近日第二军医大学附属东方肝胆外科医院在国际著名肝脏疾病杂志Hepatology上发表了最新研究成果，研究人员证实了肝脏中的TGF-β导致了肿瘤起源细胞，促进了肝癌形成。
肝细胞癌(Hepatocellular carcinoma, HCC)因恶性程度高，被称为癌中之王。在世界范围内肿瘤相关性死亡因素中排名第三，全球每年有超过50万新患者。我国是肝癌高发国家，每年约有11万人死于肝癌。肝硬化是导致肝癌的一个主要风险因子， 60％到80％的肝癌患者之前有肝硬化患病史。然而目前对于从肝硬化进展至肝癌的基础分子机制仍了解得不是很清楚。
在此次研究中研究人员发现在二乙基亚硝酸（DEN）诱导的大鼠肝癌形成以及肝癌患者的肝硬化中肝祖细胞（LPCs）和转化生长因子(TGF-β)一致增高。利用几种实验方法，包括2-乙酰氨基芴/三分之二肝切除（2-acetylaminofluorene/partial hepatectomy, AAF/PH）和3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)诱导的小鼠肝再生等，研究人员发现在缺乏TGF-β的情况下激活肝祖细胞不足以引发肝癌形成。
此外，在大鼠肝癌形成过程中以及人类肝癌细胞中，小部分的肝祖细胞被检测到共表达肿瘤起源细胞(T-IC)标记物，TGF-β水平与肿瘤起源细胞标记物表达呈正相关，表明TGF-β在肿瘤起源细胞中起重要作用。
研究人员将大鼠多能肝祖细胞样WB-F344细胞暴露于低剂量TGF-β下18个星期模拟出了肝硬化中增高的TGF-β表达。有趣的是，用TGF-β长期处理WB-F344细胞损害了肝祖细胞的潜能，但却给予了它们肿瘤起源细胞的特性包括表达肿瘤起源细胞标记物，增强了自我更新能力，更强的化学药物抗性以及在NOD/SCID（非肥胖糖尿病/重症联合免疫缺陷）小鼠中的肿瘤形成。
在TGF-β处理的WB-F344细胞中检测到Akt过度激活，Notch、 STAT3或mTOR 则无此变化。导入Akt的线性负性突变体显著地减弱了这些转化WB-F344细胞的肿瘤起源细胞特性，表明Akt是TGF-β介导的肝脏肿瘤起源细胞生成的必要条件。研究人员进一步证实TGF-β诱导的Akt激活和肝祖细胞转化受到microRNA-216a调节的PTEN抑制的调控。
实验结果表明肝细胞癌起源细胞有可能是来源于在肝硬化中暴露于慢性和持续TGF-β刺激的肝祖细胞，药物抑制microRNA-216a/PTEN/Akt信号可能是预防肝癌和靶向肝脏肿瘤起源细胞治疗的一条新策略。
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-β (TGF-β) 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-β 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-β levels were positively correlated with T-IC marker expression, which indicates a role of TGF-β in T-IC generation. Rat pluripotent LPC-like WB-F344 cells were exposed to low doses of TGF-β for 18 weeks imitating the enhanced TGF-β expression in cirrhotic liver. Interestingly, long-term treatment of TGF-β 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-β-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-β-mediated-generation of hepatic T-ICs. We further demonstrate that TGF-β-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-β 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).
