PMID- 37408008 OWN - NLM STAT- MEDLINE DCOM- 20230707 LR - 20230718 IS - 1476-4598 (Electronic) IS - 1476-4598 (Linking) VI - 22 IP - 1 DP - 2023 Jul 5 TI - A novel polypeptide CAPG-171aa encoded by circCAPG plays a critical role in triple-negative breast cancer. PG - 104 LID - 10.1186/s12943-023-01806-x [doi] LID - 104 AB - BACKGROUND: The treatment of Triple-negative breast cancer (TNBC) has always been challenging due to its heterogeneity and the absence of well-defined molecular targets. The present study aims to elucidate the role of protein-coding circRNAs in the etiology and carcinogenesis of TNBC. METHODS: CircRNA expression data in TNBC (GEO: GSE113230, GSE101123) were reanalyzed and then circCAPG was selected for further study. To identify the polypeptide-coding function of circCAPG, a series of experiments, such as Mass spectrometry and dual-luciferase reporter assays were conducted. Cell proliferation, apoptosis and metastasis parameters were determined to investigate the cancerous functions CAPG-171aa plays in both TNBC organoids and nude mice. Mechanistically, the relation between CAPG-171aa and STK38 in TNBC was verified by immunoprecipitation analyses and mass spectrometry. The interactions between SLU7 and its binding site on circCAPG were validated by RIP-qPCR experiments. RESULTS: In both TNBC clinical samples and cell lines, the expression level of circCAPG was identified to be higher compared with normal ones and positively correlated with the overall survival (n = 132) in a 10-year follow-up study, in which the area under the curve of receiver operating characteristic was 0.8723 with 100% specificity and 80% sensitivity. In addition, we found that circCAPG knockdown (KD) significantly inhibited the growth of TNBC organoids. Intriguingly, circCAPG can be translated into a polypeptide named CAPG-171aa which promotes tumor growh by disrupting the binding of serine/threonine kinase 38 (STK38) to SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) and thereby preventing MEKK2 ubiquitination and proteasomal degradation. Furthermore, we found that SLU7 Homolog- Splicing Factor (SLU7) can regulate the bio-generation of circCAPG through binding to the flanking Alu sequences of circRNA transcripts. CONCLUSIONS: circCAPG significantly enhances the proliferation and metastasis of TNBC cells by encoding a novel polypeptide CAPG-171aa and afterwards activates MEKK2-MEK1/2-ERK1/2 pathway. Additionally, the formation of circCAPG is found to be mediated by SLU7. The present study provides innovative insight into the role of protein-coding circRNAs CAPG-171aa in TNBC, and its capacity to serve as a promising prognostic biomarker and potential therapeutic target in TNBC. CI - (c) 2023. The Author(s). FAU - Song, Runjie AU - Song R AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China. FAU - Guo, Peilan AU - Guo P AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China. FAU - Ren, Xin AU - Ren X AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China. FAU - Zhou, Lijun AU - Zhou L AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China. FAU - Li, Peng AU - Li P AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China. FAU - Rahman, Nafis A AU - Rahman NA AD - Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland. AD - Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, Poland. FAU - Wolczynski, Slawomir AU - Wolczynski S AD - Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, Poland. FAU - Li, Xiru AU - Li X AD - Department of General Surgery, Chinese PLA General Hospital, Beijing, 100071, China. FAU - Zhang, Yanjun AU - Zhang Y AD - Department of General Surgery, Chinese PLA General Hospital, Beijing, 100071, China. FAU - Liu, Mei AU - Liu M AD - Department of Pathology, Chinese PLA General Hospital, Beijing, 100071, China. FAU - Liu, Jiali AU - Liu J AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China. FAU - Li, Xiangdong AU - Li X AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China. xiangdongli68@126.com. AD - Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, Poland. xiangdongli68@126.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230705 PL - England TA - Mol Cancer JT - Molecular cancer JID - 101147698 RN - 0 (MicroRNAs) RN - 0 (RNA, Circular) RN - 0 (Peptides) RN - 0 (SLU7 protein, human) RN - 0 (RNA Splicing Factors) RN - 148412-71-9 (CAPG protein, human) RN - 0 (Microfilament Proteins) RN - 0 (Nuclear Proteins) RN - EC 2.7.11.1 (STK38 protein, human) RN - EC 2.3.2.26 (SMURF1 protein, human) RN - 0 (SLU7 protein, mouse) SB - IM MH - Humans MH - Animals MH - Mice MH - *MicroRNAs/genetics MH - RNA, Circular/genetics MH - *Triple Negative Breast Neoplasms/pathology MH - Mice, Nude MH - Follow-Up Studies MH - Cell Proliferation/genetics MH - Peptides/genetics MH - Cell Line, Tumor MH - Gene Expression Regulation, Neoplastic MH - Cell Movement/genetics MH - RNA Splicing Factors/genetics MH - Microfilament Proteins/genetics MH - Nuclear Proteins/genetics PMC - PMC10320902 OTO - NOTNLM OT - CAPG-171aa OT - CircCAPG OT - MEKK2 OT - SLU7 OT - STK38 OT - TNBC OT - Therapeutic target COIS- All authors declare that they have no competing interests. EDAT- 2023/07/06 01:08 MHDA- 2023/07/07 06:42 PMCR- 2023/07/05 CRDT- 2023/07/05 23:44 PHST- 2023/01/30 00:00 [received] PHST- 2023/06/11 00:00 [accepted] PHST- 2023/07/07 06:42 [medline] PHST- 2023/07/06 01:08 [pubmed] PHST- 2023/07/05 23:44 [entrez] PHST- 2023/07/05 00:00 [pmc-release] AID - 10.1186/s12943-023-01806-x [pii] AID - 1806 [pii] AID - 10.1186/s12943-023-01806-x [doi] PST - epublish SO - Mol Cancer. 2023 Jul 5;22(1):104. doi: 10.1186/s12943-023-01806-x.