@article {231, title = {Expression profiling reveals transcriptional regulation by Fbxw7/mTOR pathway in radiation-induced mouse thymic lymphomas.}, journal = {Oncotarget}, volume = {6}, year = {2015}, month = {2015 Dec 29}, pages = {44794-805}, abstract = {

The tumor suppressor gene FBXW7 is deleted and mutated in many different types of human cancers. FBXW7 primarily exerts its tumor suppressor activity by ubiquitinating different oncoproteins including mTOR. Here we used gene transcript profiling to gain a deeper understanding of the role of FBXW7 in tumor development and to determine the influence of mTOR inhibition by rapamycin on tumor transcriptome and biological functions. In comparison to tumors from p53 single heterozygous (p53+/-) mice, we find that radiation-induced thymic lymphomas from Fbxw7/p53 double heterozygous (Fbxw7+/-p53+/-) mice show significant deregulation of cholesterol metabolic processes independent of rapamycin treatment, while cell cycle related genes were upregulated in tumors from placebo treated Fbxw7+/-p53+/- mice, but not in tumors from rapamycin treated Fbxw7+/-p53+/- mice. On the other hand, tumors from rapamycin treated Fbxw7+/-p53+/- mice were enriched for genes involved in the integrated stress response, an adaptive mechanism to survive in stressful environments. Finally, we demonstrated that the Fbxw7 gene signatures identified in mouse tumors significantly overlap with FBXW7 co-expressed genes in human cancers. Importantly these common FBXW7 gene signatures between mouse and human are predictive for disease-free survival in human colon, breast and lung adenocarcinoma cancer patients. These results provide novel insights into the role of FBXW7 in tumor development and have identified a number of potential targets for therapeutic intervention.

}, issn = {1949-2553}, doi = {10.18632/oncotarget.6328}, author = {A Snijders and Liu, Yueyong and Su, Li and Huang, Yurong and Jiang-Hua Mao} } @article {215, title = {Genetic background influences loss of heterozygosity patterns in radiation-induced mouse thymic lymphoma.}, journal = {J Nat Sci}, volume = {1}, year = {2015}, month = {2015}, pages = {e96}, abstract = {

Previous studies have revealed that p53 heterozygous (p53+/-) mice are extremely susceptible to radiation-induced tumorigenesis. To investigate whether genetic background influences radiation induced tumor susceptibility, we crossed p53+/- 129/Sv mice with genetically diverse strains to generate p53+/- F1 hybrids. The results showed that genetic background had a profound impact on tumor latency after exposure to gamma radiation, while the tumor spectrum did not change. We further characterized the thymic lymphomas that arose in the p53+/- mice by genome-wide loss of heterozygosity (LOH) analyses and found that genetic background strongly influenced the frequency of LOH and the loss of which parental allele on different chromosomes. Further research is needed to identify which genetic variations control the LOH patterns in radiation-induced thymic lymphomas and to evaluate its relevance to human cancers.

}, issn = {2377-2700}, author = {Hang, Michael and Huang, Yurong and A Snijders and Jiang-Hua Mao} } @article {214, title = {Genetic Background Modulates lncRNA-Coordinated Tissue Response to Low Dose Ionizing Radiation.}, journal = {Int J Genomics}, volume = {2015}, year = {2015}, month = {2015}, pages = {461038}, abstract = {

Long noncoding RNAs (lncRNAs) are emerging as key regulators of diverse cell functions and processes. However, the relevance of lncRNAs in the cell and tissue response to ionizing radiation has not yet been characterized. Here we used microarray profiling to determine lncRNA and mRNA expression in mammary glands of BALB/c and SPRET/EiJ mice after low-dose ionizing radiation (LDIR) exposure. We found that unirradiated mammary tissues of these strains differed significantly in baseline expressions of 290 lncRNAs. LDIR exposure (10 cGy) induced a significant change in the expression of many lncRNAs. The vast majority of lncRNAs identified to be differentially expressed after LDIR in either BALB/c or SPRET/EiJ had a significantly correlated expression pattern with at least one LDIR responsive mRNA. Functional analysis revealed that the response to LDIR in BALB/c mice is highly dynamic with enrichment for genes involved in tissue injury, inflammatory responses, and mammary gland development at 2, 4, and 8 weeks after LDIR, respectively. Our study demonstrates that genetic background strongly influences the expression of lncRNAs and their response to radiation and that lncRNAs may coordinate the tissue response to LDIR exposure via regulation of coding mRNAs.

