Identifying miR-616-Regulated Molecular Mechanisms and Novel Interacting Genes in Triple-Negative Breast Cancer miR-616 Mechanisms in TNBC
Abstract
Background: Among the major subtypes of breast cancer, Triple-Negative Breast Cancer (TNBC) is recognized as the most aggressive form of invasive breast cancer, associated with a poor prognosis and high mortality rate. Consequently, gaining insights into the underlying mechanisms of TNBC is of paramount importance. We focused on investigating the molecular mechanism of miR-616, a confirmed metastasis-related microRNA, in the pathogenesis and metastatic behavior of TNBC.
Methods: We obtained the mRNA dataset (GSE38959) from GEO to identify differentially expressed genes (DEGs). The target genes of miR-616 were predicted using the miRWalk and TargetScan databases. Subsequently, the genes that overlapped between these predictions were used to construct a protein-protein interaction network. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed. Module discovery was conducted using Molecular Complex Detection, visualized through Cytoscape, and further annotated using ClueGO. Finally, a literature review followed by a survival analysis was carried out.
Results: We identified 1725 differentially expressed genes (1109 upregulated, 616 downregulated(, 116 of which overlapped with miR-616 targets. Among these, 31 down-regulated genes were selected due to their reciprocal regulation with miR-616 expression. These genes were enriched in several cancer-associated pathways, specifically the estrogen, neurotrophin, JAK-STAT, and PI3K-Akt signaling pathways. We identified 16 novel candidate genes involved in miR-616-related TNBC pathogenesis, with KCNE1 showing a significant correlation with overall patient survival (HR=0.72, P=0.044).
Conclusion: These findings shed light on how miR-616 exerts its regulatory effect, underscoring its pivotal role in metastasis development in TNBC patients.
Full text article
References
Kolak A, Kamińska M, Sygit K, Budny A, Surdyka D, Kukiełka-Budny B, et al. Primary and secondary prevention of breast cancer. 2017;24(4).
Akram M, Iqbal M, Daniyal M, Khan AUJBr. Awareness and current knowledge of breast cancer. 2017;50(1):33.
Waks AG, Winer EPJJ. Breast cancer treatment: a review. 2019;321(3):288-300.
Garcia E, Luna I, Persad KL, Agopsowicz K, Jay DA, West FG, et al. Inhibition of triple negative breast cancer metastasis and invasiveness by novel drugs that target epithelial to mesenchymal transition. 2021;11(1):11757.
Al-Mahmood S, Sapiezynski J, Garbuzenko OB, Minko TJDd, research t. Metastatic and triple-negative breast cancer: challenges and treatment options. 2018;8(5):1483-507.
Chong ZX, Yeap SK, Ho WYJAob, biophysics. Roles of circulating microRNA (s) in human breast cancer. 2020;695:108583.
Thorsen SB, Obad S, Jensen NF, Stenvang J, Kauppinen SJTCJ. The therapeutic potential of microRNAs in cancer. 2012;18(3):275-84.
Hashimoto Y, Akiyama Y, Yuasa YJPo. Multiple-to-multiple relationships between microRNAs and target genes in gastric cancer. 2013;8(5):e62589.
Li Z, Wu L, Tan W, Zhang K, Lin Q, Zhu J, et al. MiR-20b-5p promotes hepatocellular carcinoma cell proliferation, migration and invasion by down-regulating CPEB3. 2021;23:100345.
Yuan CJOl. miR-616 promotes breast cancer migration and invasion by targeting TIMP2 and regulating MMP signaling. 2019;18(3):2348-55.
Govindarajan M, Wohlmuth C, Waas M, Bernardini MQ, Kislinger TJJoh, oncology. High-throughput approaches for precision medicine in high-grade serous ovarian cancer. 2020;13(1):134.
Barrett T, Troup DB, Wilhite SE, Ledoux P, Rudnev D, Evangelista C, et al. NCBI GEO: archive for high-throughput functional genomic data. 2009;37(suppl_1):D885-D90.
Li X, Rouchka EC, Brock GN, Yan J, O’Toole TE, Tieri DA, et al. A combined approach with gene-wise normalization improves the analysis of RNA-seq data in human breast cancer subtypes. 2018;13(8):e0201813.
Dweep H, Gretz NJNm. miRWalk2. 0: a comprehensive atlas of microRNA-target interactions. 2015;12(8):697-.
Tan M, Yu D. Molecular mechanisms of ErbB2-mediated breast cancer chemoresistance. Madame curie bioscience database [internet]: Landes Bioscience; 2013.
Raven JF, Williams V, Wang S, Tremblay ML, Muller WJ, Durbin JE, et al. Stat1 is a suppressor of ErbB2/Neu-mediated cellular transformation and mouse mammary gland tumor formation. 2011;10(5):794-804.
