Connective tissue growth factor and β‐catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma

Abstract

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.

Malignant mesothelioma as an oxidative stress-induced cancer: An update

“…Interestingly, our results using the rat mesothelioma model also revealed similar findings with significantly increased CTGF expression in the mesothelioma tumors, especially the sarcomatoid subtype. We further showed that CTGF is secreted, is increased in serum, and promotes mesothelioma tumorigenicity via a vicious autocrine loop involving the activation of the β-catenin signaling pathway [108]. Shao and colleagues recently demonstrated that YAP formed a functional complex with the FoxO1 transcription factor to promote the transcription of antioxidant genes such as catalase and manganese superoxide dismutase which protect cardiomyocytes from oxidative stress-induced cell death [109].…”

“…Further studies are necessary to determine the functional effects of CD146 and IMP3 overexpression in MM progression. In addition, our recent study has identified CTGF as a highly promising novel diagnostic and prognostic marker for MM, especially for sarcomatoid subtype, based on rat mesothelioma model [108].…”

Urokinase-type plasminogen activator receptor promotes proliferation and invasion with reduced cisplatin sensitivity in malignant mesothelioma

“…Here, we used genome-wide expressing profiling from our animal carcinogenesis model to focus on uPAR [25, 26]. For the first time, we showed that uPAR overexpression is observed in asbestos-induced rat MM, regardless of the asbestos fibers used for carcinogenesis and the histological subtype of MM.…”

“…Rat whole-genome microarrays (G4131F; Agilent Technologies, USA) were used; two normal mesothelial tissues obtained by scraping normal rat pleural and peritoneal cavities were used as controls [51], and 21 rat MM tissues (8 epithelioid subtype (EM) and 13 sarcomatoid subtype (SM)) were used as previously described [26] and registered as GEO Accession No. GSE48298 [26]. All expression data were normalized to β-actin.…”

“…Rat MM cell lines (EM 1–5 and SM 1–5) were established from the ascites of mesothelioma-bearing rats models conducted in our previous studies [26]. Regarding 8 human MM cell lines, four cell lines, ACC-MESO-4, Y-MESO-8A, Y-MESO-9 and Y-MESO-25 were established in our laboratory (Y.S.)…”