Shi Sally Yu, Luk Cynthia T, Schroer Stephanie A, Kim Min Jeong, Dodington David W, Sivasubramaniyam Tharini, Lin Lauren, Cai Erica P, Lu Shun-Yan, Wagner Kay-Uwe, Bazinet Richard P, Woo Minna
From the Toronto General Hospital Research Institute, Toronto, Ontario M5G 2C4, Canada.
the Institute of Medical Science, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
J Biol Chem. 2017 Mar 3;292(9):3789-3799. doi: 10.1074/jbc.M116.752519. Epub 2017 Jan 18.
Hepatocellular carcinoma is an end-stage complication of non-alcoholic fatty liver disease (NAFLD). Inflammation plays a critical role in the progression of non-alcoholic fatty liver disease and the development of hepatocellular carcinoma. However, whether steatosis promotes liver cancer, and the molecular mechanisms that control the progression in this disease spectrum remain largely elusive. The Janus kinase signal transducers and activators of transcription (JAK-STAT) pathway mediates signal transduction by numerous cytokines that regulate inflammation and may contribute to hepatocarcinogenesis. Mice with hepatocyte-specific deletion of JAK2 (L-JAK2 KO) develop extensive fatty liver spontaneously. We show here that this simple steatosis was insufficient to drive carcinogenesis. In fact, L-JAK2 KO mice were markedly protected from chemically induced tumor formation. Using the methionine choline-deficient dietary model to induce steatohepatitis, we found that steatohepatitis development was completely arrested in L-JAK2 KO mice despite the presence of steatosis, suggesting that JAK2 is the critical factor required for inflammatory progression in the liver. In line with this, L-JAK2 KO mice exhibited attenuated inflammation after chemical carcinogen challenge. This was associated with increased hepatocyte apoptosis without elevated compensatory proliferation, thus thwarting expansion of transformed hepatocytes. Taken together, our findings identify an indispensable role of JAK2 in hepatocarcinogenesis through regulating critical inflammatory pathways. Targeting the JAK-STAT pathway may provide a novel therapeutic option for the treatment of hepatocellular carcinoma.
肝细胞癌是非酒精性脂肪性肝病（NAFLD）的终末期并发症。炎症在非酒精性脂肪性肝病的进展以及肝细胞癌的发生中起着关键作用。然而，脂肪变性是否促进肝癌以及控制该疾病谱进展的分子机制仍 largely 难以捉摸。Janus 激酶信号转导和转录激活因子（JAK-STAT）途径介导多种调节炎症的细胞因子的信号转导，可能参与肝癌发生。肝细胞特异性缺失 JAK2 的小鼠（L-JAK2 KO）会自发发展为广泛的脂肪肝。我们在此表明，这种单纯的脂肪变性不足以驱动致癌作用。事实上，L-JAK2 KO 小鼠对化学诱导的肿瘤形成具有显著的保护作用。使用蛋氨酸胆碱缺乏饮食模型诱导脂肪性肝炎，我们发现尽管存在脂肪变性，但 L-JAK2 KO 小鼠的脂肪性肝炎发展完全停滞，这表明 JAK2 是肝脏炎症进展所需的关键因素。与此一致，L-JAK2 KO 小鼠在化学致癌物攻击后炎症减轻。这与肝细胞凋亡增加但代偿性增殖未升高有关，从而阻碍了转化肝细胞的扩增。综上所述，我们的研究结果确定了 JAK2 通过调节关键炎症途径在肝癌发生中的不可或缺的作用。靶向 JAK-STAT 途径可能为肝细胞癌的治疗提供一种新的治疗选择。