Lemoine N, Barnes D, Hollywood D, Hughes C, Smith P, Dublin E, et al. Expression of the ERBB3 gene product in breast cancer. 1992;66(6):1116-21.
Machesky LMJFl. Lamellipodia and filopodia in metastasis and invasion. 2008;582(14):2102-11.
Bhat AA, Uppada S, Achkar IW, Hashem S, Yadav SK, Shanmugakonar M, et al. Tight junction proteins and signaling pathways in cancer and inflammation: a functional crosstalk. 2019;9:1942.
Chen C-C, Chen L-L, Hsu Y-T, Liu K-J, Fan C-S, Huang T-SJJoBC. The endothelin-integrin axis is involved in macrophage-induced breast cancer cell chemotactic interactions with endothelial cells. 2014;289(14):10029-44.
Wang D, Xiao F, Feng Z, Li M, Kong L, Huang L, et al. Sunitinib facilitates metastatic breast cancer spreading by inducing endothelial cell senescence. 2020;22(1):103.
Payson RA, Chotani MA, Chiu MJTJosb, biology m. Regulation of a promoter of the fibroblast growth factor 1 gene in prostate and breast cancer cells. 1998;66(3):93-103.
Fata JE, Werb Z, Bissell MJJBcr. Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes. 2003;6(1):1.
Zhang D, Zhou P, Wang W, Wang X, Li J, Sun X, et al. MicroRNA-616 promotes the migration, invasion and epithelial-mesenchymal transition of HCC by targeting PTEN. 2016;35(1):366-74.
Henriksson ML, Edin S, Dahlin AM, Oldenborg P-A, Öberg Å, Van Guelpen B, et al. Colorectal cancer cells activate adjacent fibroblasts resulting in FGF1/FGFR3 signaling and increased invasion. 2011;178(3):1387-94.
Sun Y, Fan X, Zhang Q, Shi X, Xu G, Zou CJTB. Cancer-associated fibroblasts secrete FGF-1 to promote ovarian proliferation, migration, and invasion through the activation of FGF-1/FGFR4 signaling. 2017;39(7):1010428317712592.
Wagner W, Kania KD, Blauz A, Ciszewski WMJJPP. The lactate receptor (HCAR1/GPR81) contributes to doxorubicin chemoresistance via ABCB1 transporter up-regulation in human cervical cancer HeLa cells. 2017;68(4):555-64.
Schmall A, Al-Tamari HM, Herold S, Kampschulte M, Weigert A, Wietelmann A, et al. Macrophage and cancer cell cross-talk via CCR2 and CX3CR1 is a fundamental mechanism driving lung cancer. 2015;191(4):437-47.
Wang H, Cai J, Du S, Guo Z, Xin B, Wang J, et al. Fractalkine/CX3CR1 induces apoptosis resistance and proliferation through the activation of the AKT/NF‐κB cascade in pancreatic cancer cells. 2017;35(6):315-26.
Dawson S-J, Makretsov N, Blows F, Driver K, Provenzano E, Le Quesne J, et al. BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received. 2010;103(5):668-75.
Hwang KT, Woo JW, Shin HC, Kim HS, Ahn SK, Moon HG, et al. Prognostic influence of BCL2 expression in breast cancer. 2012;131(7):E1109-E19.
Ali HR, Dawson SJ, Blows FM, Provenzano E, Leung S, Nielsen T, et al. A Ki67/BCL2 index based on immunohistochemistry is highly prognostic in ER‐positive breast cancer. 2012;226(1):97-107.
Bouchalova K, Kharaishvili G, Bouchal J, Vrbkova J, Megova M, Hlobilkova AJCdt. Triple negative breast cancer-BCL2 in prognosis and prediction. Review. 2014;15(12):1166-75.
Voudris KV, Apostolakis S, Karyofillis P, Doukas K, Zaravinos A, Androutsopoulos VP, et al. Genetic diversity of the KCNE1 gene and susceptibility to postoperative atrial fibrillation. 2014;167(2):274-80. e1.
Luo Q, Wu T, Wu W, Chen G, Luo X, Jiang L, et al. The functional role of voltage-gated sodium channel Nav1. 5 in metastatic breast cancer. 2020;11:1111.
Ma S, Chan YP, Kwan PS, Tang KH, Vielkind J, Guan XY, et al. microRNA-616 induces androgen-independent growth of prostate cancer cells through suppression of TFPI-2 expression. 2010;70(8_Supplement):2083-.
Authors
Copyright (c) 2026 Archives of Breast Cancer
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Copyright©. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International License, which permits copy and redistribution of the material in any medium or format or adapt, remix, transform, and build upon the material for any purpose, except for commercial purposes.