Tumor-derived extracellular vesicles containing long noncoding RNA PART1 exert oncogenic effect in hepatocellular carcinoma by polarizing macrophages into M2

Aim: We explored whether tumor-derived extracellular vesicles (EVs) could deliver long noncoding RNA (lncRNA) PART1 into macrophage to orchestrate macrophage polarization in the progression of hepatocellular carcinoma (HCC).Method: The expression patterns of PART1, microRNA (miR)-372-3p and TLR4 were detected by RT-qPCR in the HCC tissues and HCC cells. PART1 was silenced or overexpressed in HCC cells to assess its effects on the HCC cell process. EVs were isolated from PART1-overexpressed HCC cells, and co-cultured with macrophages, and gain-and loss-of-function assays were implemented in macrophages to evaluate their role in macrophage polarization. Relationship among PART1, miR-372-3p, and TLR4 was evaluated. Effect of EV-PART1 on tumorigenicity in vivo was detected by subcutaneous tumorigenicity test in nude mice.Result: PART1 and TLR4 were upregulated while miR-372-3p was downregulated in HCC tissues and cells. PART1 increased HCC cell proliferation, migration, invasion, and EMT. Mechanistically, PART1 bound to miR-372-3p to downregulate its expression, whereas TLR4 was negatively targeted by miR-372-3p in the macrophages. EVs containing PART1, TLR4 overexpression, or miR-372-3p inhibition induced M2 polarization of macrophages. Also, EVs containing PART1 promoted M2 polarization of macrophages and the occurrence of HCC by affecting miR-372-3p/TLR4 axis.Conclusion: HCC cell-derived EVs might up-regulate TLR4 by inhibiting miR-372-3p via PART1 delivery to promote macrophage M2 polarization in HCC.0 2021 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.

Automated summary

This study investigated the role of tumor-derived extracellular vesicles (EVs) in the progression of hepatocellular carcinoma (HCC) by delivering long noncoding RNA (lncRNA) PART1 into macrophages to orchestrate macrophage polarization. The findings suggest that EVs released by HCC cells can promote M2 polarization of macrophages and the occurrence of HCC by regulating the miR-372-3p/TLR4 axis.