Differential tumor biological role of the tumor suppressor KAI1 and its splice variant in human breast cancer cells

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.

Oncogenic splicing abnormalities induced by DEAD‐Box Helicase 56 amplification in colorectal cancer

“…38,41 Interestingly, the expression of some tumor suppressor genes, such as LKB1 and KLF6, was controlled by splicing alterations. 2,6,42 In the present study, we showed that WEE1 expression is also altered through alternative splicing by DDX56 overexpression. RNA sequence analysis showed that knockdown of DDX56 immediately reduced the intron retention of WEE1 (truncated WEE1) and increased wild-type WEE1 mRNA expression.…”

“…The expression of WEE1 is suppressed in colon cancer and non‐small cell lung cancer . Interestingly, the expression of some tumor suppressor genes, such as LKB1 and KLF6 , was controlled by splicing alterations . In the present study, we showed that WEE1 expression is also altered through alternative splicing by DDX56 overexpression.…”

Targeting CD82/KAI1 for Precision Therapeutics in Surmounting Metastatic Potential in Breast Cancer

“…In addition, CD82 was observed to inhibit cell adhesion which could possibly be mediated via its interaction with integrins [48]. The metastasis suppressive functions of CD82 have been reported to be abrogated by the splicing of the CD82 gene [50,51], where the CD82 spliced variant was observed to enhance cell migration and proliferation, concomitant with the activation of Src kinase in MDA-MB-231 breast cancer cells [50]. Overexpression of Sulfatase 2 (Sulf 2) was also reported to promote cell migration and invasion with the concomitant downregulation of CD82 expression in MDA-MB-231 breast cancer cells [52].…”

Classes of non-conventional tetraspanins defined by alternative splicing

“…Moreover, there is another isoform with a shortened LEL (CD82 Iso4), from which the mRNA is unknown, wherefore we cannot evaluate its expression probability. Still, from published data we can safely conclude that this isoform expresses at levels that affect cellular function 43 .…”