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ANXA10 and ATP7A are the mTOR pathway downstream to predict the recurrence and progression in non-muscle invasive high grade urothelial carcinoma of the bladder

Login to Access Video or Poster Abstract: MP44-15
Sources of Funding: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology, Republic of Korea (2015R1A1A1A0500110).

Introduction

The cross-talk of mammalian target of rapamycin (mTOR) pathway is clinical limitation of mTOR inhibitor for the treatment of urothelial carcinoma (URCa) of the bladder. This study is to search mTOR pathway downstream genes to overcome cross-talk at non muscle invasive high grade (HG)-URCa of the bladder.

Methods

Gene expression patterns, gene ontology, and gene clustering by triple (p70S6K, S6K and eIF4E) siRNAs or rapamycin in 5637 and T24 cell lines were investigated by microarray analysis and we selected mTOR pathway downstream genes which were suppressed to siRNAs more than two fold, and rapamycin up-regulated or rapamycin down-regulated. And then we validated mTOR downstream genes with immunohistochemistry using tissue microarray of 125 non-muscle invasive HG-URCa patients whether genes can predict clinical aggressiveness and long-term outcomes, and knockout study to evaluate the synergistic effect with rapamycin.

Results

In the microarray analysis, we selected mTOR pathway downstream genes which consisted of 4 rapamycin up-regulated (FABP4, H19, ANXA10, and UPK3A), and 4 rapamycin down-regulated (FOXD3, ATP7A, plexin D1 and ADAMTS5). In tissue microarray, FABP4 and ATP7A were more expressed at T1, and FOXD3 was at Ta. ANXA10 and ADAMTS5 were more expressed at 3 cm or less than 3cm. In Kaplan-Meier curve, ANXA10 was a significant predictor of recurrence, and FABP4 and ATP7A were significant predictors of progression of HG-URCa of the bladder. In multivariate Cox regression model, ANXA10 was a significant predictor of recurrence and ATP7A was a significant predictors of progression in non-muscle invasive HG-URCa of the bladder. In ATP7A knock out model, rapamycin treatment showed synergistic effect to inhibit cell viability, wound healing, and invasion ability compared to rapamycin only.

Conclusions

ANXA10 and ATP7A might be mTOR pathway downstream genes to predict recurrence and progression in non-muscle invasive high-grade urothelial carcinoma of the bladder and ATP7A knockout overcome the rapamycin coss-talk.

Funding

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology, Republic of Korea (2015R1A1A1A0500110).

Authors
Byung Hoon Chi
Subin Jin
Young Mi Whang
Seung Hyun Ahn
Jae Duck Choi
Shin Young Lee
In Ho Chang
Bongsuk Shim
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