title: Progression of Human Renal Cell Carcinoma via Inhibition of RhoA-ROCK Axis by PARG1.
abstract: Renal cell carcinoma (RCC) is the most lethal urological malignancy with high risk of recurrence; thus, new prognostic biomarkers are needed. In this study, a new RCC antigen, PTPL1 associated RhoGAP1 (PARG1), was identified by using serological identification of recombinant cDNA expression cloning with sera from RCC patients. PARG1 protein was found to be differentially expressed in RCC cells among patients. High PARG1 expression is significantly correlated with various clinicopathological factors relating to cancer cell proliferation and invasion, including G3 percentage (P = .0046), Ki-67 score (p expression is also correlated with high recurrence of N0M0 patients (P = .0084) and poor prognosis in RCC patients (P = .0345). Multivariate analysis has revealed that high PARG1 expression is an independent factor for recurrence (P = .0149) of N0M0 RCC patients. In in vitro studies, depletion of PARG1by siRNA in human RCC cell lines inhibited their proliferation through inducing G1 cell cycle arrest via upregulation of p53 and subsequent p21Cip1/Waf1, which are mediated by increased RhoA-ROCK activities. Similarly, PARG1 depletion cells inhibited invasion ability via increasing RhoA-ROCK activities in the RCC cell lines. Conversely, overexpression of PARG1 on human embryonic kidney cell line HEK293T promotes its cell proliferation and invasion. These results indicate that PARG1 plays crucial roles in progression of human RCC in increasing cell proliferation and invasion ability via inhibition of the RhoA-ROCK axis, and PARG1 is a poor prognostic marker, particularly for high recurrence of N0M0 RCC patients.
authors.affiliation: Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Miyazaki
authors.affiliation: Department of Urology, National Defense Medical College, Saitama, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ito
authors.affiliation: Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Matsuzaki
authors.affiliation: Department of Urology, National Defense Medical College, Saitama, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Asano
authors.affiliation: Department of Urology, National Defense Medical College, Saitama, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hayakawa
authors.affiliation: Department of Urology, National Defense Medical College, Saitama, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Asano
authors.affiliation: Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan. Electronic address: yutakawa@keio.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawakami