STAT3 paradoxically stimulates ??catenin expression but inhibits ??catenin function

Ibrahem, Salih; Al?Ghamdi, Saleh; Baloch, Kanwal; Muhammad, Belal; Fadhil, Wakkas; Jackson, Darryl; Nateri, Abdolrahman; Ilyas, Mohammad

Abstract

Wnt signalling and the signal transducer and activator of transcription 3 (STAT3) are oncogenic signalling pathways which are deregulated in colorectal cancer (CRC). Here we investigated the interaction of these two pathways. Firstly, we investigated biochemical interaction by inhibiting STAT3 and b-catenin (through gene knockdown and dominant-negative TCF4 expression) in nine
CRC cell lines. b-catenin inhibition did not affect STAT3 levels, whereas STAT3 knock-down resulted in reduced b-catenin mRNA and protein levels. The reduction in b-catenin protein was not prevented by proteasome inhibition, and IL6-induced STAT3 activation resulted in increased b-catenin mRNA. This suggests that STAT3 positively regulates b-catenin (at a transcriptional level) and evaluation of 44 CRCs by immunostaining supported this by showing an association between nuclear STAT3 expression and nuclear b-catenin (P = 0.022). We tested the functional interaction between STAT3 and Wnt signalling by knocking down STAT3 and b-catenin individually and in combination. Knock-down of b-catenin and STAT3 individually inhibited cell proliferation (P < 0. 001 for each) through G1 arrest. However, simultaneous knockdown of STAT3 and b-catenin had a significantly weaker effect than knock-down of b-catenin alone (P < 0.01). Knock-down of STAT3 and b-catenin, individually and together, inhibited cell motility (P < 0.001) without evidence of interaction. We conclude that STAT3 regulates b-catenin but b-catenin does not regulate STAT3. The STAT3/b-catenin interaction is complex but may reduce the proliferative activity of b-catenin possibly by taking b-catenin protein beyond the optimal level. This may indicate biological differences in tumours where both STAT3 and b-catenin are activated compared to those where only one is activated.

• Journal Article Type: Article
• Acceptance Date: Sep 1, 2014
• Online Publication Date: Oct 28, 2014
• Publication Date: Dec 1, 2014
• Deposit Date: Jan 25, 2018
• Publicly Available Date: Apr 3, 2019
• Print ISSN: 0959-9673
• Electronic ISSN: 1365-2613
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 95
• Issue: 6
• Pages: 392-400
• DOI: https://doi.org/10.1111/iep.12102
• Public URL: https://nottingham-repository.worktribe.com/output/1118903
• Publisher URL: https://onlinelibrary.wiley.com/doi/abs/10.1111/iep.12102
• PMID: 00034697