Regulation of a TGF-β1-CD147 self-sustaining network in the differentiation plasticity of hepatocellular carcinoma cells
Regulation of a TGF-β1-CD147 self-sustaining network in the differentiation plasticity of hepatocellular carcinoma cells
复制标题
肝细胞癌细胞分化可塑性中 TGF-β1-CD147 自维持网络的调节
DOI：
10.1038/onc.2016.89
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发表时间：
2016-10-20
期刊：
影响因子：
8
通讯作者：
Bian, H.
中科院分区：
文献类型：
--
作者：
Wu, J.;Lu, M.;Bian, H.
细胞可塑性在肝细胞癌（HCC）的发展中起着重要作用。在这项研究中，TGF-β 1-CD 147自我维持网络参与调节的去分化进程中的HCC细胞系，肝细胞特异性basigin/CD 147基因敲除小鼠和人HCC组织中充分探索。我们证明，TGF-β 1刺激上调CD 147的表达和介导的肝癌细胞的去分化，而全反式维甲酸诱导下调CD 147和促进分化的肝癌细胞。CD 147的过表达可诱导肝癌细胞的去分化，增强肝癌细胞的恶性程度，并通过激活β-catenin增加TGF-β 1的转录表达。CD 147诱导的基质金属蛋白酶（MMP）的产生激活了pro-TGF-β 1。TGF-β 1信号通路的激活通过Smad-Snail 1信号通路抑制了HNF 4a的表达，促进了细胞的去分化进程。肝细胞特异性basigin/CD 147基因敲除小鼠通过抑制TGF-β 1-CD 147信号传导和抑制肿瘤进展过程中肝细胞的去分化，降低了对N-亚硝基二乙胺诱导的肿瘤发生的易感性。HCC组织中CD 147与TGF-β 1呈正相关，与HNF 4a呈负相关。CD 147阳性表达和肿瘤组织中HNF 4a水平较低与HCC患者的生存率显著相关。HNF 4a和Smad 7的过表达以及慢病毒载体对CD 147的缺失共同重编程了肝细胞标志物的表达谱，并减弱了HCC细胞的恶性特性，包括增殖、细胞存活和肿瘤生长。我们的研究结果强调了TGF-β 1-CD 147自我维持网络通过调节分化可塑性在驱动HCC发展中的重要作用，这为进一步研究以TGF-β 1和CD 147为靶点的HCC分化治疗提供了强有力的基础。
Cellular plasticity has an important role in the progression of hepatocellular carcinoma (HCC). In this study, the involvement of a TGF-beta 1-CD147 self-sustaining network in the regulation of the dedifferentiation progress was fully explored in HCC cell lines, hepatocyte-specific basigin/CD147-knockout mice and human HCC tissues. We demonstrated that TGF-beta 1 stimulation upregulated CD147 expression and mediated the dedifferentiation of HCC cells, whereas all-trans-retinoic acid induced the downregulation of CD147 and promoted differentiation in HCC cells. Overexpression of CD147 induced the dedifferentiation and enhanced the malignancy of HCC cells, and increased the transcriptional expression of TGF-beta 1 by activating beta-catenin. CD147-induced matrix metalloproteinase (MMP) production activated pro-TGF-beta 1. The activated TGF-beta 1 signaling subsequently repressed the HNF4a expression via Smad-Snail1 signaling and enhanced the dedifferentiation progress. Hepatocyte-specific basigin/CD147-knockout mice decreased the susceptibility to N-nitrosodiethylamine-induced tumorigenesis by suppressing TGF-beta 1-CD147 signaling and inhibiting dedifferentiation in hepatocytes during tumor progression. CD147 was positively correlated with TGF-beta 1 and negatively correlated with HNF4a in human HCC tissues. Positive CD147 staining and lower HNF4a levels in tumor tissues were significantly associated with poor survival of patients with HCC. The overexpression of HNF4a and Smad7 and the deletion of CD147 by lentiviral vectors jointly reprogrammed the expression profile of hepatocyte markers and attenuated malignant properties including proliferation, cell survival and tumor growth of HCC cells. Our results highlight the important role of the TGF-beta 1-CD147 self-sustaining network in driving HCC development by regulating differentiation plasticity, which provides a strong basis for further investigations of the differentiation therapy of HCC targeting TGF-beta 1 and CD147.