miR‑99a‑5p inhibits glycolysis and induces cell apoptosis in cervical cancer by targeting RRAGD

Wang,Gang; Lu,Yu; Di,Shi; Xie,Maohua; Jing,Fang; Dai,Xiaoyan

doi:10.3892/ol.2022.13349

miR‑99a‑5p inhibits glycolysis and induces cell apoptosis in cervical cancer by targeting RRAGD

Authors:
- Gang Wang
- Yu Lu
- Shi Di
- Maohua Xie
- Fang Jing
- Xiaoyan Dai
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Affiliations: Department of Gynecology, Wuhan Third Hospital (Tongren Hospital of Wuhan University), Wuhan, Hubei 430061, P.R. China, Department of Vasculocardiology, Wuhan Wuchang Hospital, Wuhan, Hubei 430061, P.R. China, Department of Obstetrics, Wuhan Third Hospital (Tongren Hospital of Wuhan University), Wuhan, Hubei 430061, P.R. China
Published online on: May 27, 2022 https://doi.org/10.3892/ol.2022.13349
Article Number: 228
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Cervical cancer (CC) is one of the most common gynecological malignancies that endangers women's health. A negative effect of glycolysis is that it contributes to abnormal tumor growth. MicroRNA (miR)‑99a expression has been found to be decreased in CC. The present study aimed to investigate the role of miR‑99a‑5p in glycolysis in CC. For this purpose, the association between miR‑99a and the prognosis of patients with CC from The Cancer Genome Atlas database was analyzed using Kaplan‑Meier analysis. miR‑99a‑5p expression and Ras‑related GTP binding D (RRAGD) expression were assessed using reverse transcription‑quantitative PCR and western blot analysis. Cell proliferation and apoptosis were examined using an MTT assay and flow cytometry, respectively. Glucose uptake, lactate concentration and extracellular acidification rate were measured using a glucose uptake colorimetric assay, a lactate colorimetric assay and a Seahorse XFe96 extracellular flux analyzer, respectively. The association between miR‑99a‑5p and RRAGD was predicted using TargetScan 7.1, and was confirmed using dual luciferase reporter assay. The results revealed that miR‑99a‑5p expression was decreased and that of RRAGD was increased in CC tissues and cell lines. RRAGD was negatively regulated by miR‑99a‑5p. The overexpression of miR‑99a‑5p induced apoptosis and inhibited glycolysis in CC cells by targeting RRAGD. On the whole, the present study revealed a novel mechanism through which miR‑99a‑5p regulates cell apoptosis and glycolysis in CC, thus providing a potential therapeutic target for CC.

