miR-6893-3p is a bonafide negative regulator of splicing activator, RNPS1
Tóm tắt
RNA-binding protein with serine-rich domain 1, RNPS1, is a global guardian of splicing fidelity and has implications in cervical cancer cell progression. We previously observed elevated RNPS1 expression in cervical cancer cells compared to normal cells. To understand the mechanisms that lead to the dysregulation of RNPS1 expression in cervical cancer cells, we focused on microRNAs. Using an in silico approach, we predicted potential miRNA candidates targeting RNPS1. Among the candidate miRNAs, we found miR-6893-3p as a potential regulator of RNPS1 expression. Interestingly, the expression of miR-6893-3p is downregulated in cervical cancer cells compared to normal cells and its level is negatively correlated with the expression of RNPS1. Further, qPCR, Western blot analysis, and luciferase reporter assay confirmed that miR-6893-3p negatively regulates RNPS1 in HeLa cells. In this regard, overexpression of miR-6893-3p suppresses the endogenous mRNA and protein levels of RNPS1 in HeLa cells. Further investigation revealed that miR-6893-3p mediated regulation of RNPS1 is dependent on the binding of miR-6893-3p to a microRNA response element in the 3’UTR of RNPS1 mRNA. Furthermore, mechanistic analysis showed that targeted negative regulation of RNPS1 by miR-6893-3p occurs via enhanced mRNA degradation. Collectively, our findings establish miR-6893-3p as an important player in the post-transcriptional regulation of RNPS1 in HeLa cells.
Tài liệu tham khảo
Boguslawska J, Sokol E, Rybicka B, Czubaty A, Rodzik K, Piekielko-Witkowska A (2016) microRNAs target SRSF7 splicing factor to modulate the expression of osteopontin splice variants in renal cancer cells. Gene 595:142–149
Calin GA, Cimmino A, Fabbri M, Ferracin M, Wojcik SE, Shimizu M, Taccioli C, Zanesi N, Garzon R, Aqeilan RI et al (2008) MiR-15a and miR-16-1 cluster functions in human leukemia. Proc Natl Acad Sci USA 105:5166–5171
Chen M, Ai G, Zhou J, Mao W, Li H, Guo J (2019) circMTO1 promotes tumorigenesis and chemoresistance of cervical cancer via regulating miR-6893. Biomed Pharmacother 117:109064
Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M et al (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 102:13944–13949
Deka B, Chandra P, Yadav P, Rehman A, Kumari S, Kunnumakkara AB, Singh KK (2022) RNPS1 functions as an oncogenic splicing factor in cervical cancer cells. IUBMB Life 75(6):514–529
Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F et al (2012) Landscape of transcription in human cells. Nature 489(7414):101–8. https://doi.org/10.1038/nature11233
Iorio MV, Ferracin M, Liu C-G, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M et al (2005) MicroRNA Gene Expression Deregulation in Human Breast Cancer. Can Res 65:7065–7070
Jagadeeswaran G, Zheng Y, Sumathipala N, Jiang H, Arrese EL, Soulages JL, Zhang W, Sunkar R (2010) Deep sequencing of small RNA libraries reveals dynamic regulation of conserved and novel microRNAs and microRNA-stars during silkworm development. BMC Genomics 11:52–52
Kuchenbauer F, Mah SM, Heuser M, McPherson A, Ruschmann J, Rouhi A, Berg T, Bullinger L, Argiropoulos B, Morin RD et al (2011) Comprehensive analysis of mammalian miRNA* species and their role in myeloid cells. Blood 118:3350–3358
Lee EJ, Gusev Y, Jiang J, Nuovo GJ, Lerner MR, Frankel WL, Morgan DL, Postier RG, Brackett DJ, Schmittgen TD (2007) Expression profiling identifies microRNA signature in pancreatic cancer. Int J Cancer 120:1046–1054
Murakami Y, Yasuda T, Saigo K, Urashima T, Toyoda H, Okanoue T, Shimotohno K (2006) Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene 25:2537–2545
O’Brien J, Hayder H, Zayed Y, Peng C (2018) Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Front Endocrinol 9:402
Okamura K, Phillips MD, Tyler DM, Duan H, Chou Y-T, Lai EC (2008) The regulatory activity of microRNA* species has substantial influence on microRNA and 3’ UTR evolution. Nat Struct Mol Biol 15:354–363
Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens RM, Okamoto A, Yokota J, Tanaka T et al (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9:189–198
Yang J-S, Phillips MD, Betel D, Mu P, Ventura A, Siepel AC, Chen KC, Lai EC (2011) Widespread regulatory activity of vertebrate microRNA* species. RNA (New York, NY) 17:312–326