PMID- 30925892 OWN - NLM STAT- MEDLINE DCOM- 20190801 LR - 20211204 IS - 1476-4598 (Electronic) IS - 1476-4598 (Linking) VI - 18 IP - 1 DP - 2019 Mar 29 TI - A novel protein encoded by a circular RNA circPPP1R12A promotes tumor pathogenesis and metastasis of colon cancer via Hippo-YAP signaling. PG - 47 LID - 10.1186/s12943-019-1010-6 [doi] LID - 47 AB - BACKGROUND: It has been well established that circular RNAs (circRNAs) play an important regulatory role during tumor progression. Recent studies have indicated that even though circRNAs generally regulate gene expression through miRNA sponges, they may encode small peptides in tumor pathogenesis. However, it remains largely unexplored whether circRNAs are involved in the tumorigenesis of colon cancer (CC). METHODS: The expression profiles of circRNAs in CC tissues were assessed by circRNA microarray. Quantitative real-time PCR, RNase R digestion assay and tissue microarray were used to confirm the existence and expression pattern of circPPP1R12A. The subcellular distribution of circPPP1R12A was analyzed by nuclear mass separation assay and fluorescence in situ hybridization (FISH). SDS-PAGE and LC/MS were employed to evaluate the protein-coding ability of circPPP1R12A. CC cells were stably transfected with lentivirus approach, and cell proliferation, migration and invasion, as well as tumorigenesis and metastasis in nude mice were assessed to clarify the functional roles of circPPP1R12A and its encoded protein circPPP1R12A-73aa. RNA-sequencing and Western blotting analysis were furthered employed to identify the critical signaling pathway regulated by circPPP1R12A-73aa. RESULTS: We firstly screened the expression profiles of human circRNAs in CC tissues and found that the expression of hsa_circ_0000423 (termed as circPPP1R12A) was significantly increased in CC tissues. We also found that circPPP1R12A was mostly localized in the cytoplasm of CC cells. Kaplan-Meier analysis showed that patients with higher levels of circPPP1R12A had a significantly shorter overall survival. By gain- and loss-of-function approaches, the results suggested that circPPP1R12A played a critical role in proliferation, migration and invasion of CC cells. Furthermore, we showed that circPPP1R12A carried an open reading frame (ORF), which encoded a functional protein (termed as circPPP1R12A-73aa). Next, we found that PPP1R12A-C, not circPPP1R12A, promoted the proliferation, migration and invasion abilities of CC in vitro and in vivo. Finally, we identified that circPPP1R12A-73aa promoted the growth and metastasis of CC via activating Hippo-YAP signaling pathway. In addition, the YAP specific inhibitor Peptide 17 dramatically alleviated the promotive effect of circPPP1R12A-73aa on CC cells. CONCLUSIONS: In the present study, we illustrated the coding-potential of circRNA circPPP1R12A in the progression of CC. Moreover, we identified that circPPP1R12A-73aa promoted the tumor pathogenesis and metastasis of CC via activating Hippo-YAP signaling pathway. Our findings might provide valuable insights into the development of novel potential therapeutic targets for CC. FAU - Zheng, Xiao AU - Zheng X AD - Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, People's Republic of China. AD - Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, 213003, People's Republic of China. AD - Institute of Cell Therapy, Soochow University, Changzhou, 213003, People's Republic of China. FAU - Chen, Lujun AU - Chen L AD - Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, People's Republic of China. AD - Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, 213003, People's Republic of China. AD - Institute of Cell Therapy, Soochow University, Changzhou, 213003, People's Republic of China. FAU - Zhou, You AU - Zhou Y AD - Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, People's Republic of China. AD - Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, 213003, People's Republic of China. AD - Institute of Cell Therapy, Soochow University, Changzhou, 213003, People's Republic of China. FAU - Wang, Qi AU - Wang Q AD - Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, People's Republic of China. AD - Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, 213003, People's Republic of China. AD - Institute of Cell Therapy, Soochow University, Changzhou, 213003, People's Republic of China. FAU - Zheng, Zhuojun AU - Zheng Z AD - Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, 213003, People's Republic of China. AD - Department of