Oncotarget

Research Papers:

The reciprocal regulation loop of Notch2 pathway and miR-23b in controlling gastric carcinogenesis

Tzu-Ting Huang _, Yueh-Hsin Ping, An-Ming Wang, Chia-Chi Ke, Wen-Liang Fang, Kuo-Hung Huang, Hsin-Chen Lee, Chin-Wen Chi and Tien-Shun Yeh

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Oncotarget. 2015; 6:18012-18026. https://doi.org/10.18632/oncotarget.4000

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Abstract

Tzu-Ting Huang1,2, Yueh-Hsin Ping1,*, An-Ming Wang2,*, Chia-Chi Ke2,*, Wen-Liang Fang3,4, Kuo-Hung Huang3,4, Hsin-Chen Lee1, Chin-Wen Chi1,5, Tien-Shun Yeh2,6,7,8

1Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan

2Department of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei, Taiwan

3Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan

4Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan

5Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

6Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan

7Genome Research Center, National Yang-Ming University, Taipei, Taiwan

8Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan

*These authors have contributed equally to this work

Correspondence to:

Tien-Shun Yeh, e-mail: tsyeh@ym.edu.tw

Keywords: notch2 receptor, miR-23b, Ets1, E2F1, gastric carcinogenesis

Received: March 23, 2015     Accepted: May 06, 2015     Published: May 18, 2015

ABSTRACT

Gastric carcinoma is one of the most common malignancies and the third highest cause of global cancer-related death. Notch2 receptor intracellular domain (N2IC), the activated form of Notch2 receptor, enhances gastric carcinogenesis. MicroRNAs (miRNAs) act as either oncogenes or tumor suppressors in tumorigenesis and cross-talk with Notch pathways. Herein, microRNA-23b (miR-23b) was identified as a Notch2 receptor-related miRNA and its role in gastric carcinogenesis was investigated. Levels of miR-23b in stomach adenocarcinoma samples were down-regulated, whereas those of Notch2 receptor, v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets1), and E2F1 transcripts were up-regulated. Results also showed that N2IC down-regulated miR-23b expression in gastric cancer cells through up-regulating E2F1. The miR-23b inhibited gastric tumorigenesis including growth, viability, epithelial-mesenchymal transition, and abilities of colony formation, migration, invasion, and tumorsphere formation. Mechanistically, miR-23b suppressed tumor progression and pluripotency gene expression and affected tumorsphere ultra-structure in gastric cancer cells via targeting Notch2 receptor or Ets1. Furthermore, miR-23b diminished the xenografted tumor growth and lung metastasis of SC-M1 gastric cancer cells through Notch2 pathway. Our results suggest that Notch2 pathway and miR-23b interplay in a reciprocal regulation loop in gastric cancer cells and this axis plays an important role in gastric carcinogenesis.


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