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2041-48891312022Jan13Cell death & diseaseCell Death DisExosomal circRELL1 serves as a miR-637 sponge to modulate gastric cancer progression via regulating autophagy activation.56565610.1038/s41419-021-04364-6Circular RNAs (circRNAs) play a vital role in the occurrence and development of tumors, including gastric cancer (GC). However, there are still many circRNAs related to GC whose functions and molecular mechanisms remain undetermined. Herein, we discover circRNA RELL1, which has not been investigated in GC, and it is markedly downregulated in GC tissues, which is related with poor prognosis, more pronounced lymph node metastasis and poor TNM stage. After confirming the circular structure of circRELL1, we found that circRELL1 could block cell proliferation, invasion, migration, and anti-apoptosis in patients with GC by a series of in vivo and in vitro function-related studies. Further mechanism investigation demonstrated that circRELL1 could sponge miR-637 and indirectly unregulated the expression of EPHB3 via modulating autophagy activation in GC. Additionally, circRELL1 can be transmitted by exosomal communication, and exosomal circRELL1 suppressed the malignant behavior of GC in vivo and in vitro. Taken together, this study elucidates the suppressive roles of circRELL1/miR-637/EPHB3 axis through autophagy activation in GC progression, inspiring for further understanding of the underlying molecular mechanisms of GC and providing a promising novel diagnostic circulating biomarker and therapeutic target in GC.© 2021. The Author(s).SangHuaimingH0000-0002-1668-6233Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.ZhangWeifengW0000-0003-2625-5207Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.PengLeiL0000-0002-1206-2327Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.WeiShuchunSDepartment of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China.Key Laboratory of Hubei Province for Digestive System Disease, Wuhan, Hubei Province, 430060, China.ZhuXudongX0000-0003-4966-1857Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.HuangKetingK0000-0002-5073-5983Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.YangJiajiaJDepartment of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.ChenMeihongMDepartment of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.DangYiniY0000-0002-1006-2155Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China. yeani_hi@126.com.ZhangGuoxinG0000-0002-7531-0404Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China. guoxinz@njmu.edu.cn.engJournal ArticleResearch Support, Non-U.S. Gov't20220113
EnglandCell Death Dis1015240920MIRN637 microRNA, human0MicroRNAs0RNA, CircularIMAutophagygeneticsCell Line, TumorCell ProliferationgeneticsGene Expression Regulation, NeoplasticHumansMicroRNAsgeneticsmetabolismRNA, CirculargeneticsStomach NeoplasmspathologyThe authors declare no competing interests.20215102021102020219272022114549202211560202249602022113epublish35027539PMC875873610.1038/s41419-021-04364-610.1038/s41419-021-04364-6Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424. doi: 10.3322/caac.21492.10.3322/caac.2149230207593Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–32.26808342Sitarz R, Skierucha M, Mielko J, Offerhaus GJA, Maciejewski R, Polkowski WP. Gastric cancer: epidemiology, prevention, classification, and treatment. Cancer Manag Res. 2018;10:239–48.PMC580870929445300Tan P, Yeoh KG. Genetics and molecular pathogenesis of gastric adenocarcinoma. Gastroenterology. 2015;149:1153–62..26073375Chen X, Chen Z, Yu S, Nie F, Yan S, Ma P, et al. Long noncoding RNA LINC01234 functions as a competing endogenous RNA to regulate CBFB expression by sponging miR-204-5p in gastric cancer. Clin Cancer Res. 2018;24:2002–14.29386218Hu ZQ, Zhou SL, Li J, Zhou ZJ, Wang PC, Xin HY, et al. Circular RNA sequencing identifies CircASAP1 as a key regulator in hepatocellular carcinoma metastasis. Hepatology. 