PMID- 35366893 OWN - NLM STAT- MEDLINE DCOM- 20220405 LR - 20220613 IS - 1476-4598 (Electronic) IS - 1476-4598 (Linking) VI - 21 IP - 1 DP - 2022 Apr 2 TI - Circular RNA MTCL1 promotes advanced laryngeal squamous cell carcinoma progression by inhibiting C1QBP ubiquitin degradation and mediating beta-catenin activation. PG - 92 LID - 10.1186/s12943-022-01570-4 [doi] LID - 92 AB - BACKGROUND: Circular RNAs (circRNAs) are involved in regulatory processes of ubiquitination and deubiquitination in various tumors at post-transcriptional epigenetic modification level. However, the underlying mechanism and its biological functions of circRNAs in the advanced laryngeal squamous cell carcinoma (LSCC) remain obscure. METHODS: RNA sequencing and quantitative real-time PCR (qRT-PCR) assays were applied to screen for circRNAs differentially expressed in LSCC tissues and cell lines. The candidate RNA-binding proteins and target signalling pathway were detected by RNA pull-down and mass spectrometry, in situ hybridization (ISH), immunohistochemistry (IHC), qRT-PCR assays, and bioinformatics analysis. The functional roles of these molecules were investigated using in vitro and in vivo experiments including EdU, transwell, wound healing, western blot assays, and the xenograft mice models. The molecular mechanisms were identified using RNA pull-down assays, RNA immunoprecipitation (RIP), Co-IP, ISH, Ubiquitination assay, bioinformatics analysis, and the rescue experiments. RESULTS: Here, we unveil that microtubule cross-linking factor 1 circRNA (circMTCL1, circ0000825) exerts its critical oncogenic functions by promoting complement C1q-binding protein (C1QBP)-dependent ubiquitin degradation and subsequently activating Wnt/beta-catenin signalling in laryngeal carcinoma initiation and development. Specifically, circMTCL1 was remarkably up-regulated in the paired tissues of patients with LSCC (n = 67), which predicted a worse clinical outcome. Functionally, circMTCL1 exerted oncogenic biological charactersistics by promoting cell proliferative capability and invasive and migrative abilities. Ectopic circMTCL1 augumented cell proliferation, migration, and invasion of LSCC cells, and this effect could be reversed by C1QBP knocking down in vitro and in vivo. Mechanistically, circMTCL1 directly recruited C1QBP protein by harboring the specific recognized sequence (+ 159 - + 210), thereby accelerating the translation of C1QBP expression by inhibiting its ubiquitin-proteasome-mediated degradation. Importantly, the direct interaction of C1QBP with beta-catenin protein was enhanced via suppressing the beta-catenin phosphorylation and accelerating its accumulation in cytoplasm and nucleus. CONCLUSION: Our findings manifested a novel circMTCL1-C1QBP-beta-catenin signaling axis involving in LSCC tumorigenesis and progression, which shed new light on circRNAs-ubiquitous acidic glycoprotein mediated ubiquitin degradation and provided strategies and targets in the therapeutic intervention of LSCC. CI - (c) 2022. The Author(s). FAU - Wang, Zheng AU - Wang Z AD - Department of Otorhinolaryngology, the First Affiliated Hospital of China Medical University, Shenyang, 110001, China. FAU - Sun, Anqi AU - Sun A AD - Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, the First Affiliated Hospital of China Medical University, Shenyang, 110001, China. FAU - Yan, Aihui AU - Yan A AD - Department of Otorhinolaryngology, the First Affiliated Hospital of China Medical University, Shenyang, 110001, China. FAU - Yao, Jian AU - Yao J AD - Division of Molecular Signaling, Department of the Advanced Biomedical Research, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan. FAU - Huang, Haibo AU - Huang H AD - Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, the First Affiliated Hospital of China Medical University, Shenyang, 110001, China. FAU - Gao, Ziming AU - Gao Z AD - Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, the First Affiliated Hospital of China Medical University, Shenyang, 110001, China. FAU - Han, Tao AU - Han T AD - Department of Oncology, the First Affiliated Hospital of China Medical University, Shenyang, 110001, China. FAU - Gu, Jia AU - Gu J AD - Department of Otorhinolaryngology, the First Affiliated Hospital of China Medical University, Shenyang, 110001, China. FAU - Li, Ni AU - Li N AD - Office of Cancer Screening, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences Key Laboratory for National Cancer Big Data Analysis and Implement, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. nli@cicams.ac.cn. FAU - Wu, Huizhe AU - Wu H AD - Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China. wuhz@cmu.edu.cn. FAU - Li, Kai AU - Li K AD - Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, the First Affiliated Hospital of China Medical University, Shenyang, 110001, China. kli@cmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220402 PL - England TA - Mol Cancer JT - Molecular cancer JID - 101147698 RN - 0 (C1QBP protein, human) RN - 0 (C1qbp protein, mouse) RN - 0 (Carrier Proteins) RN - 0 (MTCL1 protein, human) RN - 0 (Microtubule-Associated Proteins) RN - 0 (Mitochondrial Proteins) RN - 0 (RNA, Circular) RN - 0 (Ubiquitin) RN - 0 (beta Catenin) SB - IM MH - Animals MH - Carrier Proteins/metabolism MH - Cell Line, Tumor MH - Disease Progression MH - Gene Expression Regulation, Neoplastic MH - *Head and Neck Neoplasms/genetics MH - Humans MH - Mice MH - Microtubule-Associated Proteins/genetics MH - Mitochondrial Proteins/genetics MH - *RNA, Circular/genetics MH - Squamous Cell Carcinoma of Head and Neck/genetics MH - Ubiquitin/genetics/metabolism MH - Wnt Signaling Pathway MH - beta Catenin/genetics/metabolism PMC - PMC8976408 OTO - NOTNLM OT - C1QBP OT - Laryngeal neoplasms OT - Ubiquitylation OT - circRNA MTCL1 OT - beta-Catenin COIS- The authors declare no competing financial interests. EDAT- 2022/04/04 06:00 MHDA- 2022/04/06 06:00 PMCR- 2022/04/02 CRDT- 2022/04/03 20:21 PHST- 2021/12/17 00:00 [received] PHST- 2022/03/25 00:00 [accepted] PHST- 2022/04/03 20:21 [entrez] PHST- 2022/04/04 06:00 [pubmed] PHST- 2022/04/06 06:00 [medline] PHST- 2022/04/02 00:00 [pmc-release] AID - 10.1186/s12943-022-01570-4 [pii] AID - 1570 [pii] AID - 10.1186/s12943-022-01570-4 [doi] PST - epublish SO - Mol Cancer. 2022 Apr 2;21(1):92. doi: 10.1186/s12943-022-01570-4.