Letter Article

Downregulation of miR-125a-5p Leads to STAT3 Increased Expression in Breast Cancer Patients

Author(s): Negar Shafagh Shishavan, Soheila Talesh Sasani*, Zivar Salehi and Masoumeh Rezaei Azhang

Volume 11, Issue 3, 2022

Published on: 21 October, 2022

Page: [263 - 270] Pages: 8

DOI: 10.2174/2211536611666220907125812

Price: $65

Abstract

Background: Breast cancer (BC) is one of the main causes of cancer-related death in women worldwide. It is necessary to find methods for prognosis and early detection of BC. MicroRNAs inhibit the expression of special target genes at the post-transcriptional stage and have a fundamental role in various cancers. They function as oncogenes or tumor suppressors. MiR-125a- 5p acts as a tumor suppressor in some cancers through a signal transducer and activator of transcription 3 (STAT3) suppression. STAT3 is activated in response to cytokines and growth factors, affecting the transcription of target genes.

Objective: We examined the association between miR-125a-5p and STAT3 expression levels in breast cancer patients for the first time through a case-control study on an Iranian population.

Methods: Total RNAs were extracted from breast cancer and healthy tissues using TRIzol Reagent. Complementary DNA synthesis was performed, and Real-time PCR was done using miR-125a and STAT3-specific primers. GAPDH and U48 genes were used as internal controls. Statistical analysis of the results was conducted by SPSS v.19.0 software.

Results: We obtained a significant association between miR-125a-5p down-regulation and breast cancer disease (0.4333 in patients vs. 1.656 in controls, p-value = 0.009). STAT3 expression was significantly up-regulated in BC samples relative to healthy subjects (1.324 vs. 0.6557, respectively) and p-value <0.0001.

Conclusion: We investigated that decreased miR-125a-5p expression levels were significantly associated with increased STAT3 expression in BC tissues. Therefore, the expression changes of miR- 125a-5p can be an important potential biomarker for early diagnosis of breast cancer. Also, the miRNA molecule may have serious therapeutic potential.

Keywords: Oncogenes, microRNAs, MiR-125a-5p, STAT3, Gene expression, Breast cancer

