Convergent signaling in the regulation of connective tissue growth factor in malignant mesothelioma: TGFβ signaling and defects in the Hippo signaling cascade

Abstract

Malignant mesothelioma (MM) is a neoplasm that arises from serosal surfaces of the pleural, peritoneal and pericardial cavities with worldwide incidence, much of which is caused by asbestos exposure. Patients suffer from pain and dyspnea due to direct invasion of the chest wall, lungs and vertebral or intercostal nerves by masses of thick fibrotic tumors. Although there has been recent progress in the clinical treatment, current therapeutic approaches do not provide satisfactory results. Therefore, development of a molecularly targeted therapy for MM is urgently required. Our recent studies suggest that normal mesothelial and MM cell growth is promoted by TGFβ, and that TGFβ signaling together with intrinsic disturbances in neurofibromatosis type 2 (NF2) and Hippo signaling cascades in MM cells converges upon further expression of connective tissue growth factor (CTGF). The formation of a YAP-TEAD4–Smad3-p300 complex on the specific CTGF promoter site with an adjacent TEAD and Smad binding motif is a critical and synergistic event caused by the dysregulation of these two distinct cascades. Furthermore, we demonstrated the functional importance of CTGF through the mouse studies and human histological analyses, which may elucidate the clinical features of MM with severe fibrosis in the thoracic cavity.

Targeting YAP in malignant pleural mesothelioma

“…Hippo downstream genes, such as CTGF and AREG, have been associated with the occurrence and development of human cancer . Our study shows that in H290 and 211H cells, the expression of these Hippo downstream genes can be reduced by YAP siRNA or verteporfin treatment.…”

CTRP3 attenuates post-infarct cardiac fibrosis by targeting Smad3 activation and inhibiting myofibroblast differentiation

“…Once activated by TGF-β1, Smad3 forms a complex with co-Smad, translocates to the nucleus, and recruits co-activators such as p300 and cyclic AMP (cAMP)-response element-binding protein (CREB)-binding protein (CBP), which, in turn, stimulates transcript expression of CTGF [38], collagen I [24], and α-SMA [39]. Many molecules such as glycogen synthase kinase-3β [40], cAMP-elevating agents [41], and NAD(P)H oxidase 4 [42] inhibit the profibrotic effect of TGF-β1 via suppressing Smad3 activation, transcriptional activity, or Smad3-mediated recruitment of transcriptional co-activators.…”

Deregulated expression of connective tissue growth factor (CTGF/CCN2)is linked to poor outcome in human cancer

“…In these cancers, CTGF expression in biopsy samples is associated with worse survival outcomes and clinicopathological findings, including advanced stage, larger tumour size, increased metastasis and poorer chemotherapy response. In mesothelioma, CTGF is evident only in the sarcomatoid subtype, which is the most aggressive and has the poorest outcome . In multiple myeloma, a cleaved CTGF fragment is increased in plasma and associated with bone disease .…”

“…CTGF has a proliferative role in gallbladder cancer, hepatocellular carcinoma, malignant mesothelioma, oesophageal cancer, rhabdomyosarcoma, pancreatic cancer and thyroid cancer . In hepatocellular carcinoma, increased proliferation was attributed to changes in the cell cycle with increased numbers of cells in S‐phase .…”