NBR1 and KIF14 Downstream of the Mammarian Target of Rapamycin Pathway Predict Recurrence in Nonmuscle Invasive Low Grade Urothelial Carcinoma of the Bladder.
10.22465/kjuo.2017.15.1.28
- Author:
Dong Gi LEE
1
;
Ha Jeong KIM
;
Subin JIN
;
Jin Wook KIM
;
Young Mi WHANG
;
Tae Jin LEE
;
In Ho CHANG
Author Information
1. Department of Urology, Kyung-Hee University College of Medicine, Seoul, Korea.
- Publication Type:Original Article
- Keywords:
Urinary bladder neoplasms;
mTOR;
Biomarkers;
Microarray analysis;
Recurrence
- MeSH:
Biomarkers;
Cell Line;
Cell Survival;
Gene Expression;
Gene Ontology;
Humans;
Microarray Analysis;
Recurrence*;
RNA, Small Interfering;
Sirolimus*;
Urinary Bladder Neoplasms;
Urinary Bladder*
- From:Korean Journal of Urological Oncology
2017;15(1):28-37
- CountryRepublic of Korea
- Language:English
-
Abstract:
PURPOSE: The lack of identified mammalian target of rapamycin (mTOR) pathway downstream genes that overcome cross-talk in nonmuscle invasive low grade (LG)-urothelial carcinoma (UC) of the bladder is a clinical limitation in the use of mTOR inhibitor for the treatment of UC. MATERIALS AND METHODS: Presently, gene expression patterns, gene ontology, and gene clustering by dual (p70S6K and S6K) siRNAs or rapamycin in 253J and TR4 cell lines were investigated by microarray analysis. mTOR/S6K pathway downstream genes suppressed to siRNAs, and rapamycin up-regulated or rapamycin down-regulated genes were identified. The mTOR downstream genes examined using a tissue microarray of 90 nonmuscle invasive LG-UC patients to assess whether any of these genes predicted clinical outcomes. A knockout study evaluated the synergistic effect with rapamycin. RESULTS: In the microarray analysis, mTOR pathway downstream genes selected consisted of 4 rapamycin down-regulated (FOXM1, KIF14, MYBL2, and UHRF1), and 4 rapamycin up-regulated (GPR87, NBR1, VASH1, and PRIMA1). In the tissue microarray, FOXM1, KIF14, and NBR1 were more expressed at T1, and MYBL2, and PRIMA1 were more expressed in tumors exceeding 3 cm. In a multivariate Cox regression model, KIF14 and NBR1 were significant predictors of recurrence in nonmuscle invasive LG-UC of the bladder. In a NBR1 knock out model, rapamycin treatment synergistically inhibited cell viability and colony forming ability compared to rapamycin only. CONCLUSIONS: The results implicate KIF14 and NBR1 as mTOR/S6K pathway downstream genes that predict recurrence in nonmuscle invasive LG-UC of the bladder and demonstrate that NBR1 knockout overcomes rapamycin cross-talk.
