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Abstract
Emerging evidence has suggested that glycolysis is enhanced in cancer-associated fibroblasts (CAF), and miR-186 is downregulated during the CAF formation. However, it is not clear whether miR-186 is involved in the regulation of glycolysis and what the role of miR-186 plays during the CAF formation. In this study, quantitative PCR analysises show miR-186 is downregulated during the CAF formation. Moreover, miR-186 targets the 3' UTR of Glut1, and its overexpression results in the degradation of Glut1 mRNA, which eventually reduces the level of Glut1 protein. On the other hand, knockdown of miR-186 increased the expression of Glut1. Both time course and dose response experiments also demonstrated that the protein and mRNA levels of Glut1 increase during CAF formation, according to Western blot and quantitative PCR analyses, respectively. Most importantly, besides the regulation on cell cycle progression, miR-186 regulates glucose uptake and lactate production which is mediated by Glut1. These observations suggest that miR-186 plays important roles in glycolysis regulation as well as cell cycle checkpoint activation.
Highlights
Cancer-associated fibroblasts (CAFs) are activated fibroblasts and a major component of the tumor stroma
We have demonstrated that Glut1 protein level increases during CAF formation, and miR-186 directly targets Glut1 mRNA; in turn, miR-186 regulates glycolysis through affecting Glut1 protein level
MiR-186 was downregulated in tumor cells (Cai et al, 2013; Li et al, 2013a), and correlated with poor survival of patients bearing with lung adenocarcinoma (Cai et al, 2013)
Summary
Cancer-associated fibroblasts (CAFs) are activated fibroblasts and a major component of the tumor stroma. Glut is often overexpressed in a variety of malignant neoplasms, which suggests that this increase is required for increased glucose uptake and accelerated metabolism (Amann et al, 2009). It is not clear whether and how the expression of Glut is upregulated during the CAF formation. Knockdown of the miR-186 increased the CKIIa protein level It is unknown about the role of miR-186 in glycolysis. We have demonstrated that Glut protein level increases during CAF formation, and miR-186 directly targets Glut mRNA; in turn, miR-186 regulates glycolysis through affecting Glut protein level. Protein was separated on polyacrylamide gels, transferred to a nitrocellulose membrane and incubated with antibodies against GLUT1 (Epitomics, CA, USA); antibody against β-Actin (Santa Cruz Biotechnology, CA, USA) as an internal control
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