PMID- 34922544 OWN - NLM STAT- MEDLINE DCOM- 20220324 LR - 20220324 IS - 1476-4598 (Electronic) IS - 1476-4598 (Linking) VI - 20 IP - 1 DP - 2021 Dec 18 TI - CircIL4R activates the PI3K/AKT signaling pathway via the miR-761/TRIM29/PHLPP1 axis and promotes proliferation and metastasis in colorectal cancer. PG - 167 LID - 10.1186/s12943-021-01474-9 [doi] LID - 167 AB - BACKGROUND: Accumulating studies have revealed that aberrant expression of circular RNAs (circRNAs) is widely involved in the tumorigenesis and progression of malignant cancers, including colorectal cancer (CRC). Nevertheless, the clinical significance, levels, features, biological function, and molecular mechanisms of novel circRNAs in CRC remain largely unexplored. METHODS: CRC-related circRNAs were identified through bioinformatics analysis and verified in clinical specimens by qRT-PCR and in situ hybridization (ISH). Then, in vitro and in vivo experiments were performed to determine the clinical significance of, functional roles of, and clinical characteristics associated with circIL4R in CRC specimens and cells. Mechanistically, RNA pull-down, fluorescence in situ hybridization (FISH), luciferase reporter, and ubiquitination assays were performed to confirm the underlying mechanism of circIL4R. RESULTS: CircIL4R was upregulated in CRC cell lines and in sera and tissues from CRC patients and was positively correlated with advanced clinicopathological features and poor prognosis. Functional experiments demonstrated that circIL4R promotes CRC cell proliferation, migration, and invasion via the PI3K/AKT signaling pathway. Mechanistically, circIL4R was regulated by TFAP2C and competitively interacted with miR-761 to enhance the expression of TRIM29, thereby targeting PHLPP1 for ubiquitin-mediated degradation to activate the PI3K/AKT signaling pathway and consequently facilitate CRC progression. CONCLUSIONS: Our findings demonstrate that upregulation of circIL4R plays an oncogenic role in CRC progression and may serve as a promising diagnostic and prognostic biomarker for CRC detection and as a potential therapeutic target for CRC treatment. CI - (c) 2021. The Author(s). FAU - Jiang, Tao AU - Jiang T AD - Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China. AD - Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China. FAU - Wang, Hongyu AU - Wang H AD - Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China. AD - The Graduate School, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China. FAU - Liu, Lianyu AU - Liu L AD - Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China. AD - The Graduate School, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China. FAU - Song, Hu AU - Song H AD - Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China. AD - Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China. FAU - Zhang, Yi AU - Zhang Y AD - Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China. AD - Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China. FAU - Wang, Jiaqi AU - Wang J AD - Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China. AD - Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China. FAU - Liu, Lei AU - Liu L AD - Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China. AD - The Graduate School, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China. FAU - Xu, Teng AU - Xu T AD - Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China. AD - Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China. FAU - Fan, Ruizhi AU - Fan R AD - Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China. AD - Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China. FAU - Xu, Yixin AU - Xu Y AD - Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China. AD - Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China. FAU - Wang, Shuai AU - Wang S AD - Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China. AD - The Graduate School, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China. FAU - Shi, Linsen AU - Shi L AD - Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China. AD - Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China. FAU - Zheng, Li AU - Zheng L AD - State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China. FAU - Wang, Renhao AU - Wang R AUID- ORCID: 0000-0002-4465-9953 AD - Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China. wangrenhao@xzhmu.edu.cn. AD - Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China. wangrenhao@xzhmu.edu.cn. FAU - Song, Jun AU - Song J AUID- ORCID: 0000-0002-6350-2695 AD - Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China. songjun@xzhmu.edu.cn. AD - Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China. songjun@xzhmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211218 PL - England TA - Mol Cancer JT - Molecular cancer JID - 101147698 RN - 0 (DNA-Binding Proteins) RN - 0 (IL4R protein, human) RN - 0 (Interleukin-4 Receptor alpha Subunit) RN - 0 (MicroRNAs) RN - 0 (Nuclear Proteins) RN - 0 (RNA, Circular) RN - 0 (TRIM29 protein, human) RN - 0 (Transcription Factors) RN - 0 (microRNA761 microRNA, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 3.1.3.16 (PHLPP1 protein, human) RN - EC 3.1.3.16 (Phosphoprotein Phosphatases) SB - IM MH - Animals MH - Cell Line, Tumor MH - Colorectal Neoplasms/*etiology/*metabolism/pathology MH - Computational Biology/methods MH - DNA-Binding Proteins/*genetics MH - Disease Models, Animal MH - Gene Expression Regulation, Neoplastic MH - Heterografts MH - Humans MH - Interleukin-4 Receptor alpha Subunit/*genetics MH - Mice MH - MicroRNAs/*genetics MH - Models, Biological MH - Nuclear Proteins/*genetics MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Phosphoprotein Phosphatases/*genetics MH - Proto-Oncogene Proteins c-akt/*metabolism MH - RNA, Circular/*genetics MH - ROC Curve MH - Signal Transduction MH - Transcription Factors/*genetics MH - Transcriptome PMC - PMC8684286 OTO - NOTNLM OT - Colorectal cancer OT - PI3K/AKT pathway OT - TRIM29 OT - circIL4R OT - miR-761 COIS- There are no competing interests between all authors. EDAT- 2021/12/20 06:00 MHDA- 2022/03/25 06:00 PMCR- 2021/12/18 CRDT- 2021/12/19 20:29 PHST- 2021/08/27 00:00 [received] PHST- 2021/12/01 00:00 [accepted] PHST- 2021/12/19 20:29 [entrez] PHST- 2021/12/20 06:00 [pubmed] PHST- 2022/03/25 06:00 [medline] PHST- 2021/12/18 00:00 [pmc-release] AID - 10.1186/s12943-021-01474-9 [pii] AID - 1474 [pii] AID - 10.1186/s12943-021-01474-9 [doi] PST - epublish SO - Mol Cancer. 2021 Dec 18;20(1):167. doi: 10.1186/s12943-021-01474-9.