Abstract
Type VII collagen is the main component of anchoring fibrils, structures that are 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, which is 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 expression of OATP1B3 has yet to be determined. Here, we identify SLCO1B3 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 show that reduction of SLCO1B3 expression upon expression of full-length type VII collagen 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.
Highlights
Incidence of non-melanoma skin cancer (NMSC) is highest among all malignancies in Caucasian populations (Toms, 2004; Cancer Research UK, 2012, http://publications.cancerresearchuk. org/cancerstats/statsskin/keyfactsskin.html)
SLCO1B3 is expressed in cutaneous squamous cell carcinoma (cSCC) in vitro and in vivo We previously identified only 18 genes to be significantly differentially expressed between cultured recessive dystrophic epidermolysis bullosa (RDEB) cSCC keratinocytes and UV-induced cSCC keratinocytes using gene expression arrays, demonstrating these two tumour groups are not significantly different in this assay (Watt et al, 2011)
We investigated the link between engulfment and motility 2 (ELMO2) and SLCO1B3 expression and showed that overexpression of ELMO2 resulted in a reduction in SLCO1B3 mRNA levels in SCCT8 and SCCRDEB2 (Fig. 7A,B), whereas a reduction in ELMO2 mRNA resulted in an increase in SLCO1B3 expression in SCCT8 (Fig. 7C,D) and nonSCC RDEB keratinocytes, with a significant increase in SLCO1B3 observed in normal primary keratinocytes after ELMO2 reduction, thereby demonstrating that similar to COL7A1, ELMO2 can negatively regulate SLCO1B3
Summary
Incidence of non-melanoma skin cancer (NMSC) is highest among all malignancies in Caucasian populations (Toms, 2004; Cancer Research UK, 2012, http://publications.cancerresearchuk. org/cancerstats/statsskin/keyfactsskin.html). Inherited skin disease can predispose to developing cSCC (Ng et al, 2011); in particular, individuals diagnosed with recessive dystrophic epidermolysis bullosa (RDEB) (Reed et al, 1975; Fine et al, 2009). Patients with this disease are affected by deleterious mutations in COL7A1, leading to either defective or absent type VII collagen (Christiano et al, 1993). Despite an alarming rise in the incidence of cSCC in the general population and a relatively low 5-year survival in patients presenting with regional metastasis (Rowe et al, 1992; Czarnecki et al, 1994), little is understood about these tumours with poor prognosis
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