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mTOR Signaling Pathway Is a Target for the Treatment of Colorectal Cancer

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

mTOR signaling has been suggested to be an important factor involved in tumorigenesis, but its role in human colorectal cancer (CRC) has not been completely elucidated. Herein, the purpose of this study was to analyze the distribution pattern of mTOR signaling components in CRC and adenoma and to determine whether targeted inhibition of mTOR could be a potential therapeutic strategy for CRC.

Methods

Immunohistochemical analysis was performed on human CRC and adenoma for mTOR signaling components, including mTOR, p70s6 K, and 4EBP1. HCT116 and SW480 human CRC cell lines were treated with siRNA directed against mTOR, and cell viability, cell cycle, and apoptosis were assessed. HCT116 and SW480 cells were injected into athymic nude mice to establish a CRC xenograft model. Mice were randomly transfected with either nontargeting control or mTOR siRNA, and tumor volume, mTOR signaling activity, and apoptosis were evaluated.

Results

mTOR signaling components, including mTOR, p70s6 K, and 4EBP1, were highly activated in glandular elements of CRC and colorectal adenomas with high-grade intraepithelial neoplasia (HIN), with a correlation between staining intensity and depth of infiltration in CRC. Inhibition of mTOR expression using a specific mTOR siRNA resulted in considerably decreased in vitro and in vivo cell growth.

Conclusions

mTOR signaling is associated with the clinical pathological parameters of human CRC. siRNA-mediated gene silencing of mTOR may be a novel therapeutic strategy for CRC.

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Acknowledgment

This work was supported by grants from the National Science Fund for Distinguished Young Scholars (30625034), the National Basic Research of China 973 program (2005CB522400), the Shanghai Leading Academic Discipline Project (Y0205), and the Changjiang Plan in China to Fang JY. This work was also supported by grants from the Science and Technology Commission of Shanghai Municipality (08ZR1413100), the Shanghai Baoshan District Science Fund (07-E-2), and the Shanghai Jiaotong University School of Medicine (BXJ0721) to Zhang YJ.

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Authors and Affiliations

  1. Shanghai Institute of Digestive Disease, Shanghai Jiaotong University School of Medicine Renji Hospital, Shanghai, China

    Yan-Jie Zhang PhD, MD, Dan-Feng Sun PhD, MD, Hua Xiong PhD, MD, Xiao-Qing Tian PhD, MD & Jing-Yuan Fang PhD, MD

  2. No. 3 People’s Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China

    Yan-Jie Zhang PhD, MD, Qiang Dai MD, Feng-Hou Gao PhD & Mang-Hua Xu BA

  3. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao-Tong University School of Medicine, Shanghai, China

    Guo-Qiang Chen PhD, MD

  4. Shanghai-Ministry Key Laboratory of Disease and Health Genomics, Chinese National Human Genome Center, Shanghai, China

    Ze-Guang Han PhD, MD

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  1. Yan-Jie Zhang PhD, MD
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  2. Qiang Dai MD
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Correspondence to Jing-Yuan Fang PhD, MD.

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Zhang, YJ., Dai, Q., Sun, DF. et al. mTOR Signaling Pathway Is a Target for the Treatment of Colorectal Cancer. Ann Surg Oncol 16, 2617–2628 (2009). https://doi.org/10.1245/s10434-009-0555-9

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  • DOI: https://doi.org/10.1245/s10434-009-0555-9

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