The matricellular protein CCN1 suppresses hepatocarcinogenesis by inhibiting compensatory proliferation.
The matricellular protein CCN1 suppresses hepatocarcinogenesis by inhibiting compensatory proliferation.
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DOI：
10.1038/onc.2015.190
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发表时间：
2016-03-10
期刊：
影响因子：
8
通讯作者：
Lau LF
中科院分区：
文献类型：
--
作者：
Chen CC;Kim KH;Lau LF
肝细胞癌（HCC）是世界范围内癌症相关死亡的第三大原因，并且在美国呈上升趋势。先前的研究表明，基质细胞蛋白CCN 1（CYR 61）在肝损伤过程中被诱导，并具有限制和解决肝纤维化的功能。在这里，我们发现CCN 1通过抑制致癌物诱导的代偿性肝细胞增殖来抑制肝癌的发生，从而限制了受损和潜在致癌肝细胞的扩张。与肿瘤抑制一致，CCN 1表达在人HCC中下调。Ccn 1 ΔHep小鼠肝细胞特异性缺失Ccn 1后，肝癌致癌物二乙基亚硝胺（DEN）诱导的肝癌肿瘤多样性增加。表达整合素α6β1结合缺陷型CCN 1的敲入小鼠（CCN 1 dm/dm）表型模仿CCN 1 ΔHep小鼠，表明CCN 1在这种情况下通过其α6β1结合位点发挥作用。CCN 1通过整合素α6介导的反应氧（ROS）积累，从而触发p53激活和细胞周期阻滞，有效抑制EGFR依赖性肝细胞增殖。因此，Ccn 1dm/dm小鼠表现出p53活化减少和代偿性肝细胞增殖增加，导致HCC增加。此外，我们发现，在DEN诱导的损伤之前给予单剂量的EGFR抑制剂厄洛替尼足以阻断代偿性增殖并消灭8个月后观察到的HCC结节的发展，这表明通过靶向CCN 1可诱导的EGFR依赖性肝细胞增殖进行潜在的化学预防。总之，这些结果表明，CCN 1是一种损伤反应蛋白，其功能不仅是限制肝脏纤维化，而且还通过抑制EGFR依赖性肝细胞代偿性增殖来抑制肝癌发生。
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, and is on the rise in the United States. Previous studies showed that the matricellular protein CCN1 (CYR61) is induced during hepatic injuries and functions to restrict and resolve liver fibrosis. Here we show that CCN1 suppresses hepatocarcinogenesis by inhibiting carcinogen-induced compensatory hepatocyte proliferation, thus limiting the expansion of damaged and potentially oncogenic hepatocytes. Consistent with tumor suppression, CCN1 expression is down-regulated in human HCC. Ccn1ΔHep mice with hepatocyte-specific deletion of Ccn1 suffer increased HCC tumor multiplicity induced by the hepatocarcinogen diethylnitrosoamine (DEN). Knockin mice (Ccn1dm/dm) that express an integrin α6β1-binding defective CCN1 phenocopied Ccn1ΔHep mice, indicating that CCN1 acts through its α6β1 binding sites in this context. CCN1 effectively inhibits EGFR-dependent hepatocyte proliferation through integrin α6-mediated accumulation of reaction oxygen species (ROS), thereby triggering p53 activation and cell cycle block. Consequently, Ccn1dm/dm mice exhibit diminished p53 activation and elevated compensatory hepatocyte proliferation, resulting in increased HCC. Furthermore, we show that a single dose of the EGFR inhibitor erlotinib delivered prior to DEN-induced injury was sufficient to block compensatory proliferation and annihilate development of HCC nodules observed 8 months later, suggesting potential chemoprevention by targeting CCN1-inhibitable EGFR-dependent hepatocyte proliferation. Together, these results show that CCN1 is an injury response protein that functions not only to restrict fibrosis in the liver, but also to suppress hepatocarcinogenesis by inhibiting EGFR-dependent hepatocyte compensatory proliferation.