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MicroRNA-15a inhibits the growth and invasiveness of malignant melanoma and directly targets on CDCA4 gene

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Tumor Biology

Abstract

MicroRNAs can affect behaviors of tumor cells by modulating the expression of the target genes that involve tumor growth, invasiveness, and death. The goal of this research is to examine the effects of miR-15a on the proliferation and invasiveness of malignant melanoma cells in vitro, as well as the therapeutic effect of miR-15a in a mouse melanoma model. miR-15a displayed inhibitory effects on proliferation and invasiveness of several malignant melanoma cell lines. miR-15a also caused cell cycle arrest at G1/G0 phase. miRNA 15a downregulated the expressions of CDCA4 and AKT-3 in melanoma cell lines. In vivo, experiment showed that miRNA 15a significantly retarded the growth of melanoma tumors in the mouse model. The luciferase reporter assay demonstrated that miR15a can suppress gene expression through the binding site in the 3 ′UTR of CACD4, which is a bona fide target of miRNA 15a. In conclusion, miRNA 15a suppressed the growth and invasiveness of melanoma cells, suggesting that miRNA 15a may represent a viable microRNA-based therapy against melanoma.

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References

  1. Yu B, Huang L, Tiwari RC, Feuer EJ, Johnson KA. Modelling population-based cancer survival trends using join point models for grouped survival data. J R Stat Soc A Stat Soc. 2009;172:405–25.

    Article  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.

    Article  PubMed  Google Scholar 

  3. Slominski AT, Carlson JA. Melanoma resistance: a bright future for academicians and a challenge for patient advocates. Mayo Clin Proc. 2014;89:429–33.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14.

    Article  CAS  PubMed  Google Scholar 

  6. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gu W, Wang X, Zhai C, Zhou T, Xie X. Biological basis of miRNA action when their targets are located in human protein coding region. PLoS One. 2013;8:e63403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lytle JR, Yario TA, Steitz JA. Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR. Proc Natl Acad Sci U S A. 2007;104:9667–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009;19:92–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kozomara A, Griffiths-Jones S. miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res. 2011;39:D152–7.

    Article  CAS  PubMed  Google Scholar 

  11. Griffiths-Jones S. The microRNA registry. Nucleic Acids Res. 2004;32:D109–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet. 2007;39:673–7.

    Article  CAS  PubMed  Google Scholar 

  13. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6:857–66.

    Article  CAS  PubMed  Google Scholar 

  14. Luo C, Weber CE, Osen W, Bosserhoff AK, Eichmuller SB. The role of microRNAs in melanoma. Eur J Cell Biol. 2014;93:11–22.

    Article  CAS  PubMed  Google Scholar 

  15. Bennett PE, Bemis L, Norris DA, Shellman YG. miR in melanoma development: miRNAs and acquired hallmarks of cancer in melanoma. Physiol Genomics. 2013;45:1049–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Reuland SN, Smith SM, Bemis LT, Goldstein NB, Almeida AR, Partyka KA, et al. MicroRNA-26a is strongly downregulated in melanoma and induces cell death through repression of silencer of death domains (SODD). J Investig Dermatol. 2013;133:1286–93.

    Article  CAS  PubMed  Google Scholar 

  17. Bemis LT, Chen R, Amato CM, Classen EH, Robinson SE, Coffey DG, et al. MicroRNA-137 targets microphthalmia-associated transcription factor in melanoma cell lines. Cancer Res. 2008;68:1362–8.

    Article  CAS  PubMed  Google Scholar 

  18. Segura MF, Hanniford D, Menendez S, Reavie L, Zou X, Alvarez-Diaz S, et al. Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor. Proc Natl Acad Sci U S A. 2009;106:1814–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Felicetti F, Errico MC, Bottero L, Segnalini P, Stoppacciaro A, Biffoni M, et al. The promyelocytic leukemia zinc finger-microRNA-221/−222 pathway controls melanoma progression through multiple oncogenic mechanisms. Cancer Res. 2008;68:2745–54.

    Article  CAS  PubMed  Google Scholar 

  20. Igoucheva O, Alexeev V. MicroRNA-dependent regulation of cKit in cutaneous melanoma. Biochem Biophys Res Commun. 2009;379:790–4.

