CLIC4 mediates TGF-beta1-induced fibroblast-to-myofibroblast transdifferentiation in ovarian cancer.
Stromal myofibroblasts, activated by crosstalk signaling between the tumour and stroma, play a critical role in tumour development and progression. Chloride intracellular channel 4 (CLIC4) may be functionally import for tumour stromal fibroblast-to-myofibroblast transdifferentiaton, but the molecular mechanism of the process has not been addressed. In this study, the expression of CLIC4 in ovarian cancer tissues was analyzed by immunohistochemistry, and we used an indirect co-culture model of ovarian cancer cells and normal fibroblasts to demonstrate the molecular pathway in which CLIC4 participated during the fibroblast-to-myofibroblast transdifferentiation. The results showed that the expression of CLIC4 in 96.7% of ovarian cancer stroma and correlated with the up-regulation of myofibroblast marker alpha-SMA. Conditioned medium from ovarian cancer cells (CM) or transforming growth factor-beta1 (TGF-beta1) increased cellular reactive oxygen species (ROS) levels in fibroblasts, which initiated up-regulation of CLIC4 expression, then resulted in myofibroblast conversion. Moreover, inhibition of CLIC4 significantly reduced the expressions of factors related to the phenotype and functions of myofibroblasts, such as alpha-SMA, VEGF and HGF. These results suggest that ROS-initiated CLIC4 up-regulation is required for TGF-beta1-induced fibroblast-to-myofibroblast transdifferentiaton in ovarian cancer, indicating that inhibiting the CLIC4 might have therapeutic potential targeting tumour stroma.
Yao
Qin
Q
Department of Obstetrics and Gynaecology, Qilu Hospital, Shandong University, Ji'nan 250012, Shandong, PR China.
Qu
Xun
X
Yang
Qifeng
Q
Wei
Mingqian
M
Kong
Beihua
B
D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D054338:Cell Transdifferentiation; D018118:Chloride Channels / Q000032:analysis / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000473:pathology*; D017228:Hepatocyte Growth Factor / Q000032:analysis; D006801:Humans; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
C464459:CLIC4 protein, human; D018118:Chloride Channels; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor