lncRNA MALAT1 modulates cancer stem cell properties of liver cancer cells by regulating YAP1 expression via miR-375 sponging

Liver cancer stem cells (CSCs) are functionally defined by their ability to undergo self-renewal, and may contribute to metastasis, recurrence and drug resistance in liver cancer. The long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been implicated in tumor formation and metastasis of liver cancer. However, the exact mechanism by which MALAT1 modulates liver CSC features remains largely unknown. In the present study, the expression level of MALAT1 was elevated in cancer spheroids compared with the corresponding levels noted in parental liver cancer cells, whereas the suppression of MALAT1 resulted in markedly reduced sphere formation and decreased expression of stemness factors in liver cancer cells. Dual-luciferase assay and RNA pull-down assays further indicated an interaction between MALAT1 and microRNA (miR)-375, and identified Yes-associated protein 1 (YAP1) as a direct target of miR-375 in liver cancer cells. In addition, YAP1 expression was correlated with MALAT1 in liver cancer. The reduced expression of YAP1 caused by knockdown of MALAT1 with MALAT1 small interfering RNA (si-MALAT1) could be partially abolished by miR-375 inhibition, suggesting that MALAT1 may regulate YAP1 expression by sponging miR-375. Furthermore, YAP1 overexpression rescued the decrease in CSC features of liver cancer cells caused by si-MALAT1, further supporting that MALAT1-mediated YAP1 signaling was required for the stem-like characteristics of liver CSCs. The present study revealed that MALAT1 may promote CSC properties of liver cancer cells by upregulating YAP1 expression via sponging miR-375. The MALAT1/miR-375/YAP1 axis may serve as a novel target for liver cancer therapy, particularly for the eradication of liver CSCs.