title: Downregulation of Ral GTPase-activating protein promotes tumor invasion and metastasis of bladder cancer.
abstract: The small GTPase Ral is known to be highly activated in several human cancers, such as bladder, colon and pancreas cancers. It is reported that activated Ral is involved in cell proliferation, migration and metastasis of bladder cancer. This protein is activated by Ral guanine nucleotide exchange factors (RalGEFs) and inactivated by Ral GTPase-activating proteins (RalGAPs), the latter of which consist of heterodimers containing a catalytic α1 or α2 subunit and a common β subunit. In Ras-driven cancers, such as pancreas and colon cancers, constitutively active Ras mutant activates Ral through interaction with RalGEFs, which contain the Ras association domain. However, little is known with regard to the mechanism that governs aberrant activation of Ral in bladder cancer, in which Ras mutations are relatively infrequent. Here, we show that Ral was highly activated in invasive bladder cancer cells due to reduced expression of RalGAPα2, the dominant catalytic subunit in bladder, rather than increased expression of RalGEFs. Exogenous expression of wild-type RalGAPα2 in KU7 bladder cancer cells with invasive phenotype, but not mutant RalGAPα2-N1742K lacking RalGAP activity, resulted in attenuated cell migration in vitro and lung metastasis in vivo. Furthermore, genetic ablation of Ralgapa2 promoted tumor invasion in a chemically-induced murine bladder cancer model. Importantly, immunohistochemical analysis of human bladder cancer specimens revealed that lower expression of RalGAPα2 was associated with advanced clinical stage and poor survival of patients. Collectively, these results are highly indicative that attenuated expression of RalGAPα2 leads to disease progression of bladder cancer through enhancement of Ral activity.
authors.affiliation: Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Saito
authors.forename: R
authors.initials: R
authors.lastname: Shirakawa
authors.forename: H
authors.initials: H
authors.lastname: Nishiyama
authors.forename: T
authors.initials: T
authors.lastname: Kobayashi
authors.forename: M
authors.initials: M
authors.lastname: Kawato
authors.forename: T
authors.initials: T
authors.lastname: Kanno
authors.forename: K
authors.initials: K
authors.lastname: Nishizawa
authors.forename: Y
authors.initials: Y
authors.lastname: Matsui
authors.forename: T
authors.initials: T
authors.lastname: Ohbayashi
authors.forename: M
authors.initials: M
authors.lastname: Horiguchi
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
authors.forename: T
authors.initials: T
authors.lastname: Ikeda
authors.forename: K
authors.initials: K
authors.lastname: Yamane
authors.forename: E
authors.initials: E
authors.lastname: Nakayama
authors.forename: E
authors.initials: E
authors.lastname: Nakamura
authors.forename: Y
authors.initials: Y
authors.lastname: Toda
authors.forename: T
authors.initials: T
authors.lastname: Kimura
authors.forename: T
authors.initials: T
authors.lastname: Kita
authors.forename: O
authors.initials: O
authors.lastname: Ogawa
authors.forename: H
authors.initials: H
authors.lastname: Horiuchi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020690:GTPase-Activating Proteins; C514562:RALGAPA2 protein, human