title: Alternative splicing of KAI1 abrogates its tumor-suppressive effects on integrin αvβ3-mediated ovarian cancer biology.
abstract: Loss or downregulation of the tumor-suppressor KAI1 correlates with poor cancer patient prognosis. KAI1 functions by interacting with other proteins, including integrin cell adhesion and signaling receptors. We previously showed that KAI1 physically and functionally crosstalks with the tumor-biologically relevant integrin αvβ3, thereby suppressing ovarian cancer cell migration and proliferation. Interestingly, in metastases, a KAI1 splice variant had been identified, indicating poor patient prognosis. Thus, we here characterized differential effects of the two KAI1 proteins upon their cellular restoration. Opposite to KAI1, KAI1-splice reduced αvβ3-mediated cell adhesion, thereby inducing cell migration. This was accompanied by elevated αvβ3 levels and drastically elevated focal adhesion kinase activation, however, without any obvious colocalization with αvβ3, as observed for KAI1. Moreover, codistribution of KAI1 with the cell/cell-adhesion molecule E-cadherin was abrogated in KAI1-splice. Whereas KAI1 diminished cell proliferative activity, KAI1-splice prominently enhanced cell proliferation concomitant with elevated transcription and cell-surface expression of the epidermal growth factor receptor. Thus KAI1-splice does not only counteract the tumor-suppressive actions of KAI1, but - beyond that - promotes αvβ3-mediated biological functions in favor of tumor progression and metastasis.
authors.affiliation: Clinical Research Unit, Department for Gynecology & Obstetrics, Technische Universitaet München, Germany.
authors.forename: Sina
authors.initials: S
authors.lastname: Upheber
authors.affiliation: Clinical Research Unit, Department for Gynecology & Obstetrics, Technische Universitaet München, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Karle
authors.affiliation: Clinical Research Unit, Department for Gynecology & Obstetrics, Technische Universitaet München, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Miller
authors.affiliation: Division of Tumor Genetics, Department for Obstetrics & Gynecology, Technische Universitaet Muenchen, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schlaugk
authors.affiliation: Division of Tumor Genetics, Department for Obstetrics & Gynecology, Technische Universitaet Muenchen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Gross
authors.affiliation: Clinical Research Unit, Department for Gynecology & Obstetrics, Technische Universitaet München, Germany. Electronic address: ute.reuning@lrz.tum.de.
authors.forename: Ute
authors.initials: U
authors.lastname: Reuning
mesh_terms: D017398:Alternative Splicing; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism*; D051861:Kangai-1 Protein / Q000235:genetics* / Q000378:metabolism; D018715:Microscopy, Video; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D059008:Time-Lapse Imaging
chemical_list: D015820:Cadherins; D039302:Integrin alphaVbeta3; D051861:Kangai-1 Protein; D012333:RNA, Messenger; D066246:ErbB Receptors
keywords: E-cadherin; Epidermal growth factor receptor (promoter); Integrin αvß3; Ovarian cancer cell adhesion, motility, and proliferation; Tumor suppressor KAI1 (CD82) and its splice variant