NBR1 and KIF14 Downstream of the Mammarian Target of Rapamycin Pathway Predict Recurrence in Nonmuscle Invasive Low Grade Urothelial Carcinoma of the Bladder
Korean Journal of Urological Oncology
;
: 28-37, 2017.
Article
in English
| WPRIM
| ID: wpr-169855
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 ANDMETHODS:
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.
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Recurrence
/
Urinary Bladder
/
Urinary Bladder Neoplasms
/
Biomarkers
/
Gene Expression
/
Cell Line
/
Cell Survival
/
Sirolimus
/
RNA, Small Interfering
/
Microarray Analysis
Type of study:
Prognostic study
Limits:
Humans
Language:
English
Journal:
Korean Journal of Urological Oncology
Year:
2017
Type:
Article
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