Upregulation of DARS2 by HBV promotes hepatocarcinogenesis through the miR-30e-5p/MAPK/NFAT5 pathway

Abstract

BackgroundInfection with the hepatitis B virus (HBV) is closely associated with the development of hepatocellular carcinoma (HCC). The osmoregulatory transcription factor nuclear factor of activated T-cells 5 (NFAT5) has been shown to play an important role in the development of many types of human cancers. The role of NFAT5 in HBV-associated HCC has never previously been investigated.MethodsWe compared expression profiles of NFAT5, DARS2 and miR-30e-5p in HCC samples, adjacent nontumor tissues and different hepatoma cell lines by quantitative real-time polymerase chain reaction and /or Western blot. Clinical data of HCC patients for up to 80 months were analyzed. The regulatory mechanisms upstream and convergent downstream pathways of NFAT5 in HBV-associated HCC were investigated by ChIP-seq, MSP, luciferase report assay and bioinformation anaylsis.ResultsWe first found that higher levels of NFAT5 expression predict a good prognosis, suggesting that NFAT5 is a potential tumor-suppressing gene, and verified that NFAT5 promotes hepatoma cell apoptosis and inhibits cell growth in vitro. Second, our results showed that HBV could suppress NFAT5 expression by inducing hypermethylation of the AP1-binding site in the NFAT5 promoter in hepatoma cells. In addition, HBV also inhibited NFAT5 through miR-30e-5p targeted MAP4K4, and miR-30e-5p in turn inhibited HBV replication. Finally, we demonstrated that NFAT5 suppressed DARS2 by directly binding to its promoter. DARS2 was identified as an HCC oncogene that promotes HCC cell cycle progression and inhibits HCC cell apoptosis.ConclusionHBV suppresses NFAT5 through the miR-30e-5p/mitogen-activated protein kinase (MAPK) signaling pathway upstream of NFAT5 and inhibits the NFAT5 to enhance HCC tumorigenesis via the downstream target genes of DARS2.Electronic supplementary materialThe online version of this article (10.1186/s13046-017-0618-x) contains supplementary material, which is available to authorized users.

miR‐30e‐5p represses angiogenesis and metastasis by directly targeting AEG‐1 in squamous cell carcinoma of the head and neck

“…Based on review of the literature (present study), miR‐30e‐5p modulates diverse mRNA targets in different disease situations, including cancer. These target genes are listed as follows: NFAT5 , TUSC3 , Bim , USP22 , MYBL2 , ITGA6 , ITGB1 , LRP6 and YAP1 . In our current study, miR‐30e‐5p was found to directly link to the 3′‐UTR domain of AEG‐1 mRNA, which accelerates the degradation of AEG‐1 mRNA and eventually reduces the level of AEG‐1 protein.…”

Comprehensive analysis of the functions and prognostic significance of RNA-binding proteins in bladder urothelial carcinoma

“…CTU1 copy number ampli cations were identi ed in 25% of myxopapillary ependymomas [39]. Qin et al had demonstrated DARS2 as a hepatocarcinoma gene that could promote the progression of hepatocarcinoma cell cycle and inhibit the apoptosis of hepatocarcinoma cells [40]. EFTUD2 gene expression was upregulated in hepatocarcinoma, and had prognostic signi cance in patients with hepatocarcinoma [41].…”

NFAT5 Has a Job in the Brain

“…CDK5, c-Abl, and ATM promote the nuclear localization of NFAT5, and, in contrast, CK1 inhibits its nuclear accumulation [19]. There are many other factors that influence the activation and expression of NFAT5, such as inflammatory cytokines [16, 77], microRNAs [50, 62, 78, 79], and transcription factors [80-83]. …”