WT1 expression is increased in primary fibroblasts derived from Dupuytren’s disease tissues

Abstract

Dupuytren's disease (DD) is a fibroproliferative and contractile fibrosis of the palmar fascia that, like all other heritable fibroses, is currently incurable. While DD is invariably benign, it exhibits some molecular similarities to malignant tumours, including increased levels of ß-catenin, oncofetal fibronectin, periostin and insulin-like growth factor (IGF)-II. To gain additional insights into the pathogenesis of DD, we have assessed the expression of WT1, encoding Wilm's tumour 1, an established tumour biomarker that is syntenic with IGF2, the gene encoding IGF-II in humans. We found that WT1 expression is robustly and consistently up regulated in primary fibroblasts derived from the fibrotic palmar fascia of patients with DD (DD cells), whereas syngeneic fibroblasts derived from the macroscopically unaffected palmar fascia in these patients and allogeneic fibroblasts derived from normal palmar fascia exhibited very low or undetectable WT1 transcript levels. WT1 immunoreactivity was evident in a subset of cells in the fibrotic palmar fascia of patients with DD, but not in macroscopically unaffected palmar fascia. These findings identify WT1 expression as a novel biomarker of fibrotic palmar fascia and are consistent with the hypothesis that the pathogeneses of DD and malignant tumours have molecular similarities.

Sustained AWT1 expression by Dupuytren’s disease myofibroblasts promotes a proinflammatory milieu

“…Our original report of increased WT1 mRNA levels and WT1 immunoreactivity in DD PFMs and tissues (Crawford et al 2015) did not identify the specific WT1 transcript variants involved. As shown in Fig.…”

“…From left, molecular weight markers (MW), A: Nested forward and reverse primers targeting exons 1 and 3 of canonical WT1 sequence (234 bp amplicon), B: Nested forward and reverse primers targeting intron 1 and exon 3 to detect AWT1 transcripts (219 bp amplicon), C: Nested forward and reverse primers targeting a region encoding the 5′ untranslated region of canonical WT1 and exon 1 to detect ExtWT1 transcript amplification (152 bp amplicon), D: Sample C omitting reverse transcriptase as a control for DNA contamination. The locations of transcript‐specific primers are illustrated as red arrows and the Taqman primer set used to detect WT1 mRNA transcripts in Crawford et al (2015) is shown as blue arrows with a yellow star indicating Taqman probe location…”

“…In this study, we have expanded on our previous findings of increased WT1 gene expression and Wilms Tumor 1 (WT1) immunoreactivity in DD myofibroblasts and surgically resected tissues (Crawford et al 2015). The WT1 gene encodes multiple gene transcripts derived from different transcriptional start sites and alternative mRNA splicing, resulting in the translation of an array of proteins that function, amongst other roles, as transcription factors in cancers (Langerak et al 1995; Kennedy et al 1996; Dallosso et al 2007; Amin et al 2011).…”

Connective Tissue Degeneration: Mechanisms of Palmar Fascia Degeneration (Dupuytren’s Disease)

“…Novel players have been implicated in the pathogenesis of DD such as Wilm’s tumour protein-1 (WT1) [ 31 •] and YAP [ 32 •]. YAP1, a member of the Hippo pathway, which has recently been shown to promote differentiation of fibroblasts into myofibroblasts, potentially acts downstream of TGFβ [ 32 •].…”