Korean J Urol Oncol.
2017 Apr;15(1):28-37. 10.22465/kjuo.2017.15.1.28.
NBR1 and KIF14 Downstream of the Mammarian Target of Rapamycin Pathway Predict Recurrence in Nonmuscle Invasive Low Grade Urothelial Carcinoma of the Bladder
- Affiliations
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- 1Department of Urology, Kyung-Hee University College of Medicine, Seoul, Korea.
- 2Department of Agricultural Biology, National Academy of Agricultural Science, Rural Development Administration, Wanju, Korea.
- 3Department of Urology, Chung-Ang University College of Medicine, Seoul, Korea. caucih@cau.ac.kr
- 4Department of Pathology, Chung-Ang University College of Medicine, Seoul, Korea.
- KMID: 2379757
- DOI: http://doi.org/10.22465/kjuo.2017.15.1.28
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.
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