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Knockdown circZNF131 Inhibits Cell Progression and Glycolysis in Gastric Cancer Through miR-186-5p/PFKFB2 Axis

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Abstract

Gastric cancer (GC) is a prevalent and heterogeneous malignancy in the digestive system. Increasing studies have suggested that circular RNAs are implicated in GC pathogenesis. This study aimed to explore the biological role and underlying mechanism of circRNA zinc finger protein 131 (circZNF131) in GC. The expression pattern of circZNF131, microRNA-186-5p (miR-186-5p), and 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 2 (PFKFB2) mRNA in GC tissues and cells was detected by quantitative real-time polymerase chain reaction. The stability of circZNF131 was verified using ribonuclease R assay. Functional experiments were performed by colony formation assay for cloning ability analysis, transwell assay and wounding healing assay for cell metastasis, and flow cytometry for cell apoptosis. Glycolysis metabolism was investigated by determining the levels of glucose uptake and lactate production. The protein detection of apoptosis- or glycolysis-associated markers, PFKFB2, and Ki-67 was implemented by western blot or immunohistochemistry. Dual-luciferase reporter assay was conducted to identify the interaction between miR-186-5p and circZNF131 or PFKFB2. The role of circZNF131 on tumor growth in nude mice was investigated via xenograft tumor assay. Expression analysis indicated that circZNF131 was upregulated in GC tissues and cells in a stable structure. Functional analyses showed that circZNF131 knockdown suppressed GC cell colony formation ability, migration, invasion and glycolysis metabolism, and induced cell apoptosis. Mechanically, miR-186-5p was a target of circZNF131, and miR-186-5p could bind to PFKFB2. Rescue experiments presented that miR-186-5p inhibition reversed the effects of circZNF131 knockdown on GC cell growth and glycolysis, and PFKFB2 overexpression abolished the impacts of miR-186-5p restoration on GC cell progression. Moreover, circZNF131 could positively modulate PFKFB2 expression via sponging miR-186-5p. In vivo, circZNF131 knockdown hindered GC tumor growth by regulating the miR-186-5p/PFKFB2 axis. circZNF131 could exert an oncogenic role in GC malignant development through the miR-186-5p/PFKFB2 axis, which might provide novel targets for GC treatment.

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References

  • Akram M (2013) Mini-review on glycolysis and cancer. J Cancer Educ 28:454–457

    Article  CAS  PubMed  Google Scholar 

  • Azarbarzin S, Safaralizadeh R, Khojasteh MB, Baghbanzadeh A, Baradaran B (2020) Current perspectives on the dysregulated microRNAs in gastric cancer. Mol Biol Rep 47:7253–7264

    Article  CAS  PubMed  Google Scholar 

  • Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    Article  CAS  PubMed  Google Scholar 

  • Bolha L, Ravnik-Glavac M, Glavac D (2017) Circular RNAs: biogenesis, function, and a role as possible cancer biomarkers. Int J Genom 2017:6218353

    Google Scholar 

  • Cui N, Liu J, Xia H, Xu D (2019) LncRNA SNHG20 contributes to cell proliferation and invasion by upregulating ZFX expression sponging miR-495-3p in gastric cancer. J Cell Biochem 120:3114–3123

    Article  CAS  PubMed  Google Scholar 

  • Eun JW, Kim HS, Shen Q, Yang HD, Kim SY, Yoon JH, Park WS, Lee JY, Nam SW (2018) MicroRNA-495-3p functions as a tumor suppressor by regulating multiple epigenetic modifiers in gastric carcinogenesis. J Pathol 244:107–119

    Article  CAS  PubMed  Google Scholar 

  • Fang X, Wen J, Sun M, Yuan Y, Xu Q (2019) CircRNAs and its relationship with gastric cancer. J Cancer 10:6105–6113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Farazi TA, Hoell JI, Morozov P, Tuschl T (2013) MicroRNAs in human cancer. Adv Exp Med Biol 774:1–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ganapathy-Kanniappan S, Geschwind JF (2013) Tumor glycolysis as a target for cancer therapy: progress and prospects. Mol Cancer 12:152

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Han B, Chao J, Yao H (2018) Circular RNA and its mechanisms in disease: from the bench to the clinic. Pharmacol Ther 187:31–44

    Article  CAS  PubMed  Google Scholar 

  • Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J (2013) Natural RNA circles function as efficient microRNA sponges. Nature 495:384–388

    Article  CAS  PubMed  Google Scholar 

  • Hayes J, Peruzzi PP, Lawler S (2014) MicroRNAs in cancer: biomarkers, functions and therapy. Trends Mol Med 20:460–469

    Article  CAS  PubMed  Google Scholar 

  • Hsiao KY, Sun HS, Tsai SJ (2017) Circular RNA—new member of noncoding RNA with novel functions. Exp Biol Med 242:1136–1141