Graphical Abstract

[1]
DeSantis C, Ma J, Bryan L, Jemal A. Breast cancer statistics, 2013. CA Cancer J Clin 2014; 64(1): 52-62.
[http://dx.doi.org/10.3322/caac.21203] [PMID: 24114568]
[2]
Gustalik J, Bartusik-Aebisher D, Ostańska E, Przyczyna P, Osuchowski M, Aebisher D. Epidemiology of breast cancer in Podkapackie voivodship. Eur J Clin Exp Med 2019; 17(3): 242-5.
[http://dx.doi.org/10.15584/ejcem.2019.3.7]
[3]
Sarıekiz FG, Gürhan O, Tomatır AG. MicroRNAs and their relationship with diseases. Lokman Hekim Health Sciences 2021; 3(1): 100-8.
[http://dx.doi.org/10.14744/lhhs.2021.80008]
[4]
Seo J, Jin D, Choi CH, Lee H. Integration of microRNA, mRNA, and protein expression data for the identification of cancer-related mi-croRNAs. PLoS One 2017; 12(1): e0168412.
[http://dx.doi.org/10.1371/journal.pone.0168412] [PMID: 28056026]
[5]
Shenouda SK, Alahari SK. MicroRNA function in cancer: Oncogene or a tumor suppressor? Cancer Metastasis Rev 2009; 28(3-4): 369-78.
[http://dx.doi.org/10.1007/s10555-009-9188-5] [PMID: 20012925]
[6]
Scott GK, Goga A, Bhaumik D, Berger CE, Sullivan CS, Benz CC. Coordinate suppression of ERBB2 and ERBB3 by enforced expression of Micro-RNA miR-125a or miR-125b. J Biol Chem 2007; 282(2): 1479-86.
[http://dx.doi.org/10.1074/jbc.M609383200] [PMID: 17110380]
[7]
Jiang L, Huang Q, Zhang S, et al. Hsa-miR-125a-3p and hsa-miR-125a-5p are downregulated in non-small cell lung cancer and have in-verse effects on invasion and migration of lung cancer cells. BMC Cancer 2010; 10(1): 318.
[http://dx.doi.org/10.1186/1471-2407-10-318] [PMID: 20569443]
[8]
Yin F, Zhang JN, Wang SW, et al. MiR-125a-3p regulates glioma apoptosis and invasion by regulating Nrg1. PLoS One 2015; 10(1): e0116759.
[http://dx.doi.org/10.1371/journal.pone.0116759] [PMID: 25560389]
[9]
Ma J, Zhan Y, Xu Z, et al. ZEB1 induced miR-99b/let-7e/miR-125a cluster promotes invasion and metastasis in esophageal squamous cell carcinoma. Cancer Lett 2017; 398: 37-45.
[http://dx.doi.org/10.1016/j.canlet.2017.04.006] [PMID: 28408353]
[10]
Potenza N, Russo A. Biogenesis, evolution and functional targets of microRNA-125a. Mol Genet Genomics 2013; 288(9): 381-9.
[http://dx.doi.org/10.1007/s00438-013-0757-5] [PMID: 23783428]
[11]
Fu Y, Cao F. MicroRNA-125a-5p regulates cancer cell proliferation and migration through NAIF1 in prostate carcinoma. OncoTargets Ther 2015; 8: 3827-35.
[http://dx.doi.org/10.2147/OTT.S92314] [PMID: 26719710]
[12]
Tong Z, Liu N, Lin L, Guo X, Yang D, Zhang Q. MiR-125a-5p inhibits cell proliferation and induces apoptosis in colon cancer via target-ing BCL2, BCL2L12 and MCL1. Biomed Pharmacother 2015; 75: 129-36.
[http://dx.doi.org/10.1016/j.biopha.2015.07.036] [PMID: 26297542]
[13]
Nishida N, Mimori K, Fabbri M, et al. MicroRNA-125a-5p is an independent prognostic factor in gastric cancer and inhibits the prolifera-tion of human gastric cancer cells in combination with trastuzumab. Clin Cancer Res 2011; 17(9): 2725-33.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-2132] [PMID: 21220473]
[14]
Hsieh TH, Hsu CY, Tsai CF, et al. MiR-125a-5p is a prognostic biomarker that targets HDAC4 to suppress breast tumorigenesis. Oncotarget 2015; 6(1): 494-509.
[http://dx.doi.org/10.18632/oncotarget.2674] [PMID: 25504437]
[15]
Zhong L, Sun S, Shi J, Cao F, Han X, Chen Z. MicroRNA-125a-5p plays a role as a tumor suppressor in lung carcinoma cells by directly targeting STAT3. Tumour Biol 2017; 39(6): 1010428317697579.
[http://dx.doi.org/10.1177/1010428317697579] [PMID: 28631574]
[16]
Siveen KS, Sikka S, Surana R, Dai X, Zhang J, Kumar AP. Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors. Biochim Biophys Acta (BBA) 2014; 1845(2): 136-54.
[http://dx.doi.org/10.1016/j.bbcan.2013.12.005]
[17]
Xin P, Xu X, Deng C, et al. The role of JAK/STAT signaling pathway and its inhibitors in diseases. Int Immunopharmacol 2020; 80: 106210.
[http://dx.doi.org/10.1016/j.intimp.2020.106210] [PMID: 31972425]
[18]
Melén K, Kinnunen L, Julkunen I. Arginine/lysine-rich structural element is involved in interferon-induced nuclear import of STATs. J Biol Chem 2001; 276(19): 16447-55.
