li, Ya-Chin and Jiang-Hua Mao and Xu, Zhidong and Hsieh, Meng-Jer and Lin, Yu-Ching and Yang, Cheng-Ta and Liu, Shin-Tung and Tsai, Ying-Huang} } @article {225, title = {A new role of SNAI2 in postlactational involution of the mammary gland links it to luminal breast cancer development.}, journal = {Oncogene}, volume = {34}, year = {2015}, month = {2015 Sep 3}, pages = {4777-90}, abstract = {

Breast cancer is a major cause of mortality in women. The transcription factor SNAI2 has been implicated in the pathogenesis of several types of cancer, including breast cancer of basal origin. Here we show that SNAI2 is also important in the development of breast cancer of luminal origin in MMTV-ErbB2 mice. SNAI2 deficiency leads to longer latency and fewer luminal tumors, both of these being characteristics of pretumoral origin. These effects were associated with reduced proliferation and a decreased ability to generate mammospheres in normal mammary glands. However, the capacity to metastasize was not modified. Under conditions of increased ERBB2 oncogenic activity after pregnancy plus SNAI2 deficiency, both pretumoral defects-latency and tumor load-were compensated. However, the incidence of lung metastases was dramatically reduced. Furthermore, SNAI2 was required for proper postlactational involution of the breast. At 3 days post lactational involution, the mammary glands of Snai2-deficient mice exhibited lower levels of pSTAT3 and higher levels of pAKT1, resulting in decreased apoptosis. Abundant noninvoluted ducts were still present at 30 days post lactation, with a greater number of residual ERBB2+ cells. These results suggest that this defect in involution leads to an increase in the number of susceptible target cells for transformation, to the recovery of the capacity to generate mammospheres and to an increase in the number of tumors. Our work demonstrates the participation of SNAI2 in the pathogenesis of luminal breast cancer, and reveals an unexpected connection between the processes of postlactational involution and breast tumorigenesis in Snai2-null mutant mice.

}, keywords = {Animals, Apoptosis, Breast Neoplasms, Carcinogenesis, Carrier Proteins, Cell Line, Tumor, Cell Proliferation, Female, Gene Expression Regulation, Neoplastic, Humans, Lactation, Lung Neoplasms, Mammary Glands, Animal, Mice, Mice, Knockout, Pregnancy, Proto-Oncogene Proteins c-akt, STAT3 Transcription Factor, Transcription Factors}, issn = {1476-5594}, doi = {10.1038/onc.2015.224}, author = {Castillo-Lluva, S and Hontecillas-Prieto, L and Blanco-G{\'o}mez, A and Del Mar S{\'a}ez-Freire, M and Garc{\'\i}a-Cenador, B and Garc{\'\i}a-Criado, J and P{\'e}rez-Andr{\'e}s, M and Orfao, A and Ca{\~n}amero, M and Jiang-Hua Mao and Gridley, T and Castellanos-Mart{\'\i}n, A and Perez-Losada, J} } @article {206, title = {CUL4A induces epithelial-mesenchymal transition and promotes cancer metastasis by regulating ZEB1 expression.}, journal = {Cancer Res}, volume = {74}, year = {2014}, month = {2014 Jan 15}, pages = {520-31}, abstract = {

The ubiquitin ligase CUL4A has been implicated in tumorigenesis, but its contributions to progression and metastasis have not been evaluated. Here, we show that CUL4A is elevated in breast cancer as well as in ovarian, gastric, and colorectal tumors in which its expression level correlates positively with distant metastasis. CUL4A overexpression in normal or malignant human mammary epithelial cells increased their neoplastic properties in vitro and in vivo, markedly increasing epithelial-mesenchymal transition (EMT) and the metastatic capacity of malignant cells. In contrast, silencing CUL4A in aggressive breast cancer cells inhibited these processes. Mechanistically, we found that CUL4A modulated histone H3K4me3 at the promoter of the EMT regulatory gene ZEB1 in a manner associated with its transcription. ZEB1 silencing blocked CUL4A-driven proliferation, EMT, tumorigenesis, and metastasis. Furthermore, in human breast cancers, ZEB1 expression correlated positively with CUL4A expression and distant metastasis. Taken together, our findings reveal a pivotal role of CUL4A in regulating the metastatic behavior of breast cancer cells.

}, keywords = {Animals, Breast, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Cullin Proteins, Epithelial-Mesenchymal Transition, Female, Gene Expression Regulation, Neoplastic, Histones, Homeodomain Proteins, Humans, Kruppel-Like Transcription Factors, Mammary Neoplasms, Experimental, Mice, Mice, Nude, Neoplasm Metastasis, Neoplasm Transplantation, Promoter Regions, Genetic, Signal Transduction, Transcription Factors}, issn = {1538-7445}, doi = {10.1158/0008-5472.CAN-13-2182}, author = {Wang, Yunshan and Wen, Mingxin and Kwon, Yongwon and Xu, Yangyang and Liu, Yueyong and Zhang, Pengju and He, Xiuquan and Wang, Qin and Huang, Yurong and Jen, Kuang-Yu and LaBarge, Mark A and You, Liang and Kogan, Scott C and Gray, Joe W and Jiang-Hua Mao and Wei, Guangwei} } @article {211, title = {CUL4A overexpression enhances lung tumor growth and sensitizes lung cancer cells to erlotinib via transcriptional regulation of EGFR.}, journal = {Mol Cancer}, volume = {13}, year = {2014}, month = {2014}, pages = {252}, abstract = {

BACKGROUND: CUL4A has been proposed as oncogene in several types of human cancer, but its clinical significance and functional role in human non-small cell lung cancer (NSCLC) remain unclear.

METHODS: Expression level of CUL4A was examined by RT-PCR and Western blot. Forced expression of CUL4A was mediated by retroviruses, and CUL4A silencing by shRNAs expressing lentiviruses. Growth capacity of lung cancer cells was measured by MTT in vitro and tumorigenesis in vivo, respectively.

RESULTS: We found that CUL4A was highly expressed in human lung cancer tissues and lung cancer cell lines, and this elevated expression positively correlated with disease progression and prognosis. Overexpression of CUL4A in human lung cancer cell lines increased cell proliferation, inhibited apoptosis, and subsequently conferred resistance to chemotherapy. On other hand, silencing CUL4A expression in NSCLC cells reduced proliferation, promoted apoptosis and resulted in tumor growth inhibition in cancer xenograft model. Mechanistically, we revealed CUL4A regulated EGFR transcriptional expression and activation, and subsequently activated AKT. Targeted inhibition of EGFR activity blocked these CUL4A induced oncogenic activities.

CONCLUSIONS: Our results highlight the significance of CUL4A in NSCLC and suggest that CUL4A could be a promising therapy target and a potential biomarker for prognosis and EGFR target therapy in NSCLC patients.

}, keywords = {Apoptosis, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Proliferation, Cullin Proteins, Erlotinib Hydrochloride, Female, Humans, Lung Neoplasms, Male, Middle Aged, Protein Kinase Inhibitors, Quinazolines, Receptor, Epidermal Growth Factor, Transcription, Genetic}, issn = {1476-4598}, doi = {10.1186/1476-4598-13-252}, author = {Wang, Yunshan and Zhang, Pengju and Liu, Ziming and Wang, Qin and Wen, Mingxin and Wang, Yuli and Yuan, Hongtu and Jiang-Hua Mao and Wei, Guangwei} } @article {210, title = {Expression quantitative trait loci and receptor pharmacology implicate Arg1 and the GABA-A receptor as therapeutic targets in neuroblastoma.}, journal = {Cell Rep}, volume = {9}, year = {2014}, month = {2014 Nov 6}, pages = {1034-46}, abstract = {

The development of targeted therapeutics for neuroblastoma, the third most common tumor in children, has been limited by a poor understanding of growth signaling mechanisms unique to the peripheral nerve precursors from which tumors arise. In this study, we combined genetics with gene-expression analysis in the peripheral sympathetic nervous system to implicate arginase 1 and GABA signaling in tumor formation in vivo. In human neuroblastoma cells, either blockade of ARG1 or benzodiazepine-mediated activation of GABA-A receptors induced apoptosis and inhibited mitogenic signaling through AKT and MAPK. These results suggest that ARG1 and GABA influence both neural development and neuroblastoma and that benzodiazepines in clinical use may have potential applications for neuroblastoma therapy.