2020;72:906–22.31838741Huang S, Li X, Zheng H, Si X, Li B, Wei G, et al. Loss of super-enhancer-regulated circRNA Nfix induces cardiac regeneration after myocardial infarction in adult mice. Circulation. 2019;139:2857–76.PMC662917630947518Yang F, Fang E, Mei H, Chen Y, Li H, Li D, et al. Cis-acting circ-CTNNB1 promotes beta-catenin signaling and cancer progression via DDX3-mediated transactivation of YY1. Cancer Res. 2019;79:557–71.30563889Huang Q, Zhou B, Cai D, Zong Y, Wu Y, Liu S, et al. Rapid turnover of HBV cccDNA indicated by monitoring emergence and reversion of signature-mutation in treated chronic hepatitis B patients. Hepatology. 2021;73:41–52.PMC789870432189364Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, et al. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495:384–8.23446346Pan Z, Cai J, Lin J, Zhou H, Peng J, Liang J, et al. A novel protein encoded by circFNDC3B inhibits tumor progression and EMT through regulating Snail in colon cancer. Mol Cancer. 2020;19:71.PMC711481332241279Conn SJ, Pillman KA, Toubia J, Conn VM, Salmanidis M, Phillips CA, et al. The RNA binding protein quaking regulates formation of circRNAs. Cell. 2015;160:1125–34.25768908Chen L, Kong R, Wu C, Wang S, Liu Z, Liu S, et al. Circ-MALAT1 functions as both an mRNA translation brake and a microRNA sponge to promote self-renewal of hepatocellular cancer stem cells. Adv Sci. 2020;7:1900949.PMC702964932099751Sun YM, Wang WT, Zeng ZC, Chen TQ, Han C, Pan Q, et al. circMYBL2, a circRNA from MYBL2, regulates FLT3 translation by recruiting PTBP1 to promote FLT3-ITD AML progression. Blood. 2019;134:1533–46.PMC683995331387917Cheng Z, Yu C, Cui S, Wang H, Jin H, Wang C, et al. circTP63 functions as a ceRNA to promote lung squamous cell carcinoma progression by upregulating FOXM1. Nat Commun. 2019;10:3200.PMC664217431324812Sang Y, Chen B, Song X, Li Y, Liang Y, Han D, et al. circRNA_0025202 regulates tamoxifen sensitivity and tumor progression via regulating the miR-182-5p/FOXO3a axis in breast cancer. Mol Ther. 2019;27:1638–52.PMC673117431153828Bell ES, Coelho PP, Park M. LC3C mediates selective autophagy of the MET RTK, inhibiting cancer cell invasion. Autophagy. 2020;16:959–61.PMC714486432065021Guo J, Chen M, Ai G, Mao W, Li H, Zhou J. Hsa_circ_0023404 enhances cervical cancer metastasis and chemoresistance through VEGFA and autophagy signaling by sponging miR-5047. Biomed. Pharmacother. 2019;115:108957.31082770Pegtel DM, Gould SJ. Exosomes. Annu Rev Biochem. 2019;88:487–514.31220978Wortzel I, Dror S, Kenific CM, Lyden D. Exosome-mediated metastasis: communication from a distance. Dev. Cell. 2019;49:347–60.31063754Wu G, Zhou W, Pan X, Sun Z, Sun Y, Xu H, et al. Circular RNA profiling reveals exosomal circ_0006156 as a novel biomarker in papillary thyroid cancer. Mol Ther Nucleic Acids. 2020;19:1134–44.PMC701602732059339Wang X, Zhang H, Yang H, Bai M, Ning T, Deng T, et al. Exosome-delivered circRNA promotes glycolysis to induce chemoresistance through the miR-122-PKM2 axis in colorectal cancer. Mol Oncol. 2020;14:539–55.PMC705323831901148Chen W, Quan Y, Fan S, Wang H, Liang J, Huang L, et al. Exosome-transmitted circular RNA hsa_circ_0051443 suppresses hepatocellular carcinoma progression. Cancer Lett. 2020;475:119–28.32014458Li S, Li Y, Chen B, Zhao J, Yu S, Tang Y, et al. exoRBase: a database of circRNA, lncRNA and mRNA in human blood exosomes. Nucleic Acids Res. 2018;46:D106–D12.PMC575335730053265Han D, Li J, Wang H, Su X, Hou J, Gu Y, et al. Circular RNA circMTO1 acts as the sponge of microRNA-9 to suppress hepatocellular carcinoma progression. Hepatology. 2017;66:1151–64.28520103Zheng R, Du M, Wang X, Xu W, Liang J, Wang W, et al. Exosome-transmitted long non-coding RNA PTENP1 suppresses bladder cancer progression. Mol Cancer. 2018;17:143.PMC616907630285771Yan B, Zhang Y, Liang C, Liu B, Ding F, Wang Y, et al. Stem cell-derived exosomes prevent pyroptosis and repair ischemic muscle injury through a novel exosome/circHIPK3/ FOXO3a pathway. Theranostics. 2020;10:6728–42.PMC729504932550900Li W, Zhang L, Guo B, Deng J, Wu S, Li F, et al. Exosomal FMR1-AS1 facilitates maintaining cancer stem-like cell dynamic equilibrium via TLR7/NFkappaB/c-Myc signaling in female esophageal carcinoma. Mol Cancer. 