LGR5 induces β-catenin activation and augments tumour progression by activating STAT3 in human intrahepatic cholangiocarcinoma

Background & Aims LGR5 enhances Wnt-beta-catenin signalling; however, involvement of LGR5 or Wnt-beta-catenin signalling in ICC progression has not been reported. Methods Functions and regulations of LGR5-mediated beta-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 beta-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 beta-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-beta-catenin signalling enhanced CSC-like property and EMT by activating STAT3. In addition, LGR5 knockdown inhibited beta-catenin activation, resulting in suppression of beta-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 beta-catenin activation, and beta-catenin was unable to be activated without LGR5. Conclusions LGR5 is essential for beta-catenin activation induced by Wnt signalling. Activated beta-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.

Automated summary

The study found that LGR5 is essential for beta-catenin activation induced by Wnt signaling, leading to aggressive tumor progression and poor prognosis in patients with ICC. Inhibition of Wnt signaling suppressed beta-catenin activation, OLFM4 expression, STAT3 activation, and reduced cell invasiveness, suggesting that targeting LGR5 could be a promising therapeutic strategy for ICC.