Abstract
The transmembrane protein CD82/KAI1 suppresses the metastatic potential of various cancer cell types. Moreover, decrease or loss of CD82 expression is closely associated with malignancy and poor prognosis in many human cancers including prostate cancer. Despite intense scrutiny, the mechanisms underlying the metastasis-suppressing role of CD82 are still not fully understood. Here, we found that a fibronectin matrix induced mesenchymal phenotypes in human prostate cancer cells with no or low CD82 expression levels. However, high CD82 expression rendered prostate cancer cells to have intensified epithelial characteristics upon fibronectin engagement, along with decreased cell motility and invasiveness. The CD82 function of inhibiting fibronectin-induced epithelial-to-mesenchymal transition (EMT) was dependent not only on CD82 interactions with fibronectin-binding α3β1/α5β1 integrins but also on the integrin-mediated intracellular signaling events. Notably, CD82 attenuated the FAK-Src and ILK pathways downstream of the fibronectin-receptor integrins. Immunofluorescence staining of human prostate cancer tissue specimens illustrated a negative association of CD82 with EMT-related gene expression as well as prostate malignancy. Altogether, these results suggest that CD82 suppresses EMT in prostate cancer cells adhered to the fibronectin matrix by repressing adhesion signaling through lateral interactions with the associated α3β1 and α5β1 integrins, leading to reduced cell migration and invasive capacities.
Highlights
The membrane protein CD82 is a member of the tetraspanin superfamily that contains four transmembrane domains, short N- and C-terminal cytoplasmic domains, two extracellular loops, and a small intracellular loop [1, 2]
This study shows that high CD82 expression blocks fibronectininduced epithelial-to-mesenchymal transition (EMT) through repression of adhesion signaling mediated by CD82-interacting fibronectin-receptor integrins, which suggests a mechanism of EMT inhibition by CD82, and supports the importance of integrin signaling in EMT
High CD82 expression blocks development of mesenchymal phenotypes in human prostate cancer cells adhered to fibronectin
Summary
The membrane protein CD82 is a member of the tetraspanin superfamily that contains four transmembrane domains, short N- and C-terminal cytoplasmic domains, two extracellular loops, and a small intracellular loop [1, 2]. In TEMs, tetraspanin proteins are physically complexed with other membrane proteins including integrins, growth factor receptors, and proteases, and associate with signaling molecules such as PKC, PI4-. Since tetraspanin proteins have no enzymatic activity, tetraspanins seems instead to function by regulating the activity, function, or membrane trafficking of the associated molecules in the TEMs through lateral interactions and crosstalk. KAI1, which is identical to CD82, was initially identified as a metastasis suppressor of prostate cancer [8]. Enforced expression of CD82/KAI1 by gene transfection significantly reduced lung metastases of rat prostate cancer cells, without affecting primary tumor growth. Many aspects of how CD82/KAI1 suppresses cancer metastasis are not yet fully determined
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