}, issn = {2314-436X}, doi = {10.1155/2015/461038}, author = {Tang, Jonathan and Huang, Yurong and Nguyen, David H and Costes, Sylvain V and A Snijders and Jiang-Hua Mao} } @article {229, title = {Identification of genetic factors that modify motor performance and body weight using Collaborative Cross mice.}, journal = {Sci Rep}, volume = {5}, year = {2015}, month = {2015}, pages = {16247}, abstract = {

Evidence has emerged that suggests a link between motor deficits, obesity and many neurological disorders. However, the contributing genetic risk factors are poorly understood. Here we used the Collaborative Cross (CC), a large panel of newly inbred mice that captures 90\% of the known variation among laboratory mice, to identify the genetic loci controlling rotarod performance and its relationship with body weight in a cohort of 365 mice across 16 CC strains. Body weight and rotarod performance varied widely across CC strains and were significantly negatively correlated. Genetic linkage analysis identified 14 loci that were associated with body weight. However, 45 loci affected rotarod performance, seven of which were also associated with body weight, suggesting a strong link at the genetic level. Lastly, we show that genes identified in this study overlap significantly with those related to neurological disorders and obesity found in human GWA studies. In conclusion, our results provide a genetic framework for studies of the connection between body weight, the central nervous system and behavior.

}, issn = {2045-2322}, doi = {10.1038/srep16247}, author = {Jiang-Hua Mao and Langley, Sasha A and Huang, Yurong and Hang, Michael and Bouchard, Kristofer E and Celniker, Susan E and Brown, James B and Jansson, Janet K and Karpen, Gary H and A Snijders} } @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 {209, title = {An interferon signature identified by RNA-sequencing of mammary tissues varies across the estrous cycle and is predictive of metastasis-free survival.}, journal = {Oncotarget}, volume = {5}, year = {2014}, month = {2014 Jun 30}, pages = {4011-25}, abstract = {

The concept that a breast cancer patient{\textquoteright}s menstrual stage at the time of tumor surgery influences risk of metastases remains controversial. The scarcity of comprehensive molecular studies of menstrual stage-dependent fluctuations in the breast provides little insight in this observation. To gain a deeper understanding of the biological changes in mammary tissue and blood during the menstrual cycle and to determine the influence of environmental exposures, such as low-dose ionizing radiation (LDIR), we used the mouse to characterize estrous-cycle variations in mammary gene transcripts by RNA-sequencing, peripheral white blood cell (WBC) counts and plasma cytokine levels. We identified an estrous-variable and hormone-dependent gene cluster enriched for Type-1 interferon genes. Cox regression identified a 117-gene signature of interferon-associated genes, which correlated with lower frequencies of metastasis in breast cancer patients. LDIR (10cGy) exposure had no detectable effect on mammary transcripts. However, peripheral WBC counts varied across the estrous cycle and LDIR exposure reduced lymphocyte counts and cytokine levels in tumor-susceptible mice. Our finding of variations in mammary Type-1 interferon and immune functions across the estrous cycle provides a mechanism by which timing of breast tumor surgery during the menstrual cycle may have clinical relevance to a patient{\textquoteright}s risk for distant metastases.

