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 HBV+HCC 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 HBV+HCC 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 HBV+HCC 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 HBV+HCC cells through the M2 macrophage-derived exosomes, promoting cell proliferation. Our findings show that HBV+HCC cell-secreted HBeAg upregulates MAAS expression in M2 macrophages by affecting its m(6)A modification. The upregulated MAAS is then transferred to HBV+HCC cells via exosomes, facilitating the proliferation of HBV+HCC cells by targeting c-Myc. The present study reveals that the hepatitis-B (HBV) antigen HBeAg found in HBV+HCC upregulates long non-coding RNA MAPKAPK5_AS1 (MAAS) expression in M2 macrophages by affecting its m6A modification. MAAS is transferred to HBV+HCC cells via exosomes, which in turn facilitates their proliferation. This is a novel role for MAAS and further elucidates the mechanism of HBeAg-induced HBV-related HCC development.

Automated summary

Our study reveals that the hepatitis-B antigen HBeAg found in HBV+HCC upregulates long non-coding RNA MAPKAPK5_AS1 (MAAS) expression in M2 macrophages by affecting its m6A modification. MAAS is transferred to HBV+HCC cells via exosomes, which in turn facilitates their proliferation. This is a novel role for MAAS and further elucidates the mechanism of HBeAg-induced HBV-related HCC development.