Serum miR-486-5p as a diagnostic marker in cervical cancer: with investigation of potential mechanisms
Tóm tắt
Around the world, cervical cancer is the fourth most common cancer among women. MicroRNAs (miRNAs) and agents that target mRNAs have been introduced as novel diagnostic markers and therapeutic approaches, respectively, in cancer. MiRNA-486-5p is a candidate regulator of phosphatase and tensin homolog (PTEN) in silico, and the downregulation of PTEN in cervical cancer is not consistent with its mutation, which suggests that PTEN may be subjected to post-transcription modification moderated by miRNAs. Here, we aimed to explore whether miR-486-5p is a regulator in the development of cervical cancer through the PI3K/Akt pathway by targeting PTEN. The expression level of miR-486-5p in human cervical cancer serum and tissues were analyzed through quantitative RT-PCR. Human cervical cancer cell lines HeLa and SiHa were selected to explore the effects of miR-486-5p downregulated or overexpression on cell proliferation, migration, and invasion, respectively. Moreover, we observed the effect of miR-486-5p downregulated on tumorigenesis using HeLa cell in vivo. Besides, the relationship between miR-486-5p and PTEN were determined by dual luciferase reporter gene assay. Compared to control subjects, miR-486-5p was significantly overexpressed in cervical cancer patients’ serum and tissues. Suppression of miR-486-5p expression significantly inhibited HeLa cell proliferation, colony formation, migration, and invasion, as well as tumor growth in nude mice, while miR-486-5p overexpression stimulated SiHa cell proliferation, colony formation, migration, and invasion. We also confirmed that miR-486-5p directly targeted the 3′-untranslated region of the tumor-suppressor gene PTEN, inhibiting its expression, and that overexpression of miR-486-5p activated the PI3K/Akt pathway. We conclude that miR-486-5p stimulates cell proliferation, migration, and invasion through inhibition of PTEN expression and activation of the oncogenic PI3K/Akt pathway in cervical cancer. Our findings implicate serum miR-486-5p as a novel molecular biomarker that may provide effective approaches to both diagnosis and treatment in cervical cancer.
Tài liệu tham khảo
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30. https://doi.org/10.3322/caac.21332.
Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. https://doi.org/10.3322/caac.21262.
Fitzmaurice C, Dicker D, Pain A, et al. The global burden of cancer 2013. JAMA Oncol. 2015;1(4):505–27. https://doi.org/10.1001/jamaoncol.2015.0735.
Cervical Cancer Treatment (PDQ(R)): Health Professional VersionBTI - PDQ Cancer Information Summaries. 2002;doi: NBK66058 [bookaccession].
Gonzalez-Quintana V, Palma-Berre L, Campos-Parra AD, et al. MicroRNAs are involved in cervical cancer development, progression, clinical outcome and improvement treatment response (review). Oncol Rep. 2016;35(1):3–12. https://doi.org/10.3892/or.2015.4369.
Almeida MI, Reis RM, Calin GA. MicroRNA history: discovery, recent applications, and next frontiers. Mutat Res. 2011;717(1-2):1–8. https://doi.org/10.1016/j.mrfmmm.2011.03.009.
Munker R, Calin GA. MicroRNA profiling in cancer. Clin Sci (Lond). 2011;121(4):141–58. https://doi.org/10.1042/CS20110005.
Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 2010;11(9):597–610. https://doi.org/10.1038/nrg2843.
Cortez MA, Bueso-Ramos C, Ferdin J, et al. MicroRNAs in body fluids--the mix of hormones and biomarkers. Nat Rev Clin Oncol. 2011;8(8):467–77. https://doi.org/10.1038/nrclinonc.2011.76.
Di LG, Croce CM. Roles of small RNAs in tumor formation. Trends Mol Med. 2010;16(6):257–67. https://doi.org/10.1016/j.molmed.2010.04.001.
Shaham L, Vendramini E, Ge Y, et al. MicroRNA-486-5p is an erythroid oncomiR of the myeloid leukemias of down syndrome. Blood. 2015;125(8):1292–301. https://doi.org/10.1182/blood-2014-06-581892.
Wang LS, Li L, Li L, et al. MicroRNA-486 regulates normal erythropoiesis and enhances growth and modulates drug response in CML progenitors. Blood. 2015;125(8):1302–13. https://doi.org/10.1182/blood-2014-06-581926.
Chen H, Ren C, Han C, et al. Expression and prognostic value of miR-486-5p in patients with gastric adenocarcinoma. PLoS One. 2015;10(3):e0119384. https://doi.org/10.1371/journal.pone.0119384.
Wang J, Tian X, Han R, et al. Downregulation of miR-486-5p contributes to tumor progression and metastasis by targeting protumorigenic ARHGAP5 in lung cancer. Oncogene. 2014;33(9):1181–9. https://doi.org/10.1038/onc.2013.42.
Yang X, Yang Y, Gan R, et al. Down-regulation of mir-221 and mir-222 restrain prostate cancer cell proliferation and migration that is partly mediated by activation of SIRT1. PLoS One. 2014;9(6):e98833. https://doi.org/10.1371/journal.pone.0098833.
Li W, Wang Y, Zhang Q, et al. MicroRNA-486 as a biomarker for early diagnosis and recurrence of non-small cell lung cancer. PLoS One. 2015;10(8):e0134220. https://doi.org/10.1371/journal.pone.0134220.
Alexander MS, Casar JC, Motohashi N, et al. MicroRNA-486-dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy-associated symptoms. J Clin Invest. 2014;124(6):2651–67. https://doi.org/10.1172/JCI73579.
Xu J, Li R, Workeneh B, et al. Transcription factor FoxO1, the dominant mediator of muscle wasting in chronic kidney disease, is inhibited by microRNA-486. Kidney Int. 2012;82(4):401–11. https://doi.org/10.1038/ki.2012.84.