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MicroRNA-125b suppresses the epithelial–mesenchymal transition and cell invasion by targeting ITGA9 in melanoma

  • Original Article
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Tumor Biology

Abstract

Increasing evidence has shown that aberrant miRNAs contribute to the development and progression of human melanoma. Previous studies have shown that miR-125b functions as a suppressor in malignant melanoma. However, the molecular function and mechanism by which miR-125b influences melanoma growth and invasion are still unclear. In this study, we aimed to investigate the role of miR-125b in melanoma progression and metastasis. We found that miR-125b expression is significantly downregulated in primary melanoma, and an even greater downregulation was observed in metastatic invasion. Restored expression of miR-125b in melanoma suppressed cell proliferation and invasion both in vitro and in vivo. Furthermore, our findings demonstrate that upregulating miR-125b significantly inhibits malignant phenotypes by repressing the expression of integrin alpha9 (ITGA9). Finally, our data reveal that upregulated expression of ITGA9 in melanoma tissues is inversely associated with miR-125b levels. Together, our results demonstrate that upregulation of ITGA9 in response to the decrease in miR-125b in metastatic melanoma is responsible for melanoma tumor cell migration and invasion.

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References

  1. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75:843–54.

    Article  CAS  PubMed  Google Scholar 

  2. Iorio MV, Croce CM. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med. 2012;4:143–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Winter J, Jung S, Keller S, Gregory RI, Diederichs S. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol. 2009;11:228–34.

    Article  CAS  PubMed  Google Scholar 

  4. Bushati N, Cohen SM. microRNA functions. Annu Rev Cell Dev Biol. 2007;23:175–205.

    Article  CAS  PubMed  Google Scholar 

  5. Zhang F, Huang W, Sheng M, Liu T. MiR-451 inhibits cell growth and invasion by targeting CXCL16 and is associated with prognosis of osteosarcoma patients. Tumour Biol. 2015;36:2041–8.

    Article  CAS  PubMed  Google Scholar 

  6. Qi X, Li J, Zhou C, Lv C, Tian M. MicroRNA-320a inhibits cell proliferation, migration and invasion by targeting BMI-1 in nasopharyngeal carcinoma. FEBS Lett. 2014;588:3732–8.

    Article  CAS  PubMed  Google Scholar 

  7. Srinivasan S, Selvan ST, Archunan G, Gulyas B, Padmanabhan P. MicroRNAs—the next generation therapeutic targets in human diseases. Theranostics. 2013;3:930–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zehavi L, Schayek H, Jacob-Hirsch J, Sidi Y, Leibowitz-Amit R, Avni D. MiR-377 targets E2F3 and alters the NF-kB signaling pathway through MAP3K7 in malignant melanoma. Mol Cancer. 2015;14:68.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–69.

    Article  CAS  PubMed  Google Scholar 

  10. Berrocal A, Cabanas L, Espinosa E, Fernandez-de-Misa R, Martin-Algarra S, Martinez-Cedres JC, et al. Melanoma: diagnosis, staging, and treatment. Consensus group recommendations. Adv Ther. 2014;31:945–60.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang P, Fu C, Bai H, Song E, Dong C, Song Y. Corrigendum to “CD44 variant, but not standard CD44 isoforms, mediate disassembly of endothelial VE-cadherin junction on metastatic melanoma cells” [FEBS Lett. 588 (24) (2014) 4573–4582]. FEBS Lett. 2015;589:553.

    Article  CAS  PubMed  Google Scholar 

  12. Chapman PB 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 

  13. Klusmann JH et al. miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia. Genes Dev. 2010;24:478–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shi XB et al. An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells. Proc Natl Acad Sci U S A. 2007;104:19983–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Han Y, Liu Y, Zhang H, Wang T, Diao R, Jiang Z, et al. Hsa-miR-125b suppresses bladder cancer development by down-regulating oncogene SIRT7 and oncogenic long noncoding RNA MALAT1. FEBS Lett. 2013;587(23):3875–82.

    Article  CAS  PubMed  Google Scholar 

  16. Zhang Y, Yan LX, Wu QN, Du ZM, Chen J, Liao DZ, et al. miR-125b is methylated and functions as a tumor suppressor by regulating the ETS1 proto-oncogene in human invasive breast cancer. Cancer Res. 2011;71:3552–62.

    Article  CAS  PubMed  Google Scholar 

  17. Nyholm AM, Lerche CM, Manfé V, Biskup E, Johansen P, Morling N, et al. miR-125b induces cellular senescence in malignant melanoma. BMC Dermatol. 2014;14:8.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Xie X, Hu Y, Xu L, Fu Y, Tu J, Zhao H, et al. The role of miR-125b-mitochondria-caspase-3 pathway in doxorubicin resistance and therapy in human breast cancer. Tumour Biol. 2015.

