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Abstract
The tetraspanin and tumor suppressor KAI1 is downregulated or lost in many cancers which correlates with poor prognosis. KAI1 acts via physical/functional crosstalk with other membrane receptors. Also, a splice variant of KAI1 (KAI1-SP) has been identified indicative of poor prognosis. We here characterized differential effects of the two KAI1 variants on tumor biological events involving integrin (αvß3) and/or epidermal growth factor receptor (EGF-R). In MDA-MB-231 and -435 breast cancer cells, differential effects were documented on the expression levels of the tumor biologically relevant integrin αvß3 which colocalized with KAI1-WT but not with KAI1-SP. Cellular motility was assessed by video image processing, including motion detection and vector analysis for the quantification and visualization of cell motion parameters. In MDA-MB-231 cells, KAI1-SP provoked a quicker wound gap closure and higher closure rates than KAI1-WT, also reflected by different velocities and average motion amplitudes of singular cells. KAI1-SP induced highest cell motion adjacent to the wound gap borders, whereas in MDA-MB-435 cells a comparable induction of both KAI1 variants was noticed. Moreover, while KAI1-WT reduced cell growth, KAI1-SP significantly increased it going along with a pronounced EGF-R upregulation. KAI1-SP-induced cell migration and proliferation was accompanied by the activation of the focal adhesion and Src kinase. Our findings suggest that splicing of KAI1 does not only abrogate its tumor suppressive functions, but even more, promotes tumor biological effects in favor of cancer progression and metastasis.
Highlights
Tumor progression involves well characterized cascades of events that enable metastasis formation
In MDA-MB-231 and -435 breast cancer cells, differential effects were documented on the expression levels of the tumor biologically relevant integrin αvß3 which colocalized with KAI1-WT but not with KAI1-SP
Significant elevation of KAI1 expression levels over wild type or vector-transfected cells was documented by immunocytochemical staining using the monoclonal antibodies (mAb) from Diaclone, Stamford, CT, USA (Figure 1A)
Summary
Tumor progression involves well characterized cascades of events that enable metastasis formation. KAI1 (CD82, kangai, or C33), one tetraspanin relevant to tumor metastasis [2, 3], has first been identified in prostate cancer and later, in other tumor entities, including those of the stomach, colon, cervix, skin, bladder, lung, pancreas, liver, thyroid, ovary, and breast [4,5,6,7]. KAI1 expression inversely correlated with cancer metastasis. High KAI1-WT mRNA was detected in tumors with low metastatic potential, whereas it is significantly lower in most aggressive and metastatic tumors [6, 9, 17]. In invasive ductal breast cancer, even no differences of KAI1-WT expression among different tumor grades had been detected, it correlated with TNM staging and patient survival [18]. Its experimental cellular reintroduction inhibited in vitro cancer cell migration/invasion and suppressed cancer metastasis in animal models [19,20,21,22,23,24]
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