}, keywords = {Animals, Disease-Free Survival, Estrous Cycle, Female, Humans, Interferons, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasm Metastasis, RNA, Messenger}, issn = {1949-2553}, doi = {10.18632/oncotarget.2148}, author = {A Snijders and Langley, Sasha and Jiang-Hua Mao and Bhatnagar, Sandhya and Bjornstad, Kathleen A and Rosen, Chris J and Lo, Alvin and Huang, Yurong and Blakely, Eleanor A and Karpen, Gary H and Bissell, Mina J and Wyrobek, Andrew J} } @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 {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 {196, title = {Temporal mTOR inhibition protects Fbxw7-deficient mice from radiation-induced tumor development.}, journal = {Aging (Albany NY)}, volume = {5}, year = {2013}, month = {2013 Feb}, pages = {111-9}, abstract = {

FBXW7 acts as a tumor suppressor in numerous types of human cancers through ubiquitination of different oncoproteins including mTOR. However, how the mutation/loss of Fbxw7 results in tumor development remains largely unknown. Here we report that downregulation of mTOR by radiation is Fbxw7-dependent, and short-term mTOR inhibition by rapamycin after exposure to radiation significantly postpones tumor development in Fbxw7/p53 double heterozygous (Fbxw7+/-p53+/-) mice but not in p53 single heterozygous (p53+/-) mice. Tumor latency of rapamycin treated Fbxw7+/-p53+/- mice is remarkably similar to those of p53+/- mice while placebo treatedFbxw7+/-p53+/- mice develop tumor significantly earlier than placebo treated p53+/- mice. Furthermore, we surprisingly find that, although temporal treatment of rapamycin is given at a young age, the inhibition of mTOR activity sustainably remains in tumors. These results indicate that inhibition of mTOR signaling pathway suppresses the contribution of Fbxw7 loss toward tumor development.

}, keywords = {Animals, Cell Transformation, Neoplastic, F-Box Proteins, Genes, Tumor Suppressor, Mice, Mutation, Neoplasms, Radiation-Induced, Signal Transduction, Sirolimus, TOR Serine-Threonine Kinases, Ubiquitin-Protein Ligases}, issn = {1945-4589}, doi = {10.18632/aging.100535}, author = {Liu, Yueyong and Huang, Yurong and Wang, Zeran and Huang, Yong and Li, Xiaohua and Louie, Alexander and Wei, Guangwei and Jiang-Hua Mao} } @article {193, title = {Low-dose ionizing radiation-induced blood plasma metabolic response in a diverse genetic mouse population.}, journal = {Radiat Res}, volume = {178}, year = {2012}, month = {2012 Dec}, pages = {551-5}, abstract = {

Understanding the biological effects and biochemical mechanisms of low-dose ionizing radiation (LDIR) is important for setting exposure limits for the safe use of nuclear power and medical diagnostic procedures. Although several studies have highlighted the effects of ionizing radiation on metabolism, most studies have focused on uniform genetic mouse populations. Here, we report the metabolic response to LDIR (10 cGy X ray) on a genetically diverse mouse population (142 mice) generated from a cross of radiation-sensitive (BALB/c) and radiation-resistant (SPRET/EiJ) parental strains. GC-TOF profiling of plasma metabolites was used to compare exposed vs. sham animals. From this, 16 metabolites were significantly altered in the LDIR treated vs. sham group. Use of two significantly altered metabolites, thymine and 2-monostearin, was found to effectively segregate the two treatments. Multivariate statistical analysis was used to identify genetic polymorphisms correlated with metabolite abundance (e.g., amino acids, fatty acids, nucleotides and TCA cycle intermediates). Genetic analysis of metabolic phenotypes showed suggestive linkages for fatty acid and amino acid metabolism. However, metabolite abundance was found to be a function of low-dose ionizing radiation exposure, and not of the underlying genetic variation.

}, keywords = {Animals, Blood, Crosses, Genetic, Dose-Response Relationship, Radiation, Female, Genetic Variation, Male, Metabolome, Mice, Mice, Inbred BALB C, Species Specificity, Transcriptome}, issn = {1938-5404}, doi = {10.1667/RR2990.1}, author = {Lee, Do Yup and Bowen, Benjamin P and Nguyen, David H and Parsa, Sara and Huang, Yurong and Jiang-Hua Mao and Northen, Trent R} } @article {182, title = {Multiple novel alternative splicing forms of FBXW7α have a translational modulatory function and show specific alteration in human cancer.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e49453}, abstract = {

