STATs signalling in human bladder cancer : potential chemopreventive role for indoles
thesisposted on 15.12.2014, 10:32 by Yiyang Sun
In patient tissues, STAT1, STAT3and STAT5 were observed in normal bladder epithelium, while expression of phosphorylated proteins was essentially absent. In contrast, phospho-STAT3 in superficial tumours and phospho-STAT1, 3 and 5 in muscle invasive tumours were present. Thus their increased expression, activation and nuclear localisation, may be associated with bladder tumour progression. Three epithelial bladder cancer lines (RT112, RT4, HT1376) had constitutive phospho-STAT5, while three mesenchymal lines (J82, T24, UMUC3) had activated STAT3. Specific knockdown of STAT3 in J82 cells increased STAT1 expression and phosphorylation. STAT1 and/or STAT3 knockdown led to inhibition of cell-matrix adhesion to fibronectin or collagen and suppression of cell migration. The dietary molecules, Indole-3-carbinol (I3C) (â‰¥100microM) or 3, 3'-diindolylmethane (DIM) (â‰¥50microM) induced apoptosis in J82 and RT112 cells by 48 hours. DIM-induced apoptosis in J82 cells was accompanied by downregulation of STAT1, 5a and 5b and inhibition of phospho-STAT1 and phospho-STAT3. In RT112 cells, DIM inhibited STAT5a, 5b and phospho-STAT5, but had no effect on STAT3. DIM (â‰¥10microM) inhibited J82 cell adhesion to fibronectin and collagen, accompanied by decreased N-cadherin, P-cadherin and beta-catenin expression. Furthermore, DIM (1microM) was able to significantly decrease cell adhesion following STAT1 and/or STAT3 knockdown, suggesting inhibition of cell adhesion by DIM may involve the STAT pathway. Phosphorylated STATs may be a potential marker of invasiveness in human bladder cancer. Elucidation of the effects of indoles and DIM in particular, at a molecular level has given an insight as to how these dietary agents may be useful in the therapy and/or prevention of bladder tumours.