Downregulation of estrogen-related receptor alpha inhibits human cutaneous squamous cell carcinoma cell proliferation and migration by regulating EMT via fibronectin and STAT3 signaling pathways

Abstract

Estrogen-related receptor alpha (ERRα), one of orphan nuclear receptors, has been recently revealed as an oncogenic regulator in a variety of cancers. However, the linking gain of ERRα expression and cancer progression in cutaneous squamous cell carcinoma (cSCC) is largely unknown. Here, we showed that the mRNA and protein expression levels of ERRα were markedly higher in A431 cells compared with human keratinocyte cell line HaCaT, and targeted inhibition of ERRα by shRNA or its inverse agonist XCT790 significantly suppressed A431 cells proliferation and migration, while overexpression of ERRα promoted cell proliferation and migration. In addition, the data revealed that ERRα downregulation markedly inhibited the epithelial mesenchymal transition (EMT) of A431 cells with increasing the expression of E-cadherin and decreasing fibronectin (FN) and vimentin. Results from further experiments using Western blot suggested that ERRα suppression inhibited signal transducer and activator of transcription (STAT3) protein expression. In contrast, overexpression of ERRα promoted EMT and the activation of STAT3 pathway. Moreover, treatment with specific STAT3 inhibitor reversed EMT markers in ERRα-overexpressing A431 cells. In tumor xenografts of A431 cells, we further showed that ERRα depletion inhibited cSCC tumor growth in vivo. Taken together, these results demonstrate, for the first time, that ERRα may function as an oncoprotein in cSCC to accelerate tumor aggressiveness by promoting EMT via FN and STAT3 pathway, and it could be a novel target for cSCC therapy.

Keywords: Cutaneous squamous cell carcinoma; Epithelial mesenchymal transition; Estrogen-related receptor alpha; Fibronectin; Signal transducer and activator of transcription.