title: STAT3 paradoxically stimulates β-catenin expression but inhibits β-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 β-catenin (through gene knock-down and dominant-negative TCF4 expression) in nine CRC cell lines. β-catenin inhibition did not affect STAT3 levels, whereas STAT3 knock-down resulted in reduced β-catenin mRNA and protein levels. The reduction in β-catenin protein was not prevented by proteasome inhibition, and IL6-induced STAT3 activation resulted in increased β-catenin mRNA. This suggests that STAT3 positively regulates β-catenin (at a transcriptional level) and evaluation of 44 CRCs by immunostaining supported this by showing an association between nuclear STAT3 expression and nuclear β-catenin (P = 0.022). We tested the functional interaction between STAT3 and Wnt signalling by knocking down STAT3 and β-catenin individually and in combination. Knock-down of β-catenin and STAT3 individually inhibited cell proliferation (P < 0. 001 for each) through G1 arrest. However, simultaneous knock-down of STAT3 and β-catenin had a significantly weaker effect than knock-down of β-catenin alone (P < 0.01). Knock-down of STAT3 and β-catenin, individually and together, inhibited cell motility (P < 0.001) without evidence of interaction. We conclude that STAT3 regulates β-catenin but β-catenin does not regulate STAT3. The STAT3/β-catenin interaction is complex but may reduce the proliferative activity of β-catenin possibly by taking β-catenin protein beyond the optimal level. This may indicate biological differences in tumours where both STAT3 and β-catenin are activated compared to those where only one is activated.
authors.affiliation: Academic Unit of Molecular Pathology, Nottingham University, Nottingham, UK.
authors.forename: Salih
authors.initials: S
authors.lastname: Ibrahem
authors.forename: Saleh
authors.initials: S
authors.lastname: Al-Ghamdi
authors.forename: Kanwal
authors.initials: K
authors.lastname: Baloch
authors.forename: Belal
authors.initials: B
authors.lastname: Muhammad
authors.forename: Wakkas
authors.initials: W
authors.lastname: Fadhil
authors.forename: Darryl
authors.initials: D
authors.lastname: Jackson
authors.forename: Abdolrahman S
authors.initials: AS
authors.lastname: Nateri
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ilyas
mesh_terms: D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D019073:HT29 Cells; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051176:beta Catenin
keywords: STAT3 signalling; Wnt signalling; colorectal cancer; oncogene interaction