Downregulation of KLF6 is an early event in hepatocarcinogenesis, and stimulates proliferation while reducing differentiation
Downregulation of KLF6 is an early event in hepatocarcinogenesis, and stimulates proliferation while reducing differentiation
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DOI：
10.1016/j.jhep.2006.10.012
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发表时间：
2007-04-01
影响因子：
25.7
通讯作者：
Friedman, Scott L.
中科院分区：
文献类型：
--
作者：
Kremer-Tal, Sigal;Narla, Goutham;Friedman, Scott L.
背景/目的：肝细胞癌（HCC）在美国和欧洲的癌症发病率上升最快。KLF 6肿瘤抑制因子经常失活的杂合性丢失（洛）和/或mutation.Methods：在这里，我们分析了33 HBV和40 HCV相关的肝癌野生型KLF 6（wtKLF 6）的mRNA表达以及KLF 6变体1（SV 1），一个截短的，促进生长的变体，拮抗wtKLF 6功能。HCV相关的肿瘤分析代表了完整的组织学谱，从肝硬化和异型增生转移cancer.Results：KLF 6 mRNA的表达下降73%的HBV相关的肝癌相比，匹配的周围组织（ST），减少了类似的三分之一的患者80%。KLF 6 mRNA在HCV患者的异型增生结节中的表达也比在肝硬化患者的异型增生结节中的表达降低（p < 0.005），在非常晚期的转移性阶段中的表达也显著降低（p < 0.05）。KLF 6SV 1/wt KLF 6的比例增加存在于一个子集中，通过逆转录病毒感染在HepG 2细胞中重建KLF 6降低了增殖和相关标志物，包括细胞周期蛋白D1和β-连环蛋白，基于白蛋白、E-钙粘蛋白的诱导增加了细胞分化，并降低了甲胎蛋白。我们的结论是，KLF 6表达减少是常见的HBV和HCV相关的肝癌，并发生在癌症进展的关键阶段。KLF 6的作用可归因于控制肝细胞生长和分化的基因的调节。(c)2006年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
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 similar to 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. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.