Circular RNA circ‐FIRRE interacts with HNRNPC to promote esophageal squamous cell carcinoma progression by stabilizing GLI2 mRNA

• DOI: 10.1111/cas.15899
• Publication Date: 2023-07-07T11:00:36Z
• Authors: Yongjia Zhou; Xia Xue; Junwen Luo; Peiwei Li; Zhaohua Xiao; Wenhao Zhang; Jie Zhou; Peichao Li; Jiangfeng Zhao; Haibo Ge; Zhongxian Tian; Xiaogang Zhao
• Keywords: Esophageal Neoplasms; Heterogeneous-Nuclear Ribonucleoprotein Group C; Nuclear Proteins; Original Articles; RNA, Circular; Zinc Finger Protein Gli2; 3. Good health; Gene Expression Regulation, Neoplastic; MicroRNAs; Cell Line, Tumor; Humans; Hedgehog Proteins; Esophageal Squamous Cell Carcinoma; RNA, Messenger; Cell Proliferation

AbstractIncreasing evidence has shown that circular RNAs (circRNAs) interact with RNA‐binding proteins (RBPs) and promote cancer progression. However, the function and mechanism of the circRNA/RBP complex in esophageal squamous cell carcinoma (ESCC) are still largely unknown. Herein, we first characterized a novel oncogenic circRNA, circ‐FIRRE, by RNA sequencing (Ribo‐free) profiling of ESCC samples. Furthermore, we observed marked circ‐FIRRE overexpression in ESCC patients with high TNM stage and poor overall survival. Mechanistic studies indicated that circ‐FIRRE, as a platform, interacts with the heterogeneous nuclear ribonucleoprotein C (HNRNPC) protein to stabilize GLI2 mRNA by directly binding to its 3’‐UTR in the cytoplasm, thereby resulting in elevated GLI2 protein expression and subsequent transcription of its target genes MYC, CCNE1, and CCNE2, ultimately contributing to ESCC progression. Moreover, HNRNPC overexpression in circ‐FIRRE knockdown cells notably abolished circ‐FIRRE knockdown‐mediated Hedgehog pathway inhibition and ESCC progression impairment in vitro and in vivo. Clinical specimen results showed that circ‐FIRRE and HNRNPC expression was positively correlated with GLI2 expression, which reveals the clear significance of the circ‐FIRRE/HNRNPC‐GLI2 axis in ESCC. In summary, our results indicate that circ‐FIRRE could serve as a valuable biomarker and potential therapeutic target for ESCC and highlight a novel mechanism of the circ‐FIRRE/HNRNPC complex in ESCC progression regulation.