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

Q Xu1, L-Z Liu2, Y Yin1,3

  • 1State Key lab of Reproductive Medicine, Department of Pathology, Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing, China.

Oncogene
|February 24, 2015
PubMed

Insights

Insulin-like growth factor 1 (IGF-1) signaling and pyruvate kinase M2 (PKM2) interact to drive cancer. This study reveals a feedback loop involving PKM2, NF-κB, and microRNAs that, when disrupted, impacts cancer growth and triple-negative breast cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Pyruvate kinase M2 (PKM2) is upregulated in cancer, influencing cell metabolism and development.
  • The precise mechanisms driving PKM2 overexpression in cancer remain unclear.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of PKM2 overexpression.
  • To investigate the role of the IGF-1/IGF-IR pathway and microRNAs in PKM2 regulation.
  • To explore the PKM2/NF-κB/miR-148a/152 feedback loop in cancer, particularly in triple-negative breast cancer (TNBC).

Main Methods:

  • Investigated the interaction between IGF-1/IGF-IR, HIF-1α, and the PKM2 promoter.
  • Analyzed the regulation of PKM2 by miR-148a/152 suppression.
  • Examined the interaction of PKM2 with NF-κB p65 and its effect on EGR1 and the miR-148a/152 feedback circuit.
  • Assessed the impact of DNA hypermethylation on miR-148a/152 gene promoters in cancer cells.
  • Studied the consequences of disrupting the PKM2/NF-κB/miR-148a/152 feedback loop on cancer cell growth, angiogenesis, and TNBC phenotype.

Main Results:

  • IGF-1/IGF-IR signaling enhances PKM2 expression via HIF-1α-p65 complex binding to the PKM2 promoter.
  • PKM2 expression is suppressed by miR-148a/152.
  • In normal cells, PKM2 interacts with NF-κB p65 to promote EGR1, regulating a miR-148a/152 feedback circuit.
  • Cancer cells exhibit hypermethylation of miR-148a/152 promoters, disrupting this feedback loop and leading to PKM2, NF-κB, or IGF-IR overexpression.
  • Disruption of this feedback loop correlates with cancer cell growth, angiogenesis, and the TNBC phenotype.

Conclusions:

  • The IGF-1/IGF-IR pathway, through HIF-1α and NF-κB, plays a crucial role in regulating PKM2 expression.
  • A feedback loop involving PKM2, NF-κB, and miR-148a/152 is critical in normal cells but is dysregulated in cancer due to promoter hypermethylation.
  • This dysregulation contributes to cancer development and is linked to TNBC, suggesting potential diagnostic and therapeutic applications.

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