}, keywords = {Animals, Apoptosis, Arginase, Brain Neoplasms, Cell Line, Tumor, Cell Survival, Chromosomes, Mammalian, gamma-Aminobutyric Acid, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Linkage, Genetic Predisposition to Disease, Humans, Mice, Molecular Targeted Therapy, Neuroblastoma, Quantitative Trait Loci, Receptors, GABA-A, Survival Analysis}, issn = {2211-1247}, doi = {10.1016/j.celrep.2014.09.046}, author = {Hackett, Christopher S and Quigley, David A and Wong, Robyn A and Chen, Justin and Cheng, Christine and Song, Young K and Wei, Jun S and Pawlikowska, Ludmila and Bao, Yun and Goldenberg, David D and Nguyen, Kim and Gustafson, W Clay and Rallapalli, Sundari K and Cho, Yoon-Jae and Cook, James M and Kozlov, Serguei and Jiang-Hua Mao and Van Dyke, Terry and Kwok, Pui-Yan and Khan, Javed and Balmain, Allan and Fan, QiWen and Weiss, William A} } @article {208, title = {Lung tumourigenesis in a conditional Cul4A transgenic mouse model.}, journal = {J Pathol}, volume = {233}, year = {2014}, month = {2014 Jun}, pages = {113-23}, abstract = {

Cullin4A (Cul4A) is a scaffold protein that assembles cullin-RING ubiquitin ligase (E3) complexes and regulates many cellular events, including cell survival, development, growth and cell cycle control. Our previous study suggested that Cul4A is oncogenic in vitro, but its oncogenic role in vivo has not been studied. Here, we used a Cul4A transgenic mouse model to study the potential oncogenic role of Cul4A in lung tumour development. After Cul4A over-expression was induced in the lungs for 32 weeks, atypical epithelial cells were observed. After 40 weeks, lung tumours were visible and were characterized as grade I or II adenocarcinomas. Immunohistochemistry (IHC) revealed decreased levels of Cul4A-associated proteins p21(CIP1) and tumour suppressor p19(ARF) in the lung tumours, suggesting that Cul4A regulated their expression in these tumours. Increased levels of p27(KIP1) and p16(INK4a) were also detected in these tumours. Moreover, the protein level of DNA replication licensing factor CDT1 was decreased. Genomic instability in the lung tumours was further analysed by the results from pericentrin protein expression and array comparative genomic hybridization analysis. Furthermore, knocking down Cul4A expression in lung cancer H2170 cells increased their sensitivity to the chemotherapy drug cisplatin in vitro, suggesting that Cul4A over-expression is associated with cisplatin resistance in the cancer cells. Our findings indicate that Cul4A is oncogenic in vivo, and this Cul4A mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A.

}, keywords = {Adenocarcinoma, Animals, Antineoplastic Agents, Cell Cycle Proteins, Cell Line, Tumor, Cell Survival, Cell Transformation, Neoplastic, Cisplatin, Cullin Proteins, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p19, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Disease Models, Animal, DNA-Binding Proteins, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Genomic Instability, Humans, Lung, Lung Neoplasms, Mice, Mice, Transgenic, Neoplasm Grading, Proliferating Cell Nuclear Antigen, RNA Interference, Time Factors, Transfection, Up-Regulation}, issn = {1096-9896}, doi = {10.1002/path.4352}, author = {Yang, Yi-Lin and Hung, Ming-Szu and Wang, Yang and Ni, Jian and Jiang-Hua Mao and Hsieh, David and Au, Alfred and Kumar, Atul and Quigley, David and Fang, Li Tai and Yeh, Che-Chung and Xu, Zhidong and Jablons, David M and You, Liang} } @article {243, title = {PINK1 and its familial Parkinson{\textquoteright}s disease-associated mutation regulate brain vascular endothelial inflammation.}, journal = {J Mol Neurosci}, volume = {53}, year = {2014}, month = {2014 May}, pages = {109-16}, abstract = {

Parkinson{\textquoteright}s disease (PD) is a debilitating disorder that affects movement. Inflammation-mediated endothelial dysfunction has been found to be involved in neurodegenerative diseases, including PD. More than 40 PTEN-induced putative kinase 1 (PINK1) mutations have been found in PD patients. The effects of PINK1 in vascular inflammation are as yet unknown. In this study, our findings revealed that PINK1 can be increased by the inflammatory cytokine tumor necrosis factor-α in primary human brain microvascular endothelial cells (HBMECs). We found that wild-type PINK1 prevents expression of the adhesion molecule vascular cell adhesion molecule-1 (VCAM-1), thus inhibiting the attachment of monocytes to brain endothelial cells. However, PINK1G309D, the loss-of-function mutation associated with early-onset familial PD, promotes expression of VCAM-1 and exacerbates attachment of monocytes to brain endothelial cells. Mechanism studies revealed that overexpression of wild-type PINK1 inhibits the VCAM-1 promoter by inhibiting the transcriptional activity of interferon regulatory factor 1 (IRF-1). However, PINK1G309D promotes the VCAM-1 promoter by increasing the transcriptional activity of IRF-1.

}, keywords = {Brain, Cell Line, Tumor, Cells, Cultured, Endothelial Cells, Endothelium, Vascular, Humans, Inflammation, Interferon Regulatory Factor-1, Mutation, Parkinson Disease, Protein Kinases, Tumor Necrosis Factor-alpha, Vascular Cell Adhesion Molecule-1}, issn = {1559-1166}, doi = {10.1007/s12031-013-0207-1}, author = {Wang, Yunfu and Guangjian, Liu and Ping, Zhong and Yanpeng, Sun and Xiaoxia, Fang and Wei, Hu and Jiang, Yuan and Jingquan, Hu and Songlin, Wang and Hongyan, Zhang and Yong, Liu and Shi, Chen} } @article {81, title = {Breast fibroblasts modulate early dissemination, tumorigenesis, and metastasis through alteration of extracellular matrix characteristics}, journal = {Neoplasia}, volume = {15}, year = {2013}, month = {2013 Mar}, pages = {249-62}, abstract = {

A wealth of evidence has now demonstrated that the microenvironment in which a tumorigenic cell evolves is as critical to its evolution as the genetic mutations it accrues. However, there is still relatively little known about how signals from the microenvironment contribute to the early events in the progression to malignancy. To address this question, we used a premalignant mammary model to examine how fibroblasts, and the extracellular matrix (ECM) proteins they secrete, influence progression to malignancy. Their effect on metastatic malignant cells was also assessed for comparison. We found that carcinoma-associated fibroblasts, and the distinct aligned ECM they deposit, can cause both premalignant and malignant mammary epithelial cells to assume a mesenchymal morphology that is associated with increased dissemination and metastasis, while benign reduction mammoplasty fibroblasts favor the maintenance of an epithelial morphology and constrain early dissemination, tumor growth, and metastasis. Our results suggest that normalizing the organization of the ECM could be effective in limiting systemic dissemination and tumor growth.

