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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Finegold, Milton J. Jenkins, Nancy A. Wu, Hao Newberg, Justin Y. Kodama, Takahiro Yoshihara, Kosuke Copeland, Neal G. Parsons, Pamela H. Kodama, Michiko Tien, Jean C. Rangel, Roberto |
| Description | Author Affiliation: Kodama T ( Cancer Research Program, Houston Methodist Research Institute, Houston, TX 77030); Newberg JY ( Cancer Research Program, Houston Methodist Research Institute, Houston, TX 77030); Kodama M ( Cancer Research Program, Houston Methodist Research Institute, Houston, TX 77030); Rangel R ( Cancer Research Program, Houston Methodist Research Institute, Houston, TX 77030); Yoshihara K ( Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 9518510, Japan); Tien JC ( Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, MI 48109); Parsons PH ( Department of Pathology and Immunology, Baylor College of Mecidine and Texas Children's Hospital, Houston, TX 77030.); Wu H ( Department of Pathology and Immunology, Baylor College of Mecidine and Texas Children's Hospital, Houston, TX 77030.); Finegold MJ ( Department of Pathology and Immunology, Baylor College of Mecidine and Texas Children's Hospital, Houston, TX 77030.); Copeland NG ( Cancer Research Program, Houston Methodist Research Institute, Houston, TX 77030); Jenkins NA ( Cancer Research Program, Houston Methodist Research Institute, Houston, TX 77030); |
| Abstract | Epithelial-mesenchymal transition (EMT) is thought to contribute to metastasis and chemoresistance in patients with hepatocellular carcinoma (HCC), leading to their poor prognosis. The genes driving EMT in HCC are not yet fully understood, however. Here, we show that mobilization of Sleeping Beauty (SB) transposons in immortalized mouse hepatoblasts induces mesenchymal liver tumors on transplantation to nude mice. These tumors show significant down-regulation of epithelial markers, along with up-regulation of mesenchymal markers and EMT-related transcription factors (EMT-TFs). Sequencing of transposon insertion sites from tumors identified 233 candidate cancer genes (CCGs) that were enriched for genes and cellular processes driving EMT. Subsequent trunk driver analysis identified 23 CCGs that are predicted to function early in tumorigenesis and whose mutation or alteration in patients with HCC is correlated with poor patient survival. Validation of the top trunk drivers identified in the screen, including MET (MET proto-oncogene, receptor tyrosine kinase), GRB2-associated binding protein 1 (GAB1), HECT, UBA, and WWE domain containing 1 (HUWE1), lysine-specific demethylase 6A (KDM6A), and protein-tyrosine phosphatase, nonreceptor-type 12 (PTPN12), showed that deregulation of these genes activates an EMT program in human HCC cells that enhances tumor cell migration. Finally, deregulation of these genes in human HCC was found to confer sorafenib resistance through apoptotic tolerance and reduced proliferation, consistent with recent studies showing that EMT contributes to the chemoresistance of tumor cells. Our unique cell-based transposon mutagenesis screen appears to be an excellent resource for discovering genes involved in EMT in human HCC and potentially for identifying new drug targets. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 24 |
| Volume Number | 113 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2016-06-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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