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

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-1α-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.

• Authors: 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
• Journal: Oncogene (Oncogene) Vol. 34 Issue 43 Pg. 5482-93 (Oct 2015) ISSN: 1476-5594 [Electronic] England
• PMID: 25703326 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Carrier Proteins
• EGR1 protein, human
• Early Growth Response Protein 1
• MIRN148 microRNA, human
• MIRN152 microRNA, human
• Membrane Proteins
• MicroRNAs
• NF-kappa B
• Thyroid Hormones
• thyroid hormone-binding proteins

Topics

• Biomarkers, Tumor (genetics)
• Carrier Proteins (genetics)
• Cell Line
• Cell Line, Tumor
• Cell Proliferation (genetics)
• DNA Methylation (genetics)
• Disease Progression
• Early Growth Response Protein 1 (genetics)
• HEK293 Cells
• Humans
• Membrane Proteins (genetics)
• MicroRNAs (genetics)
• NF-kappa B (genetics)
• Neovascularization, Pathologic (genetics)
• Promoter Regions, Genetic (genetics)
• Thyroid Hormones (genetics)
• Triple Negative Breast Neoplasms (genetics, pathology)
• Up-Regulation (genetics)