}, keywords = {Animals, Breast, Cell Line, Tumor, Cell Transformation, Neoplastic, Coculture Techniques, Epithelial Cells, Extracellular Matrix, Extracellular Signal-Regulated MAP Kinases, Female, Fibroblasts, Humans, Lung Neoplasms, Mammary Neoplasms, Experimental, Neoplasm Metastasis, Phenotype, Proto-Oncogene Proteins c-jun, rho GTP-Binding Proteins, Signal Transduction, Transforming Growth Factor beta}, issn = {1476-5586}, author = {Dumont, Nancy and Liu, Bob and DeFilippis, Rosa Anna and Hang Chang and Rabban, Joseph T and Karnezis, Anthony N and Tjoe, Judy A and Marx, James and Parvin, Bahram and Tlsty, Thea D} } @article {202, title = {C2ORF40 suppresses breast cancer cell proliferation and invasion through modulating expression of M phase cell cycle genes.}, journal = {Epigenetics}, volume = {8}, year = {2013}, month = {2013 Jun}, pages = {571-83}, abstract = {

Recently, it has been suggested that C2ORF40 is a candidate tumor suppressor gene in breast cancer. However, the mechanism for reduced expression of C2ORF40 and its functional role in breast cancers remain unclear. Here we show that C2ORF40 is frequently silenced in human primary breast cancers and cell lines through promoter hypermethylation. C2ORF40 mRNA level is significantly associated with patient disease-free survival and distant cancer metastasis. Overexpression of C2ORF4 0 inhibits breast cancer cell proliferation, migration and invasion. By contrast, silencing C2ORF40 expression promotes these biological phenotypes. Bioinformatics and FACS analysis reveal C2ORF40 functions at G2/M phase by downregulation of mitotic genes expression, including UBE2C. Our results suggest that C2ORF40 acts as a tumor suppressor gene in breast cancer pathogenesis and progression and is a candidate prognostic marker for this disease.

}, keywords = {Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, DNA Methylation, Female, Gene Expression Regulation, Neoplastic, Genes, cdc, Genes, Tumor Suppressor, Humans, Mitosis, Neoplasm Invasiveness, Neoplasm Proteins, Prognosis}, issn = {1559-2308}, doi = {10.4161/epi.24626}, author = {Lu, Jing and Wen, Mingxin and Huang, Yurong and He, Xiuquan and Wang, Yunshan and Wu, Qi and Li, Zengchun and Castellanos-Mart{\'\i}n, Andr{\'e}s and Abad, Mar and Cruz-Hernandez, Juan J and Rodriguez, Cesar A and Perez-Losada, Jesus and Jiang-Hua Mao and Wei, Guangwei} } @article {205, title = {FAM83D promotes cell proliferation and motility by downregulating tumor suppressor gene FBXW7.}, journal = {Oncotarget}, volume = {4}, year = {2013}, month = {2013 Dec}, pages = {2476-86}, abstract = {

Amplification of chromosome 20q is frequently found in various types of human cancers, including breast cancer. The list of candidate oncogenes in 20q has expanded over the past decade. Here, we investigate whether FAM83D (family with sequence similarity 83, member D) on chromosome 20q plays any role in breast cancer development. The expression level of FAM83D is significantly elevated in breast cancer cell lines and primary human breast cancers. High expression levels of FAM83D are significantly associated with poor clinical outcome and distant metastasis in breast cancer patients. We show that ectopic expression of FAM83D in human mammary epithelial cells promotes cell proliferation, migration and invasion along with epithelial-mesenchymal transition (EMT). Ablation of FAM83D in breast cancer cells induces apoptosis and consequently inhibits cell proliferation and colony formation. Mechanistic studies reveal that overexpression of FAM83D downregulates FBXW7 expression levels through a physical interaction, which results in elevated protein levels of oncogenic substrates downstream to FBXW7, such as mTOR, whose inhibition by rapamycin can suppress FAM83D-induced cell migration and invasion. The results demonstrate that FAM83D has prognostic value for breast cancer patients and is a novel oncogene in breast cancer development that at least in part acts through mTOR hyper-activation by inhibiting FBXW7.

}, keywords = {Apoptosis, Breast Neoplasms, Cell Cycle Proteins, Cell Growth Processes, Cell Line, Tumor, Chromosomal Proteins, Non-Histone, Down-Regulation, Epithelial-Mesenchymal Transition, F-Box Proteins, Genes, Tumor Suppressor, Humans, Microtubule-Associated Proteins, Prognosis, Transfection, Ubiquitin-Protein Ligases}, issn = {1949-2553}, doi = {10.18632/oncotarget.1581}, author = {Wang, Zeran and Liu, Yueyong and Zhang, Pengju and Zhang, Weiguo and Wang, Weijing and Curr, Kenneth and Wei, Guangwei and Jiang-Hua Mao} } @article {194, title = {Mass spectrometry imaging for in situ kinetic histochemistry.}, journal = {Sci Rep}, volume = {3}, year = {2013}, month = {2013}, pages = {1656}, abstract = {

Tissues are composed of diverse cell subpopulations each with distinct metabolic characteristics that influence overall behavior. Unfortunately, traditional histopathology imaging techniques are {\textquoteright}blind{\textquoteright} to the spatially ordered metabolic dynamics within tissue. While mass spectrometry imaging enables spatial mapping of molecular composition, resulting images are only a static snapshot in time of molecules involved in highly dynamic processes; kinetic information of flux through metabolic pathways is lacking. To address this limitation, we developed kinetic mass spectrometry imaging (kMSI), a novel technique integrating soft desorption/ionization mass spectrometry with clinically accepted in vivo metabolic labeling of tissue with deuterium to generate images of kinetic information of biological processes. Applied to a tumor, kMSI revealed heterogeneous spatial distributions of newly synthesized versus pre-existing lipids, with altered lipid synthesis patterns distinguishing region-specific intratumor subpopulations. Images also enabled identification and correlation of metabolic activity of specific lipids found in tumor regions of varying grade.

}, keywords = {Cell Line, Tumor, Equipment Design, Equipment Failure Analysis, Humans, Lipids, Mass Spectrometry, Molecular Imaging, Neoplasms, Experimental}, issn = {2045-2322}, doi = {10.1038/srep01656}, author = {Louie, Katherine B and Bowen, Benjamin P and McAlhany, Stephanie and Huang, Yurong and Price, John C and Jiang-Hua Mao and Hellerstein, Marc and Northen, Trent R} } @article {77, title = {NFkB disrupts tissue polarity in 3D by preventing integration of microenvironmental signals}, journal = {Oncotarget}, volume = {4}, year = {2013}, month = {2013 Nov}, pages = {2010-20}, abstract = {

The microenvironment of cells controls their phenotype, and thereby the architecture of the emerging multicellular structure or tissue. We have reported more than a dozen microenvironmental factors whose signaling must be integrated in order to effect an organized, functional tissue morphology. However, the factors that prevent integration of signaling pathways that merge form and function are still largely unknown. We have identified nuclear factor kappa B (NFkB) as a transcriptional regulator that disrupts important microenvironmental cues necessary for tissue organization. We compared the gene expression of organized and disorganized epithelial cells of the HMT-3522 breast cancer progression series: the non-malignant S1 cells that form polarized spheres ({\textquoteright}acini{\textquoteright}), the malignant T4-2 cells that form large tumor-like clusters, and the {\textquoteright}phenotypically reverted{\textquoteright} T4-2 cells that polarize as a result of correction of the microenvironmental signaling. We identified 180 genes that display an increased expression in disorganized compared to polarized structures. Network, GSEA and transcription factor binding site analyses suggested that NFkB is a common activator for the 180 genes. NFkB was found to be activated in disorganized breast cancer cells, and inhibition of microenvironmental signaling via EGFR, beta1 integrin, MMPs, or their downstream signals suppressed its activation. The postulated role of NFkB was experimentally verified: Blocking the NFkB pathway with a specific chemical inhibitor or shRNA induced polarization and inhibited invasion of breast cancer cells in 3D cultures. These results may explain why NFkB holds promise as a target for therapeutic intervention: Its inhibition can reverse the oncogenic signaling involved in breast cancer progression and integrate the essential microenvironmental control of tissue architecture.

