STAT3 paradoxically stimulates β-catenin expression but inhibits β-catenin function

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.