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Metabolic regulation via a nuclear receptor/miRNA Pathway

Authors
Publisher
McGill University
Publication Date
Keywords
  • Biology - Molecular
Disciplines
  • Biology
  • Medicine
  • Musicology

Abstract

Cancer cell metabolism is often characterized by a shift from an oxidative to a glycolytic bioenergetic pathway, a phenomenon known as the Warburg effect. miR-378* is embedded within PPARGC1b which encodes PGC-1beta, a transcriptional regulator of oxidative energy metabolism. We show that miR-378* acts as a molecular switch involved in the orchestration of the Warburg effect in breast cancer cells via interference with the PGC-1beta/ERRgamma bioenergetics transcriptional pathway. Moreover, we identify that the expression of miR-378* is regulated by the breast cancer oncogene ERBB2, and that its expression in human breast cancer correlates with disease progression. Furthermore, we uncover that CAMKK2, the upstream kinase of the cellular energy sensor AMPK, is a functional direct target of miR-378* in breast cancer cells, through which miR-378* represses AMPK pathway activity.We have identified that modulation of the relative availabilities of the Estrogen-Related Receptor (ERR) isoforms ERRalpha and gamma is capable of inducing the Warburg effect. We then turned to an in-vivo system to further investigate the role of ERR in breast cancer. We found that the absence of ERRalpha delays ERBB2-induced mammary tumor onset but accelerates disease progression after onset. Moreover, tumor bearing ERRalpha KO mice exhibit signs of cancer cachexia, including failure to maintain normal body weight, heightened inflammation, and metabolic derangements such as elevated serum amino acids, molecular markers in the skeletal muscle and adipose tissue, and reduced adipose mass. Together, we identify that systemic ablation or inhibition of ERRalpha may render the host more susceptible to cancer cachexia, a disease characterized by elevated inflammation, metabolic derangements and tissue atrophy. The absence of mir-378 mouse models limited such in-vivo study of the functionally-related miRNA. Therefore, we produced mir-378 conditional and total knockout mouse models, which revealed thermogenesis-related phenotypes in the brown adipose tissue (BAT).

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