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Overexpression of NRG1 promotes progression of gastric cancer by regulating the self-renewal of cancer stem cells

Journal of Gastroenterology volume 50, pages 645–656 (2015)Cite this article

Abstract

Background

Gastric cancer stem cells (GCSCs) have been successfully isolated from patients. However, the molecular mechanisms underlying the self-renewal of GCSCs and their relationship with the microenvironment are poorly characterized.

Methods

GCSCs and cancer-associated fibroblasts (CAFs) were cultured directly from gastric cancer patients. The self-renewal of GCSCs was assayed by sphere formation assay and in vivo tumorigenicity. Expression of neuregulin1 (NRG1) was examined by immunohistochemistry, real-time PCR and western blotting.

Results

CAFs increased the self-renewal of GCSCs by secreting NRG1. NRG1 activated NF-κB signaling and this activation regulated GCSC self-renewal. Moreover, NF-κB-active GCSCs were tumorigenic, however NF-κB-inactive GCSCs were not. The overexpression of NRG1 in stromal cells and cancer cells was observed in the tumor tissues of gastric cancer patients and was associated with clinical stage lymph node metastasis and survival in gastric cancer patients. In addition, we also found that NRG1 can regulate the proliferation and invasion of gastric cancer cells.

Conclusions

These results indicate that NRG1, which can be secreted by CAFs or cancer cells, promotes progression of gastric cancer by regulating the self-renewal of GCSCs and its overexpression is associated with a prognosis of gastric cancer.

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Acknowledgments

This work was supported by the Bio & Medical Technology Development Program (2012M3A9C6050213) and the Basic Science Research Foundation (2012R1A1A3010521) of the National Research Foundation (NRF) funded by the Korean government (MEST) and a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (0920050).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Anatomy, School of Medicine, Pusan National University, Beomeo-Ri, Mulgeum-Eup, Yangsan, 626-870, South Korea

    Myoung-Eun Han, Hyun-Jung Kim & Sae-Ock Oh

  2. Department of Pathology, School of Medicine, Pusan National University, Yangsan, Republic of Korea

    Dong Hoon Shin

  3. Department of Surgery, School of Medicine, Pusan National University, Yangsan, Republic of Korea

    Sun-Hwi Hwang

  4. Department of Biochemistry, School of Medicine, Pusan National University, Yangsan, Republic of Korea

    Chi-Dug Kang

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  1. Myoung-Eun Han
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Correspondence to Sae-Ock Oh.

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Han, ME., Kim, HJ., Shin, D.H. et al. Overexpression of NRG1 promotes progression of gastric cancer by regulating the self-renewal of cancer stem cells. J Gastroenterol 50, 645–656 (2015). https://doi.org/10.1007/s00535-014-1008-1

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  • DOI: https://doi.org/10.1007/s00535-014-1008-1

Keywords

  • NRG1
  • Gastric cancer stem cells
  • Cancer-associated fibroblasts