Hepatic Transforming Growth Factor Beta Gives Rise to Tumor-Initiating Cells and Promotes Liver Cancer Development
Hepatic Transforming Growth Factor Beta Gives Rise to Tumor-Initiating Cells and Promotes Liver Cancer Development
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肝转化生长因子β可产生肿瘤起始细胞并促进肝癌的发展
DOI：
10.1002/hep.26007
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发表时间：
2012-12-01
期刊：
影响因子：
13.5
通讯作者：
Wang, Hong-Yang
中科院分区：
文献类型：
--
作者：
Wu, Kun;Ding, Jin;Wang, Hong-Yang
肝硬化是肝细胞癌（HCC）的主要危险因素。然而，从肝硬化进展到HCC的机制仍不清楚。在此，我们报告了肝祖细胞（LPCs）和转化生长因子-β（TGF-β）在二乙基亚硝胺（DEN）诱导的大鼠肝癌发生和HCC患者的肝硬化中的同时增加。使用几种实验方法，包括2-乙酰氨基芴/部分肝切除术（2-AAF/PHx）和3，5-二乙氧羰基-1，4-二氢可力丁（DDC）-引起小鼠肝再生，我们发现，在没有TGF-β诱导的情况下，LPCs的激活不足以触发肝癌发生。此外，在大鼠肝癌发生过程中和人HCC中，检测到一小部分LPC共表达肿瘤起始细胞（T-IC）标志物，TGF-β水平与T-IC标志物表达呈正相关，这表明TGF-β在T-IC生成中的作用。将大鼠多能LPC样WB-F344细胞暴露于低剂量的TGF-β 18周，模拟在肝硬化中增强的TGF-β表达。有趣的是，长期对WB-F344细胞进行TGF-β处理损害了它们的LPC潜力，但赋予了它们T-IC特性，包括T-IC标志物的表达、自我更新能力的增加、更强的化学抗性和NOD-SCID小鼠的致瘤性。在TGF-β处理的WB-F344细胞中检测到Akt的过度激活，但Notch、信号转导和转录激活因子3（STAT 3）或哺乳动物雷帕霉素靶蛋白（mTOR）未被检测到。引入Akt的显性负突变体显著减弱了这些转化的WB-F344细胞的T-IC特性，表明Akt在TGF-β介导的肝T-IC产生中是必需的。我们进一步证明了TGF-β诱导的Akt激活和LPC转化是由microRNA-216 a调节的磷酸酶和10号染色体上缺失的张力蛋白同源物（PTEN）抑制介导的。总结：肝癌起始细胞可能来源于暴露于慢性和恒定的TGF-β刺激的肝祖细胞，药物抑制microRNA-216 a/PTEN/Akt信号传导可能是一种新的策略，用于HCC预防和治疗靶向肝T-IC。（肝脏学2012;56：2255-2267）
Liver cirrhosis is a predominant risk factor for hepatocellular carcinoma (HCC). However, the mechanism underlying the progression from cirrhosis to HCC remains unclear. Herein we report the concurrent increase of liver progenitor cells (LPCs) and transforming growth factor-beta (TGF-beta) in diethylnitrosamine (DEN)-induced rat hepatocarcinogenesis and cirrhotic livers of HCC patients. Using several experimental approaches, including 2-acetylaminofluorene/partial hepatectomy (2-AAF/PHx) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-elicited murine liver regeneration, we found that activation of LPCs in the absence of TGF-beta induction was insufficient to trigger hepatocarcinogenesis. Moreover, a small fraction of LPCs was detected to coexpress tumor initiating cell (T-IC) markers during rat hepatocarcinogenesis and in human HCCs, and TGF-beta levels were positively correlated with T-IC marker expression, which indicates a role of TGF-beta in T-IC generation. Rat pluripotent LPC-like WB-F344 cells were exposed to low doses of TGF-beta for 18 weeks imitating the enhanced TGF-beta expression in cirrhotic liver. Interestingly, long-term treatment of TGF-beta on WB-F344 cells impaired their LPC potential but granted them T-IC properties including expression of T-IC markers, increased self-renewal capacity, stronger chemoresistance, and tumorigenicity in NOD-SCID mice. Hyperactivation of Akt but not Notch, signal transducer and activator of transcription 3 (STAT3), or mammalian target of rapamycin (mTOR) was detected in TGF-beta-treated WB-F344 cells. Introduction of the dominant-negative mutant of Akt significantly attenuated T-IC properties of those transformed WB-F344 cells, indicating Akt was required in TGF-beta-mediated-generation of hepatic T-ICs. We further demonstrate that TGF-beta-induced Akt activation and LPC transformation was mediated by microRNA-216a-modulated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) suppression. Conclusion: Hepatoma-initiating cells may derive from hepatic progenitor cells exposed to chronic and constant TGF-beta stimulation in cirrhotic liver, and pharmaceutical inhibition of microRNA-216a/PTEN/Akt signaling could be a novel strategy for HCC prevention and therapy targeting hepatic T-ICs. (HEPATOLOGY 2012;56:2255-2267)