Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Integrin β3 expression is regulated by let-7a miRNA in malignant melanoma

Abstract

Although integrin β3 is known to play an important role in melanoma progression and invasion, regulation of integrin β3 expression in melanoma has not been analysed in detail until today. As transcriptional regulation of integrin β3 was ruled out by our analysis, we concentrated on the regulation by microRNAs (miRNAs). Comparing primary melanocytes and malignant melanoma cell lines, we found that one candidate miRNA, miR-let-7a, was lost in melanoma and sequence analysis suggested an interaction with the 3′-untranslated region (3′-UTR) of integrin β3 mRNA. Transfection of melanoma cells with let-7a pre-miRTM molecules resulted in the downregulation of integrin β3 mRNA and protein expression. In addition, we cloned the 3′-UTR of the integrin β3 mRNA containing the let-7a target sequence into a reporter plasmid and revealed that let-7a negatively regulates reporter gene expression. The repressed expression of integrin β3 accompanies with reduced invasive potential of melanoma cells transfected with synthetic let-7a molecules observed in Boyden chamber assays. On the other hand, the induction of integrin β3 expression was achieved in melanocytes by transfection with let-7a anti-miRs, resulting in invasive behavior of transfected melanocytes. In summary, we determined miRNA let-7a to be an important regulator of integrin β3 expression and showed that the loss of let-7a expression is involved in development and progression of malignant melanoma.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

References

  • Albelda SM, Mette SA, Elder DE, Stewart R, Damjanovich L, Herlyn M et al. (1990). Integrin distribution in malignant melanoma: association of the beta 3 subunit with tumor progression. Cancer Res 50: 6757–6764.

    CAS  PubMed  Google Scholar 

  • Brooks PC, Clark RA, Cheresh DA . (1994). Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 264: 569–571.

    CAS  Article  PubMed  Google Scholar 

  • Danen EH, Jansen KF, Van Kraats AA, Cornelissen IM, Ruiter DJ, Van Muijen GN . (1995). Alpha v-integrins in human melanoma: gain of alpha v beta 3 and loss of alpha v beta 5 are related to tumor progression in situ but not to metastatic capacity of cell lines in nude mice. Int J Cancer 61: 491–496.

    CAS  Article  PubMed  Google Scholar 

  • Danen EH, Ten Berge PJ, Van Muijen GN, Van ‘t Hof-Grootenboer AE, Brocker EB, Ruiter DJ . (1994). Emergence of alpha 5 beta 1 fibronectin- and alpha v beta 3 vitronectin-receptor expression in melanocytic tumour progression. Histopathology 24: 249–256.

    CAS  Article  PubMed  Google Scholar 

  • Gaur A, Jewell DA, Liang Y, Ridzon D, Moore JH, Chen C et al. (2007). Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. Cancer Res 67: 2456–2468.

    CAS  Article  PubMed  Google Scholar 

  • Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ . (2006). miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res 34: D140–D144.

    CAS  Article  PubMed  Google Scholar 

  • Haass NK, Smalley KS, Li L, Herlyn M . (2005). Adhesion, migration and communication in melanocytes and melanoma. Pigment Cell Res 18: 150–159.

    CAS  Article  PubMed  Google Scholar 

  • Hwang HW, Mendell JT . (2006). MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer 94: 776–780.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Jin Y, Wilhide CC, Dang C, Li L, Li SX, Villa-Garcia M et al. (1998). Human integrin beta3 gene expression: evidence for a megakaryocytic cell-specific cis-acting element. Blood 92: 2777–2790.

    CAS  PubMed  Google Scholar 

  • Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A et al. (2005). RAS is regulated by the let-7 microRNA family. Cell 120: 635–647.

    CAS  Article  PubMed  Google Scholar 

  • Kim VN . (2005). Small RNAs: classification, biogenesis, and function. Mol Cells 19: 1–15.

    CAS  Article  PubMed  Google Scholar 

  • Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, Epstein EJ et al. (2005). Combinatorial microRNA target predictions. Nat Genet 37: 495–500.

    CAS  Article  PubMed  Google Scholar 

  • Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M et al. (2005). Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438: 685–689.

    Article  PubMed  Google Scholar 

  • Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB . (2003). Prediction of mammalian microRNA targets. Cell 115: 787–798.

    CAS  Article  PubMed  Google Scholar 

  • Li X, Chen B, Blystone SD, McHugh KP, Ross FP, Ramos DM . (1998). Differential expression of alphav integrins in K1735 melanoma cells. Invasion Metastasis 18: 1–14.

    Article  PubMed  Google Scholar 

  • Park SM, Shell S, Radjabi AR, Schickel R, Feig C, Boyerinas B et al. (2007). Let-7 prevents early cancer progression by suppressing expression of the embryonic gene HMGA2. Cell Cycle 6: 2585–2590.

    CAS  Article  PubMed  Google Scholar 

  • Porkka KP, Pfeiffer MJ, Waltering KK, Vessella RL, Tammela TL, Visakorpi T . (2007). MicroRNA expression profiling in prostate cancer. Cancer Res 67: 6130–6135.

    CAS  Article  PubMed  Google Scholar 

  • Poser I, Tatzel J, Kuphal S, Bosserhoff AK . (2004). Functional role of MIA in melanocytes and early development of melanoma. Oncogene 23: 6115–6124.

    CAS  Article  PubMed  Google Scholar 

  • Rothhammer T, Poser I, Soncin F, Bataille F, Moser M, Bosserhoff AK . (2005). Bone morphogenic proteins are overexpressed in malignant melanoma and promote cell invasion and migration. Cancer Res 65: 448–456.

    CAS  PubMed  Google Scholar 

  • Tatzel J, Poser I, Schroeder J, Bosserhoff AK . (2005). Inhibition of melanoma inhibitory activity (MIA) expression in melanoma cells leads to molecular and phenotypic changes. Pigment Cell Res 18: 92–101.

    CAS  Article  PubMed  Google Scholar 

  • Van Belle PA, Elenitsas R, Satyamoorthy K, Wolfe JT, Guerry D, Schuchter L et al. (1999). Progression-related expression of beta3 integrin in melanomas and nevi. Hum Pathol 30: 562–567.

    CAS  Article  PubMed  Google Scholar 

  • Woods D, Cherwinski H, Venetsanakos E, Bhat A, Gysin S, Humbert M et al. (2001). Induction of beta3-integrin gene expression by sustained activation of the Ras-regulated Raf–MEK–extracellular signal-regulated kinase signaling pathway. Mol Cell Biol 21: 3192–3205.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Zhang HH, Wang XJ, Li GX, Yang E, Yang NM . (2007). Detection of let-7a microRNA by real-time PCR in gastric carcinoma. World J Gastroenterol 13: 2883–2888.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Sibylla Lodermeyer and Susanne Wallner for excellent technical assistance as well as Alexandra Denk for preliminary work. Integrin β3 promoter constructs were a kind gift of Paul F Bray, Jefferson Medical College and the Cardeza Foundation for Hematologic Research (Philadelphia, USA).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A-K Bosserhoff.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Müller, D., Bosserhoff, AK. Integrin β3 expression is regulated by let-7a miRNA in malignant melanoma. Oncogene 27, 6698–6706 (2008). https://doi.org/10.1038/onc.2008.282

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2008.282

Keywords

  • microRNA
  • integrins
  • post-transcriptional silencing
  • melanoma progression

Further reading

Search

Quick links