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Suppression of growth and migration by blocking the hedgehog signaling pathway in gastric cancer cells

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Abstract

Purpose

Previous studies have indicated that Hedgehog signaling is essential for gastric cancer development, but its precise role is still unclear. The aim of this study was to clarify the role of Hedgehog signaling in gastric cancer development.

Methods

The expression of key Hedgehog signaling components in clinical samples of sequential gastric cancer stages was assessed by immunohistochemistry. The roles and regulatory mechanisms of Hedgehog signaling in human gastric cancer cells and normal gastric epithelial cells were investigated using multiple cell biological approaches and cDNA microarray analyses.

Results

Hedgehog signaling was found to be abnormally activated in a ligand-independent manner during gastric cancer development. Gli1 over-expression and reduced SuFu expression were found to be typical events in gastric cancer tissues. Gli1 over-expression was found to correlate with a poorly differentiated histology, advanced clinical stage, membrane serosa infiltration and lymph node metastasis in patients with gastric cancer. Data obtained from multiple cell biological assays showed that human gastric cancer cells require active Hedgehog signaling for survival, proliferation, migration and colony formation. N-Shh treatment significantly enhanced the migration, invasion and colony formation of gastric cancer cells. Moreover, the results of cDNA microarray analyses indicated that after treatment with cyclopamine or GANT61 (inhibitors of Hedgehog signaling), differentially expressed genes in gastric cancer cells were enriched in the apoptosis and MAPK pathways. Inhibitors of the Hedgehog pathway were found to suppress gastric cancer cell growth via apoptosis induction.

Conclusions

Our findings indicate a vital role of the activated Hedgehog signaling pathway in promoting gastric initiation and progression. The Hedgehog signaling pathway may serve as a target for gastric cancer therapy.

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Acknowledgments

We thank Dr. Libin Deng and Miss Yujia Zhou for analysis of cDNA microarray data. Further, we greatly acknowledge Drs. Yong Li and Xuan Huang for the technical assistance. This work was supported in part by grants from the China National Basic Research Program (2010CB535001), the National Natural Science Foundation of China (31260278, 81060095 and 31171359), the Natural Science Foundation of Jiangxi Province (2009GZY0209, 20114BAB205035, 20114BAB215029) and the National Science and Technology Major Projects program for “Major New Drugs Innovation and Development” of China (2011ZX09302-007-03).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, No.17 Yongwai street, Donghu district, Nanchang, 330006, China

    Runwei Yan, Xiang Peng, Xiaogang Yuan, Jiang Chen & Nonghua Lv

  2. Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, No.17 Yongwai street, Donghu district, Nanchang, 330006, China

    Dengliang Huang & Shiwen Luo

  3. Department of Biostatistics & Epidemiology, School of Public Health, Nanchang University, Nanchang, 330006, China

    Quqin Lu

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  1. Runwei Yan
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Correspondence to Nonghua Lv or Shiwen Luo.

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Yan, R., Peng, X., Yuan, X. et al. Suppression of growth and migration by blocking the hedgehog signaling pathway in gastric cancer cells. Cell Oncol. 36, 421–435 (2013). https://doi.org/10.1007/s13402-013-0149-1

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  • DOI: https://doi.org/10.1007/s13402-013-0149-1

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