Aims
LGR5 enhances Wnt-β-catenin signalling; however, involvement of LGR5 or Wnt-β-catenin signalling in ICC progression has not been reported.
Background & aims
LGR5 enhances Wnt-β-catenin signalling; however, involvement of LGR5 or Wnt-β-catenin signalling in ICC progression has not been reported.
Conclusions
LGR5 is essential for β-catenin activation induced by Wnt signalling. Activated β-catenin further activates STAT3 and enhances CSC-like property and EMT, leading to aggressive tumour progression and poor prognosis in patients with ICC. Therefore, LGR5 is an excellent prognostic predictor and a promising therapeutic target for ICC.
Methods
Functions and regulations of LGR5-mediated β-catenin activation in ICC progression were evaluated using surgical specimens collected from 61 ICC patients or 2 ICC cell lines.
Results
LGR5 expression was increased in some cases of ICC. It was positively correlated with β-catenin activation, OLFM4 expression and STAT3 activation, and negatively correlated with GRIM19 expression in ICC, thereby enhancing cancer stem cell (CSC)-like property and EMT. High LGR5 expression was an independent factor for poor prognosis in ICC after operation. In vitro, Wnt inhibition by IWP-2 suppressed β-catenin activation, OLFM4 expression and STAT3 activation. IWP-2 treatment decreased expression of EpCAM, CD133, vimentin and increased E-cadherin expression. The rate of mesenchymal cells was decreased and cell invasiveness was suppressed after IWP-2 treatment, suggesting that Wnt-β-catenin signalling enhanced CSC-like property and EMT by activating STAT3. In addition, LGR5 knockdown inhibited β-catenin activation, resulting in suppression of β-catenin-induced STAT3 activation through inhibition of OLFM4-GRIM19 cascade. As these results, LGR5 knockdown suppressed CSC-like property and EMT. Therefore, LGR5 was a key regulator for β-catenin activation, and β-catenin was unable to be activated without LGR5. Conclusions: LGR5 is essential for β-catenin activation induced by Wnt signalling. Activated β-catenin further activates STAT3 and enhances CSC-like property and EMT, leading to aggressive tumour progression and poor prognosis in patients with ICC. Therefore, LGR5 is an excellent prognostic predictor and a promising therapeutic target for ICC.