Duan Rui, Li Caiyan, Wang Fan, Han Fei, Zhu Ling
Department of Hepatological Surgery, The First People's Hospital of Jingmen, Jingmen, Hubei 448000, People's Republic of China.
Department of Clinical Laboratory, The Second People's Hospital of Jingmen, Jingmen 448000, Hubei, People's Republic of China.
Onco Targets Ther. 2020 May 19;13:4431-4444. doi: 10.2147/OTT.S246278. eCollection 2020.
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.
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.
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.
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.
长链非编码RNA（lncRNA）锌指蛋白X1反义RNA 1（ZFAS1）在包括肝细胞癌（HCC）在内的多种癌症中表达增加，导致恶性肿瘤的发生和进展。然而，ZFAS1与微小RNA-624（miRNA-624）相互作用的机制仍不清楚。因此，本研究旨在探讨ZFAS1在HCC发生发展中的作用及其潜在机制。
首先，通过基因芯片筛选出HCC组织中差异表达的lncRNAs。随后，利用Kaplan-Meier分析和癌症基因组图谱数据库分析ZFAS1对HCC患者的预后影响。将si-ZFAS1和/或miRNA-624抑制剂转染到HepG2和SMMC7721细胞系中，检测ZFAS1对miRNA-624的调控作用。最后，通过体内肿瘤发生和转移实验观察ZFAS1对HCC生长和转移的影响。
ZFAS1在HCC组织和细胞中高表达，提示HCC患者预后较差，生存期较短。沉默ZFAS1可抑制HCC细胞的恶性表型，但miRNA-624抑制剂可部分逆转si-ZFAS1的抑制作用。此外，ZFAS1通过miRNA-624与中期因子（MDK）结合，激活细胞外调节蛋白激酶/ c-Jun氨基末端激酶（ERK/JNK）/ P38信号通路，从而促进HCC的发生。
综上所述，ZFAS1的缺失通过恢复miRNA-624的表达，下调MDK/ERK/JNK/P38信号通路，抑制HCC的发生。抑制ZFAS1可能成为抑制HCC发生的新靶点。
