Gastric cancer (GC) is one of the most common malignancies, leading to millions of deaths each year. Here, we investigated the molecular mechanisms of GC, with a focus on circXRCC5/miR-655-3p/RREB1/UBA2 axis. circXRCC5 was identified in 62 paired cancer specimens and adjacent normal tissues by genome-wide bioinformatics analysis and verified by qRT-PCR and Sanger sequencing. Knockdown or exogenous expression of circXRCC5 was performed to validate the functional significance of circXRCC5 using both in vitro and in vivo assays, including CCK-8, colony formation, EdU incorporation, transwell system, as well as animal experiments. RNA immunoprecipitation, biotinylated RNA pull-down, ChIP, and dual-luciferase assays were employed to validate the regulatory network of circXRCC5/miR-655-3p/RREB1/UBA2. Frequently elevated circXRCC5 in GC tissues and cell lines was associated with poor prognosis of GC patients. Functionally, circXRCC5 overexpression facilitated GC cell proliferation, migration, and invasion, as well as promoted tumor growth and metastasis in vivo. Mechanistically, circXRCC5 served as a sponge of miR-655-3p to induce upregulation of RREB1. RREB1 was identified as a transcriptional activator of UBA2, thus contributing to GC tumorigenesis. Moreover, RNA binding protein (RBP) HNRNPC was proved to interact with circXRCC5 to promote circXRCC5 biogenesis. Collectively, circXRCC5 facilitates GC progression through the HNRNPC/circXRCC5/miR-655-3p/RREB1/UBA2 axis, which might bring novel therapeutic strategies for GC treatment.
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Rawla P, Barsouk A. Epidemiology of gastric cancer: global trends, risk factors and prevention. Prz Gastroenterol. 2019;14:26–38.
Lyons K, Le LC, Pham YT, Borron C, Park JY, Tran CTD, et al. Gastric cancer: epidemiology, biology, and prevention: a mini review. Eur J Cancer Prev. 2019;28:397–412.
Machlowska J, Baj J, Sitarz M, Maciejewski R, Sitarz R. Gastric cancer: epidemiology, risk factors, classification, genomic characteristics and treatment strategies. Int J Mol Sci. 2020;21:4012.
Tan P, Yeoh KG. Genetics and molecular pathogenesis of gastric adenocarcinoma. Gastroenterology. 2015;149:1153–62 e3.
Barrett SP, Salzman J. Circular RNAs: analysis, expression and potential functions. Development. 2016;143:1838–47.
Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet. 2019;20:675–91.
Yu CY, Kuo HC. The emerging roles and functions of circular RNAs and their generation. J Biomed Sci. 2019;26:29.
Yang CM, Qiao GL, Song LN, Bao S, Ma LJ. Circular RNAs in gastric cancer: Biomarkers for early diagnosis. Oncol Lett. 2020;20:465–73.
Su M, Xiao Y, Ma J, Tang Y, Tian B, Zhang Y, et al. Circular RNAs in Cancer: emerging functions in hallmarks, stemness, resistance and roles as potential biomarkers. Mol Cancer. 2019;18:90.
Ma C, Wang X, Yang F, Zang Y, Liu J, Wang X, et al. Circular RNA hsa_circ_0004872 inhibits gastric cancer progression via the miR-224/Smad4/ADAR1 successive regulatory circuit. Mol Cancer. 2020;19:157.
Zhu Z, Rong Z, Luo Z, Yu Z, Zhang J, Qiu Z, et al. Circular RNA circNHSL1 promotes gastric cancer progression through the miR-1306-3p/SIX1/vimentin axis. Mol Cancer. 2019;18:126.
Rathmell WK, Chu G. Involvement of the Ku autoantigen in the cellular response to DNA double-strand breaks. Proc Natl Acad Sci USA. 1994;91:7623–7.
Gu Z, Li Y, Yang X, Yu M, Chen Z, Zhao C, et al. Overexpression of CLC-3 is regulated by XRCC5 and is a poor prognostic biomarker for gastric cancer. J Hematol Oncol. 2018;11:115. https://doi.org/10.1186/s13045-018-0660-y.
Zhang Z, Zheng F, Yu Z, Hao J, Chen M, Yu W, et al. XRCC5 cooperates with p300 to promote cyclooxygenase-2 expression and tumor growth in colon cancers. PLoS One. 2017;12:e0186900.
Gebert LFR, MacRae IJ. Regulation of microRNA function in animals. Nat Rev Mol Cell Biol. 2019;20:21–37.
Tan HL, Chiu SL, Zhu Q, Huganir RL. GRIP1 regulates synaptic plasticity and learning and memory. Proc Natl Acad Sci USA. 2020;117:25085–91.
Tan HL, Queenan BN, Huganir RL. GRIP1 is required for homeostatic regulation of AMPAR trafficking. Proc Natl Acad Sci USA. 2015;112:10026–31.
Deng YN, Xia Z, Zhang P, Ejaz S, Liang S. Transcription factor RREB1: from target genes towards biological functions. Int J Biol Sci. 2020;16:1463–73.
