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Connective tissue growth factor and β ‐catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma
Author(s) -
Jiang Li,
Yamashita Yoriko,
Chew ShanHwu,
Akatsuka Shinya,
Ukai Shun,
Wang Shenqi,
Nagai Hirotaka,
Okazaki Yasumasa,
Takahashi Takashi,
Toyokuni Shinya
Publication year - 2014
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4377
Subject(s) - ctgf , autocrine signalling , mesothelioma , growth factor , connective tissue , cancer research , biology , pathology , medicine , receptor
Due to the formerly widespread use of asbestos, malignant mesothelioma ( MM ) is increasingly frequent worldwide. MM is classified into epithelioid ( EM ), sarcomatoid ( SM ), and biphasic subtypes. SM is less common than EM but is recognized as the most aggressive type of MM , and these patients have a poor prognosis. To identify genes responsible for the aggressiveness of SM , we induced EM and SM in rats, using asbestos, and compared their transcriptomes. Based on the results, we focused on connective tissue growth factor ( Ctgf ), whose expression was significantly increased in SM compared with EM ; EM itself exhibited an increased expression of Ctgf compared with normal mesothelium. Particularly in SM , Ctgf was a major regulator of MM proliferation and invasion through activation of the β ‐catenin– TCF–LEF signalling pathway, which is autocrine and formed a positive feedback loop via LRP6 as a receptor for secreted Ctgf. High Ctgf expression also played a role in the epithelial–mesenchymal transition in MM . Furthermore, Ctgf is a novel serum biomarker for both early diagnosis and determining the MM prognosis in rats. These data link Ctgf to SM through the LRP6–GSK3 β–β ‐catenin– TCF –Ctgf autocrine axis and suggest Ctgf as a therapeutic target. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.