Hematology, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, People's Republic of China. FAU - Xu, Bin AU - Xu B AD - Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, People's Republic of China. AD - Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, 213003, People's Republic of China. AD - Institute of Cell Therapy, Soochow University, Changzhou, 213003, People's Republic of China. FAU - Wu, Chen AU - Wu C AD - Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, 213003, People's Republic of China. AD - Institute of Cell Therapy, Soochow University, Changzhou, 213003, People's Republic of China. AD - Department of Oncology, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, People's Republic of China. FAU - Zhou, Qi AU - Zhou Q AD - Department of Oncology, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, People's Republic of China. FAU - Hu, Wenwei AU - Hu W AD - Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, People's Republic of China. AD - Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, 213003, People's Republic of China. AD - Department of Oncology, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, People's Republic of China. FAU - Wu, Changping AU - Wu C AD - Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, People's Republic of China. AD - Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, 213003, People's Republic of China. AD - Department of Oncology, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, People's Republic of China. FAU - Jiang, Jingting AU - Jiang J AD - Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, People's Republic of China. jiangjingting@suda.edu.cn. AD - Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, 213003, People's Republic of China. jiangjingting@suda.edu.cn. AD - Institute of Cell Therapy, Soochow University, Changzhou, 213003, People's Republic of China. jiangjingting@suda.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190329 PL - England TA - Mol Cancer JT - Molecular cancer JID - 101147698 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Biomarkers, Tumor) RN - 0 (Phosphoproteins) RN - 0 (RNA, Circular) RN - 0 (Transcription Factors) RN - 0 (YAP-Signaling Proteins) RN - 0 (YAP1 protein, human) RN - 63231-63-0 (RNA) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 3.1.3.53 (Myosin-Light-Chain Phosphatase) RN - EC 3.1.3.53 (PPP1R12A protein, human) EIN - Mol Cancer. 2021 Feb 25;20(1):42. PMID: 33632217 MH - Adaptor Proteins, Signal Transducing/genetics/*metabolism MH - Animals MH - Apoptosis MH - Biomarkers, Tumor/genetics/metabolism MH - Case-Control Studies MH - Cell Cycle MH - Cell Proliferation MH - Colonic Neoplasms/genetics/metabolism/*pathology MH - Female MH - Follow-Up Studies MH - *Gene Expression Regulation, Neoplastic MH - Hippo Signaling Pathway MH - Humans MH - Liver Neoplasms/genetics/metabolism/*secondary MH - Male MH - Mice MH - Mice, Nude MH - Middle Aged MH - Myosin-Light-Chain Phosphatase/*genetics MH - Neoplasm Invasiveness MH - Phosphoproteins/genetics/*metabolism MH - Prognosis MH - Protein Serine-Threonine Kinases/genetics/*metabolism MH - RNA/*genetics MH - RNA, Circular MH - *Signal Transduction MH - Survival Rate MH - Transcription Factors MH - Tumor Cells, Cultured MH - Xenograft Model Antitumor Assays MH - YAP-Signaling Proteins PMC - PMC6440158 OTO - NOTNLM OT - Circular RNA (circRNA) OT - Colon cancer OT - Metastasis OT - Proliferation OT - Protein coding COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Written informed consent for the biological studies was obtained from each patient involved in the study, and the study was approved by the Ethics Committee of the Third Affiliated Hospital of Soochow University. All animal studies were approved by the Animal Experimental Committee of the Third Affiliated Hospital of Soochow University. CONSENT FOR PUBLICATION: Written consents for publication were obtained from all the patients involved in our study. COMPETING INTERESTS: The authors declare no conflict of interest. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2019/03/31 06:00 MHDA- 2019/08/02 06:00 PMCR- 2019/03/29 CRDT- 2019/03/31 06:00 PHST- 2018/08/31 00:00 [received] PHST- 2019/03/25 00:00 [accepted] PHST- 2019/03/31 06:00 [entrez] PHST- 2019/03/31 06:00 [pubmed] PHST- 2019/08/02 06:00 [medline] PHST- 2019/03/29 00:00 [pmc-release] AID - 10.1186/s12943-019-1010-6 [pii] AID - 1010 [pii] AID - 10.1186/s12943-019-1010-6 [doi] PST - epublish SO - Mol Cancer. 2019 Mar 29;18(1):47. doi: 10.1186/s12943-019-1010-6.