title: Gelsolin induces colorectal tumor cell invasion via modulation of the urokinase-type plasminogen activator cascade.
abstract: Gelsolin is a cytoskeletal protein which participates in actin filament dynamics and promotes cell motility and plasticity. Although initially regarded as a tumor suppressor, gelsolin expression in certain tumors correlates with poor prognosis and therapy-resistance. In vitro, gelsolin has anti-apoptotic and pro-migratory functions and is critical for invasion of some types of tumor cells. We found that gelsolin was highly expressed at tumor borders infiltrating into adjacent liver tissues, as examined by immunohistochemistry. Although gelsolin contributes to lamellipodia formation in migrating cells, the mechanisms by which it induces tumor invasion are unclear. Gelsolin's influence on the invasive activity of colorectal cancer cells was investigated using overexpression and small interfering RNA knockdown. We show that gelsolin is required for invasion of colorectal cancer cells through matrigel. Microarray analysis and quantitative PCR indicate that gelsolin overexpression induces the upregulation of invasion-promoting genes in colorectal cancer cells, including the matrix-degrading urokinase-type plasminogen activator (uPA). Conversely, gelsolin knockdown reduces uPA levels, as well as uPA secretion. The enhanced invasiveness of gelsolin-overexpressing cells was attenuated by treatment with function-blocking antibodies to either uPA or its receptor uPAR, indicating that uPA/uPAR activity is crucial for gelsolin-dependent invasion. In summary, our data reveals novel functions of gelsolin in colorectal tumor cell invasion through its modulation of the uPA/uPAR cascade, with potentially important roles in colorectal tumor dissemination to metastatic sites.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Jingli
authors.initials: J
authors.lastname: Zhuo
authors.forename: Ee Hong
authors.initials: EH
authors.lastname: Tan
authors.forename: Benedict
authors.initials: B
authors.lastname: Yan
authors.forename: Lalchhandami
authors.initials: L
authors.lastname: Tochhawng
authors.forename: Manikandan
authors.initials: M
authors.lastname: Jayapal
authors.forename: Shiuan
authors.initials: S
authors.lastname: Koh
authors.forename: Hwee Kee
authors.initials: HK
authors.lastname: Tay
authors.forename: Sutherland K
authors.initials: SK
authors.lastname: Maciver
authors.forename: Shing Chuan
authors.initials: SC
authors.lastname: Hooi
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.forename: Alan Prem
authors.initials: AP
authors.lastname: Kumar
authors.forename: Yaw Chong
authors.initials: YC
authors.lastname: Goh
authors.forename: Yaw Chyn
authors.initials: YC
authors.lastname: Lim
authors.forename: Celestial T
authors.initials: CT
authors.lastname: Yap
mesh_terms: D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology*; D005341:Fibrinolysin / Q000378:metabolism; D018260:Gelsolin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism; D015398:Signal Transduction; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: D018260:Gelsolin; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator