Imbalance of TGF-β1/BMP-7 pathways induced by M2-polarized macrophages promotes hepatocellular carcinoma aggressiveness
Imbalance of TGF-β1/BMP-7 pathways induced by M2-polarized macrophages promotes hepatocellular carcinoma aggressiveness
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DOI：
10.1016/j.ymthe.2021.02.016
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发表时间：
2021-06-02
影响因子：
12.4
通讯作者：
Yu, Jinpu
中科院分区：
文献类型：
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作者：
Ning, Junya;Ye, Yingnan;Yu, Jinpu
转化生长因子- β (tgf - β)信号通路是肝细胞癌（HCC）发生发展的主要细胞因子信号通路。骨形态发生蛋白（Bone morphogenetic protein， BMP）是tgf - β超家族的另一成员，经常被发现参与tgf - β通路的串扰。然而，tgf - β和BMP通路之间复杂的相互作用在HCC中尚未完全阐明。我们发现tgf - β 1/ BMP-7通路失衡与HCC的侵袭性病理特征和不良临床结果相关。诱导肝癌细胞tgf - β 1/BMP-7通路失衡，可通过增加分化抑制因子1 （inhibitor of differentiation 1, ID1）的表达，显著促进肝癌细胞的侵袭和分化。我们还发现，起源于m2极化肿瘤相关巨噬细胞（m2 - tam）的细胞外囊泡（ev）的microRNA (miR)-17-92簇通过靶向Smad泛素化调节因子1 （Smurf1）诱导tgf - β 2型受体（TGFBR2）转录后沉默和抑制激活素A受体1型（ACVR1）翻译后泛素化，从而刺激HCC细胞中tgf - β 1/BMP-7通路的失衡。在体内，短发夹(sh)-MIR17HG和ACVR1抑制剂通过纠正tgf - β 1/BMP-7通路的不平衡，深刻地减弱了HCC细胞的生长和转移。因此，我们提出tgf - β 1/BMP-7通路失衡是一种可行的预后生物标志物，恢复tgf - β 1/BMP-7通路失衡可能是HCC的潜在治疗策略。
The transforming growth factor-beta (TGF-beta) signaling pathway is the predominant cytokine signaling pathway in the development and progression of hepatocellular carcinoma (HCC). Bone morphogenetic protein (BMP), another member of the TGF-beta superfamily, has been frequently found to participate in crosstalk with the TGF-beta pathway. However, the complex interaction between the TGF-beta and BMP pathways has not been fully elucidated in HCC. We found that the imbalance of TGF-beta 1/ BMP-7 pathways was associated with aggressive pathological features and poor clinical outcomes in HCC. The induction of the imbalance of TGF-beta 1/BMP-7 pathways in HCC cells could significantly promote HCC cell invasion and stemness by increasing inhibitor of differentiation 1 (ID1) expression. We also found that the microRNA (miR)-17-92 cluster, originating from the extracellular vesicles (EVs) of M2-polarized tumor-associated macrophages (M2-TAMs), stimulated the imbalance of TGF-beta 1/BMP-7 pathways in HCC cells by inducing TGF-beta type II receptor (TGFBR2) post-transcriptional silencing and inhibiting activin A receptor type 1 (ACVR1) post-translational ubiquitylation by targeting Smad ubiquitylation regulatory factor 1 (Smurf1). In vivo, short hairpin (sh)-MIR17HG and ACVR1 inhibitors profoundly attenuated HCC cell growth and metastasis by rectifying the imbalance of TGF-beta 1/BMP-7 pathways. Therefore, we proposed that the imbalance of TGF-beta 1/ BMP-7 pathways is a feasible prognostic biomarker and recovering the imbalance of TGF-beta 1/BMP-7 pathways might be a potential therapeutic strategy for HCC.