}, keywords = {Breast Neoplasms, Cell Line, Tumor, Female, Gene Expression, Humans, Imaging, Three-Dimensional, Microarray Analysis, NF-kappa B, Phenotype, Signal Transduction, Transcriptional Activation, Tumor Microenvironment}, issn = {1949-2553}, doi = {10.18632/oncotarget.1451}, author = {Becker-Weimann, Sabine and Xiong, Gaofeng and Furuta, Saori and Ju Han and Kuhn, Irene and Akavia, Uri-David and Pe{\textquoteright}er, Dana and Bissell, Mina J and Xu, Ren} } @article {203, title = {The prostate cancer-up-regulated long noncoding RNA PlncRNA-1 modulates apoptosis and proliferation through reciprocal regulation of androgen receptor.}, journal = {Urol Oncol}, volume = {31}, year = {2013}, month = {2013 Oct}, pages = {1117-23}, abstract = {

OBJECTIVE: Emerging evidences implicate long noncoding RNAs (lncRNAs) are deregulated in cancer development. The purpose of the current study is to investigate the role of new lncRNA, named PlncRNA-1, in prostate cancer (CaP) pathogenesis.

MATERIALS AND METHODS: In this study, real-time q-PCR was used to demonstrate the expression of PlncRNA-1 in 16 pairs CaP tissues and matched normal tissues, 14 pairs CaP tissues and BPH tissues, 4 CaP cell lines, including LNCaP, LNCaP-AI, PC3, and C4-2, and 2 normal prostate epithelial cell lines RWPE-1 and PWR-1E. After PlncRNA-1 was suppressed by siRNA in LNCaP and LNCaP-AI cell lines, cell proliferation and apoptosis were assessed using CCK-8 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). After PlncRNA-1 and AR was suppressed by siRNA in LNCaP and LNCaP-AI cell lines, real-time q-PCR and Western blotting were used to measure reciprocal regulation of PlncRNA-1 and AR.

RESULTS: We showed that expression PlncRNA-1, was significantly higher in CaP cells relative to normal prostate epithelial cells, as well as higher in human CaPs compared with normal tissues and benign prostatic hyperplasia (BPH). Silencing of PlncRNA-1 significantly reduced cell proliferation and induced apoptosis in CaP cell lines LNCaP and LNCaP-AI. Mechanistically, PlncRNA-1 suppression by siRNA resulted in a decrease of androgen receptor (AR) mRNA, protein and AR downstream target. Of note, blockade of AR signaling with siRNA also resulted in a suppression of PlncRNA-1 expression in CaP cell lines.

CONCLUSIONS: Our study suggests reciprocal regulation of PlncRNA-1 and androgen receptor contribute to CaP pathogenesis and that PlncRNA-1 is a potential therapy target.

}, keywords = {Apoptosis, Base Sequence, Blotting, Western, Cell Line, Cell Line, Tumor, Cell Proliferation, Gene Expression Regulation, Neoplastic, Humans, Male, Molecular Sequence Data, Prostatic Neoplasms, Receptors, Androgen, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, RNA, Long Noncoding, Up-Regulation}, issn = {1873-2496}, doi = {10.1016/j.urolonc.2011.11.030}, author = {Cui, Zilian and Ren, Shancheng and Lu, Ji and Wang, Fubo and Xu, Weidong and Sun, Yi and Wei, Min and Chen, Junyi and Gao, Xu and Xu, Chuanliang and Jiang-Hua Mao and Sun, Yinghao} } @article {187, title = {Development of a rapid and practical mutation screening assay for human lung adenocarcinoma.}, journal = {Int J Oncol}, volume = {40}, year = {2012}, month = {2012 Jun}, pages = {1900-6}, abstract = {

Mortality after initial diagnosis of lung cancer is higher than from any other cancer. Although mutations in several genes, such as EGFR and K-ras, have been associated with clinical outcome, technical complexity, cost and time have rendered routine screening prohibitive for most lung cancer patients prior to treatment. In this study, using both novel and established technologies, we developed a clinically practical assay to survey the status of three frequently mutated genes in lung cancer (EGFR, K-ras and TP53) and two genes (BRAF and β-catenin) with known hotspot mutations in many other cancers. A single 96-well plate was designed targeting a total of 14 fragments (16 exons) from EGFR, K-ras, TP53, BRAF and β-catenin. In 96 lung adenocarcinoma patients, the mutation frequencies of three major genes (EGFR, K-ras and TP53) were between 21-24\%. Fifty-six out of 96 (58\%) patients had a mutation in at least one of the five genes. K-ras mutations positively correlated with smoking pack-years (p=0.035). EGFR mutations were frequent in never-smokers (p=0.0007), Asians (p=0.0204) and non-stage I lung cancer (p=0.016). There was also a trend towards an association between the presence of any mutation and improved recurrence-free survival (p=0.070). We demonstrate that our novel multigene mutation assay technology can rapidly and cost-effectively screen for mutations in lung adenocarcinoma. This screening assay can be used in the clinical setting for the large-scale validation of prognosis and/or predicting therapeutic response so that the majority of lung cancer patients can benefit from leveraging up-to-date knowledge on how mutation profiles may influence treatment options.

}, keywords = {Adenocarcinoma, Aged, Base Sequence, beta Catenin, Cell Line, Tumor, DNA Mutational Analysis, Female, Frameshift Mutation, Genetic Association Studies, Humans, Kaplan-Meier Estimate, Lung Neoplasms, Male, Middle Aged, Molecular Sequence Data, Mutagenesis, Insertional, Mutation, Missense, Prognosis, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins p21(ras), Receptor, Epidermal Growth Factor, Tumor Suppressor Protein p53}, issn = {1791-2423}, doi = {10.3892/ijo.2012.1396}, author = {Choi, Helen and Kratz, Johannes and Pham, Patrick and Lee, Sharon and Ray, Roshni and Kwon, Yong-Won and Jiang-Hua Mao and Kang, Hio Chung and Jablons, David and Kim, Il-Jin} } @article {190, title = {The expression of Dishevelled-3 and glutamine metabolism in malignant pleural mesothelioma.}, journal = {J Clin Pathol}, volume = {65}, year = {2012}, month = {2012 Sep}, pages = {855-8}, keywords = {Adaptor Proteins, Signal Transducing, Cell Line, Tumor, Excitatory Amino Acid Transporter 1, Glutamine, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Mesothelioma, Multivariate Analysis, Phosphoproteins, Pleural Neoplasms, Polymerase Chain Reaction, Prognosis, Proportional Hazards Models, Tissue Array Analysis}, issn = {1472-4146}, doi = {10.1136/jclinpath-2011-200628}, author = {Li, Tong and Hou, Sheng-Cai and Jiang-Hua Mao and Wang, Yu-Cheng and Lu, Xiao-Dan and Tan, Jia-Li and You, Bin and Liu, Yu-Ping and Ni, Jian and Au, Alfred and Jablons, David M and Xu, Zhidong and You, Liang} } @article {183, title = {Gremlin is overexpressed in lung adenocarcinoma and increases cell growth and proliferation in normal lung cells.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e42264}, abstract = {

BACKGROUND: Gremlin, a member of the Dan family of BMP antagonists, is a glycosylated extracellular protein. Previously Gremlin has been shown to play a role in dorsal-ventral patterning, in tissue remodeling, and recently in angiogenesis. Evidence has previously been presented showing both over- and under-expression of Gremlin in different tumor tissues. Here, we sought to quantify expression of Gremlin in cancers of the lung and performed in vitro experiments to check whether Gremlin promotes cell growth and proliferation.

METHODOLOGY/PRINCIPAL FINDINGS: Expression of Gremlin in 161 matched tumor and normal lung cancer specimens is quantified by quantitative real-time PCR and protein level is measured by immunohistochemistry. GREM1 was transfected into lung fibroblast and epithelial cell lines to assess the impact of overexpression of Gremlin in vitro.

RESULTS: Lung adenocarcinoma but not squamous cell carcinoma shows a significant increase in Gremlin expression by mRNA and protein level. Lung fibroblast and epithelial cell lines transfected with GREM1 show significantly increased cell proliferation.

CONCLUSIONS/SIGNIFICANCE: Our data suggest that Gremlin acts in an oncogenic manner in lung adenocarcinoma and could hold promise as a new diagnostic marker or potential therapeutic target in lung AD or general thoracic malignancies.

