TY - JOUR
T1 - Downregulation of KLF6 is an early event in hepatocarcinogenesis, and stimulates proliferation while reducing differentiation
AU - Kremer-Tal, Sigal
AU - Narla, Goutham
AU - Chen, Yingbei
AU - Hod, Eldad
AU - DiFeo, Analisa
AU - Yea, Steven
AU - Lee, Ju Seog
AU - Schwartz, Myron
AU - Thung, Swan N.
AU - Fiel, Isabel M.
AU - Banck, Michaela
AU - Zimran, Eran
AU - Thorgeirsson, Snorri S.
AU - Mazzaferro, Vincenzo
AU - Bruix, Jordi
AU - Martignetti, John A.
AU - Llovet, Josep M.
AU - Friedman, Scott L.
PY - 2007/4
Y1 - 2007/4
N2 - 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.
AB - 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.
KW - Alternative splicing
KW - Dysplasia
KW - E-cadherin
KW - Hepatocellular carcinoma
KW - KLF6SV1
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U2 - 10.1016/j.jhep.2006.10.012
DO - 10.1016/j.jhep.2006.10.012
M3 - Article
C2 - 17196295
AN - SCOPUS:33947162353
VL - 46
SP - 645
EP - 654
JO - Journal of Hepatology
JF - Journal of Hepatology
SN - 0168-8278
IS - 4
ER -