Distinct functions of transforming growth factor-β signaling in c-MYC driven hepatocellular carcinoma initiation and progression.
Distinct functions of transforming growth factor-β signaling in c-MYC driven hepatocellular carcinoma initiation and progression.
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DOI：
10.1038/s41419-021-03488-z
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发表时间：
2021-02-19
影响因子：
9
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Wang H;Wang P;Xu M;Song X;Wu H;Evert M;Calvisi DF;Zeng Y;Chen X
转化生长因子-β（TGFβ）信号转导的失调与肝癌的发生有关，具有肿瘤促进和抑制活性。c-MYC原癌基因的激活是肝细胞癌（HCC）中的另一个关键遗传事件。然而，c-MYC和TGFβ信号通路之间的精确功能串扰仍不清楚。在本研究中，我们研究了TGFβ信号在c-MYC扩增的人HCC样品中的表达，以及TGFβ在启动和进展过程中调节c-Myc驱动的肝癌发生的机制。我们发现几种TGFβ靶基因在具有c-MYC扩增的人HCC中过表达。在体内，TGFβ1的活化损害了c-Myc小鼠HCC的起始，而TGFβ通路的抑制加速了这一过程。相反，TGFβ1的过表达通过促进肿瘤细胞转移而促进c-Myc HCC的进展。在HCC进展过程中，TGFβ的活化促进肿瘤微环境重编程，而不是诱导上皮细胞向间质细胞转化。此外，我们确定PMEPA 1为潜在的TGFβ1靶点。总之，我们的数据强调了TGFβ信号传导在c-MYC诱导的HCC发生和发展过程中的不同作用。
Dysregulation of transforming growth factor-beta (TGFβ) signaling has been implicated in liver carcinogenesis with both tumor promoting and inhibiting activities. Activation of the c-MYC protooncogene is another critical genetic event in hepatocellular carcinoma (HCC). However, the precise functional crosstalk between c-MYC and TGFβ signaling pathways remains unclear. In the present investigation, we investigated the expression of TGFβ signaling in c-MYC amplified human HCC samples as well as the mechanisms whereby TGFβ modulates c-Myc driven hepatocarcinogenesis during initiation and progression. We found that several TGFβ target genes are overexpressed in human HCCs with c-MYC amplification. In vivo, activation of TGFβ1 impaired c-Myc murine HCC initiation, whereas inhibition of TGFβ pathway accelerated this process. In contrast, overexpression of TGFβ1 enhanced c-Myc HCC progression by promoting tumor cell metastasis. Mechanistically, activation of TGFβ promoted tumor microenvironment reprogramming rather than inducing epithelial-to-mesenchymal transition during HCC progression. Moreover, we identified PMEPA1 as a potential TGFβ1 target. Altogether, our data underline the divergent roles of TGFβ signaling during c-MYC induced HCC initiation and progression.
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