FBXW7 acts as a tumor suppressor through ubiquitination and degradation of multiple oncoproteins. Loss of FBXW7 expression, which could be partially attributed by the genomic deletion or mutation of FBXW7 locus, is frequently observed in various human cancers. However, the mechanisms regulating FBXW7 expression still remain poorly understood. Here we examined the 5{\textquoteright} region of FBXW7 gene to investigate the regulation of FBXW7 expression. We identified seven alternative splicing (AS) 5{\textquoteright}-UTR forms of FBXW7α that are composed of multiple novel non-coding exons. A significant difference in translational efficiency among these 5{\textquoteright}-UTRs variants was observed by in vivo Luciferase reporter assay and Western blot. Furthermore, we found that the mRNA level of the AS form with high translational efficiency was specifically reduced in more than 80\% of breast cancer cell lines and in more than 50\% of human primary cancers from various tissues. In addition, we also identified mutations of FBXW7 in prostate cancers (5.6\%), kidney cancers (16.7\%), and bladder cancers (18.8\%). Our results suggest that in addition to mutation, differential expression of FBXW7α AS forms with different translational properties may serve as a novel mechanism for inactivation of FBXW7 in human cancer.

}, keywords = {Alternative Splicing, Analysis of Variance, Blotting, Western, Cell Cycle Proteins, Computational Biology, DNA Mutational Analysis, Exons, F-Box Proteins, Gene Components, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Luciferases, Neoplasms, Protein Biosynthesis, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Ubiquitin-Protein Ligases}, issn = {1932-6203}, doi = {10.1371/journal.pone.0049453}, author = {Liu, Yueyong and Ren, Shancheng and Castellanos-Mart{\'\i}n, Andr{\'e}s and Perez-Losada, Jesus and Kwon, Yong-Won and Huang, Yurong and Wang, Zeran and Abad, Mar and Cruz-Hernandez, Juan J and Rodriguez, Cesar A and Sun, Yinghao and Jiang-Hua Mao} } @article {188, title = {Pten regulates Aurora-A and cooperates with Fbxw7 in modulating radiation-induced tumor development.}, journal = {Mol Cancer Res}, volume = {10}, year = {2012}, month = {2012 Jun}, pages = {834-44}, abstract = {

The Aurora-A kinase gene is frequently amplified and/or overexpressed in a variety of human cancers, leading to major efforts to develop therapeutic agents targeting this pathway. Here, we show that Aurora-A is targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7 in a process that is regulated by GSK3β. Using a series of truncated Aurora-A proteins and site-directed mutagenesis, we identified distinct FBXW7 and GSK3β-binding sites in Aurora-A. Mutation of critical residues in either site substantially disrupts degradation of Aurora-A. Furthermore, we show that loss of Pten results in the stabilization of Aurora-A by attenuating FBXW7-dependent degradation of Aurora-A through the AKT/GSK3β pathway. Moreover, radiation-induced tumor latency is significantly shortened in Fbxw7(+/-)Pten(+/-) mice as compared with either Fbxw7(+/-) or Pten(+/-) mice, indicating that Fbxw7 and Pten appear to cooperate in suppressing tumorigenesis. Our results establish a novel posttranslational regulatory network in which the Pten and Fbxw7 pathways appear to converge on the regulation of Aurora-A level.

}, keywords = {Animals, Aurora Kinase A, Aurora Kinases, Binding Sites, Blotting, Western, Cell Line, F-Box Proteins, Female, Gamma Rays, Glycogen Synthase Kinase 3, HCT116 Cells, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Neoplasms, Radiation-Induced, NIH 3T3 Cells, Protein Binding, Protein-Serine-Threonine Kinases, PTEN Phosphohydrolase, Time Factors, Ubiquitin, Ubiquitin-Protein Ligases}, issn = {1557-3125}, doi = {10.1158/1541-7786.MCR-12-0025}, author = {Kwon, Yong-Won and Kim, Il-Jin and Wu, Di and Lu, Jing and Stock, William A and Liu, Yueyong and Huang, Yurong and Kang, Hio Chung and DelRosario, Reyno and Jen, Kuang-Yu and Perez-Losada, Jesus and Wei, Guangwei and Balmain, Allan and Jiang-Hua Mao} }