LncRNA DBH-antisense RNA 1 modulates the miR-612/SOX4 axis as a CeRNA to regulate the properties of liver cancer stem cells and their resistance to lenvatinib

Abstract

Existing studies reported that Long non-coding RNA (lncRNA) modulates the stemness of CSCs. Here, we found that LncRNA DBH-antisense RNA 1(AS1) is upregulated in liver CSCs. Forced LncRNA DBH-AS1 promotes tumorigenesis and liver CSCs self-renewal. On the other hand, LncRNA DBH-AS1 expression knockdown prevents liver CSCs from self-renewing. Mechanistically, LncRNA DBH-AS1 mediated regulation of SRY-box transcription factor 4 (SOX4), acting as a ceRNA to sponge miR-612 in liver CSCs. LncRNA DBH-AS1 enhanced liver CSCs self-renew and tumorigenesis via upregulating SOX4. Furthermore, liver cells with LncRNA DBH-AS1 knockdown are susceptible to apoptosis caused by Lenvatinib. Furthermore, the sensitivity of HCC cells with LncRNA DBH-AS1 knockdown to lenvatinib-induced cell death could be reversed by adding SOX4. In conclusion, experimental evidence revealed that METTL3-dependent m⁶A methylation was the mechanism mediating the elevated lncRNADBH-AS1 in HCC. This study demonstrated the critical role that LncRNA DBH-AS1 plays in the carcinogenesis and self-renewal of liver CSCs, which renders it the perfect target for HCC therapy.