Overexpression of miR-4669 Enhances Tumor Aggressiveness and Generates an Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma: Its Clinical Value as a Predictive Biomarker

• Published in: International journal of molecular sciences 2023-04, Vol.24 (9), p.7908
• Main Authors: Nakano, Toshiaki, Chen, Chao-Long, Chen, I-Hsuan, Tseng, Hui-Peng, Chiang, Kuei-Chen, Lai, Chia-Yun, Hsu, Li-Wen, Goto, Shigeru, Lin, Chih-Che, Cheng, Yu-Fan
• Format: Article
• Language: English
• Subjects: Biomarkers; Biomarkers, Tumor - genetics; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - therapy; Cell Line, Tumor; Cell Proliferation - genetics; Drug resistance; Exosomes; Exosomes - genetics; Exosomes - pathology; Gene Expression Regulation, Neoplastic; Glyceraldehyde-3-phosphate dehydrogenase; Hepatocellular carcinoma; Hepatoma; Humans; Liver cancer; Liver Neoplasms - pathology; Macrophages; Medical research; Medicine, Experimental; MicroRNAs; MicroRNAs - genetics; Microvasculature; miRNA; Nakano, T; Retrospective Studies; Risk assessment; Tumor microenvironment; Tumor Microenvironment - genetics; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24097908

Accumulating evidence suggests the involvement of tumor-derived exosomes in the development and recurrence of hepatocellular carcinoma (HCC). We previously identified miR-4669 as a highly expressed microRNA in circulating exosomes obtained from patients with post-transplant HCC recurrence. This study aimed to explore how overexpression of miR-4669 affects HCC development and recurrence. The impact of miR-4669 overexpression in Hep3B cells on tumor cell behavior and the tumor microenvironment was evaluated in vitro. In addition, the clinical value of exosomal miR-4669 for the prediction of treatment response to HCC downstaging therapies and following post-transplant HCC recurrence was explored. Overexpression of miR-4669 enhanced migration ability and led to acquired sorafenib resistance with an elevation of sirtuin 1 and long noncoding RNA associated with microvascular invasion. Active release of tumor-derived exosomes and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) contributed to generating an immunosuppressive tumor microenvironment through the induction of M2 macrophage polarization. The retrospective analysis demonstrated the clinical value of exosomal miR-4669 for predicting treatment response to HCC downstaging therapies and for risk assessment of post-transplant HCC recurrence. In summary, the present data demonstrate the impact of exosomal miR-4669 on HCC recurrence through the enhancement of tumor aggressiveness and generation of an immunosuppressive tumor microenvironment.