Journal of Hepatology ( IF 26.8 ) Pub Date : 2021-12-11 , DOI: 10.1016/j.jhep.2021.11.031 Xiaobo Wang 1 , Sharon Zeldin 1 , Hongxue Shi 1 , Changyu Zhu 1 , Yoshinobu Saito 1 , Kathleen E Corey 2 , Stephanie A Osganian 3 , Helen E Remotti 4 , Elizabeth C Verna 1 , Utpal B Pajvani 5 , Robert F Schwabe 5 , Ira Tabas 6
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Background & Aims
Non-alcoholic steatohepatitis (NASH) is a leading cause of hepatocellular carcinoma (HCC), but mechanisms linking NASH to eventual tumor formation remain poorly understood. Herein, we investigate the role of TAZ/WWTR1, which is induced in hepatocytes in NASH, in the progression of NASH to HCC.
Methods
The roles of hepatocyte TAZ and its downstream targets were investigated in diet-induced and genetic models of NASH-HCC using gene-targeting, adeno-associated virus 8 (AAV8)-H1-mediated gene silencing, or AAV8-TBG-mediated gene expression. The biochemical signature of the newly elucidated pathway was probed in liver specimens from humans with NASH-HCC.
Results
When hepatocyte-TAZ was silenced in mice with pre-tumor NASH using AAV8-H1-shTaz (short-hairpin Taz), subsequent HCC tumor development was suppressed. In this setting, the tumor-suppressing effect of shTaz was not dependent of TAZ silencing in the tumors themselves and could be dissociated from the NASH-suppressing effects of shTaz. The mechanism linking pre-tumor hepatocyte-TAZ to eventual tumor formation involved TAZ-mediated induction of the NOX2-encoding gene Cybb, which led to NADPH-mediated oxidative DNA damage. As evidence, DNA damage and tumor formation could be suppressed by treatment of pre-tumor NASH mice with AAV8-H1-shCybb; AAV8-TBG-OGG1, encoding the oxidative DNA-repair enzyme 8-oxoguanine glycosylase; or AAV8-TBG-NHEJ1, encoding the dsDNA repair enzyme non-homologous end-joining factor 1. In surrounding non-tumor tissue from human NASH-HCC livers, there were strong correlations between TAZ, NOX2, and oxidative DNA damage.
Conclusions
TAZ in pre-tumor NASH-hepatocytes, via induction of Cybb and NOX2-mediated DNA damage, contributes to subsequent HCC tumor development. These findings illustrate how NASH provides a unique window into the early molecular events that can lead to tumor formation and suggest that NASH therapies targeting TAZ might also prevent NASH-HCC.
Lay summary
Non-alcoholic steatohepatitis (NASH) is emerging as the leading cause of a type of liver cancer called hepatocellular carcinoma (HCC), but molecular events in pre-tumor NASH hepatocytes leading to HCC remain largely unknown. Our study shows that a protein called TAZ in pre-tumor NASH-hepatocytes promotes damage to the DNA of hepatocytes and thereby contributes to eventual HCC. This study reveals a very early event in HCC that is induced in pre-tumor NASH, and the findings suggest that NASH therapies targeting TAZ might also prevent NASH-HCC.
中文翻译：
TAZ 诱导的 Cybb 有助于非酒精性脂肪性肝炎中肝肿瘤的形成
背景与目标
非酒精性脂肪性肝炎 (NASH) 是肝细胞癌 (HCC) 的主要原因，但将 NASH 与最终肿瘤形成联系起来的机制仍知之甚少。在此，我们研究了在 NASH 的肝细胞中诱导的 TAZ/WWTR1 在 NASH 向 HCC 的进展中的作用。
方法
使用基因靶向、腺相关病毒 8 (AAV8)-H1 介导的基因沉默或 AAV8-TBG 介导的基因表达，在饮食诱导的 NASH-HCC 遗传模型中研究了肝细胞 TAZ 及其下游靶标的作用. 在患有 NASH-HCC 的人的肝脏样本中探索了新阐明的途径的生化特征。
结果
当使用 AAV8-H1-shTaz（短发夹 Taz）在患有癌前 NASH 的小鼠中沉默肝细胞 TAZ 时，随后的 HCC 肿瘤发展受到抑制。在这种情况下，shTaz 的肿瘤抑制作用不依赖于肿瘤本身的 TAZ 沉默，并且可以与 shTaz 的 NASH 抑制作用分离。将肿瘤前肝细胞-TAZ 与最终肿瘤形成联系起来的机制涉及 TAZ 介导的 NOX2 编码基因Cybb的诱导, 这导致了 NADPH 介导的氧化 DNA 损伤。作为证据，用 AAV8-H1-shCybb 治疗肿瘤前 NASH 小鼠可以抑制 DNA 损伤和肿瘤形成；AAV8-TBG-OGG1，编码氧化 DNA 修复酶 8-氧代鸟嘌呤糖基化酶；或 AAV8-TBG-NHEJ1，编码 dsDNA 修复酶非同源末端连接因子 1。在来自人类 NASH-HCC 肝脏的周围非肿瘤组织中，TAZ、NOX2 和氧化性 DNA 损伤之间存在很强的相关性。
结论
肿瘤前 NASH 肝细胞中的 TAZ，通过诱导Cybb和 NOX2 介导的 DNA 损伤，有助于随后的 HCC 肿瘤发展。这些发现说明了 NASH 如何为可导致肿瘤形成的早期分子事件提供一个独特的窗口，并表明靶向 TAZ 的 NASH 疗法也可能预防 NASH-HCC。
外行总结
非酒精性脂肪性肝炎 (NASH) 正在成为一种称为肝细胞癌 (HCC) 的肝癌的主要原因，但导致 HCC 的癌前 NASH 肝细胞中的分子事件在很大程度上仍然未知。我们的研究表明，肿瘤前 NASH 肝细胞中一种名为 TAZ 的蛋白质会促进肝细胞 DNA 的损伤，从而导致最终的 HCC。这项研究揭示了在肿瘤前 NASH 中诱发的 HCC 中一个非常早期的事件，并且研究结果表明针对 TAZ 的 NASH 疗法也可能预防 NASH-HCC。
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