Correlation between HGF/c-Met and Notch1 signaling pathways in human gastric cancer cells

Huang,Kuo-Hung; Sung,I-Cheng; Fang,Wen-Liang; Chi,Chin-Wen; Yeh,Tien-Shun; Lee,Hsin-Chen; Yin,Pen-Hui; Li,Anna Fen-Yau; Wu,Chew-Wun; Shyr,Yi-Ming; Yang,Muh-Hwa

doi:10.3892/or.2018.6447

Correlation between HGF/c-Met and Notch1 signaling pathways in human gastric cancer cells

Authors:
- Kuo-Hung Huang
- I-Cheng Sung
- Wen-Liang Fang
- Chin-Wen Chi
- Tien-Shun Yeh
- Hsin-Chen Lee
- Pen-Hui Yin
- Anna Fen-Yau Li
- Chew-Wun Wu
- Yi-Ming Shyr
- Muh-Hwa Yang
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Affiliations: Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan, R.O.C., Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan, R.O.C., Department of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan, R.O.C., Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan, R.O.C., Department of Pathology, Taipei Veterans General Hospital, Taipei 112, Taiwan, R.O.C., Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan, R.O.C.
Published online on: May 16, 2018 https://doi.org/10.3892/or.2018.6447
Pages: 294-302
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

In recent decades, research concerning gastric carcinogenesis has rapidly progressed. It is evident that hepatocyte growth factor (HGF) is clinically related to gastric cancer progression and metastasis. In addition, previous studies have found that expression of Notch ligand Jagged1 is correlated with the poor prognosis of gastric cancer. However, the interaction between the HGF/c-Met and Notch1 signaling pathways remains unknown. In the present study, we found that gastric cancer patients with positive c-Met expression exhibited poorer overall survival than patients without c-Met expression (P=0.043) and that Jagged1 expression was significantly correlated with c-Met expression (r=0.301; P=0.004) in human gastric cancer specimens. In addition, Jagged1 activity increased after HGF stimulation, which in turn increased the downstream expression of cyclooxygenase 2 (COX-2) in a time-dependent manner. After knockdown of Notch1 intracellular domain (N1IC), HGF was found to increase the proliferation and migration ability in human gastric cancer cells. However, overexpression of N1IC still had no effect after HGF stimulation. Our study found a feedback loop between HGF/c-Met and Jagged1/Notch1 signaling. Furthermore, both HGF/c-Met and Notch1 signaling triggered COX-2 activity. These results suggest that gastric cancer progression is not associated with a unique signaling pathway and that a feedback loop may exist between the HGF/c-Met and Notch1 signaling pathways, which may result in therapeutic resistance. Therefore, multi-modality therapies should be considered for treating gastric cancer.

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