}, keywords = {Adenocarcinoma, Cell Line, Tumor, Cell Proliferation, Epithelial Cells, Female, Fibroblasts, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Intercellular Signaling Peptides and Proteins, Lung Neoplasms, Male, Neoplasm Proteins, Real-Time Polymerase Chain Reaction, Respiratory Mucosa, RNA, Messenger, RNA, Neoplasm}, issn = {1932-6203}, doi = {10.1371/journal.pone.0042264}, author = {Mulvihill, Michael S and Kwon, Yong-Won and Lee, Sharon and Fang, Li Tai and Choi, Helen and Ray, Roshni and Kang, Hio Chung and Jiang-Hua Mao and Jablons, David and Kim, Il-Jin} } @article {181, title = {Inhibition of CK2α down-regulates Hedgehog/Gli signaling leading to a reduction of a stem-like side population in human lung cancer cells.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e38996}, abstract = {

Protein kinase CK2 is frequently elevated in a variety of human cancers. The Hedgehog (Hh) signaling pathway has been implicated in stem cell maintenance, and its aberrant activation has been indicated in several types of cancer, including lung cancer. In this study, we show that CK2 is positively involved in Hh/Gli signaling in lung cancer cell lines A549 and H1299. First, we found a correlation between CK2α and Gli1 mRNA levels in 100 primary lung cancer tissues. Down-regulation of Gli1 expression and transcriptional activity were demonstrated after the silencing of CK2α in lung cancer cells. In addition, CK2α siRNA down-regulated the expression of Hh target genes. Furthermore, two small-molecule CK2α inhibitors led to a dose-dependent inhibition of Gli1 expression and transcriptional activity in lung cancer cells. Reversely, forced over-expression of CK2α resulted in an increase both in Gli1 expression and transcriptional activity in A549 cells. Finally, the inhibition of Hh/Gli by CK2α siRNA led to a reduction of a cancer stem cell-like side population that shows higher ABCG2 expression level. Thus, we report that the inhibition of CK2α down-regulates Hh/Gli signaling and subsequently reduces stem-like side population in human lung cancer cells.

}, keywords = {ATP-Binding Cassette Transporters, Carcinoma, Non-Small-Cell Lung, Casein Kinase II, Cell Count, Cell Line, Tumor, Down-Regulation, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Gene Silencing, Humans, Lung Neoplasms, Neoplasm Proteins, Neoplastic Stem Cells, Protein Kinase Inhibitors, Proteolysis, Side-Population Cells, Signal Transduction, Small Molecule Libraries, Transcription Factors, Transcription, Genetic, Transcriptional Activation, Up-Regulation}, issn = {1932-6203}, doi = {10.1371/journal.pone.0038996}, author = {Zhang, Shulin and Wang, Yucheng and Jiang-Hua Mao and Hsieh, David and Kim, Il-Jin and Hu, Li-Min and Xu, Zhidong and Long, Hao and Jablons, David M and You, Liang} } @article {191, title = {Oncogenic CUL4A determines the response to thalidomide treatment in prostate cancer.}, journal = {J Mol Med (Berl)}, volume = {90}, year = {2012}, month = {2012 Oct}, pages = {1121-32}, abstract = {

Thalidomide is experimentally used to treat various human cancers; however, clinical responses to thalidomide are sporadic. Here we demonstrate that CUL4A plays an oncogenic role in prostate cancer development and prostate cancer cells with higher level of CUL4A are particularly sensitive to thalidomide treatment. We show that CUL4A is frequently overexpressed in human primary prostate cancer and cell lines. Notably, subjects with tumors that highly expressed CUL4A had poor overall survival. CUL4A downregulation inhibited cell proliferation and induced apoptosis in vitro and in vivo, whereas CUL4A overexpression transformed human normal prostate epithelial cells and promoted invasion, which was attenuated by the extracellular signal-regulated kinase (ERK) inhibitor. We further show that the sensitivity to thalidomide is positively correlated with CUL4A expression in a panel of prostate cell lines. Ectopic CUL4A expression greatly enhanced sensitivity to thalidomide, while its downregulation conferred resistance to this drug. Mechanistically, thalidomide decreased CUL4A in a time- and dose-dependent manner, consequently leading to inaction of ERK pathway. Finally, we show that cereblon level is correlated with CUL4A expression and downregulated in thalidomide-resistant prostate cancer cell. Our results offer the first evidence that CUL4A is a potential therapeutic target for prostate cancer and may serve as a biomarker for assessing prognosis of human prostate cancer and response to thalidomide treatment.

}, keywords = {Angiogenesis Inhibitors, Animals, Apoptosis, Cell Line, Tumor, Cell Survival, Cullin Proteins, Gene Expression, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Kaplan-Meier Estimate, Male, MAP Kinase Signaling System, Mice, Mice, Nude, Neoplasm Transplantation, Peptide Hydrolases, Prostatic Neoplasms, RNA Interference, Thalidomide, Tissue Array Analysis, Tumor Burden}, issn = {1432-1440}, doi = {10.1007/s00109-012-0885-0}, author = {Ren, Shancheng and Xu, Chuanliang and Cui, Zilian and Yu, Yongwei and Xu, Weidong and Wang, Fubo and Lu, Ji and Wei, Min and Lu, Xin and Gao, Xu and Liang, You and Jiang-Hua Mao and Sun, Yinghao} } @article {173, title = {Cul4A is an oncogene in malignant pleural mesothelioma.}, journal = {J Cell Mol Med}, volume = {15}, year = {2011}, month = {2011 Feb}, pages = {350-8}, abstract = {

Cullin 4A (Cul4A) is important in cell survival, development, growth and the cell cycle, but its role in mesothelioma has not been studied. For the first time, we identified amplification of the Cul4A gene in four of five mesothelioma cell lines. Consistent with increased Cul4A gene copy number, we found that Cul4A protein was overexpressed in mesothelioma cells as well. Cul4A protein was also overexpressed in 64\% of primary malignant pleural mesothelioma (MPM) tumours. Furthermore, knockdown of Cul4A with shRNA in mesothelioma cells resulted in up-regulation of p21 and p27 tumour suppressor proteins in a p53-independent manner in H290, H28 and MS-1 mesothelioma cell lines. Knockdown of Cul4A also resulted in G0/G1 cell cycle arrest and decreased colony formation in H290, H28 and MS-1 mesothelioma cell lines. Moreover, G0/G1 cell cycle arrest was partially reversed by siRNA down-regulation of p21 and/or p27 in Cul4A knockdown H290 cell line. In the contrary, overexpression of Cul4A resulted in down-regulation of p21 and p27 proteins and increased colony formation in H28 mesothelioma cell line. Both p21 and p27 showed faster degradation rates in Cul4A overexpressed H28 cell line and slower degradation rates in Cul4A knockdown H28 cell line. Our study indicates that Cul4A amplification and overexpression play an oncogenic role in the pathogenesis of mesothelioma. Thus, Cul4A may be a potential therapeutic target for MPM.

}, keywords = {Cell Cycle, Cell Line, Tumor, Cullin Proteins, Humans, Mesothelioma, Oncogenes, Pleural Neoplasms, Proliferating Cell Nuclear Antigen, rho GTP-Binding Proteins, RNA Interference, RNA, Small Interfering, Signal Transduction}, issn = {1582-4934}, doi = {10.1111/j.1582-4934.2009.00971.x}, author = {Hung, Ming-Szu and Jiang-Hua Mao and Xu, Zhidong and Yang, Cheng-Ta and Yu, Jau-Song and Harvard, Chansonette and Lin, Yu-Ching and Bravo, Dawn Therese and Jablons, David M and You, Liang} } @article {179, title = {Progressive genomic instability in the FVB/Kras(LA2) mouse model of lung cancer.}, journal = {Mol Cancer Res}, volume = {9}, year = {2011}, month = {2011 Oct}, pages = {1339-45}, abstract = {

Alterations in DNA copy number contribute to the development and progression of cancers and are common in epithelial tumors. We have used array Comparative Genomic Hybridization (aCGH) to visualize DNA copy number alterations across the genomes of lung tumors in the Kras(LA2) model of lung cancer. Copy number gain involving the Kras locus, as focal amplification or whole chromosome gain, is the most common alteration in these tumors and with a prevalence that increased significantly with increasing tumor size. Furthermore, Kras amplification was the only major genomic event among the smallest lung tumors, suggesting that this alteration occurs early during the development of mutant Kras-driven lung cancers. Recurring gains and deletions of other chromosomes occur progressively more frequently among larger tumors. These results are in contrast to a previous aCGH analysis of lung tumors from Kras(LA2) mice on a mixed genetic background, in which relatively few DNA copy number alterations were observed regardless of tumor size. Our model features the Kras(LA2) allele on the inbred FVB/N mouse strain, and in this genetic background, there is a highly statistically significant increase in level of genomic instability with increasing tumor size. These data suggest that recurring DNA copy alterations are important for tumor progression in the Kras(LA2) model of lung cancer and that the requirement for these alterations may be dependent on the genetic background of the mouse strain.

