Regulatory circuit of PKM2/NF-κB/MIR-148a/152-modulated tumor angiogenesis and cancer progression

Q. Xu, L. Z. Liu, Y. Yin, J. He, Q. Li, X. Qian, Y. You, Z. Lu, S. C. Peiper, Y. Shu, B. H. Jiang

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38 Scopus citations

Abstract

Upregulation of the embryonic M2 isoform of pyruvate kinase (PKM2) emerges as a critical player in the cancer development and metabolism, yet the underlying mechanism of PKM2 overexpression remains to be elucidated. Here we demonstrate that IGF-1/IGF-IR regulates PKM2 expression by enhancing HIF-1-p65 complex binding to PKM2 promoter. PKM2 expression is regulated by miR-148a/152 suppression. PKM2 directly interacts with NF-κB p65 subunit to promote EGR1 expression for regulating miR-148a/152 feedback circuit in normal cells, but not in cancer cells because of the DNA hypermethylation of miR-148a and miR-152 gene promoters. The silencing of miR-148a/152 contributes to the overexpression of PKM2, NF-κB or/and IGF-IR in some cancer cells. We show that disruption of PKM2/NF-κB/miR-148a/152 feedback loop can regulate cancer cell growth and angiogenesis, and is also associated with triple-negative breast cancer (TNBC) phenotype, which may have clinical implication for providing novel biomarker(s) of TNBC and potential therapeutic target(s) in the future.

Original languageEnglish (US)
Pages (from-to)5482-5493
Number of pages12
JournalOncogene
Volume34
Issue number43
DOIs
StatePublished - Oct 1 2015

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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Xu, Q., Liu, L. Z., Yin, Y., He, J., Li, Q., Qian, X., You, Y., Lu, Z., Peiper, S. C., Shu, Y., & Jiang, B. H. (2015). Regulatory circuit of PKM2/NF-κB/MIR-148a/152-modulated tumor angiogenesis and cancer progression. Oncogene, 34(43), 5482-5493. https://doi.org/10.1038/onc.2015.6