Type VII collagen regulates tumour expression of organic anion transporting polypeptide OATP1B3, promotes front to rear polarity and increases structural organisation in 3D spheroid cultures of recessive dystrophic epidermolysis bullosa tumour keratinocytes

Abstract

Type VII collagen is the main component of anchoring fibrils, structures integral to basement membrane homeostasis in skin. Mutations in the gene encoding type VII collagen, COL7A1, cause recessive dystrophic epidermolysis bullosa (RDEB) an inherited skin blistering condition complicated by frequent aggressive cutaneous squamous cell carcinoma (cSCC). OATP1B3, encoded by the gene SLCO1B3, is a member of the OATP (organic anion transporting polypeptide) superfamily responsible for transporting a wide range of endogenous and xenobiotic compounds. OATP1B3 expression is limited to the liver in healthy tissues but is frequently detected in multiple cancer types and is reported to be associated with differing clinical outcome. The mechanism and functional significance of tumour specific OATP1B3 expression has yet to be determined. Here, we identify SLCO1B3 (encoding OATP1B3) expression in tumour keratinocytes isolated from RDEB and UV induced cSCC and demonstrate that SLCO1B3 expression and promoter activity are modulated by type VII collagen. We demonstrate that reduction of SLCO1B3 expression upon full length type VII collagen expression in RDEB cSCC coincides with acquisition of front to rear polarity and increased organisation of 3D spheroid cultures. In addition we show that type VII collagen positively regulates the abundance of markers implicated in cellular polarity, namely ELMO2, PAR3, E-cadherin, B-catenin, ITGA6 and Ln332.