Long non-coding RNA DARS-AS1 facilitates breast cancer progression by modulating the miR-6835-3p/ATF3 axis
Long non-coding RNAs (lncRNAs) play crucial roles in various cellular processes associated with cancer progression, including invasion, proliferation, and metastasis. Despite this understanding, the specific role of DARS-AS1 in breast cancer remains underexplored. In this study, we employed quantitative reverse transcription-polymerase chain reaction to measure the expression levels of DARS-AS1 and miR-6835-3p. Functional assessments, including the cell invasion and CCK-8 assays, were conducted to investigate cellular behaviors. In addition, a luciferase reporter assay was employed to elucidate the mechanistic interaction between DARS-AS1 and miR-6835-3p. Notably, DARS-AS1 expression was elevated in breast cancer cell lines (MCF7 and MDA-MB-231) relative to the non-cancerous MCF-10A cells. Overexpression of DARS-AS1 enhanced cell growth and invasion in MDA-MB-231 breast cancer cells. Further investigation revealed that DARS-AS1 acts as a sponge for miR-6835-3p in breast cancer cells. Overexpression of miR-6835-3p inhibited luciferase activity, specifically in the presence of wild-type DARS-AS1, highlighting a direct interaction. Ectopic expression of DARS-AS1 suppressed miR-6835-3p in MDA-MB-231 cells. Concurrently, miR-6835-3p levels were downregulated in breast cancer cells, and miR-6835-3p exhibited a negative correlation with DARS-AS1 expression. Mechanistically, miR-6835-3p targeted ATF3 expression in breast cancer cells. Increased levels of DARS-AS1 were found to enhance cellular proliferation and invasion by modulating ATF3. Our findings indicate that DARS-AS1 acts as an oncogene in breast cancer, partially through regulation of the miR-6835-3p/ATF3 pathway. This study provides valuable insights into the molecular mechanisms contributing to breast cancer progression, offering potential targets for therapeutic interventions.
- Polyak K. Heterogeneity in breast cancer. J Clin Investig. 2011;121:3786-3788. doi: 10.1172/JCI60534
- Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98:10869-10874. doi: 10.1073/pnas.191367098
- Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747-752. doi: 10.1038/35021093
- Onitilo AA, Engel JM, Greenlee RT, Mukesh BN. Breast cancer subtypes based on ER/PR and Her2 expression: Comparison of clinicopathologic features and survival. Clin Med Res. 2009;7:4-13. doi: 10.3121/cmr.2009.825
- Brewster AM, Chavez-MacGregor M, Brown P. Epidemiology, biology, and treatment of triple-negative breast cancer in women of African ancestry. Lancet Oncol. 2014;15:e625-e634. doi: 10.1016/S1470-2045(14)70364-X
- Gao Y, Shang S, Guo S, et al. Lnc2Cancer 3.0: An updated resource for experimentally supported lncRNA/circRNA cancer associations and web tools based on RNA-seq and scRNA-seq data. Nucleic Acids Res. 2021;49:D1251-D1258. doi: 10.1093/nar/gkaa1006
- Han L, Yan Y, Zhao L, et al. LncRNA HOTTIP facilitates the stemness of breast cancer via regulation of miR-148a-3p/ WNT1 pathway. J Cell Mol Med. 2020;24:6242-6252. doi: 10.1111/jcmm.15261
- Hunt SE, McLaren W, Gil L, et al. Ensembl variation resources. Database (Oxford). 2018;2018:bay119. doi: 10.1093/database/bay119
- Kong X, Duan Y, Sang Y, et al. LncRNA-CDC6 promotes breast cancer progression and function as ceRNA to target CDC6 by sponging microRNA-215. J Cell Physiol. 2019;234:9105-9117. doi: 10.1002/jcp.27587
- Lakshmi S, Hughes TA, Priya S. Exosomes and exosomal RNAs in breast cancer: A status update. Eur J Cancer. 2021;144:252-268. doi: 10.1016/j.ejca.2020.11.033
- Sun J, Zheng G, Gu Z, Guo Z. MiR-137 inhibits proliferation and angiogenesis of human glioblastoma cells by targeting EZH2. J Neurooncol. 2015;122:481-489. doi: 10.1007/s11060-015-1753-x
- Cheetham SW, Gruhl F, Mattick JS, Dinger ME. Long noncoding RNAs and the genetics of cancer. Br J Cancer. 2013;108:2419-2425. doi: 10.1038/bjc.2013.233
- Shin VY, Chu KM. MiRNA as potential biomarkers and therapeutic targets for gastric cancer. World J Gastroenterol. 2014;20:10432-10439. doi: 10.3748/wjg.v20.i30.10432
- Huang J, Zhang SY, Gao YM, et al. MicroRNAs as oncogenes or tumour suppressors in oesophageal cancer: Potential biomarkers and therapeutic targets. Cell Prolif. 2014;47:277-286. doi: 10.1111/cpr.12109
- Tay HL, Plank M, Collison A, Mattes J, Kumar RK, Foster PS. MicroRNA: Potential biomarkers and therapeutic targets for allergic asthma? Ann Med. 2014;46:633-639. doi: 10.3109/07853890.2014.958196