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1	Cohen PA, Jhingran A, Oaknin A and Denny L: Cervical cancer. Lancet. 393:169–182. 2019. View Article : Google Scholar : PubMed/NCBI
2	Torre LA, Siegel RL, Ward EM and Jemal A: Global cancer incidence and mortality rates and trends-an update. Cancer Epidemiol Biomarkers Prev. 25:16–27. 2016. View Article : Google Scholar : PubMed/NCBI
3	Lunt SY and Vander Heiden MG: Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol. 27:441–464. 2011. View Article : Google Scholar : PubMed/NCBI
4	Schwartz L, Supuran CT and Alfarouk KO: The Warburg effect and the Hallmarks of cancer. Anticancer Agents Med Chem. 17:164–170. 2017. View Article : Google Scholar : PubMed/NCBI
5	Vander Heiden MG, Cantley LC and Thompson CB: Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 324:1029–1033. 2009. View Article : Google Scholar : PubMed/NCBI
6	Ganapathy-Kanniappan S and Geschwind JF: Tumor glycolysis as a target for cancer therapy: Progress and prospects. Mol Cancer. 12:1522013. View Article : Google Scholar : PubMed/NCBI
7	Li Z, Peng Y, Li J, Chen Z, Chen F, Tu J, Lin S and Wang H: N⁶-methyladenosine regulates glycolysis of cancer cells through PDK4. Nat Commun. 11:25782020. View Article : Google Scholar : PubMed/NCBI
8	Kroemer G and Pouyssegur J: Tumor cell metabolism: Cancer's Achilles' heel. Cancer Cell. 13:472–482. 2008. View Article : Google Scholar : PubMed/NCBI
9	DeBerardinis RJ, Lum JJ, Hatzivassiliou G and Thompson CB: The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 7:11–20. 2008. View Article : Google Scholar : PubMed/NCBI
10	Krol J, Loedige I and Filipowicz W: The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 11:597–610. 2010. View Article : Google Scholar : PubMed/NCBI
11	Bushati N and Cohen SM: MicroRNA functions. Annu Rev Cell Dev Biol. 23:175–205. 2007. View Article : Google Scholar : PubMed/NCBI
12	Iorio MV and Croce CM: MicroRNA dysregulation in cancer: Diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med. 4:143–159. 2012. View Article : Google Scholar : PubMed/NCBI
13	Rupaimoole R and Slack FJ: MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 16:203–222. 2017. View Article : Google Scholar : PubMed/NCBI
14	Sadri Nahand J, Moghoofei M, Salmaninejad A, Bahmanpour Z, Karimzadeh M, Nasiri M, Mirzaei HR, Pourhanifeh MH, Bokharaei-Salim F, Mirzaei H and Hamblin MR: Pathogenic role of exosomes and microRNAs in HPV-mediated inflammation and cervical cancer: A review. Int J Cancer. 146:305–320. 2020. View Article : Google Scholar : PubMed/NCBI
15	Pardini B, De Maria D, Francavilla A, Di Gaetano C, Ronco G and Naccarati A: MicroRNAs as markers of progression in cervical cancer: A systematic review. BMC Cancer. 18:6962018. View Article : Google Scholar : PubMed/NCBI
16	Gao C, Zhou C, Zhuang J, Liu L, Liu C, Li H, Liu G, Wei J and Sun C: MicroRNA expression in cervical cancer: Novel diagnostic and prognostic biomarkers. J Cell Biochem. 119:7080–7090. 2018. View Article : Google Scholar : PubMed/NCBI
17	Sun D, Han L, Cao R, Wang H, Jiang J, Deng Y and Yu X: Prediction of a miRNA-mRNA functional synergistic network for cervical squamous cell carcinoma. FEBS Open Bio. 9:2080–2092. 2019. View Article : Google Scholar : PubMed/NCBI
18	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
19	Di Malta C, Siciliano D, Calcagni A, Monfregola J, Punzi S, Pastore N, Eastes AN, Davis O, De Cegli R, Zampelli A, et al: Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth. Science. 356:1188–1192. 2017. View Article : Google Scholar : PubMed/NCBI
20	Wang L, Chang L, Li Z, Gao Q, Cai D, Tian Y, Zeng L and Li M: MiR-99a and −99b inhibit cervical cancer cell proliferation and invasion by targeting mTOR signaling pathway. Med Oncol. 31:9342014. View Article : Google Scholar : PubMed/NCBI
21	Ribas V, García-Ruiz C and Fernández-Checa JC: Mitochondria, cholesterol and cancer cell metabolism. Clin Transl Med. 5:222016. View Article : Google Scholar : PubMed/NCBI
22	Ding L and Liang X: Ras related GTP binding D promotes aerobic glycolysis of hepatocellular carcinoma. Ann Hepatol. 23:1003072021. View Article : Google Scholar : PubMed/NCBI
23	Liu Y, Li B, Yang X and Zhang C: MiR-99a-5p inhibits bladder cancer cell proliferation by directly targeting mammalian target of rapamycin and predicts patient survival. J Cell Biochem. 120:19330–19337. 2019. View Article : Google Scholar : PubMed/NCBI