    Article  CAS  PubMed  Google Scholar 

  21. Dar AA, Majid S, de Semir D, Nosrati M, Bezrookove V, Kashani-Sabet M. miRNA-205 suppresses melanoma cell proliferation and induces senescence via regulation of E2F1 protein. J Biol Chem. 2011;286:16606–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mueller DW, Rehli M, Bosserhoff AK. miRNA expression profiling in melanocytes and melanoma cell lines reveals miRNAs associated with formation and progression of malignant melanoma. J Investig Dermatol. 2009;129:1740–51.

    Article  CAS  PubMed  Google Scholar 

  23. Li P, Xie XB, Chen Q, Pang GL, Luo W, JC T, et al. MiRNA-15a mediates cell cycle arrest and potentiates apoptosis in breast cancer cells by targeting synuclein-gamma. Asian Pac J Cancer Prev. 2014;15:6949–54.

    Article  PubMed  Google Scholar 

  24. Pekarsky Y, Croce CM. Role of miR-15/16 in CLL. Cell Death Differ. 2015;22:6–11.

    Article  CAS  PubMed  Google Scholar 

  25. Yang T, Thakur A, Chen T, Yang L, Lei G, Liang Y, et al. MicroRNA-15a induces cell apoptosis and inhibits metastasis by targeting BCL2L2 in non-small cell lung cancer. Tumour Biol. 2015;36:4357–65.

    Article  CAS  PubMed  Google Scholar 

  26. Shinden Y, Akiyoshi S, Ueo H, Nambara S, Saito T, Komatsu H, et al. Diminished expression of MiR-15a is an independent prognostic marker for breast cancer cases. Anticancer Res. 2015;35:123–7.

    PubMed  Google Scholar 

  27. Poliseno L, Haimovic A, Segura MF, Hanniford D, Christos PJ, Darvishian F, et al. Histology-specific microRNA alterations in melanoma. J Investig Dermatol. 2012;132:1860–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bonazzi VF, Stark MS, Hayward NK. MicroRNA regulation of melanoma progression. Melanoma Res. 2012;22:101–13.

    Article  CAS  PubMed  Google Scholar 

  29. Bell RE, Levy C. The three M’s: melanoma, microphthalmia-associated transcription factor and microRNA. Pigment Cell Melanoma Res. 2011;24:1088–106.

    Article  CAS  PubMed  Google Scholar 

  30. Guo S, Xu X, Tang Y, Zhang C, Li J, Ouyang Y, et al. miR-15a inhibits cell proliferation and epithelial to mesenchymal transition in pancreatic ductal adenocarcinoma by down-regulating Bmi-1 expression. Cancer Lett. 2014;344:40–6.

    Article  CAS  PubMed  Google Scholar 

  31. Tian X, Zhang J, Yan L, Dong JM, Guo Q. MiRNA-15a inhibits proliferation, migration and invasion by targeting TNFAIP1 in human osteosarcoma cells. Int J Clin Exp Pathol. 2015;8:6442–9.

    PubMed  PubMed Central  Google Scholar 

  32. Renjie W, Haiqian L. MiR-132, miR-15a and miR-16 synergistically inhibit pituitary tumor cell proliferation, invasion and migration by targeting Sox5. Cancer Lett. 2015;356:568–78.

    Article  PubMed  Google Scholar 

  33. Komabayashi Y, Kishibe K, Nagato T, Ueda S, Takahara M, Harabuchi Y. Downregulation of miR-15a due to LMP1 promotes cell proliferation and predicts poor prognosis in nasal NK/T-cell lymphoma. Am J Hematol. 2014;89:25–33.

    Article  CAS  PubMed  Google Scholar 

  34. Kang W, Tong JH, Lung RW, Dong Y, Zhao J, Liang Q, et al. Targeting of YAP1 by microRNA-15a and microRNA-16-1 exerts tumor suppressor function in gastric adenocarcinoma. Mol Cancer. 2015;14:52.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Hao M, Zhang L, An G, Meng H, Han Y, Xie Z, et al. Bone marrow stromal cells protect myeloma cells from bortezomib induced apoptosis by suppressing microRNA-15a expression. Leuk Lymphoma. 2011;52:1787–94.

    Article  CAS  PubMed  Google Scholar 

  36. Slominski A, Kim TK, Brozyna AA, Janjetovic Z, Brooks DL, Schwab LP, et al. The role of melanogenesis in regulation of melanoma behavior: melanogenesis leads to stimulation of HIF-1alpha expression and HIF-dependent attendant pathways. Arch Biochem Biophys. 2014;563:79–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Slominski A, Tobin DJ, Shibahara S, Wortsman J. Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev. 2004;84:1155–228.