- Xiong DD, Li ZY, Liang L, et al. The LncRNA NEAT1 accelerates lung adenocarcinoma deterioration and binds to Mir-193a-3p as a competitive endogenous RNA. Cell Physiol Biochem. 2018;48:905-918. doi: 10.1159/000491958
- Zhang S, Ma H, Zhang D, et al. LncRNA KCNQ1OT1 regulates proliferation and cisplatin resistance in tongue cancer via miR-211-5p mediated Ezrin/Fak/Src signaling. Cell Death Dis. 2018;9:742. doi: 10.1038/s41419-018-0793-5
- Chi Y, Wang D, Wang J, Yu W, Yang J. Long non-coding RNA in the pathogenesis of cancers. Cells. 2019;8:1015. doi: 10.3390/cells8091015
- Cai Y, Yu X, Hu S, Yu J. A brief review on the mechanisms of miRNA regulation. Genomics Proteomics Bioinformatics. 2009;7:147-154. doi: 10.1016/S1672-0229(08)60044-3
- Cuperus JT, Fahlgren N, Carrington JC. Evolution and functional diversification of MIRNA genes. Plant Cell. 2011;23:431-442. doi: 10.1105/tpc.110.082784
- Reddy KB. MicroRNA (miRNA) in cancer. Cancer Cell Int. 2015;15:38. doi: 10.1186/s12935-015-0185-1
- Hill M, Tran N. miRNA interplay: Mechanisms and consequences in cancer. Dis Model Mech. 2021;14:dmm047662. doi: 10.1242/dmm.047662
- Pereira DM, Rodrigues PM, Borralho PM, Rodrigues CM. Delivering the promise of miRNA cancer therapeutics. Drug Discov Today. 2013;18:282-289. doi: 10.1016/j.drudis.2012.10.002
- Wang KJ, Zhao X, Liu YZ, et al. Circulating MiR-19b-3p, MiR- 134-5p and MiR-186-5p are promising novel biomarkers for early diagnosis of acute myocardial infarction. Cell Physiol Biochem. 2016;38:1015-1029. doi: 10.1159/000443053
- Feng Z, Zhang L, Wang S, Hong Q. Circular RNA circDLGAP4 exerts neuroprotective effects via modulating miR-134-5p/CREB pathway in Parkinson’s disease. Biochem Biophys Res Commun. 2020;522:388-394. doi: 10.1016/j.bbrc.2019.11.102
- Chi J, Liu T, Shi C, et al. Long non-coding RNA LUCAT1 promotes proliferation and invasion in gastric cancer by regulating miR-134-5p/YWHAZ axis. Biomed Pharmacother. 2019;118:109201. doi: 10.1016/j.biopha.2019.109201
- He J, Yang T, He W, et al. Liver X receptor inhibits the growth of hepatocellular carcinoma cells via regulating HULC/miR- 134-5p/FOXM1 axis. Cell Signal. 2020;74:109720. doi: 10.1016/j.cellsig.2020.109720
- Zhong BZ, Wang Q, Liu F, He JL, Xiong Y, Cao J. Effects of miR-384 and miR-134-5p acting on YY1 signaling transduction on biological function of gastric cancer cells. Onco Targets Ther. 2020;13:9631-9641. doi: 10.2147/OTT.S259988
- Bartel DP. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 2004;116:281-297. doi: 10.1016/S0092-8674(04)00045-5
- Chen JF, Mandel EM, Thomson JM, et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet. 2006;38:228-233. doi: 10.1038/ng1725
- Alvarez-Garcia I, Miska EA. MicroRNA functions in animal development and human disease. Development. 2005;132:4653-4662. doi: 10.1242/dev.02073
- Hu K, Liang M. Upregulated microRNA-224 promotes ovarian cancer cell proliferation by targeting KLLN. In Vitro Cell Dev Biol Anim. 2017;53:149-156. doi: 10.1007/s11626-016-0093-2
- Wang Y, He X, Yu Q, Eng C. Androgen receptor-induced tumor suppressor, KLLN, inhibits breast cancer growth and transcriptionally activates p53/p73-mediated apoptosis in breast carcinomas. Hum Mol Genet. 2013;22:2263-2272. doi: 10.1093/hmg/ddt077
- Wang Y, Radhakrishnan D, He X, Peehl DM, Eng C. Transcription factor KLLN inhibits tumor growth by AR suppression, induces apoptosis by TP53/TP73 stimulation in prostate carcinomas, and correlates with cellular differentiation. J Clin Endocrinol Metab. 2013;98:E586-E594. doi: 10.1210/jc.2012-3490
- Zou A, Liu X, Mai Z, et al. LINC00472 acts as a tumor suppressor in NSCLC through KLLN-mediated p53-signaling pathway via MicroRNA-149-3p and MicroRNA-4270. Mol Ther Nucleic Acids. 2019;17:563-577. doi: 10.1016/j.omtn.2019.06.003
- David CJ, Massagué J. Contextual determinants of TGFβ action in development, immunity and cancer. Nat Rev Mol Cell Biol. 2018;19:419-435. doi: 10.1038/s41580-018-0007-0
- Feng XH, Derynck R. Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol. 2005;21:659-693. doi: 10.1146/annurev.cellbio.21.022404.142018
- Jiang M, Chen J, Zhang W, et al. Interleukin-6 trans-signaling pathway promotes immunosuppressive myeloid-derived suppressor cells via suppression of suppressor of cytokine signaling 3 in breast cancer. Front Immunol. 2017;8:1840. doi: 10.3389/fimmu.2017.01840