A Noncoding Regulatory RNAs Network Driven by Circ‐CDYL Acts Specifically in the Early Stages Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the fastest‐rising causes of cancer‐related death worldwide, but its deficiency of specific biomarkers and therapeutic targets in the early stages lead to severe inadequacy in the early diagnosis and treatment of HCC. Covalently closed circular RNA (circRNA), which was once considered an aberrant splicing by‐product, is now drawing new interest in cancer research because of its remarkable functionality. Beneath the surface of the dominant functional proteins events, a hidden circRNA‐centric noncoding regulatory RNAs network active in the very early stage of HCC is here revealed by a genome‐wide analysis of mRNA, circRNA, and microRNA (miRNA) expression profiles. Circ‐CDYL (chromodomain Y like) is specifically up‐regulated in the early stages of HCC and therefore contributes to the properties of epithelial cell adhesion molecule (EPCAM)‐positive liver tumor‐initiating cells. Circ‐CDYL interacts with mRNAs encoding hepatoma‐derived growth factor (HDGF) and hypoxia‐inducible factor asparagine hydroxylase (HIF1AN) by acting as the sponge of miR‐892a and miR‐328‐3p, respectively. Subsequently, activation of the phosphoinositide 3‐kinase (PI3K)‐AKT serine/threonine kinase‐mechanistic target of rapamycin kinase complex 1/β‐catenin and NOTCH2 pathways, which promote the expression of the effect proteins, baculoviral IAP repeat containing 5 (BIRC5 or SURVIVIN) and MYC proto‐oncogene, is influenced by circ‐CDYL. A treatment incorporating circ‐CDYL interference and traditional enzyme inhibitors targeting PI3K and HIF1AN demonstrated highly effective inhibition of stem‐like characteristics and tumor growth in HCC. Finally, we demonstrated that circ‐CDYL expression or which combined with HDGF and HIF1AN are both independent markers for discrimination of early stages of HCC with the odds ratios of 1.09 (95% confidence interval [CI], 1.02‐1.17) and 124.58 (95% CI, 13.26‐1170.56), respectively. Conclusion: These findings uncover a circRNA‐centric noncoding regulatory RNAs network in the early stages of HCC and thus provide a possibility for surveillance and early treatment of HCC.

M6A-mediated upregulation of LINC00958 increases lipogenesis and acts as a nanotherapeutic target in hepatocellular carcinoma

“…To investigate the target gene of the LINC00958/ miR-3619-5p pathway in HCC, we combined four bioinformatics algorithms and RNA sequencing results and found that HDGF was the downstream effector of the LINC00958/miR-3619-5p axis. HDGF has been established as an oncogene that facilitates the progression of HCC [40,41]. One recent study suggested that HDGF could affect lipid metabolism via SREBP1 in HCC [25].…”

Exosomal circRNA-100338 promotes hepatocellular carcinoma metastasis via enhancing invasiveness and angiogenesis

“…circRNAs were identified to be important regulators in human cancers. In HCC, we, together with other research teams [5][6][7], have identified that a series of cir-cRNAs were dysregulated in cancer samples and associated with tumor progression, which may serve as promising biomarkers for cancer. CircRNAs are involved in regulating multiple cancer-related biological processes and pathways, including cell growth [8], metastasis [9], and apoptosis [10].…”

“…For example, circRNA cSMARCA5 can suppress cell metastasis by binding to miR-17-3p to promote TIMP3 expression in HCC [11]. Circ-CDYL interacts with HDGF and HIF1AN to regulate HCC stemness and growth [6]. We previously identified a series of dysregulated circRNAs in HCC and focused on examining the roles of circRNA-100,338 in HCC [5,12].…”

The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma

“…Consistent with the idea that certain cell states determine drug sensitivity, miRNAs, as well as other ncRNAs including lncRNAs that mostly act as sponges of miRNAs, modulated sorafenib sensitivity through regulating EMT and stemness in HCC [85]. There are no studies reporting the role of circular RNAs (circRNAs) in sorafenib resistance yet, however, circRNA was involved in regulating stemness features of HCC cells [86]. In addition, acidic microenvironment, energy stress, and immune cell infiltration enhanced the transcription of ncRNAs in HCC cells, and promoted EMT, stemness, and angiogenesis in a HIF-dependent manner or with the help of stroma-derived growth factors [15,27,87,88].…”