}, keywords = {Animals, Cell Line, Tumor, Chromosome Aberrations, Disease Models, Animal, Disease Progression, DNA Copy Number Variations, DNA, Neoplasm, Gene Dosage, Gene Expression Regulation, Neoplastic, Genes, ras, Genomic Instability, Lung Neoplasms, Mice, Mice, Inbred C57BL, Proto-Oncogene Proteins p21(ras)}, issn = {1557-3125}, doi = {10.1158/1541-7786.MCR-11-0219}, author = {To, Minh D and Quigley, David A and Jiang-Hua Mao and Del Rosario, Reyno and Hsu, Jeff and Hodgson, Graeme and Jacks, Tyler and Balmain, Allan} } @article {167, title = {The expression level of HJURP has an independent prognostic impact and predicts the sensitivity to radiotherapy in breast cancer.}, journal = {Breast Cancer Res}, volume = {12}, year = {2010}, month = {2010}, pages = {R18}, abstract = {

INTRODUCTION: HJURP (Holliday Junction Recognition Protein) is a newly discovered gene reported to function at centromeres and to interact with CENPA. However its role in tumor development remains largely unknown. The goal of this study was to investigate the clinical significance of HJURP in breast cancer and its correlation with radiotherapeutic outcome.

METHODS: We measured HJURP expression level in human breast cancer cell lines and primary breast cancers by Western blot and/or by Affymetrix Microarray; and determined its associations with clinical variables using standard statistical methods. Validation was performed with the use of published microarray data. We assessed cell growth and apoptosis of breast cancer cells after radiation using high-content image analysis.

RESULTS: HJURP was expressed at higher level in breast cancer than in normal breast tissue. HJURP mRNA levels were significantly associated with estrogen receptor (ER), progesterone receptor (PR), Scarff-Bloom-Richardson (SBR) grade, age and Ki67 proliferation indices, but not with pathologic stage, ERBB2, tumor size, or lymph node status. Higher HJURP mRNA levels significantly decreased disease-free and overall survival. HJURP mRNA levels predicted the prognosis better than Ki67 proliferation indices. In a multivariate Cox proportional-hazard regression, including clinical variables as covariates, HJURP mRNA levels remained an independent prognostic factor for disease-free and overall survival. In addition HJURP mRNA levels were an independent prognostic factor over molecular subtypes (normal like, luminal, Erbb2 and basal). Poor clinical outcomes among patients with high HJURP expression were validated in five additional breast cancer cohorts. Furthermore, the patients with high HJURP levels were much more sensitive to radiotherapy. In vitro studies in breast cancer cell lines showed that cells with high HJURP levels were more sensitive to radiation treatment and had a higher rate of apoptosis than those with low levels. Knock down of HJURP in human breast cancer cells using shRNA reduced the sensitivity to radiation treatment. HJURP mRNA levels were significantly correlated with CENPA mRNA levels.

CONCLUSIONS: HJURP mRNA level is a prognostic factor for disease-free and overall survival in patients with breast cancer and is a predictive biomarker for sensitivity to radiotherapy.

}, keywords = {Biomarkers, Tumor, Blotting, Western, Breast Neoplasms, Cell Line, Tumor, Disease-Free Survival, DNA-Binding Proteins, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Oligonucleotide Array Sequence Analysis, Predictive Value of Tests, Prognosis, RNA Interference, RNA, Messenger}, issn = {1465-542X}, doi = {10.1186/bcr2487}, author = {Hu, Zhi and Huang, Ge and Sadanandam, Anguraj and Gu, Shenda and Lenburg, Marc E and Pai, Melody and Bayani, Nora and Blakely, Eleanor A and Gray, Joe W and Jiang-Hua Mao} } @article {170, title = {Functional polymorphism of the CK2alpha intronless gene plays oncogenic roles in lung cancer.}, journal = {PLoS One}, volume = {5}, year = {2010}, month = {2010}, pages = {e11418}, abstract = {

Protein kinase CK2 is frequently up-regulated in human cancers, although the mechanism of CK2 activation in cancer remains unknown. In this study, we investigated the role of the CK2alpha intronless gene (CSNK2A1P, a presumed CK2alpha pseudogene) in the pathogenesis of human cancers. We found evidence of amplification and over-expression of the CSNK2A1P gene in non-small cell lung cancer and leukemia cell lines and 25\% of the lung cancer tissues studied. The mRNA expression levels correlated with the copy numbers of the CSNK2A1P gene. We also identified a novel polymorphic variant (398T/C, I133T) of the CSNK2A1P gene and showed that the 398T allele is selectively amplified over the 398C allele in 101 non-small cell lung cancer tissue samples compared to those in 48 normal controls (p = 0.013<0.05). We show for the first time CSNK2A1P protein expression in transfected human embryonic kidney 293T and mouse embryonic fibroblast NIH-3T3 cell lines. Both alleles are transforming in these cell lines, and the 398T allele appears to be more transforming than the 398C allele. Moreover, the 398T allele degrades PML tumor suppressor protein more efficiently than the 398C allele and shows a relatively stronger binding to PML. Knockdown of the CSNK2A1P gene expression with specific siRNA increased the PML protein level in lung cancer cells. We report, for the first time, that the CSNK2A1P gene is a functional proto-oncogene in human cancers and its functional polymorphism appears to degrade PML differentially in cancer cells. These results are consistent with an important role for the 398T allele of the CSNK2A1P in human lung cancer susceptibility.

}, keywords = {Animals, Blotting, Western, Casein Kinase II, Cell Line, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Immunoprecipitation, In Situ Hybridization, Fluorescence, In Vitro Techniques, Lung Neoplasms, Mice, NIH 3T3 Cells, Nuclear Proteins, Polymorphism, Genetic, Protein Binding, Reverse Transcriptase Polymerase Chain Reaction, RNA, Small Interfering, Sequence Analysis, DNA, Transcription Factors, Tumor Suppressor Proteins}, issn = {1932-6203}, doi = {10.1371/journal.pone.0011418}, author = {Hung, Ming-Szu and Lin, Yu-Ching and Jiang-Hua Mao and Kim, Il-Jin and Xu, Zhidong and Yang, Cheng-Ta and Jablons, David M and You, Liang} } @article {87, title = {Molecular predictors of 3D morphogenesis by breast cancer cell lines in 3D culture}, journal = {PLoS Comput Biol}, volume = {6}, year = {2010}, month = {2010 Feb}, pages = {e1000684}, abstract = {

Correlative analysis of molecular markers with phenotypic signatures is the simplest model for hypothesis generation. In this paper, a panel of 24 breast cell lines was grown in 3D culture, their morphology was imaged through phase contrast microscopy, and computational methods were developed to segment and represent each colony at multiple dimensions. Subsequently, subpopulations from these morphological responses were identified through consensus clustering to reveal three clusters of round, grape-like, and stellate phenotypes. In some cases, cell lines with particular pathobiological phenotypes clustered together (e.g., ERBB2 amplified cell lines sharing the same morphometric properties as the grape-like phenotype). Next, associations with molecular features were realized through (i) differential analysis within each morphological cluster, and (ii) regression analysis across the entire panel of cell lines. In both cases, the dominant genes that are predictive of the morphological signatures were identified. Specifically, PPARgamma has been associated with the invasive stellate morphological phenotype, which corresponds to triple-negative pathobiology. PPARgamma has been validated through two supporting biological assays.

