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.

Circ3823 contributes to growth, metastasis and angiogenesis of colorectal cancer: involvement of miR-30c-5p/TCF7 axis

“…Besides, circ-Erbin mediated HIF-1α activation by miR-125a-5p/4EBP-1 axis [ 13 ]. Moreover, circSOD2 inhibits miR-502-5p expression and rescues the target gene DNMT3a [ 36 ]. In this study, circ3823 exerted its function as a ceRNA that competitively bound to miR-30c-5p, then abolished the endogenous suppressive effect of miR-30c-5p on the target gene TCF7.…”

Circular RNAs: Emerging Regulators of the Major Signaling Pathways Involved in Cancer Progression

“…The effect of circRNAs on the JAK/STAT signaling pathway has been investigated in several instances so far, in the context of tumor progression ( Table 4 ). Firstly, two recent studies have elucidated the oncogenic role of circRNAs in hepatocellular carcinoma, and interestingly, both have evidenced a positive feedback loop involved in each regulatory axis, as shown in Figure 5 [ 127 , 128 ]. More specifically, circ-LRIG3 expression is linked with aggressive tumor features, including increased tumor size, advanced TNM stage, and vascular invasion [ 127 ].…”

“…The subsequent formation of this temporary complex induces the activation of STAT3, which then binds to the promoter of circ-LRIG3, thus regulating its expression in a positive feedback way. The progression of hepatocellular carcinoma is mediated by circ-SOD2 as well, through the induction of epigenetic alterations [ 128 ]. In particular, circ-SOD2 sequesters miR-502-5p and drives the restoration of DNMT3A expression levels, which is a direct target of this miRNA.…”

CircEHD2, CircNETO2 and CircEGLN3 as Diagnostic and Prognostic Biomarkers for Patients with Renal Cell Carcinoma

“…Although we could not confirm a diagnostic relevance for any of these circRNA, they have been associated with oncogenic functions in cancer in former studies: circSCARB1 promoted RCC progression by sequestering miR-510-5p and indirectly up-regulating SDC3 expression [22], and circCOL5A1 acted as a miR-1224-5p sponge, thereby activating CREB1 expression and promoting cellular proliferation in bladder cancer [23]. circSOD2 expression enhanced cancer cell growth, cell migration, cell cycle progression, and in vivo tumor growth in hepatocellular cancer; circSOD2 inhibited miR-502-5p expression, thereby upregulating DNMT3A expression [24].…”