    Article  CAS  Google Scholar 

  • Huang GM, Zang HL, Geng YX, Li YH (2020) LncRNA FAM83A-AS1 aggravates the malignant development of esophageal cancer by binding to miR-495-3p. Eur Rev Med Pharmacol, Sci 24:9408–9415

    Google Scholar 

  • Hui C, Tian L, He X (2020) Circular RNA circNHSL1 contributes to gastric cancer progression through the miR-149-5p/YWHAZ axis. Cancer Manag Res 12:7117–7130

    Article  PubMed  PubMed Central  Google Scholar 

  • Ishiguro H, Kimura M, Takeyama H (2014) Role of microRNAs in gastric cancer. World J Gastroenterol 20:5694–5699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang C, Chen X, Alattar M, Wei J, Liu H (2015) MicroRNAs in tumorigenesis, metastasis, diagnosis and prognosis of gastric cancer. Cancer Gene Ther 22:291–301

    Article  CAS  PubMed  Google Scholar 

  • Li T, Shao Y, Fu L, Xie Y, Zhu L, Sun W, Yu R, Xiao B, Guo J (2018) Plasma circular RNA profiling of patients with gastric cancer and their droplet digital RT-PCR detection. J Mol Med 96:85–96

    Article  CAS  PubMed  Google Scholar 

  • Liu H, Chen K, Wang L, Zeng X, Huang Z, Li M, Dong P, Chen X (2019a) miR-613 inhibits Warburg effect in gastric cancer by targeting PFKFB2. Biochem Biophys Res Commun 515:37–43

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Song S, Lin S, Zhang M, Du Y, Zhang D, Xu W, Wang H (2019) Circ-SERPINE2 promotes the development of gastric carcinoma by sponging miR-375 and modulating YWHAZ. Cell Prolif 52:e12648

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu J, Liu H, Zeng Q, Xu P, Liu M, Yang N (2020a) Circular RNA circ-MAT2B facilitates glycolysis and growth of gastric cancer through regulating the miR-515-5p/HIF-1alpha axis. Cancer Cell Int 20:171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Y, Jiang Y, Xu L, Qu C, Zhang L, Xiao X, Chen W, Li K, Liang Q, Wu H (2020b) circ-NRIP1 promotes glycolysis and tumor progression by regulating miR-186-5p/MYH9 axis in gastric cancer. Cancer Manag Res 12:5945–5956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma Y, Zhang D, Wu H, Li P, Zhao W, Yang X, Xing X, Li S, Li J (2020) Circular RNA PRKCI silencing represses esophageal cancer progression and elevates cell radiosensitivity through regulating the miR-186-5p/PARP9 axis. Life Sci 259:118168

    Article  CAS  PubMed  Google Scholar 

  • Ning Y, Bai Z (2020) DSCAM-AS1 accelerates cell proliferation and migration in osteosarcoma through miR-186-5p/GPRC5A signaling. Cancer Biomark 30:29–39

    Article  CAS  Google Scholar 

  • Niu Q, Dong Z, Liang M, Luo Y, Lin H, Lin M, Zhong X, Yao W, Weng J, Zhou X (2020) Circular RNA hsa_circ_0001829 promotes gastric cancer progression through miR-155-5p/SMAD2 axis. J Exp Clin Cancer Res 39:280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ouyang Y, Li Y, Huang Y, Li X, Zhu Y, Long Y, Wang Y, Guo X, Gong K (2019) CircRNA circPDSS1 promotes the gastric cancer progression by sponging miR-186-5p and modulating NEK2. J Cell Physiol 234:10458–10469

    Article  CAS  PubMed  Google Scholar 

  • Ouyang J, Long Z, Li G (2020) Circular RNAs in gastric cancer: potential biomarkers and therapeutic targets. Biomed Res Int 2020:2790679

    Article  PubMed  PubMed Central  Google Scholar 

  • Ozcan SC, Sarioglu A, Altunok TH, Akkoc A, Guzel S, Guler S, Imbert-Fernandez Y, Muchut RJ, Iglesias AA, Gurpinar Y, Clem AL, Chesney JA, Yalcin A (2020) PFKFB2 regulates glycolysis and proliferation in pancreatic cancer cells. Mol Cell Biochem 470:115–129

    Article  CAS  PubMed  Google Scholar 

  • Pan X, Li H, Tan J, Weng X, Zhou L, Weng Y, Cao X (2020) miR-1297 suppresses osteosarcoma proliferation and aerobic glycolysis by regulating PFKFB2. Onco Targets Ther 13:11265–11275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Panda AC (2018) Circular RNAs act as miRNA sponges. Adv Exp Med Biol 1087:67–79

    Article  CAS  PubMed  Google Scholar 

  • Qu S, Yang X, Li X, Wang J, Gao Y, Shang R, Sun W, Dou K, Li H (2015) Circular RNA: a new star of noncoding RNAs. Cancer Lett 365:141–148