}, keywords = {Biomarkers, Tumor, Breast Neoplasms, Cell Culture Techniques, Cell Line, Tumor, Female, Gene Expression Profiling, Histocytochemistry, Humans, Image Processing, Computer-Assisted, Models, Biological, Phenotype, PPAR gamma, Receptor, ErbB-2, Reproducibility of Results}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1000684}, author = {Han, Ju and Chang, Hang and Giricz, Orsi and Lee, Genee Y and Baehner, Frederick L and Gray, Joe W and Bissell, Mina J and Kenny, Paraic A and Parvin, Bahram} } @article {166, title = {Identification of hematein as a novel inhibitor of protein kinase CK2 from a natural product library.}, journal = {BMC Cancer}, volume = {9}, year = {2009}, month = {2009}, pages = {135}, abstract = {

BACKGROUND: Casein kinase 2 (CK2) is dysregulated in various human cancers and is a promising target for cancer therapy. To date, there is no small molecular CK2 inhibitor in clinical trial yet. With the aim to identify novel CK2 inhibitors, we screened a natural product library.

METHODS: We adopted cell-based proliferation and CK2 kinase assays to screen CK2 inhibitors from a natural compound library. Dose-dependent response of CK2 inhibitors in vitro was determined by a radioisotope kinase assay. Western blot analysis was used to evaluate down stream Akt phosphorylation and apoptosis. Apoptosis was also evaluated by annexin-V/propidium iodide (PI) labeling method using flow cytometry. Inhibition effects of CK2 inhibitors on the growth of cancer and normal cells were evaluated by cell proliferation and viability assays.

RESULTS: Hematein was identified as a novel CK2 inhibitor that is highly selective among a panel of kinases. It appears to be an ATP non-competitive and partially reversible CK2 inhibitor with an IC50 value of 0.55 muM. In addition, hematein inhibited cancer cell growth partially through down-regulation of Akt phosphorylation and induced apoptosis in these cells. Furthermore, hematein exerted stronger inhibition effects on the growth of cancer cells than in normal cells.

CONCLUSION: In this study, we showed that hematein is a novel selective and cell permeable small molecule CK2 inhibitor. Hematein showed stronger growth inhibition effects to cancer cells when compared to normal cells. This compound may represent a promising class of CK2 inhibitors.

}, keywords = {Adenosine Triphosphate, Apoptosis, Casein Kinase II, Cell Growth Processes, Cell Line, Tumor, Dose-Response Relationship, Drug, HCT116 Cells, HeLa Cells, Hematoxylin, Humans, Lung Neoplasms, Neoplasms, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Substrate Specificity}, issn = {1471-2407}, doi = {10.1186/1471-2407-9-135}, author = {Hung, Ming-Szu and Xu, Zhidong and Lin, Yu-Ching and Jiang-Hua Mao and Yang, Cheng-Ta and Chang, Pey-Jium and Jablons, David M and You, Liang} } @article {273, title = {FBXW7 and DNA copy number instability.}, journal = {Breast Cancer Res Treat}, volume = {109}, year = {2008}, month = {2008 May}, pages = {47-54}, abstract = {

SKP1-cullin-F-box protein (SCF) type ubiquitin ligases degrade proteins controlling the G1/S transition. Deficiency for FBXW7 (also known as hCDC4), which encodes the F-box protein of the SCF type ubiquitin ligase is associated with genomic instability. Here, we investigated the association of FBXW7 deficiency with chromosomal instability in breast cancer. We screened 49 tumors previously profiled by array CGH for mutations in conserved regions of FBXW7, but found no mutations. Copy number loss of FBXW7, however was associated with enhanced genomic instability in the Complex breast tumor subtype, but instability may not be due to FBXW7 haploinsufficiency, since transcript levels were not reduced in tumors with loss of the locus, whereas reduced expression was observed for other neighboring genes involved in maintenance of genome stability. We also investigated whether cells deficient for FBXW7 showed enhanced instability by challenging cells with methotrexate and assessing numbers of genomic alterations arising in resistant cells. Although methotrexate resistant colonies formed at high frequencies in HCT116 FBXW7+/- and HCT116 FBXW7-/- cells compared to parental HCT116, few copy number alterations were detected in the resistant cells. Taken together these studies suggest that FBXW7 deficiency is unlikely to contribute to the extensive copy number aberrations associated with breast and possibly other tumor types.

}, keywords = {Breast Neoplasms, Cell Cycle Proteins, Cell Line, Tumor, Chromosomal Instability, Disease Progression, DNA, Drug Resistance, Neoplasm, Exons, F-Box Proteins, Genetic Techniques, Genomic Instability, Humans, Methotrexate, Mutation, Nucleic Acid Hybridization, Oligonucleotide Array Sequence Analysis, Ubiquitin-Protein Ligases}, issn = {0167-6806}, doi = {10.1007/s10549-007-9623-7}, author = {Byrd, Kristin N and Huey, Bing and Roydasgupta, Ritu and Fridlyand, Jane and A Snijders and Albertson, Donna G} } @article {162, title = {FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression.}, journal = {Science}, volume = {321}, year = {2008}, month = {2008 Sep 12}, pages = {1499-502}, abstract = {

The enzyme mTOR (mammalian target of rapamycin) is a major target for therapeutic intervention to treat many human diseases, including cancer, but very little is known about the processes that control levels of mTOR protein. Here, we show that mTOR is targeted for ubiquitination and consequent degradation by binding to the tumor suppressor protein FBXW7. Human breast cancer cell lines and primary tumors showed a reciprocal relation between loss of FBXW7 and deletion or mutation of PTEN (phosphatase and tensin homolog), which also activates mTOR. Tumor cell lines harboring deletions or mutations in FBXW7 are particularly sensitive to rapamycin treatment, which suggests that loss of FBXW7 may be a biomarker for human cancers susceptible to treatment with inhibitors of the mTOR pathway.

}, keywords = {Animals, Breast Neoplasms, Cell Cycle Proteins, Cell Line, Cell Line, Tumor, F-Box Proteins, Gene Deletion, Gene Dosage, Gene Silencing, Genes, Tumor Suppressor, Humans, Mice, Mice, Nude, Mutation, Neoplasm Transplantation, Phosphorylation, Protein Binding, Protein Kinases, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Signal Transduction, Sirolimus, TOR Serine-Threonine Kinases, Transfection, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Ubiquitination}, issn = {1095-9203}, doi = {10.1126/science.1162981}, author = {Jiang-Hua Mao and Kim, Il-Jin and Wu, Di and Climent, Joan and Kang, Hio Chung and DelRosario, Reyno and Balmain, Allan} } @article {272, title = {Genome position and gene amplification.}, journal = {Genome Biol}, volume = {8}, year = {2007}, month = {2007}, pages = {R120}, abstract = {

BACKGROUND: Amplifications, regions of focal high-level copy number change, lead to overexpression of oncogenes or drug resistance genes in tumors. Their presence is often associated with poor prognosis; however, the use of amplification as a mechanism for overexpression of a particular gene in tumors varies. To investigate the influence of genome position on propensity to amplify, we integrated a mutant form of the gene encoding dihydrofolate reductase into different positions in the human genome, challenged cells with methotrexate and then studied the genomic alterations arising in drug resistant cells.

RESULTS: We observed site-specific differences in methotrexate sensitivity, amplicon organization and amplification frequency. One site was uniquely associated with a significantly enhanced propensity to amplify and recurrent amplicon boundaries, possibly implicating a rare folate-sensitive fragile site in initiating amplification. Hierarchical clustering of gene expression patterns and subsequent gene enrichment analysis revealed two clusters differing significantly in expression of MYC target genes independent of integration site.

