Harbor-UCLA Medical Center, Department of Pathology, Torrance, CA 90502, United States.
Harbor-UCLA Medical Center, Department of Pathology, Torrance, CA 90502, United States.
Exp Mol Pathol. 2019 Jun;108:156-163. doi: 10.1016/j.yexmp.2019.04.002. Epub 2019 Apr 3.
As the fifth most common cancer and the second leading cause of cancer related deaths worldwide, hepatocellular carcinoma (HCC) causes up to one million deaths annually. Alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH) are becoming the two major risk factors because both may develop liver fibrosis and hepatocellular carcinoma (HCC) if left untreated. However, compared with 3-10% of patients with ASH may progress to HCC annually, about only 0.5% NASH patients may progress to HCC annually. The present study is to clarify the protein expression differences of tumor suppressor genes (TSGs) between ASH and NASH. In liver biopsied specimens from NASH and ASH patients, using an immunofluorescence method and morphometrically quantitating the fluorescence intensity, we studied the protein expression within hepatocytes cytoplasm of candidate TSGs including RUNX3, GSTP1, and RASSF1A. Compared with the control group of patients, the expression levels of all three proteins were upregulated in the ASH group of patients (p < .001 in all molecules). While RUNX3 was upregulated, GSTP1 and RASSF1 did not change in the NASH group of patients. The most important finding is that compared with the ASH group of patients, the expression levels of all three TSG proteins, RUNX3, GSTP1, and RASSF1, were significantly lower in the NASH group of patients (p < .001 in all three molecules). These results confirmed our previous finding that there are significant differences of many molecules including TSGs that changed in NASH compared to ASH. Thus, we conclude that there are significantly different TSGs and pathways involved during the pathogenesis of HCC development in NASH compared to ASH that may help to develop different strategies for prevention and treatment of NASH and ASH patients.
作为全球第五大常见癌症和第二大癌症相关死亡原因，肝细胞癌 (HCC) 每年导致多达 100 万人死亡。酒精性脂肪性肝炎 (ASH) 和非酒精性脂肪性肝炎 (NASH) 正成为两个主要的风险因素，因为如果不治疗，两者都可能发展为肝纤维化和肝细胞癌 (HCC)。然而，与每年有 3-10%的 ASH 患者可能进展为 HCC 相比，每年只有约 0.5%的 NASH 患者可能进展为 HCC。本研究旨在阐明 ASH 和 NASH 之间肿瘤抑制基因 (TSG) 的蛋白表达差异。在 NASH 和 ASH 患者的肝活检标本中，我们使用免疫荧光法并通过形态计量学定量荧光强度，研究了候选 TSG 蛋白（包括 RUNX3、GSTP1 和 RASSF1A）在肝细胞细胞质中的蛋白表达。与对照组患者相比，所有三种蛋白在 ASH 组患者中的表达水平均上调（所有分子均 p<0.001）。虽然 RUNX3 上调，但 GSTP1 和 RASSF1 在 NASH 组患者中没有变化。最重要的发现是，与 ASH 组患者相比，NASH 组患者中所有三种 TSG 蛋白（RUNX3、GSTP1 和 RASSF1）的表达水平均显著降低（所有三种分子均 p<0.001）。这些结果证实了我们之前的发现，即在 NASH 中与 ASH 相比，许多分子（包括 TSG）的表达发生了显著变化。因此，我们得出结论，在 NASH 中与 ASH 相比，HCC 发展的发病机制中涉及到明显不同的 TSG 和途径，这可能有助于为 NASH 和 ASH 患者制定不同的预防和治疗策略。