2019;18:22.PMC636780930736860White E, Mehnert JM, Chan CS. Autophagy, metabolism, and cancer. Clin Cancer Res. 2015;21:5037–46.PMC464672826567363Wu Q, Ma J, Wei J, Meng W, Wang Y, Shi M. lncRNA SNHG11 promotes gastric cancer progression by activating the Wnt/beta-catenin pathway and oncogenic autophagy. Mol Ther. 2021;29:1258–78.PMC793445533068778Zhou RM, Shi LJ, Shan K, Sun YN, Wang SS, Zhang SJ, et al. Circular RNA-ZBTB44 regulates the development of choroidal neovascularization. Theranostics. 2020;10:3293–307.PMC705320832194869Liu F, Zhang H, Xie F, Tao D, Xiao X, Huang C, et al. Hsa_circ_0001361 promotes bladder cancer invasion and metastasis through miR-491-5p/MMP9 axis. Oncogene. 2020;39:1696–709.31705065Zhang X, Chu H, Wen L, Shuai H, Yang D, Wang Y, et al. Competing endogenous RNA network profiling reveals novel host dependency factors required for MERS-CoV propagation. Emerg Microbes Infect. 2020;9:733–46.PMC717035232223537Zhu KP, Zhang CL, Ma XL, Hu JP, Cai T, Zhang L. Analyzing the interactions of mRNAs and ncRNAs to predict competing endogenous RNA networks in osteosarcoma chemo-resistance. Mol Ther. 2019;27:518–30.PMC640119330692017Park SH, Jo MJ, Kim BR, Jeong YA, Na YJ, Kim JL, et al. Sonic hedgehog pathway activation is associated with cetuximab resistance and EPHB3 receptor induction in colorectal cancer. Theranostics. 2019;9:2235–51.PMC653130431149041Xu TP, Wang WY, Ma P, Shuai Y, Zhao K, Wang YF, et al. Upregulation of the long noncoding RNA FOXD2-AS1 promotes carcinogenesis by epigenetically silencing EphB3 through EZH2 and LSD1, and predicts poor prognosis in gastric cancer. Oncogene. 2018;37:5020–36.29789713Lee SY, Na YJ, Jeong YA, Kim JL, Oh SC, Lee DH. Upregulation of EphB3 in gastric cancer with acquired resistance to a FGFR inhibitor. Int J Biochem Cell Biol. 2018;102:128–37.30044964Blessing AM, Rajapakshe K, Reddy Bollu L, Shi Y, White MA, Pham AH, et al. Transcriptional regulation of core autophagy and lysosomal genes by the androgen receptor promotes prostate cancer progression. Autophagy. 2017;13:506–21.PMC536160927977328Xu Z, Li Z, Wang W, Xia Y, He Z, Li B, et al. MIR-1265 regulates cellular proliferation and apoptosis by targeting calcium binding protein 39 in gastric cancer and, thereby, impairing oncogenic autophagy. Cancer Lett. 2019;449:226–36.30779944Zhang Z, Zhu H, Hu J. CircRAB11FIP1 promoted autophagy flux of ovarian cancer through DSC1 and miR-129. Cell Death Dis. 2021;12:219.PMC791044933637694Du WW, Yang W, Li X, Awan FM, Yang Z, Fang L, et al. A circular RNA circ-DNMT1 enhances breast cancer progression by activating autophagy. Oncogene. 2018;37:5829–42.29973691Chen X, Mao R, Su W, Yang X, Geng Q, Guo C, et al. Circular RNA circHIPK3 modulates autophagy via MIR124-3p-STAT3-PRKAA/AMPKalpha signaling in STK11 mutant lung cancer. Autophagy. 2020;16:659–71.PMC713822131232177Ma L, Wang Z, Xie M, Quan Y, Zhu W, Yang F, et al. Silencing of circRACGAP1 sensitizes gastric cancer cells to apatinib via modulating autophagy by targeting miR-3657 and ATG7. Cell Death Dis. 2020;11:169.PMC705807332139670Zhang H, Cui Z, Cheng D, Du Y, Guo X, Gao R, et al. RNF186 regulates EFNB1 (ephrin B1)-EPHB2-induced autophagy in the colonic epithelial cells for the maintenance of intestinal homeostasis. Autophagy. 2020;17:1–18.PMC852592433280498Thery C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2006;Chapter 3:22.18228490Luo H, Chen Z, Wang S, Zhang R, Qiu W, Zhao L, et al. c-Myc-miR-29c-REV3L signalling pathway drives the acquisition of temozolomide resistance in glioblastoma. Brain. 2015;138:3654–72.26450587Wang S, Zhang X, Li Z, Wang W, Li B, Huang X, et al. Circular RNA profile identifies circOSBPL10 as an oncogenic factor and prognostic marker in gastric cancer. Oncogene. 2019;38:6985–7001.31409903Bartfeld S, Bayram T, van de Wetering M, Huch M, Begthel H, Kujala P, et al. In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection. Gastroenterology. 2015;148:126–36.PMC427419925307862