@article {224, title = {FBXW7 negatively regulates ENO1 expression and function in colorectal cancer.}, journal = {Lab Invest}, volume = {95}, year = {2015}, month = {2015 Sep}, pages = {995-1004}, abstract = {

FBXW7 (F-box and WD40 domain protein 7) is a tumor suppressor frequently inactivated in human cancers. The precise molecular mechanisms by which FBXW7 exerts antitumor activity remain under intensive investigation and are thought to relate in part to FBXW7-mediated destruction of key cancer-relevant proteins. Enolase 1 (ENO1) possesses oncogenic activity and is often overexpressed in various human cancers, besides its critical role in glycolysis. However, the detailed regulatory mechanisms of ENO1 expression remain unclear. Here we show that the elevated expression of ENO1 was identified in FBXW7-depletion HCT116 cells through two-dimensional protein electrophoresis and mass spectrometry assays (2DE-MS). Subsequent western blotting and immunohistochemical assays confirmed that ENO1 expression reversely correlates with FBXW7 expression in several cells and colon cancer tissues. Furthermore, we show that FBXW7 physically binds to ENO1 and targets ENO1 for ubiquitin-mediated degradation. Functionally, we found that FBXW7 suppresses the ENO1-induced gene expression, lactate production, cell proliferation and migration. These findings suggest that ENO1 is a novel substrate of FBXW7, and its activity can be negatively regulated by FBXW7 at the posttranslational level. Our work provides a novel molecular insight into FBXW7-directed tumor suppression through regulation of ENO1.

}, keywords = {Biomarkers, Tumor, Blotting, Western, Cell Cycle Proteins, Colorectal Neoplasms, DNA Primers, DNA-Binding Proteins, Electrophoresis, Gel, Two-Dimensional, F-Box Proteins, Gene Expression Regulation, Neoplastic, HCT116 Cells, Humans, Immunohistochemistry, Mass Spectrometry, Phosphopyruvate Hydratase, Real-Time Polymerase Chain Reaction, Regression Analysis, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases}, issn = {1530-0307}, doi = {10.1038/labinvest.2015.71}, author = {Zhan, Panpan and Wang, Yuli and Zhao, Shihu and Liu, Chunyan and Wang, Yunshan and Wen, Mingxin and Jiang-Hua Mao and Wei, Guangwei and Zhang, Pengju} } @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 {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 {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 {201, title = {Rapamycin inhibits FBXW7 loss-induced epithelial-mesenchymal transition and cancer stem cell-like characteristics in colorectal cancer cells.}, journal = {Biochem Biophys Res Commun}, volume = {434}, year = {2013}, month = {2013 May 3}, pages = {352-6}, abstract = {

Increased cell migration and invasion lead to cancer metastasis and are crucial to cancer prognosis. In this study, we explore whether FBXW7 plays any role in metastatic process. We show that depletion of FBXW7 induces epithelial-mesenchymal transition (EMT) in human colon cancer cells along with the increase in cell migration and invasion. Moreover, FBXW7 deficiency promotes the generation of colon cancer stem-like cells in tumor-sphere culture. mTOR inhibition by rapamycin suppresses FBXW7 loss-driven EMT, invasion and stemness. Our results define the FBXW7/mTOR axis as a novel EMT pathway that mediates cancer invasion.

}, keywords = {Blotting, Western, Cell Cycle Proteins, Cell Movement, Cell Shape, Colorectal Neoplasms, Epithelial-Mesenchymal Transition, F-Box Proteins, Gene Expression Regulation, Neoplastic, HCT116 Cells, Humans, Neoplasm Invasiveness, Neoplastic Stem Cells, Sirolimus, TOR Serine-Threonine Kinases, Ubiquitin-Protein Ligases}, issn = {1090-2104}, doi = {10.1016/j.bbrc.2013.03.077}, author = {Wang, Yuli and Liu, Yueyong and Lu, Jing and Zhang, Pengju and Wang, Yunshan and Xu, Yangyang and Wang, Zeran and Jiang-Hua Mao and Wei, Guangwei} } @article {189, title = {Evaluating the prognostic significance of FBXW7 expression level in human breast cancer by a meta-analysis of transcriptional profiles.}, journal = {J Cancer Sci Ther}, volume = {4}, year = {2012}, month = {2012 Aug 31}, pages = {299-305}, abstract = {

The tumor suppressor gene FBXW7 is mutated in numerous types of human cancers leading to loss of its function and/or expression. However the clinic significance of FBXW7 alterations remains largely unknown. Here, we carried out a meta-analysis of 10 gene expression microarray studies for a total 1900 patients of breast cancer with clinic information to evaluate the prognostic impact of FBXW7 mRNA expression. The FBXW7 mRNA levels significantly reduced in breast cancer compared to normal tissues. In addition, significant difference in the FBXW7 mRNA levels was found among molecular subtypes (normal-like, luminal A, luminal B, ERBB2 and basal). ERBB2 and basal tumors had significantly lower average FBXW7 mRNA level than normal-like tumors, whereas luminal A and B tumors have the lowest average FBXW7 mRNA level. The patients with higher FBXW7 mRNA level significantly increased disease-free survival, particularly in the group of patients with ER negative and basal subtype tumors. Moreover, higher FBXW7 mRNA level also significantly increased overall survival in the patients with ER negative tumors. But we strikingly found opposite effect of FBXW7 expression on overall survival in different subtypes. The patients with higher FBXW7 mRNA level significantly decreased overall survival in normal-like subtype while the patients with higher FBXW7 mRNA level significantly increased overall survival in ERBB2 and Basal subtype. Taken together, our results suggest that FBXW7 mRNA levels were a prognostic factor for disease-free and overall survival according to ER status and molecular subtypes.

}, issn = {1948-5956}, doi = {10.4172/1948-5956.1000158}, author = {Wei, Guangwei and Wang, Yunshan and Zhang, Pengju and Lu, Jing and Jiang-Hua Mao} }