Downregulation of KLF6 is an early event in hepatocarcinogenesis, and stimulates proliferation while reducing differentiation

Sigal Kremer-Tal, Goutham Narla, Yingbei Chen, Eldad Hod, Analisa DiFeo, Steven Yea, Ju Seog Lee, Myron Schwartz, Swan N. Thung, Isabel M. Fiel, Michaela Banck, Eran Zimran, Snorri S. Thorgeirsson, Vincenzo Mazzaferro, Jordi Bruix, John A. Martignetti, Josep M. Llovet, Scott L. Friedman

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

Background/Aims: Hepatocellular carcinoma (HCC) has the most rapidly rising cancer incidence in the US and Europe. The KLF6 tumor suppressor is frequently inactivated in HCC by loss-of-heterozygosity (LOH) and/or mutation. Methods: Here we have analyzed 33 HBV- and 40 HCV-related HCCs for mRNA expression of wildtype KLF6 (wtKLF6) as well as the KLF6 variant 1 (SV1), a truncated, growth-promoting variant that antagonizes wtKLF6 function. The HCV-related tumors analyzed represented the full histologic spectrum from cirrhosis and dysplasia to metastatic cancer. Results: Expression of KLF6 mRNA is decreased in 73% of HBV-associated HCCs compared to matched surrounding tissue (ST), with reductions of ∼80% in one-third of the patients. KLF6 mRNA expression is also reduced in dysplastic nodules from patients with HCV compared to cirrhotic livers (p < 0.005), with an additional, marked decrease in the very advanced, metastatic stage (p < 0.05). An increased ratio of KLF6SV1/wt KLF6 is present in a subset (6/33, 18%) of the HBV-related HCCs compared to matched ST. Reconstituting KLF6 in HepG2 cells by retroviral infection decreased proliferation and related markers including cyclin D1 and beta-catenin, increased cellular differentiation based on induction of albumin, E-cadherin, and decreased alpha fetoprotein. Conclusions: We conclude that reduced KLF6 expression is common in both HBV- and HCV-related HCCs and occurs at critical stages during cancer progression. Effects of KLF6 are attributable to regulation of genes controlling hepatocyte growth and differentiation.

Original languageEnglish (US)
Pages (from-to)645-654
Number of pages10
JournalJournal of hepatology
Volume46
Issue number4
DOIs
StatePublished - Apr 1 2007

Keywords

  • Alternative splicing
  • Dysplasia
  • E-cadherin
  • Hepatocellular carcinoma
  • KLF6SV1

ASJC Scopus subject areas

  • Hepatology

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    Kremer-Tal, S., Narla, G., Chen, Y., Hod, E., DiFeo, A., Yea, S., Lee, J. S., Schwartz, M., Thung, S. N., Fiel, I. M., Banck, M., Zimran, E., Thorgeirsson, S. S., Mazzaferro, V., Bruix, J., Martignetti, J. A., Llovet, J. M., & Friedman, S. L. (2007). Downregulation of KLF6 is an early event in hepatocarcinogenesis, and stimulates proliferation while reducing differentiation. Journal of hepatology, 46(4), 645-654. https://doi.org/10.1016/j.jhep.2006.10.012