The miRNA-17 ∼ 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation

E. Rao, C. Jiang, M. Ji, X. Huang, Javeed Iqbal, G. Lenz, G. Wright, L. M. Staudt, Y. Zhao, T. W. McKeithan, W. C. Chan, Kai Fu

129 Scopus citations

Abstract

The median survival of patients with mantle cell lymphoma (MCL) ranges from 3 to 5 years with current chemotherapeutic regimens. A common secondary genomic alteration detected in MCL is chromosome 13q31-q32 gain/amplification, which targets a microRNA (miRNA) cluster, miR-17∼92. On the basis of gene expression profiling, we found that high level expression of C13orf25, the primary transcript from which these miRNAs are processed, was associated with poorer survival in patients with MCL (P0.021). We demonstrated that the protein phosphatase PHLPP2, an important negative regulator of the PI3K/AKT pathway, was a direct target of miR-17∼92 miRNAs, in addition to PTEN and BIM. These proteins were down-modulated in MCL cells with overexpression of the miR-17∼92 cluster. Overexpression of miR-17∼92 activated the PI3K/AKT pathway and inhibited chemotherapy-induced apoptosis in MCL cell lines. Conversely, inhibition of miR-17∼92 expression suppressed the PI3K/AKT pathway and inhibited tumor growth in a xenograft MCL mouse model. Targeting the miR-17∼92 cluster may therefore provide a novel therapeutic approach for patients with MCL.

Original languageEnglish (US)
Pages (from-to)1064-1072
Number of pages9
JournalLeukemia
Volume26
Issue number5
DOIs
StatePublished - May 2012

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Keywords

  • MiR-17B92 cluster
  • PHLPP2
  • PI3K/AKT pathway
  • PTEN
  • mantle cell lymphoma

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Rao, E., Jiang, C., Ji, M., Huang, X., Iqbal, J., Lenz, G., Wright, G., Staudt, L. M., Zhao, Y., McKeithan, T. W., Chan, W. C., & Fu, K. (2012). The miRNA-17 ∼ 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation. Leukemia, 26(5), 1064-1072. https://doi.org/10.1038/leu.2011.305