  19. Chen J, Fu X, Wan Y, Wang Z, Jiang D, Shi L. miR-125b inhibitor enhance the chemosensitivity of glioblastoma stem cells to temozolomide by targeting Bak1. Tumour Biol. 2014;35:6293–302.

    Article  CAS  PubMed  Google Scholar 

  20. Gupta SK, Oommen S, Aubry MC, Williams BP, Vlahakis NE. Integrin alpha9beta1 promotes malignant tumor growth and metastasis by potentiating epithelial-mesenchymal transition. Oncogene. 2013;32:141–50.

    Article  CAS  PubMed  Google Scholar 

  21. Mostovich LA, Prudnikova TY, Kondratov AG, Loginova D, Vavilov PV, Rykova VI, et al. Integrin alpha9 (ITGA9) expression and epigenetic silencing in human breast tumors. Cell Adh Migr. 2011;5:395–401.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Rathinam R, Alahari SK. Important role of integrins in the cancer biology. Cancer Metastasis Rev. 2010;29:223–37.

    Article  CAS  PubMed  Google Scholar 

  23. Lydolph MC, Morgan-Fisher M, Hoye AM, Couchman JR, Wewer UM, Yoneda A. Alpha9beta1 integrin in melanoma cells can signal different adhesion states for migration and anchorage. Exp Cell Res. 2009;315:3312–24.

    Article  CAS  PubMed  Google Scholar 

  24. Zhang J, Lu L, Xiong Y, Qin W, Zhang Y, Qian Y, et al. MLK3 promotes melanoma proliferation and invasion and is a target of microRNA-125b. Clin Exp Dermatol. 2014;39:376–84.

    Article  CAS  PubMed  Google Scholar 

  25. Glud M, Rossing M, Hother C, Holst L, Hastrup N, Nielsen FC, et al. Downregulation of miR-125b in metastatic cutaneous malignant melanoma. Melanoma Res. 2010;20:479–84.

    Article  CAS  PubMed  Google Scholar 

  26. Kappelmann M, Kuphal S, Meister G, Vardimon L, Bosserhoff AK. MicroRNA miR-125b controls melanoma progression by direct regulation of c-Jun protein expression. Oncogene. 2013;32:2984–91.

    Article  CAS  PubMed  Google Scholar 

  27. Voulgari A, Pintzas A. Epithelial–mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim Biophys Acta. 2009;1796:75–90.

    CAS  PubMed  Google Scholar 

  28. Thiery JP, Sleeman JP. Complex networks orchestrate epithelial–mesenchymal transitions. Nat Rev Mol Cell Biol. 2006;7:131–42.

    Article  CAS  PubMed  Google Scholar 

  29. Schreiber TD, Steinl C, Essl M, Abele H, Geiger K, Muller CA, et al. The integrin alpha9beta1 on hematopoietic stem and progenitor cells: involvement in cell adhesion, proliferation and differentiation. Haematologica. 2009;94:1493–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gupta SK, Vlahakis NE. Integrin alpha9beta1: unique signaling pathways reveal diverse biological roles. Cell Adh Migr. 2010;4:194–8.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by the Jiangxi Province Science and Technology Support Program (No. 20141BBG70024) and Jiangxi Province Postdoctoral Science Foundation Funded Project (No.2015KY20) and China Postdoctoral Science Foundation Funded Project (No.2015M582048).

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    Authors and Affiliations

    1. Department of Plastic Surgery, The First Affiliated Hospital to Nanchang University, No.17 Yongwaizheng Street, Nanchang, Jiangxi, 330006, China

      Jie Zhang

    2. Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital to Nanchang University, Nanchang, Jiangxi, 330006, China

      Sijia Na, Shuting Pan & Jiaxuan Qiu

    3. Department of Plastic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China

      Caiyue Liu

    4. Department of Anesthesiology, The Second Affiliated Hospital to Nanchang University, Nanchang, Jiangxi, 330006, China

      Junying Cai

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    1. Jie Zhang
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    Correspondence to Jiaxuan Qiu.

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    All patients provided written informed consent, and the study conformed to the Declaration of Helsinki and was approved by the Ethics Committee of The First Affiliated Hospital of Nanchang University with the permit number of 2014D0307.

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    Additional information

    Jie Zhang and Sijia Na contributed equally to this work.

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    Cite this article

    Zhang, J., Na, S., Liu, C. et al. MicroRNA-125b suppresses the epithelial–mesenchymal transition and cell invasion by targeting ITGA9 in melanoma. Tumor Biol. 37, 5941–5949 (2016). https://doi.org/10.1007/s13277-015-4409-8

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    • DOI: https://doi.org/10.1007/s13277-015-4409-8

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