The Long Noncoding RNA ZFAS1 Potentiates the Development of Hepatocellular Carcinoma via the microRNA-624/MDK/ERK/JNK/P38 Signaling Pathway

BACKGROUND: A long noncoding RNA (lncRNA), ZNFX1 antisense RNA 1 (ZFAS1), was increased in multiple cancers, including hepatocellular carcinoma (HCC), resulting in malignancy development and progression. However, the mechanisms involving the interaction between ZFAS1 and microRNA-624 (miRNA-624) remain largely unknown. Therefore, the goal of this study was to probe the functional role of ZFAS1 in the development of HCC and its underlying mechanism. METHODS: Firstly, differentially expressed lncRNAs in HCC tissues were screened out by microarray. Subsequently, the prognostic effect of ZFAS1 patients with HCC was analyzed by the Kaplan–Meier analysis and The Cancer Genome Atlas database. ZFAS1 regulation on miRNA-624 was determined after si-ZFAS1 and/or miRNA-624 inhibitor were transfected into HepG2 and SMMC7721 cell lines. Finally, the effects of ZFAS1 on the growth and metastasis of HCC were observed by in vivo tumorigenesis and metastasis tests. RESULTS: ZFAS1 was overexpressed in HCC tissues and cells and indicated worse prognosis and shorter survival in patients with HCC. Silencing of ZFAS1 inhibited the malignancy of HCC cells, but miR-624 inhibitor could partially reverse the repressive role of si-ZFAS1. Moreover, ZFAS1 induced the extracellular-regulated protein kinases/c-Jun N-terminal kinase (ERK/JNK)/P38 pathway by binding to midkine (MDK) through miR-624, thus promoting the occurrence of HCC. CONCLUSION: Collectively, ZFAS1 depletion inhibited the occurrence of HCC by downregulating the MDK/ERK/JNK/P38 pathway through restoring miR-624 expression. Inhibition of ZFAS1 may act as an innovative target to suppress occurrence in HCC.