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LGR5 induces β activation and augments tumor progression by activating STAT3 in human intrahepatic cholangiocarcinoma

Background & aims: LGR5 enhances Wnt- β-catenin signaling; however, involvement of LGR5 or Wnt- β-catenin signaling in ICC progression has not been reported.

Methods: Functions and regulations of LGR5-mediated β-catenin activation in ICC progression were evaluated using surgical specimens collected from 61 ICC patients or two 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 signaling 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 signaling. Activated β-catenin further activates STAT3 and enhances CSC-like property and EMT, leading to aggressive tumor progression and poor prognosis in patients with ICC. Therefore, LGR5 is an excellent prognostic predictor and a promising therapeutic target for ICC.

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S7085 IWP-2 IWP-2 is an inhibitor of Wnt processing and secretion with IC50 of 27 nM in a cell-free assay, selective blockage of Porcn-mediated Wnt palmitoylation, does not affect Wnt/β-catenin in general and displays no effect against Wnt-stimulated cellular responses. IWP-2 specifically inhibits CK1δ. (46) (3)

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