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- Title
Regulatory circuit of PKM2/NF-κB/miR-148a/152-modulated tumor angiogenesis and cancer progression.
- Authors
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
- 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.
- Subjects
CANCER invasiveness; PYRUVATE kinase; MICRORNA; NEOVASCULARIZATION; NF-kappa B; GENETIC regulation
- Publication
Oncogene, 2015, Vol 34, Issue 43, p5482
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2015.6