Valletta, Daniela and Czech, Barbara and Spruss, Thilo and Ikenberg, Kristian and Wild, Peter and Hartmann, Arndt and Weiss, Thomas S. and Oefner, Peter J. and Mueller, Martina and Bosserhoff, Anja-Katrin and Hellerbrand, Claus (2014) Regulation and function of the atypical cadherin FAT1 in hepatocellular carcinoma. CARCINOGENESIS, 35 (6). pp. 1407-1415. ISSN 0143-3334, 1460-2180
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In human cancers, giant cadherin FAT1 may function both, as an oncogene and a tumor suppressor. Here, we investigated the expression and function of FAT1 in hepatocellular carcinoma (HCC). FAT1 expression was increased in human HCC cell lines and tissues compared with primary human hepatocytes and non-tumorous liver tissue as assessed by quantitative PCR and western blot analysis. Combined immunohistochemical and tissue microarray analysis showed a significant correlation of FAT1 expression with tumor stage and proliferation. Suppression of FAT1 expression by short hairpin RNA impaired proliferation and migration as well as apoptosis resistance of HCC cells in vitro. In nude mice, tumors formed by FAT1-suppressed HCC cells showed a delayed onset and more apoptosis compared with tumors of control cells. Both hepatocyte growth factor and hypoxia-mediated hypoxia-inducible factor 1 alpha activation were identified as strong inducers of FAT1 in HCC. Moreover, demethylating agents induced FAT1 expression in HCC cells. Hypoxia lead to reduced levels of the methyl group donor S-adenosyl-l-methionine (SAM) and hypoxia-induced FAT1 expression was inhibited by SAM supplementation in HCC cells. Together, these findings indicate that FAT1 expression in HCC is regulated via promotor methylation. FAT1 appears as relevant mediator of hypoxia and growth receptor signaling to critical tumorigenic pathways in HCC. This knowledge may facilitate the rational design of novel therapeutics against this highly aggressive malignancy.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SUPPRESSOR GENE FAT; TUMOR-SUPPRESSOR; GROWTH-FACTOR; S-ADENOSYLMETHIONINE; ADHESION MOLECULE; HEPATOMA-CELLS; LIVER-DISEASE; IN-VITRO; EXPRESSION; HYPOXIA; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin I |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 18 Sep 2019 07:25 |
| Last Modified: | 18 Sep 2019 07:25 |
| URI: | https://pred.uni-regensburg.de/id/eprint/10066 |
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