NBR1 and KIF14 Downstream of the Mammarian Target of Rapamycin Pathway Predict Recurrence in Nonmuscle Invasive Low Grade Urothelial Carcinoma of the Bladderopen access
- Authors
- Lee, Dong-Gi; Kim, Ha Jeong; Jin, Subin; Kim, Jin Wook; Whang,Young Mi; Lee, Tae-Jin; Chang, In Ho
- Issue Date
- 2017
- Publisher
- 대한비뇨기종양학회
- Keywords
- Urinary bladder neoplasms; mTOR; Biomarkers; Microarray analysis; Recurrence
- Citation
- 대한비뇨기종양학술지, v.15, no.1, pp 28 - 37
- Pages
- 10
- Journal Title
- 대한비뇨기종양학술지
- Volume
- 15
- Number
- 1
- Start Page
- 28
- End Page
- 37
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/5791
- DOI
- 10.22465/kjuo.2017.15.1.28
- ISSN
- 1598-8341
2233-5633
- 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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