Regulation and function of the atypical cadherin FAT1 in hepatocellular carcinoma

Valletta D, Czech B, Spruss T, Ikenberg K, Wild P, Hartmann A, Weiss TS, Oefner PJ, Mueller M, Hellerbrand C, Bosserhoff AK (2014)

Publication Type: Journal article

Publication year: 2014

Journal

Carcinogenesis Oxford University Press (OUP): Policy B - Oxford Open Option B

Book Volume: 35

Pages Range: 1407-15

Journal Issue: 6

DOI: 10.1093/carcin/bgu054

Abstract

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.

Authors with CRIS profile

Arndt Hartmann Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie Anja Katrin Boßerhoff

Involved external institutions

Universitätsklinikum Regensburg DE Germany (DE) Universität Regensburg DE Germany (DE) Universitätsspital Zürich (USZ) CH Switzerland (CH)

How to cite

APA:

Valletta, D., Czech, B., Spruss, T., Ikenberg, K., Wild, P., Hartmann, A.,... Bosserhoff, A.K. (2014). Regulation and function of the atypical cadherin FAT1 in hepatocellular carcinoma. Carcinogenesis, 35(6), 1407-15. https://doi.org/10.1093/carcin/bgu054

MLA:

Valletta, Daniela, et al. "Regulation and function of the atypical cadherin FAT1 in hepatocellular carcinoma." Carcinogenesis 35.6 (2014): 1407-15.

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