Abstract
The progression of colorectal carcinoma (CRC) to invasive and metastatic disease may involve localized occurrences of epithelial-mesenchymal transition (EMT). However, mechanisms of the EMT process in CRC progression are not fully understood. We previously showed that knockdown of signal transducer and activator of transcription 3 (STAT3) up-regulated E-cadherin (a key component in EMT progression) in CRC. In this study, we examined the roles of STAT3 in CRC EMT and ZEB1, an EMT inducer, in STAT3-induced down-regulation of E-cadherin. Knockdown of STAT3 significantly increased E-cadherin and decreased N-cadherin and vimentin expressions in highly invasive LoVo CRC cells. Meanwhile, overexpression of STAT3 significantly reduced E-cadherin and enhanced N-cadherin and vimentin expressions in weakly invasive SW1116 CRC cells. Activation of STAT3 significantly increased CRC cell invasiveness and resistance to apoptosis. Knockdown of STAT3 dramatically enhanced chemosensitivity of CRC cells to fluorouracil. STAT3 regulated ZEB1 expression in CRC cells, and the STAT3-induced decrease in E-cadherin and cell invasion depended on activation of ZEB1 in CRC cells. Additionally, pSTAT3(Tyr-705) and ZEB1 expressions were significantly correlated with TNM (tumor, lymph node, and metastasis stages) (p < 0.01). In conclusion, STAT3 may directly mediate EMT progression and regulate ZEB1 expression in CRC. ZEB1 may participate in STAT3-induced cell invasion and E-cadherin down-regulation in CRC cells. The expressions of pSTAT3(Tyr-705) and ZEB1 may be positively associated with CRC metastasis. Our data may provide potential targets to prevent and/or treat CRC invasion and metastasis.
Highlights
Colorectal cancer (CRC) to metastatic disease may involve the epithelial-mesenchymal transition (EMT)
Effect of signal transducer and activator of transcription 3 (STAT3) on E-cadherin, N-cadherin, and Vimentin Expressions in CRC Cells—We previously showed that activated STAT3 is constitutively expressed in CRC and mediates cell proliferation, whereas knockdown of STAT3 significantly restores E-cadherin expression [18]
To determine whether STAT3 mediates EMT initiation in CRC cells, the effect of STAT3 Small Interfering RNA (siRNA) was evaluated in highly invasive LoVo CRC cells
Summary
Colorectal cancer (CRC) to metastatic disease may involve the epithelial-mesenchymal transition (EMT). We previously showed that knockdown of signal transducer and activator of transcription 3 (STAT3) up-regulated E-cadherin (a key component in EMT progression) in CRC. Whether STAT3 contributes to the EMT process of CRC progression and the mechanisms of STAT3-induced E-cadherin down-regulation are not known. We show that STAT3 may directly induce cell invasion and participate in resistance to chemotherapy drugs and apoptosis during EMT of CRC progression. To our knowledge, this is the first study to report that STAT3 may directly mediate the EMT process and ZEB1 expression of CRC progression. STAT3-induced cell invasion and decrease in E-cadherin expression depend on activation of ZEB1 in CRC cells. The combination of pSTAT3Tyr-705/ZEB1 may be a novel predictor of CRC metastasis and a potential therapeutic target
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