Abstract
CD26/dipeptidyl peptidase IV is a cell surface glycoprotein which consists of multiple functional domains beside its ectopeptidase site. A growing body of evidence indicates that elevated expression of CD26 correlates with disease aggressiveness and invasive potential of selected malignancies. To further explore the molecular mechanisms involved in this clinical behavior, our current work focused on the interaction between CD26 and CD9, which were recently identified as novel markers for cancer stem cells in malignant mesothelioma. We found that CD26 and CD9 co-modulated and co-precipitated with each other in the malignant mesothelioma cell lines ACC-MESO1 and MSTO-211H. SiRNA study revealed that depletion of CD26 led to increased CD9 expression, while depletion of CD9 resulted in increased CD26 expression. Consistent with these findings was the fact that gene transfer of CD26 into CD26-negative MSTO-211H cells reduced CD9 expression. Cell invasion assay showed that overexpression of CD26 or gene depletion of CD9 led to enhanced invasiveness, while CD26 gene depletion resulted in reduced invasive potential. Furthermore, our work suggested that this enhanced invasiveness may be partly mediated by α5β1 integrin, since co-precipitation studies demonstrated an association between CD26 and α5β1 integrin. Finally, gene depletion of CD9 resulted in elevated protein levels and tyrosine phosphorylation of FAK and Cas-L, which are downstream of β1 integrin, while depletion of CD26 led to a reduction in the levels of these molecules. Collectively, our findings suggest that CD26 potentiates tumor cell invasion through its interaction with α5β1 integrin, and CD9 negatively regulates tumor cell invasion by reducing the level of CD26-α5β1 integrin complex through an inverse correlation between CD9 and CD26 expression. Our results also suggest that CD26 and CD9 serve as potential biomarkers as well as promising molecular targets for novel therapeutic approaches in malignant mesothelioma and other malignancies.
Highlights
Malignant pleural mesothelioma is an aggressive malignancy arising from the mesothelial cells lining the pleura [1]
We recently reported that CD26 and CD9 are cancer stem cell markers of malignant mesothelioma [22,23]
Since CD26 and CD9 have been reported to be associated with specific molecules [4,24], we attempted to determine the relationship between CD26 and CD9 in malignant mesothelioma cell lines
Summary
Malignant pleural mesothelioma is an aggressive malignancy arising from the mesothelial cells lining the pleura [1]. It is generally associated with a history of asbestos exposure and has a very poor prognosis [1]. The incident of malignant mesothelioma has increased in industrialized nations as a result of past widespread exposure to asbestos [2]. CD26 activity is dependent on cell type and the microenvironment factors that can influence its multiple biological roles [3,4,5,6]. As a result of its various interactions, CD26 has an important, but complex, function in cellular behavior, with its biologic effect dependent on the cell type and the microenvironment
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