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LGR5 induces β‐catenin activation and augments tumour progression by activating STAT3 in human intrahepatic cholangiocarcinoma
Author(s) -
Kawasaki Keishi,
Kuboki Satoshi,
Furukawa Katsunori,
Takayashiki Tsukasa,
Takano Shigetsugu,
Ohtsuka Masayuki
Publication year - 2021
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.14747
Subject(s) - lgr5 , wnt signaling pathway , cancer research , catenin , cancer stem cell , beta catenin , gene knockdown , stem cell , biology , signal transduction , microbiology and biotechnology , cell culture , genetics
Background & Aims LGR5 enhances Wnt‐β‐catenin signalling; however, involvement of LGR5 or Wnt‐β‐catenin signalling 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 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.