CONCLUSION: These studies suggest that genome context together with the particular challenges to genome stability experienced during the progression to cancer contribute to the propensity to amplify a specific oncogene or drug resistance gene, whereas the overall functional response to drug (or other) challenge may be independent of the genomic location of an oncogene.

}, keywords = {Cell Line, Tumor, Gene Amplification, Gene Expression Regulation, Neoplastic, Humans, Methotrexate, Tetrahydrofolate Dehydrogenase}, issn = {1474-760X}, doi = {10.1186/gb-2007-8-6-r120}, author = {Gajduskova, Pavla and A Snijders and Kwek, Serena and Roydasgupta, Ritu and Fridlyand, Jane and Tokuyasu, Taku and Pinkel, Daniel and Albertson, Donna G} } @article {270, title = {Increased gene copy numbers at chromosome 20q are frequent in both squamous cell carcinomas and adenocarcinomas of the cervix.}, journal = {J Pathol}, volume = {209}, year = {2006}, month = {2006 Jun}, pages = {220-30}, abstract = {

Genome-wide microarray-based comparative genomic hybridization (array CGH) was used to identify common chromosomal alterations involved in cervical carcinogenesis as a first step towards the discovery of novel biomarkers. The genomic profiles of nine squamous cell carcinomas (SCCs) and seven adenocarcinomas (AdCAs), as well as four human papillomavirus (HPV)-immortalized keratinocyte cell lines, were assessed. On a genome-wide scale, SCCs showed significantly more gains than AdCAs. More specifically, there was a striking and highly significant difference between the two histological types for gain at 3q12.1-28, which was predominantly observed in SCC. Other frequent alterations included gains of 1q21.1-31.1 and 20q11.21-13.33, and losses of 11q22.3-25 and 13q14.3-21.33. Subsequent FISH analysis for hTR, located at 3q26, confirmed the presence of 3q gain in SCCs and HPV-immortalized cell lines. Fine mapping of chromosome 20q using multiplex ligation-dependent probe amplification (MLPA) showed copy number increases for a number of genes located at 20q11-q12, including DNMT3B and TOP1. For DNMT3B, this correlated with elevated mRNA expression in 79\% of cases. In conclusion, the assessment of frequent genomic alterations resulted in the identification of potential novel biomarkers, which may ultimately enable a better risk stratification of high-risk (hr)-HPV-positive women.

}, keywords = {Adenocarcinoma, Adult, Aged, Carcinoma, Squamous Cell, Cell Line, Tumor, Chromosome Aberrations, Chromosome Mapping, Chromosomes, Human, Chromosomes, Human, Pair 20, DNA (Cytosine-5-)-Methyltransferase, Female, Genome, Human, Humans, In Situ Hybridization, Fluorescence, Middle Aged, Oligonucleotide Array Sequence Analysis, Papillomaviridae, RNA, Messenger, RNA, Neoplasm, Uterine Cervical Neoplasms}, issn = {0022-3417}, doi = {10.1002/path.1966}, author = {Wilting, S M and Snijders, P J F and Meijer, G A and Ylstra, B and van den Ijssel, P R L A and A Snijders and Albertson, D G and Coffa, J and Schouten, J P and van de Wiel, M A and Meijer, C J L M and Steenbergen, R D M} } @article {265, title = {Centromeric chromosomal translocations show tissue-specific differences between squamous cell carcinomas and adenocarcinomas.}, journal = {Oncogene}, volume = {24}, year = {2005}, month = {2005 Feb 24}, pages = {1571-9}, abstract = {

Structural chromosomal aberrations are common in epithelial tumors. Here, we compared the location of centromeric breaks associated with whole arm translocations in seven adenocarcinoma cell lines and nine squamous cell carcinoma cell lines using SKY, microarray-based comparative genomic hybridization (array CGH) and fluorescence in situ hybridization (FISH). Whole arm translocations were more frequent in squamous cell carcinomas (112 in nine cell lines and nine in one short-term culture) than in adenocarcinomas (13 in seven cases) and most often resulted in copy number alterations. Array CGH analysis demonstrated that in all squamous cell carcinomas and in most adenocarcinomas, the breakpoints of unbalanced whole arm translocations occurred between the two clones on the array flanking the centromeres. However, FISH with centromeric probes revealed that in squamous cell carcinomas, the marker chromosomes with whole arm translocations contained centromeres comprised of material from both participating chromosomes, while in adenocarcinomas centromeric material from only one of the chromosomes was present. These observations suggest that different mechanisms of centromeric instability underlie the formation of chromosomal aberrations in adenocarcinomas and squamous cell carcinomas.

}, keywords = {Adenocarcinoma, Carcinoma, Squamous Cell, Cell Line, Tumor, Centromere, Chromosome Mapping, Chromosomes, Human, Diagnosis, Differential, Humans, In Situ Hybridization, Fluorescence, Karyotyping, Nucleic Acid Hybridization, Oligonucleotide Array Sequence Analysis, Translocation, Genetic}, issn = {0950-9232}, doi = {10.1038/sj.onc.1208294}, author = {Hermsen, Mario and A Snijders and Guerv{\'o}s, Marta Alonso and Taenzer, Simone and Koerner, Ulrike and Baak, Jan and Pinkel, Daniel and Albertson, Donna and van Diest, Paul and Meijer, Gerrit and Schrock, Evelin} } @article {144, title = {A mouse skin multistage carcinogenesis model reflects the aberrant DNA methylation patterns of human tumors.}, journal = {Cancer Res}, volume = {64}, year = {2004}, month = {2004 Aug 15}, pages = {5527-34}, abstract = {

Whereas accepted models of tumorigenesis exist for genetic lesions, the timing of epigenetic alterations in cancer is not clearly understood. We have analyzed the profile of aberrations in DNA methylation occurring in cells lines and primary tumors of one of the best-characterized mouse carcinogenesis systems, the multistage skin cancer progression model. Initial analysis using high-performance capillary electrophoresis and immunolocalization revealed a loss of genomic 5-methylcytosine associated with the degree of tumor aggressiveness. Paradoxically, this occurs in the context of a growing number of hypermethylated CpG islands of tumor suppressor genes at the most malignant stages of carcinogenesis. We have observed this last phenomenon using two approaches, a candidate gene approach, studying genes with well-known methylation-associated silencing in human tumors, and a mouse cDNA microarray expression analysis after treatment with DNA demethylating drugs. The transition from epithelial to spindle cell morphology is particularly associated with major epigenetic alterations, such as E-cadherin methylation, demethylation of the Snail promoter, and a decrease of the global DNA methylation. Analysis of data obtained from the cDNA microarray strategy led to the identification of new genes that undergo methylation-associated silencing and have growth-inhibitory effects, such as the insulin-like growth factor binding protein-3. Most importantly, all of the above genes were also hypermethylated in human cancer cell lines and primary tumors, underlining the value of the mouse skin carcinogenesis model for the study of aberrant DNA methylation events in cancer cells.

}, keywords = {5-Methylcytosine, Animals, Cell Line, Tumor, DNA Methylation, DNA Modification Methylases, DNA, Neoplasm, Gene Expression Regulation, Neoplastic, Gene Silencing, Genes, Tumor Suppressor, Histones, Humans, Insulin-Like Growth Factor Binding Protein 3, LIM Domain Proteins, Mice, Muscle Proteins, Nuclear Proteins, Oligonucleotide Array Sequence Analysis, Skin Neoplasms}, issn = {0008-5472}, doi = {10.1158/0008-5472.CAN-03-4061}, author = {Fraga, Mario F and Herranz, Michel and Espada, Jes{\'u}s and Ballestar, Esteban and Paz, Maria F and Ropero, Santiago and Erkek, Emel and Bozdogan, Onder and Peinado, H{\'e}ctor and Niveleau, Alain and Jiang-Hua Mao and Balmain, Alan and Cano, Amparo and Esteller, Manel} }