Higashi Takaaki, Hayashi Hiromitsu, Kitano Yuki, Yamamura Kensuke, Kaida Takayoshi, Arima Kota, Taki Katsunobu, Nakagawa Shigeki, Okabe Hirohisa, Nitta Hidetoshi, Imai Katsunori, Hashimoto Daisuke, Chikamoto Akira, Beppu Toru, Baba Hideo
Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
Med Oncol. 2016 Nov;33(11):123. doi: 10.1007/s12032-016-0845-6. Epub 2016 Oct 12.
Diabetes and obesity are associated with non-alcoholic steatohepatitis and an increased incidence of hepatocellular carcinoma (HCC). TAZ and YAP are equivalently placed downstream effectors of the Hippo pathway with oncogenic roles in human cancers. Statins are commonly used to patients with metabolic problems as hypercholesterolemia. Statins also have anti-cancer properties, and the cross-talk between mevalonate pathway and Hippo pathway was known. The aim of this study is to confirm the statin's anti-cancer effects on HCC cells and its survival benefits in HCC patients with curative surgery. TAZ expression level in HCC cell lines was analyzed by western blot. Two cell lines (HLF and HuH1) were used in this study. Then the mechanism of statin's anti-proliferative effect was examined in HLF and HuH1 cells. In clinical setting, overall survival and recurrence-free survival (RFS) rate were examined in comparison between statin intake and statin non-intake group. The proliferation assay using four different statins (atorvastatin, pravastatin, fluvastatin, simvastatin). Simvastatin and fluvastatin showed very strong growth suppressive effects, and induced apoptosis in HLF cells, but not HuH1 cells. TAZ expression was suppressed in HLF cells by fluvastatin and simvastatin treatment. The similar change pattern was confirmed in p-ERK1/2 and ERK. In HuH1 cells, such expression change was not confirmed. In clinical setting, statin intake was significantly associated with longer RFS in the HCC patients with hepatectomy (P = 0.038). The statin had the anti-proliferative effects and induced apoptosis in HCC cells and improved the prognosis of HCC patients.
糖尿病和肥胖与非酒精性脂肪性肝炎以及肝细胞癌（HCC）发病率增加相关。TAZ和YAP是Hippo信号通路同等重要的下游效应因子，在人类癌症中具有致癌作用。他汀类药物常用于患有代谢问题如高胆固醇血症的患者。他汀类药物也具有抗癌特性，并且甲羟戊酸途径和Hippo途径之间的相互作用是已知的。本研究的目的是证实他汀类药物对HCC细胞的抗癌作用及其在接受根治性手术的HCC患者中的生存益处。通过蛋白质印迹法分析HCC细胞系中TAZ的表达水平。本研究使用了两种细胞系（HLF和HuH1）。然后在HLF和HuH1细胞中研究他汀类药物抗增殖作用的机制。在临床环境中，比较了服用他汀类药物组和未服用他汀类药物组的总生存期和无复发生存期（RFS）率。使用四种不同的他汀类药物（阿托伐他汀、普伐他汀、氟伐他汀、辛伐他汀）进行增殖试验。辛伐他汀和氟伐他汀显示出非常强的生长抑制作用，并诱导HLF细胞凋亡，但不诱导HuH1细胞凋亡。氟伐他汀和辛伐他汀处理可抑制HLF细胞中TAZ的表达。在p-ERK1/2和ERK中也证实了类似的变化模式。在HuH1细胞中，未证实这种表达变化。在临床环境中，服用他汀类药物与肝切除术后HCC患者更长的RFS显著相关（P = 0.038）。他汀类药物具有抗增殖作用，可诱导HCC细胞凋亡并改善HCC患者的预后。
