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MicroRNA-149*, a p53-responsive microRNA, functions as an oncogenic regulator in human melanoma

Lei Jin1, Wang Lai Hu, Chen Chen Jiang

  • 1Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei 230027, People's Republic of China.

Proceedings of the National Academy of Sciences of the United States of America
|September 8, 2011
PubMed

Insights

The tumor suppressor p53 activates microRNA-149* (miR-149*) in melanoma. This promotes cancer cell survival by increasing Mcl-1 and resisting apoptosis, explaining p53

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • The tumor suppressor p53 is crucial for preventing cancer by initiating DNA repair or apoptosis.
  • Despite high expression in melanoma, p53 often fails to suppress this cancer effectively.
  • Understanding p53's role in melanoma is critical for developing targeted therapies.

Purpose of the Study:

  • To investigate the mechanism by which wild-type p53 (WT p53) fails to suppress melanoma.
  • To elucidate the role of microRNA-149* (miR-149*) in p53-mediated melanoma cell survival.
  • To identify novel therapeutic targets within the p53-miR-149*-Mcl-1 pathway.

Main Methods:

  • Analysis of p53-mediated gene expression in melanoma cells.
  • Investigating the regulatory relationship between p53, miR-149*, and glycogen synthase kinase-3α (GSK-3α).
  • Utilizing a mouse xenograft model to assess the impact of miR-149* deficiency on melanoma growth.
  • Quantifying miR-149* expression in human metastatic melanoma samples.

Main Results:

  • p53 directly up-regulates miR-149* in melanoma cells.
  • miR-149* targets and down-regulates GSK-3α, leading to increased Mcl-1 expression.
  • Mcl-1 overexpression confers resistance to apoptosis in melanoma cells.
  • Inhibition of miR-149* reduced melanoma cell survival and tumor growth in vivo.
  • Elevated miR-149* levels correlate with decreased GSK-3α and increased Mcl-1 in human metastatic melanoma.

Conclusions:

  • A novel p53-dependent pathway involving miR-149* promotes melanoma cell survival.
  • This pathway explains the paradoxical ineffectiveness of p53 in suppressing melanoma.
  • miR-149* is a key mediator of Mcl-1 overexpression and apoptosis resistance in melanoma.

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