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

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

SUBMITTER: Ibrahem S 

PROVIDER: S-EPMC4285465 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature