Liver Transplantation Division, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
Cell Death Dis. 2021 Feb 19;12(2):200. doi: 10.1038/s41419-021-03488-z.
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.
转化生长因子-β（TGFβ）信号的失调与肿瘤促进和抑制活性都与肝癌的发生有关。原癌基因 c-MYC 的激活是肝细胞癌（HCC）的另一个关键遗传事件。然而，c-MYC 和 TGFβ 信号通路之间的确切功能串扰仍不清楚。在本研究中，我们研究了 TGFβ 信号在 c-MYC 扩增的人类 HCC 样本中的表达，以及 TGFβ 调节 c-Myc 驱动的肝癌发生在起始和进展过程中的机制。我们发现，在具有 c-MYC 扩增的人类 HCC 中，几种 TGFβ 靶基因过表达。在体内，TGFβ1 的激活损害了 c-Myc 小鼠 HCC 的起始，而 TGFβ 途径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来增强 c-Myc HCC 的进展。从机制上讲，TGFβ 的激活促进了肿瘤微环境的重新编程，而不是在 HCC 进展过程中诱导上皮-间充质转化。此外，我们确定了 PMEPA1 是 TGFβ1 的一个潜在靶点。总之，我们的数据强调了 TGFβ 信号在 c-MYC 诱导的 HCC 起始和进展中的不同作用。
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