TY - JOUR
T1 - Progression of Human Renal Cell Carcinoma via Inhibition of RhoA-ROCK Axis by PARG1
AU - Miyazaki, Junichiro
AU - Ito, Keiichi
AU - Fujita, Tomonobu
AU - Matsuzaki, Yuriko
AU - Asano, Takako
AU - Hayakawa, Masamichi
AU - Asano, Tomohiko
AU - Kawakami, Yutaka
N1 - Funding Information:
This work was supported by Grants-in-Aid for Scientific Research ( JP14104013 , JP17016070 , JP23240128 , and JP26221005 ), from the Ministry of Education, Culture, Sports, Science, and Technology of Japan ; the Japan Society for Promotion of Science (KAKENHI), and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor, Welfare ( 15-10 , 15-17 ), the P-DIRECT, P-CREATE from Japan Agency for Medical Research and development (AMED), and Keio University Grant-in-Aid for Encouragement of Young Medical Scientists .
Publisher Copyright:
© 2016 The Authors
PY - 2017/4/1
Y1 - 2017/4/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.tranon.2016.12.004
DO - 10.1016/j.tranon.2016.12.004
M3 - Article
AN - SCOPUS:85026425250
SN - 1944-7124
VL - 10
SP - 142
EP - 152
JO - Translational Oncology
JF - Translational Oncology
IS - 2
ER -
