CAVEOLIN-1: A NOVEL REGULATOR OF EPITHELIAL TO MESENCHYMAL TRANSITION IN HUMAN GINGIVAL FIBROBLAST CELLS UNDER HYPOXIA

Abstract

The interplay of multiple signaling pathways was identified in the development of tissue fibrosis. Caveolin- 1 played a paramount role in the integration of molecular cell signaling pathways that ultimately resulted to epithelial mesenchymal transition (EMT) in human gingival fibroblast (hGF) cells, kept under a hypoxic milieu. The present investigation demonstrated an upregulated expression of the transcription factor hypoxia inducible factor- 1α (HIF-1α) along with the molecular chaperon HSP90 with concomitant downregulation of Caveolin-1. Under hypoxic microenvironment, upregulated Smad2/3 complexed with Smad4 and translocated to the nucleus, activating the transcription of LEF-1. Similarly, the attenuated expression of pMst1/2 and pLats2 resulted in the nuclear localization of dephosphorylated Yap and Taz, and the transcription of Connective Tissue Growth Factor (CTGF) inducing the formation of myofibroblast and excessive synthesis of extracellular matrix (ECM). Upregulated expression of β- catenin, with respect to the activated Wnt signaling pathway in hGF cells during hypoxia, resulted its nuclear introduction and interaction with LEF-1/TCF transcription factors, ultimately promoting the elevated expression of mesenchymal markers (Snail, Slug, Twist) and diminished expression of epithelial marker, E- cadherin. Thus, the present study characterized the role of HSP90 inhibition in the regulation of EMT through the integrated signaling network of TGF-β, Wnt and Hippo pathways and identified Caveolin-1 as a novel regulator of EMT in human gingival fibroblasts (hGF), under hypoxia