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STAT 3 paradoxically stimulates β‐catenin expression but inhibits β‐catenin function
Author(s) -
Ibrahem Salih,
AlGhamdi Saleh,
Baloch Kanwal,
Muhammad Belal,
Fadhil Wakkas,
Jackson Darryl,
Nateri Abdolrahman S.,
Ilyas Mohammad
Publication year - 2014
Publication title -
international journal of experimental pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.671
H-Index - 72
eISSN - 1365-2613
pISSN - 0959-9673
DOI - 10.1111/iep.12102
Subject(s) - catenin , wnt signaling pathway , stat protein , stat3 , biology , cell growth , stat , beta catenin , chemistry , microbiology and biotechnology , cancer research , signal transduction , genetics
Summary Wnt signalling and the signal transducer and activator of transcription 3 ( STAT 3) 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 STAT 3 and β‐catenin (through gene knock‐down and dominant‐negative TCF 4 expression) in nine CRC cell lines. β‐catenin inhibition did not affect STAT 3 levels, whereas STAT 3 knock‐down resulted in reduced β‐catenin m RNA and protein levels. The reduction in β‐catenin protein was not prevented by proteasome inhibition, and IL 6‐induced STAT 3 activation resulted in increased β‐catenin m RNA . This suggests that STAT 3 positively regulates β‐catenin (at a transcriptional level) and evaluation of 44 CRC s by immunostaining supported this by showing an association between nuclear STAT 3 expression and nuclear β‐catenin ( P = 0.022). We tested the functional interaction between STAT 3 and W nt signalling by knocking down STAT 3 and β‐catenin individually and in combination. Knock‐down of β‐catenin and STAT 3 individually inhibited cell proliferation ( P < 0. 001 for each) through G 1 arrest. However, simultaneous knock‐down of STAT 3 and β‐catenin had a significantly weaker effect than knock‐down of β‐catenin alone ( P < 0.01). Knock‐down of STAT 3 and β‐catenin, individually and together, inhibited cell motility ( P < 0.001) without evidence of interaction. We conclude that STAT 3 regulates β‐catenin but β‐catenin does not regulate STAT 3. The STAT 3/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 STAT 3 and β‐catenin are activated compared to those where only one is activated.