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Molecular Cancer
Published in: Molecular Cancer 1/2013

Open Access 01-12-2013 | Research

miR-99b-targeted mTOR induction contributes to irradiation resistance in pancreatic cancer

Authors: Feng Wei, Yan Liu, Yanhai Guo, An Xiang, Guangyi Wang, Xiaochang Xue, Zifan Lu

Published in: Molecular Cancer | Issue 1/2013

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Abstract

Background

Radiation exerts direct antitumor effects and is widely used in clinics, but the efficacy is severely compromised by tumor resistance. Therefore uncovering the mechanism of radioresistance might promote the development of new strategies to overcome radioresistance by manipulating activity of the key molecules.

Methods

Immunohistochemistry were used to find whether mTOR were over-activated in radioresistant patients’ biopsies. Then Western blot, real-time PCR and transfection were used to find whether radiotherapy regulates the expression and activity of mTOR by modulating its targeting microRNA in human pancreatic cancer cell lines PANC-1, Capan-2 and BxPC-3. Finally efficacy of radiation combined with mTOR dual inhibitor AZD8055 was assessed in vitro and in vivo.

Results

Ionizing radiation promoted mTOR expression and activation in pancreatic cancer cells through reducing miR-99b expression, which negatively regulated mTOR. Novel mTOR inhibitor, AZD8055 (10 nM, 100 nM, 500 nM) synergistically promoted radiation (0–10 Gy) induced cell growth inhibition and apoptosis. In human pancreatic cancer xenografts, fractionated radiation combined with AZD8055 treatment further increased the anti-tumor effect, the tumor volume was shrinked to 278 mm3 after combination treatment for 3 weeks compared with single radiation (678 mm3) or AZD8055 (708 mm3) treatment (P < 0.01).

Conclusions

Our data provide a rationale for overcoming radio-resistance by combined with mTOR inhibitor AZD8055 in pancreatic cancer therapy.
Appendix
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Metadata
Title
miR-99b-targeted mTOR induction contributes to irradiation resistance in pancreatic cancer
Authors
Feng Wei
Yan Liu
Yanhai Guo
An Xiang
Guangyi Wang
Xiaochang Xue
Zifan Lu
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2013
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-12-81

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