iRHOM2 in skin disease and oesophageal cancer

Abstract

Mutations in RHBDF2, the gene encoding inactive rhomboid protein iRHOM2, result in the dominantly inherited condition Tylosis with oesophageal cancer (TOC). TOC causes plamoplantar keratoderma, oral precursor lesions and up to a 95 % life-time risk of oesophageal squamous cell carcinoma (SCC). The role of iRHOM2 in the epidermis is not well characterised, although we previously showed dysregulated epidermal growth factor receptor (EGFR) signalling and accelerated migration in TOC keratinocytes, and a role for iRHOM2 was shown in trafficking the metalloproteinase ADAM17. Substrates of ADAM17 include EGFR ligands and adhesion molecules. iRHOM2 localisation and function were investigated in frozen sections and keratinocyte cell lines from control and TOC epidermis. Although iRHOM2 was predicted to be an ER-membrane protein, it showed cell-surface expression in control epidermis, with variable localisation in TOC. Increased processing and activation of ADAM17 was seen in TOC keratinocytes compared with control cells, suggesting that increased ADAM17-mediated processing of EGFR ligands may cause the changes in EGFR signalling. Downstream of iRHOM2-ADAM17, Eph/Ephrin and NOTCH signalling also appeared affected. Additionally, desmosomes in TOC epidermis lacked the electron-dense midline of the mature desmosomes seen in normal skin; this was accompanied by increased processing of desmoglein 2, a substrate of ADAM17. Expression and localisation of iRHOM2 was also investigated in TOC and sporadic SCC. iRHOM2 expression varied between SCC cell lines, and appeared to correlate with ADAM17 and NOTCH1 expression in oesophageal SCC and head and neck SCC cells. In summary, iRHOM2 mutations in TOC appear to be gain-of-function in nature, resulting in increased ADAM17 processing and enhanced EGFR signalling. Questions remaining include the reason why iRHOM2 is found at the plasma membrane. Future study of the iRHOM2-ADAM17 pathway may provide additional insight into the mechanism of epidermal wound healing and the pathogenesis of oesophageal SCC.