The online version of this article (https://doi.org/10.1186/s13046-018-0679-5) contains supplementary material, which is available to authorized users.
Leilei Zhang, Xiaoyu He and Fang Li contributed equally to this report.
Xiaofang Xu, Renbing Jia and Xianqun Fan are senior authors of this report.
MicroRNAs (miRNAs) have been shown to function in many different cellular processes, including proliferation, apoptosis, differentiation and development. miR-181a, -181b, -181c and -181d are miR-181 members of the family, which has been rarely studied, especially uveal melanoma.
The expression level of miR-181 family in human uveal melanoma cell lines was measured via real-time PCR (RT-PCR). The function of miR-181 on cell cycle was detected through Flow Cytometry assay. Microarray assay and Bioinformatics analysis were used to find the potential target of miR-181b, and dual-luciferase reporter assays further identified the target gene.
MiR-181 family members were found to be highly homologous across different species and their upregulation significantly induces UM cell cycle progression. Of the family members, miR-181b was significantly overexpressed in UM tissues and most UM cells. Bioinformatics and dual luciferase reporter assay confirmed CTDSPL as a target of miR-181b. miR-181b over-expression inhibited CTDSPL expression, which in turn led to the phosphorylation of RB and an accumulation of the downstream cell cycle effector E2F1, promoting cell cycle progression in UM cells. Knockdown CTDSPL using siRNAs showing the same effect, including increase of E2F1 and the progression of cell cycle.
MiR-181 family members are key negative regulators of CTDSPL-mediated cell cycle progression. These results highlight that miR-181 family members, especially miR-181b, may be useful in the development of miRNA-based therapies and may serve as novel diagnostic and therapeutic candidate for UM.
Additional file 1: There are no interactions between CTDSPL and RB1, cyclins and CTDSPL. (TIF 9130 kb)13046_2018_679_MOESM1_ESM.tif
Collaborative Ocular Melanoma Study Group. Assessment of metastatic disease status at death in 435 patients with large choroidal melanoma in the collaborative ocular melanoma study (COMS): COMS report no. 15. Arch Ophthalmol. 2001;119(5):670–6. CrossRef
Ma YB, Song DW, Nie RH, Mu GY. MicroRNA-32 functions as a tumor suppressor and directly targets EZH2 in uveal melanoma. Genet Mol Res. 2016;15(2):gmr7935.
Schwind S, Maharry K, Radmacher MD, Mrozek K, Holland KB, Margeson D, Whitman SP, Hickey C, Becker H, Metzeler KH, et al. Prognostic significance of expression of a single microRNA, miR-181a, in cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol. 2010;28(36):5257–64. CrossRefPubMedPubMedCentral
Xu X, Jia R, Zhou Y, Song X, Wang J, Qian G, Ge S, Fan X. Microarray-based analysis: identification of hypoxia-regulated microRNAs in retinoblastoma cells. Int J Oncol. 2011;38(5):1385–93. PubMed
Schaefer A, Jung M, Mollenkopf HJ, Wagner I, Stephan C, Jentzmik F, Miller K, Lein M, Kristiansen G, Jung K. Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma. Int J Cancer. 2010;126(5):1166–76. PubMed
Senchenko VN, Anedchenko EA, Kondratieva TT, Krasnov GS, Dmitriev AA, Zabarovska VI, Pavlova TV, Kashuba VI, Lerman MI, Zabarovsky ER. Simultaneous down-regulation of tumor suppressor genes RBSP3/CTDSPL, NPRL2/G21 and RASSF1A in primary non-small cell lung cancer. BMC Cancer. 2010;10:75. CrossRefPubMedPubMedCentral
Beniaminov AD, Krasnov GS, Dmitriev AA, Puzanov GA, Snopok BA, Senchenko VN, Kashuba VI. Interaction of two tumor suppressors: Phosphatase CTDSPL and Rb protein. Mol Biol. 2016;50(3):504–8. CrossRef
Krasnov GS, Puzanov GA, Kudryavtseva AV, Dmitriev AA, Beniaminov AD, Kondratieva TT, Senchenko VN. Differential expression of an ensemble of the key genes involved in cell-cycle regulation in lung cancer. Mol Biol. 2017;51(5):849–56. CrossRef
Sapkota G, Knockaert M, Alarcon C, Montalvo E, Brivanlou AH, Massague J. Dephosphorylation of the linker regions of Smad1 and Smad2/3 by small C-terminal domain phosphatases has distinct outcomes for bone morphogenetic protein and transforming growth factor-beta pathways. J Biol Chem. 2006;281(52):40412–9. CrossRefPubMed
- The miR-181 family promotes cell cycle by targeting CTDSPL, a phosphatase-like tumor suppressor in uveal melanoma
- BioMed Central
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