    Article  CAS  PubMed  Google Scholar 

  38. Luo Q, Li X, Li J, Kong X, Zhang J, Chen L, et al. MiR-15a is underexpressed and inhibits the cell cycle by targeting CCNE1 in breast cancer. Int J Oncol. 2013;43:1212–8.

    CAS  PubMed  Google Scholar 

  39. Zariwala M, Liu J, Xiong Y. Cyclin E2, a novel human G1 cyclin and activating partner of CDK2 and CDK3, is induced by viral oncoproteins. Oncogene. 1998;17:2787–98.

    Article  CAS  PubMed  Google Scholar 

  40. Gibson L, Holmgreen SP, Huang DC, Bernard O, Copeland NG, Jenkins NA, et al. Bcl-w, a novel member of the bcl-2 family, promotes cell survival. Oncogene. 1996;13:665–75.

    CAS  PubMed  Google Scholar 

  41. Hayashi R, Goto Y, Ikeda R, Yokoyama KK, Yoshida K. CDCA4 is an E2F transcription factor family-induced nuclear factor that regulates E2F-dependent transcriptional activation and cell proliferation. J Biol Chem. 2006;281:35633–48.

    Article  CAS  PubMed  Google Scholar 

  42. Wang L, Zhu G, Yang D, Li Q, Li Y, Xu X, et al. The spindle function of CDCA4. Cell Motil Cytoskeleton. 2008;65:581–93.

    Article  CAS  PubMed  Google Scholar 

  43. Tategu M, Nakagawa H, Hayashi R, Yoshida K. Transcriptional co-factor CDCA4 participates in the regulation of JUN oncogene expression. Biochimie. 2008;90:1515–22.

    Article  CAS  PubMed  Google Scholar 

  44. Spinetti G, Fortunato O, Caporali A, Shantikumar S, Marchetti M, Meloni M, et al. MicroRNA-15a and microRNA-16 impair human circulating proangiogenic cell functions and are increased in the proangiogenic cells and serum of patients with critical limb ischemia. Circ Res. 2013;112:335–46.

    Article  CAS  PubMed  Google Scholar 

  45. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120:15–20.

    Article  CAS  PubMed  Google Scholar 

  46. Stahl JM, Sharma A, Cheung M, Zimmerman M, Cheng JQ, Bosenberg MW, et al. Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res. 2004;64:7002–10.

    Article  CAS  PubMed  Google Scholar 

  47. Cheung M, Sharma A, Madhunapantula SV, Robertson GP. Akt3 and mutant V600E B-Raf cooperate to promote early melanoma development. Cancer Res. 2008;68:3429–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Shao Y, Aplin AE. Akt3-mediated resistance to apoptosis in B-RAF-targeted melanoma cells. Cancer Res. 2010;70:6670–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This project was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20 GM103418 (PI: Dr. Yixin Yang) and the Emporia State University Faculty Research and Creativity Grant (PI: Dr. Yixin Yang). This project was also supported by the grants from the National Natural Science Foundation of China (Beijing, People’s Republic of China) with the grant number of 81471373 (PI: Dr. Zhaoyang Xiao) and the Liaoning Province Natural Science Foundation with the grant number of 2014023007 (PI: Dr. Zhaoyang Xiao).

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The authors (Christopher Alderman, Ayoub Sehlaoui, Zhaoyang Xiao, Yixin Yang) of the manuscript entitled “MicroRNA-15a Inhibits the Growth and Invasiveness of Malignant Melanoma and Directly Targets on CDCA4 Gene” have NO affiliations with or involvement in any organization or entity with any financial interest, or non-financial interest in the subject matter or materials discussed in this manuscript.

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Christopher Alderman and Ayoub Sehlaoui are equal contributors to this project.

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Alderman, C., Sehlaoui, A., Xiao, Z. et al. MicroRNA-15a inhibits the growth and invasiveness of malignant melanoma and directly targets on CDCA4 gene. Tumor Biol. 37, 13941–13950 (2016). https://doi.org/10.1007/s13277-016-5271-z

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  • DOI: https://doi.org/10.1007/s13277-016-5271-z

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