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.

Citation

Ibrahem, S., Al‐Ghamdi, S., Baloch, K., Muhammad, B., Fadhil, W., Jackson, D., …Ilyas, M. (2014). STAT3 paradoxically stimulates β‐catenin expression but inhibits β‐catenin function. International Journal of Experimental Pathology, 95(6), 392-400. https://doi.org/10.1111/iep.12102

• 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