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.
Highlights
Colorectal cancer (CRC) represents one of the most common causes of cancer-related death around the world (Stewart & Kleihues 2003)
Given the mixed published data regarding the nature of the biochemical interaction of signal transducer and activator of transcription 3 (STAT3) and b-catenin, we first sought to ascertain whether STAT3 and b-catenin were able to regulate each other
We extended our study by knocking down STAT3 only in a further three cell lines that is HT29, C106 and HCT116 and, our observations were identical (Figure 1b)
Summary
Colorectal cancer (CRC) represents one of the most common causes of cancer-related death around the world (Stewart & Kleihues 2003). The development of CRC is a paradigm of multistep carcinogenesis with tumours arising from normal epithelium as a consequence of the stepwise accumulation of mutations (Ilyas et al 1999). The ‘order’ of mutation [first described in the Fearon and Vogelstein model (Fearon & Vogelstein 1990)] is generally well conserved allowing mutations to be categorized as ‘early’ or ‘late’ events. The selection of mutations is driven by Darwinian evolution with mutations which confer a selective advantage allowing clonal expansion to occur (Greaves & Maley 2012). A new mutation will interact with the antecedent mutations, and there may be functional overlap between different mutations. It is possible that some mutations may become redundant due to either a functional redundancy with subsequent mutations or a change in growth restraints (known as ‘oncogene amnesia’)
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