Connective tissue growth factor and β-catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma.
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-GSK3β-β-catenin-TCF-Ctgf autocrine axis and suggest Ctgf as a therapeutic target.
Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Japan.
Li
L
Jiang
Yoriko
Y
Yamashita
Shan-Hwu
SH
Chew
Shinya
S
Akatsuka
Shun
S
Ukai
Shenqi
S
Wang
Hirotaka
H
Nagai
Yasumasa
Y
Okazaki
Takashi
T
Takahashi
Shinya
S
Toyokuni
D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008654:Mesothelioma / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000086002:Mesothelioma, Malignant; D051381:Rats; D011916:Rats, Inbred F344; D012509:Sarcoma / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology; D051820:TCF Transcription Factors / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
D014408:Biomarkers, Tumor; C526316:CCN2 protein, rat; D051820:TCF Transcription Factors; D051176:beta Catenin; D055513:Connective Tissue Growth Factor; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3
connective tissue growth factor; mesothelioma; sarcomatoid mesothelioma; serum marker; β-catenin