LncRNA MAPKAPK5_AS1 facilitates cell proliferation in hepatitis B virus -related hepatocellular carcinoma.

We explored the biological role of long non-coding RNA (lncRNA) MAPKAPK5_AS1 (MAAS) and the mechanism of its differential expression in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Differentially expressed lncRNAs in HBV-related HCC were determined using bioinformatics analysis. Gain-of-function experiments were conducted to evaluate the effect of MAAS on cell proliferation. A xenograft model was established for in vivo experiments. Dual-luciferase reporter assays, chromatin immunoprecipitation, co-immunoprecipitation, and methylated RNA immunoprecipitation were performed to elucidate the underlying molecular mechanisms. MAAS was upregulated in HBV-related HCC cancerous tissues and its high expression was closely related to the poor survival probability of patients. Functional assays revealed that MAAS overexpression facilitated the proliferation of HBVHCC cells in vitro and in vivo. Mechanistically, MAAS promoted the MYC proto-oncogene (c-Myc)-induced transcriptional activation of cyclin-dependent kinase 4 (CDK4), CDK6, and S-phase kinase associated protein 2 via stabilizing c-Myc protein, thereby facilitating G1/S transition. The latter contributed to the paradoxical proliferation of HBVHCC cells. Although MAAS was upregulated in HBV-related HCC cancerous tissues, it was highly expressed in M2 macrophages, a major phenotype of tumor-associated macrophages in HBV-related HCC, instead of in HBVHCC cells. HBeAg, an HBV-associated antigen, further elevated the MAAS level in M2 macrophages by enhancing the methyltransferase-like 3-mediated N6-methyladenosine modification of MAAS. The increased MAAS in the M2 macrophages was then transferred to HBVHCC cells through the M2 macrophage-derived exosomes, promoting cell proliferation. Our findings show that HBVHCC cell-secreted HBeAg upregulates MAAS expression in M2 macrophages by affecting its mA modification. The upregulated MAAS is then transferred to HBVHCC cells via exosomes, facilitating the proliferation of HBVHCC cells by targeting c-Myc.