    Article  CAS  PubMed  Google Scholar 

  • Qu J, Yang J, Chen M, Wei R, Tian J (2020) CircFLNA acts as a sponge of miR-646 to facilitate the proliferation, metastasis, glycolysis, and apoptosis inhibition of gastric cancer by targeting PFKFB2. Cancer Manag Res 12:8093–8103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F (2020) Gastric cancer. Lancet 396:635–648

    Article  CAS  PubMed  Google Scholar 

  • Tang J, Hu Y, Zhang C, Gong C (2021) miR-4636 inhibits tumor cell proliferation, migration and invasion, and serves as a candidate clinical biomarker for gastric cancer. Oncol Lett 21:33

    CAS  PubMed  Google Scholar 

  • Wang H, Sun G, Xu P, Lv J, Zhang X, Zhang L, Wang S, Cao J, Xia Y, Xuan Z, Li B, Huang X, Jiang T, Fang L, Xu Z (2020) Circular RNA TMEM87A promotes cell proliferation and metastasis of gastric cancer by elevating ULK1 via sponging miR-142-5p. J Gastroenterol 56:125–138

    Article  PubMed  CAS  Google Scholar 

  • Wei G, Zhu J, Hu HB, Liu JQ (2020) Circular RNAs: promising biomarkers for cancer diagnosis and prognosis. Gene 771:145365

    Article  PubMed  CAS  Google Scholar 

  • Yan C, Kong X, Gong S, Liu F, Zhao Y (2020) Recent advances of the regulation roles of MicroRNA in glioblastoma. Int J Clin Oncol 25:1215

    Article  PubMed  Google Scholar 

  • Yang G, Zhang Y, Yang J (2019) Identification of potentially functional CircRNA-miRNA-mRNA regulatory network in gastric carcinoma using bioinformatics analysis. Med Sci Monit 25:8777–8796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoon H, Kim N (2015) Diagnosis and management of high risk group for gastric cancer. Gut Liver 9:5–17

    Article  PubMed  PubMed Central  Google Scholar 

  • Yuan X, Yang T, Xu Y, Ou S, Shi P, Cao M, Zuo X, Liu Q, Yao J (2020) SNHG10 promotes cell proliferation and migration in gastric cancer by targeting miR-495-3p/CTNNB1 axis. Dig Dis Sci 66:2627–2636

    Article  PubMed  CAS  Google Scholar 

  • Zhang XY, Zhang PY (2017) Gastric cancer: somatic genetics as a guide to therapy. J Med Genet 54:305–312

    Article  CAS  PubMed  Google Scholar 

  • Zhao ZJ, Shen J (2017) Circular RNA participates in the carcinogenesis and the malignant behavior of cancer. RNA Biol 14:514–521

    Article  PubMed  Google Scholar 

  • Zhong Y, Du Y, Yang X, Mo Y, Fan C, Xiong F, Ren D, Ye X, Li C, Wang Y, Wei F, Guo C, Wu X, Li X, Li Y, Li G, Zeng Z, Xiong W (2018) Circular RNAs function as ceRNAs to regulate and control human cancer progression. Mol Cancer 17:79

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Gastroenterology, Jinan Central Hospital Affiliated to Shandong First Medical University, No.105 Jiefang Road, Lixia District, Jinan City, 250013, Shandong Province, China

    Xingjie Shen, Xiaoyan Zhu, Peixin Hu, Tingting Ji, Ying Qin & Jingyu Zhu

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  1. Xingjie Shen
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  2. Xiaoyan Zhu
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  3. Peixin Hu
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  4. Tingting Ji
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  5. Ying Qin
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Contributions

XS was responsible for drafting the manuscript. XS, XZ, and PH contributed to the analysis and interpretation of data. XS, TJ, YQ, and JZ contributed in the data collection. All authors read and approved the final manuscript.

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Correspondence to Xingjie Shen.

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10528_2021_10165_MOESM1_ESM.tif

Supplementary file1 Supplementary Figure 1. The expression of candidate miRNAs and genes in GC tissues. (A and B) The expression of candidate miRNAs (miR-186-5p, miR-448, miR-605-3p, miR-545-5p, and miR-4766-5p) and genes (PFKFB2, CASK, ERBB4, HMGA2, and FOXK1) in GC tissues and adjacent normal tissues was examined by qRT-PCR assay (TIF 184 kb)

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Shen, X., Zhu, X., Hu, P. et al. Knockdown circZNF131 Inhibits Cell Progression and Glycolysis in Gastric Cancer Through miR-186-5p/PFKFB2 Axis. Biochem Genet 60, 1567–1584 (2022). https://doi.org/10.1007/s10528-021-10165-5

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  • DOI: https://doi.org/10.1007/s10528-021-10165-5

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