[http://dx.doi.org/10.1074/jbc.M008821200] [PMID: 11150296]
[19]
Ernst S, Müller-Newen G. Nucleocytoplasmic shuttling of stats. A target for intervention? Cancers (Basel) 2019; 11(11): 1815.
[http://dx.doi.org/10.3390/cancers11111815] [PMID: 31752278]
[20]
Yan S, Li Z, Thiele CJ. Inhibition of STAT3 with orally active JAK inhibitor, AZD1480, decreases tumor growth in neuroblastoma and pediatric sarcomas in vitro and in vivo. Oncotarget 2013; 4(3): 433-45.
[http://dx.doi.org/10.18632/oncotarget.930] [PMID: 23531921]
[21]
Jing N, Tweardy DJ. Targeting Stat3 in cancer therapy. Anticancer Drugs 2005; 16(6): 601-7.
[http://dx.doi.org/10.1097/00001813-200507000-00002] [PMID: 15930886]
[22]
Hsieh FC, Cheng G, Lin J. Evaluation of potential Stat3-regulated genes in human breast cancer. Biochem Biophys Res Commun 2005; 335(2): 292-9.
[http://dx.doi.org/10.1016/j.bbrc.2005.07.075] [PMID: 16081048]
[23]
Wang X, Crowe PJ, Goldstein D, Yang JL. STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers. Int J Oncol 2012; 41(4): 1181-91.
[http://dx.doi.org/10.3892/ijo.2012.1568] [PMID: 22842992]
[24]
Ramezani S, Talesh Sasani S, Fakor F, Alizadehsefat S. Relationship of the expression of circulating hsa-miR-125a-3p and hsa-miR-125b with breast cancer. Br J Biomed Sci 2020; 77(1): 41-3.
[http://dx.doi.org/10.1080/09674845.2019.1674470] [PMID: 31575334]
[25]
He B, Zhao Z, Cai Q, et al. MiRNA-based biomarkers, therapies, and resistance in cancer. Int J Biol Sci 2020; 16(14): 2628-47.
[http://dx.doi.org/10.7150/ijbs.47203] [PMID: 32792861]
[26]
Vo DT, Karanam NK, Ding L, et al. MiR-125a-5p functions as tumor suppressor microRNA and is a marker of locoregional recurrence and poor prognosis in head and neck cancer. Neoplasia 2019; 21(9): 849-62.
[http://dx.doi.org/10.1016/j.neo.2019.06.004] [PMID: 31325708]
[27]
Xu X, Tao Y, Niu Y, et al. MiR-125a-5p inhibits tumorigenesis in hepatocellular carcinoma. Aging (Albany NY) 2019; 11(18): 7639-62.
[http://dx.doi.org/10.18632/aging.102276] [PMID: 31527306]
[28]
Coppola N, de Stefano G, Panella M, et al. Lowered expression of microRNA-125a-5p in human hepatocellular carcinoma and up-regulation of its oncogenic targets sirtuin-7, matrix metalloproteinase-11, and c-Raf. Oncotarget 2017; 8(15): 25289-99.
[http://dx.doi.org/10.18632/oncotarget.15809] [PMID: 28445974]
[29]
Dechow TN, Pedranzini L, Leitch A, et al. Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C. Proc Natl Acad Sci USA 2004; 101(29): 10602-7.
[http://dx.doi.org/10.1073/pnas.0404100101] [PMID: 15249664]
[30]
Xie T, Wei D, Liu M, et al. Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene 2004; 23(20): 3550-60.
[http://dx.doi.org/10.1038/sj.onc.1207383] [PMID: 15116091]
[31]
Xiong H, Zhang ZG, Tian XQ, et al. Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells. Neoplasia 2008; 10(3): 287-97.
[http://dx.doi.org/10.1593/neo.07971] [PMID: 18320073]
[32]
Jarnicki A, Putoczki T, Ernst M. Stat3: linking inflammation to epithelial cancer - more than a “gut” feeling? Cell Div 2010; 5(1): 14.
[http://dx.doi.org/10.1186/1747-1028-5-14] [PMID: 20478049]
[33]
Kesanakurti D, Chetty C, Rajasekhar Maddirela D, Gujrati M, Rao JS. Essential role of cooperative NF-κB and Stat3 recruitment to ICAM-1 intronic consensus elements in the regulation of radiation-induced invasion and migration in glioma. Oncogene 2013; 32(43): 5144-55.
[http://dx.doi.org/10.1038/onc.2012.546] [PMID: 23178493]
[34]
Page BDG, Ball DP, Gunning PT. Signal transducer and activator of transcription 3 inhibitors: A patent review. Expert Opin Ther Pat 2011; 21(1): 65-83.
[http://dx.doi.org/10.1517/13543776.2011.539205] [PMID: 21114420]
[35]
He H, Xu F, Huang W, et al. MiR-125a-5p expression is associated with the age of breast cancer patients. Genet Mol Res 2015; 14(4): 17927-33.
[http://dx.doi.org/10.4238/2015.December.22.17] [PMID: 26782438]
[36]
Fan Z, Cui H, Xu X, et al. MiR-125a suppresses tumor growth, invasion and metastasis in cervical cancer by targeting STAT3. Oncotarget 2015; 6(28): 25266-80.
[http://dx.doi.org/10.18632/oncotarget.4457] [PMID: 26389681]

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