LAUSR

The transforming growth factor-beta (TGF-β) signaling represented the predominant cytokine signaling involved in the development and progression of hepatocellular carcinoma (HCC). Bone morphogenetic protein (BMP), another member of TGF-β superfamily, was frequently found to have cross-talk with TGF-β pathway. However, the complex interaction between TGF-β and BMP pathways has not been fully elucidated in HCC. In this study, we found that the imbalance of TGF-β1/BMP-7 pathway was associated with aggressive pathological features and poor clinical outcome in HCC, and it could significantly promote HCC cells invasion and stemness by increasing inhibitor of differentiation 1 (ID1). Next, we indicated that the miR-17-92 cluster could disrupted the balance of TGF-β1/BMP-7 pathway in HCC cells by inducing TGFBR2 post-transcriptional silence and inhibiting ACVR1 post-translational ubiquitylation via targeting Smurf1. Furthermore, we demonstrated that miR-17-92 cluster was originated from the extracellular vesicles (EVs) of M2-polarized tumor associated macrophages (M2-TAMs) infiltrated in HCC microenvironment and induced the imbalance of TGF-β1/BMP-7 pathway. Finally, we found that sh-MIR17HG lentivirus, TGFBR2 lentivirus and ACVR1 inhibitor could profoundly inhibit M2-TAMs-stimulated the growth and metastasis of HCC xenografts in vivo. We propose that imbalance of TGF-β1/BMP-7 pathway may serve as a prognostic biomarker, M2-TAMs and miR-17-92 cluster could be a therapeutic target for this subtype of HCC. Citation Format: Junya Ning, Yingnan Ye, Jinpu Yu. Imbalance of TGF-β1/BMP-7 pathway induced by M2-polarized macrophages promotes hepatocellular carcinoma aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB232.