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

Abstract

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.

Shedding more light on the role of Midkine in hepatocellular carcinoma: New perspectives on diagnosis and therapy

“…Non‐coding RNAs, including micro‐RNAs (miRNAs) and long non‐coding RNAs (lncRNAs), have been established as potential tumor suppressors or oncogenes and play key regulators in tumor development. lncRNA ZNFX1 antisense RNA 1 (ZFAS1) has been shown to be involved in HCC progress, and its upregulation correlates with poor prognosis and promotes malignant phenotype 30,31 . It has been speculated that there is a relation between ZFAS1, miR‐624 (a tumor suppressor micro‐RNA), and MDK in HCC.…”

Clinical value of lncRNA ZFAS1 in various cancers: an updated meta-analysis of 2263 cancer patients

“…And the carcinogenic molecular mechanism of ZFAS1 has been partly clari ed that it usually functions as CeRNA of miRNA to regulate downstream mRNA expression to affect manifold biological behaviors of tumor cell. Duan et al found that ZFAS1 was obviously overexpressed in HCC and connected with worse prognosis of HCC patients, and silencing of ZFAS1 can suppress cell proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) through regulation of the miR-624/MDK/ERK/JNK/AKT signaling pathway [11]. Several researchers have demonstrated that ZFAS1 was upregulated in CRC and can serve as a prognostic factor for CRC patients.…”

“…The included 2263 patients all come from China. 16 types of tumors were included in this study, which contains pancreatic adenocarcinoma (PAAD) [10], hepatocellular carcinoma (HCC) [11,18], melanoma [12], esophageal squamous cell carcinoma (ESCC) [13,19], hepatoblastoma (HB) [20], cholangiocarcinoma (CCA) [14], papillary thyroid carcinoma (PTC) [21], prostate cancer (PCa) [22], clear cell renal cell carcinoma (ccRCC) [15], colorectal cancer (CRC) [16,23,24], bladder cancer [25,26], nasopharyngeal carcinoma (NPC) [27], gastric cancer (GC) [28], epithelial ovarian cancer (EOC) [29], non-small cell lung cancer (NSCLC) [30], glioma [31]. ZFAS1 expression in tumor tissues were all detected by qRT-PCR.…”

Proteomic Profiling and Artificial Intelligence for Hepatocellular Carcinoma Translational Medicine

“…MDK plays an important role in resistance of CTCs to anoikis through activation of PI3K/Akt/NF-kB/TrkB signaling. MDK can be involved in HCC progression and metastasis via ERK/JNK/p38MAPK-mediated signaling promoted by long lncRNA ZFAS1 [ 145 ]. The ZFAS1 expression is elevated in HCC but can be suppressed by miR-624.…”