CircSOD2 induced epigenetic alteration drives hepatocellular carcinoma progression through activating JAK2/STAT3 signaling pathway

Abstract

Background：Emerging evidence suggests that circular RNAs play critical roles in disease development especially in cancers. Previous genome-wide RNA-seq studies found that a circular RNA derived from SOD2 gene was highly upregulated in hepatocellular carcinoma (HCC), however, the role of circSOD2 in HCC remains largely unknown. Methods: The expression profiling of circSOD2 and microRNA in HCC patients were assessed by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR). SiRNA or CRISPR-CAS9 were used to silence gene expression. The biological function of circSOD2 in HCC was investigated using in vitro and in vivo studies including, trans-well cell migration, cell apoptosis, cell cycle, CCK8, siRNA interference, western blots, and xenograft mouse model. The underlying molecular mechanism was determined by Chromatin Immunoprecipitation quantitative real time PCR (ChIP-qPCR), bioinformatic analysis, biotin-pull down, RNA immunoprecipitation, 5-mc DNA pulldown and luciferase assays. Results: In accordance with previous sequencing results, here, we demonstrated that circSOD2 was highly expressed in HCC tumor tissues compared with normal liver tissues. Mechanically, we showed that histone writer EP300 and WDR5 bind to circSOD2 promoter and trigger its promoter H3K27ac and H3K4me3 modification, respectively, which further activates circSOD2 expression. SiRNA mediated circSOD2 suppression impaired liver cancer cell growth, cell migration, prohibited cell cycle progression and in vivo tumor growth. By acting as a sponge, circSOD2 inhibits miR-502-5p expression and rescues miR-502-5p target gene DNMT3a expression. As a DNA methyltransferase, upregulated DNMA3a suppresses SOCS3 expression by increasing SOCS3 promoter DNA methylation. This event further accelerates SOCS3 downstream JAK2/STAT3 signaling pathway activation. In addition, we also found that activated STAT3 regulates circSOD2 expression in a feedback way. Conclusion: The novel signaling axis circSOD2/miR-502-5p/DNMT3a/JAK2/STAT3/circSOD2 provides a better understanding of HCC tumorigenesis. The molecular mechanism underlying this signaling axis offers new prevention and treatment of HCC.

Circular RNA Circ-0006302 Promotes the Growth, Migration, and Invasion of Cholangiocarcinoma Cells by Regulating the Mir-1299/PD-L1 Axis as a Competing Endogenous RNA

“…For example, circHIPK3 acts as a tumor-suppressive function in ovarian cancer [28]. Via activating JAK2/STAT3 signaling pathway, hepatocellular carcinoma progression was driven by circSOD2 induced epigenetic alteration [29] Circ-0000284 modulates the biological functions of peripheral cells via cellular communication and arouses malignant phenotype of CCA cells [30]. In this study, we observed circ-0006302 expression levels in CCA tissues are distinctly higher than that in non-tumorous tissues.…”

Long non-coding RNA 01126 activates IL-6/JAK2/STAT3 pathway via serving as a sponge of miR-655-3p in periodontitis

“…Increased IL-6 leads to IL-6 receptor activation, which then activates IL-6-related cell signaling pathways, especially IL-6/JAK2/STAT3 pathway 46 . According to most current studies, aberrant activation of JAK2/STAT3 signaling pathway promotes disease progression and is detrimental to the control of diseases, including liver cancer 47 , in ammation 48 and neurological disease 49 . In our study, it was observed that the expressions of IL-6, p-JAK2, and p-STAT3 were abnormal up-regulated in HGFs after LPS induction, and the effect of LPS stimulation was partially reversed following transfection with miR-655-3p mimics.…”

A curcumin analog GL63 inhibits the malignant behaviors of hepatocellular carcinoma by inactivating the JAK2/STAT3 signaling pathway via the circular RNA zinc finger protein 83/microRNA‐324‐5p/cyclin‐dependent kinase 16 axis

“…17 CircSOD2 contributed to the HCC progression by targeting the miR-502-5p/ DNMT3a axis to activate the JAK2/STAT3 pathway. 18 Also, GL63 has suppressed cell proliferation by blocking the JAK2/STAT3 signaling pathway in HCC cells. 7 This study concentrated on the anti-tumor mechanism of GL63 in HCC.…”