Abstract 43: MicroRNA-130b mediates a metabolic switch to promote cutaneous squamous cell carcinoma development

Abstract

Abstract Metabolic reprogramming has been emerging as a hallmark of cancer. Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with about 700,000 new cases annually in the U.S. We aim to investigate the role of miR-130b in reprogramming metabolism as a driver of cSCC development. Since skin cancers have the highest mutational loads among any human cancers, we used well-controlled comparisons across tissues and across species to narrow down the number of important candidate drivers. Using the approach of matched isogenic human samples and cross-species analysis using our UV-driven hairless mouse model, we identified aberrantly expressed microRNAs (miRNAs) and their target mRNAs in order to unravel additional mechanisms behind cSCC progression. We focus on miRNAs because they regulate numerous mRNA targets and can be manipulated for cancer therapy. We observed that miR-130b is increased in both human and mouse cSCC by 3.3-fold, and 2.6-fold, respectively. In adipocytes, miR-130b is known to reduce fat deposition and cell differentiation through targeting PPARγ. Our data and the TargetScan algorithm suggested that in keratinocytes, miR-130b suppresses PPARγ, FBP1, PGC-1α and PDK4. These genes are down-regulated in SCC tumors (compared to normal skin). Also, they are regulators of glycolysis, mitochondrial activity and lipid biosynthesis. Specifically, PPARγ promotes lipid biosynthesis; PGC-1α and PDK4 control mitochondrial activity; FBP1 suppresses glycolysis. Thus, we hypothesize that the cSCC metabolic phenotype is driven mostly by glycolysis and that miR-130b is a regulator of this metabolic switch. We found that in cSCC cell lines, proliferation is reduced by up to 30% when miR-130b was inhibited. Also in the same setting, less glucose was consumed and less lactate was produced, suggesting that miR-130b promotes glycolysis. Realtime-PCR shows that miR-130b levels are up-regulated in SCC tumors and in SCC cell lines (compared to normal skin and primary keratinocytes, respectively). On the other hand, PPARγ and PGC-1α gene expression decreases during SCC development. To study the long-term effects of miR-130b depletion, we have also developed an inducible CRISPRi system that suppresses microRNA expression. Finally, rosiglitazone, a PPARγ agonist, suppresses the proliferation of several SCC cell lines and is under several trials for breast cancer and liposarcoma, thus suggesting that this pathway may be targetable in SCC as well. Our current studies are focused on the precise roles of PPARγ transcriptional targets, which may include FBH1, PGC-1α and PDK4 in cSCC. Citation Format: Tran N. Nguyen, Sydney Moyer, Charles H. Adelmann, Vida Chitsazzadeh, Kenneth Y. Tsai. MicroRNA-130b mediates a metabolic switch to promote cutaneous squamous cell carcinoma development. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 43.