Wu Y, Zhao W, Liu Y, Tan X, Li X, Zou Q, et al. Function of HNRNPC in breast cancer cells by controlling the dsRNA-induced interferon response. EMBO J. 2018;37.e99017. https://doi.org/10.15252/embj.201899017.
Konig J, Zarnack K, Rot G, Curk T, Kayikci M, Zupan B, et al. iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nat Struct Mol Biol. 2010;17:909–15.
Orditura M, Galizia G, Sforza V, Gambardella V, Fabozzi A, Laterza MM, et al. Treatment of gastric cancer. World J Gastroenterol. 2014;20:1635–49.
Servetas SL, Bridge DR, Merrell DS. Molecular mechanisms of gastric cancer initiation and progression by Helicobacter pylori. Curr Opin Infect Dis. 2016;29:304–10.
Liu J, Zhang X, Yan M, Li H. Emerging role of circular RNAs in cancer. Front Oncol. 2020;10:663.
Peng Y, Wang HH. Cir-ITCH inhibits gastric cancer migration, invasion and proliferation by regulating the Wnt/beta-catenin pathway. Sci Rep. 2020;10:17443.
Zhang L, Song X, Chen X, Wang Q, Zheng X, Wu C, et al. Circular RNA CircCACTIN promotes gastric cancer progression by sponging MiR-331-3p and regulating TGFBR1 expression. Int J Biol Sci. 2019;15:1091–103.
Zha JF, Chen DX. MiR-655-3p inhibited proliferation and migration of ovarian cancer cells by targeting RAB1A. Eur Rev Med Pharm Sci. 2019;23:3627–34.
Zhao XQ, Liang B, Jiang K, Zhang HY. Down-regulation of miR-655-3p predicts worse clinical outcome in patients suffering from hepatocellular carcinoma. Eur Rev Med Pharm Sci. 2017;21:748–52.
Wang W, Cao R, Su W, Li Y, Yan H. miR-655-3p inhibits cell migration and invasion by targeting pituitary tumor-transforming 1 in non-small cell lung cancer. Biosci Biotechnol Biochem. 2019;83:1703–8.
Wu G, Zheng K, Xia S, Wang Y, Meng X, Qin X, et al. MicroRNA-655-3p functions as a tumor suppressor by regulating ADAM10 and beta-catenin pathway in Hepatocellular Carcinoma. J Exp Clin Cancer Res. 2016;35:89.
Nitz MD, Harding MA, Smith SC, Thomas S, Theodorescu D. RREB1 transcription factor splice variants in urologic cancer. Am J Pathol. 2011;179:477–86.
Hui B, Ji H, Xu Y, Wang J, Ma Z, Zhang C, et al. RREB1-induced upregulation of the lncRNA AGAP2-AS1 regulates the proliferation and migration of pancreatic cancer partly through suppressing ANKRD1 and ANGPTL4. Cell Death Dis. 2019;10:207.
Mukhopadhyay NK, Cinar B, Mukhopadhyay L, Lutchman M, Ferdinand AS, Kim J, et al. The zinc finger protein ras-responsive element binding protein-1 is a coregulator of the androgen receptor: implications for the role of the Ras pathway in enhancing androgenic signaling in prostate cancer. Mol Endocrinol. 2007;21:2056–70.
Rahrmann EP, Wolf NK, Otto GM, Heltemes-Harris L, Ramsey LB, Shu J, et al. Sleeping beauty screen identifies RREB1 and other genetic drivers in human B-cell lymphoma. Mol Cancer Res. 2019;17:567–82.
Jiang B, Fan X, Zhang D, Liu H, Fan C. Identifying UBA2 as a proliferation and cell cycle regulator in lung cancer A549 cells. J Cell Biochem. 2019;120:12752–61.
He P, Sun X, Cheng HJ, Zou YB, Wang Q, Zhou CL, et al. UBA2 promotes proliferation of colorectal cancer. Mol Med Rep. 2018;18:5552–62.
Li J, Sun X, He P, Liu WQ, Zou YB, Wang Q, et al. Ubiquitin-like modifier activating enzyme 2 promotes cell migration and invasion through Wnt/beta-catenin signaling in gastric cancer. World J Gastroenterol. 2018;24:4773–86.
Rodriguez MS, Desterro JM, Lain S, Midgley CA, Lane DP, Hay RT. SUMO-1 modification activates the transcriptional response of p53. EMBO J. 1999;18:6455–61.
Desterro JM, Rodriguez MS, Hay RT. SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation. Mol Cell. 1998;2:233–9.
This work was supported by Natural Science Foundation of Jilin Province (20200201458JC).
The authors declare no competing interests.
The protocol has been approved by the First Hospital of Jilin University. All patients have been informed of the study and consented with a written form. All animal experiments have been reviewed and received approval by the Animal Care and Use Committee of the First Hospital of Jilin University.
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Liu, ZL., Wang, SK., Pang, L. et al. circXRCC5 foster gastric cancer growth and metastasis by the HNRNPC/circXRCC5/miR-655-3p/RREB1/UBA2 positive feedback loop. Cancer Gene Ther (2022). https://doi.org/10.1038/s41417-022-00482-1