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.
Highlights
Gastric carcinoma is the third leading cause of global cancer mortality [1]
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
Results showed that expressions of miR-23b were significantly down-regulated in numerous stomach adenocarcinoma samples compared with normal counterparts, whereas those of Notch2 receptor, E2F1, and v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets1) mRNAs were up-regulated (Figure 1A)
Summary
Gastric carcinoma is the third leading cause of global cancer mortality [1]. The regulatory mechanisms modulating aggressiveness of gastric cancer are incompletely elucidated. There are four Notch receptors (Notch1–4) in mammals [2, 3]. Notch receptors are activated after cleavage induced by ligand-binding to release their Notch receptor intracellular domains, the activated forms of Notch receptors. Notch receptors act as oncogenes or tumor suppressors in controlling tumorigenesis [2, 3]. Notch and Notch receptor intracellular domains (N1IC and N2IC, respectively) enhance carcinogenesis through up-regulating cyclooxygenase-2 [4, 5]. Notch receptor mRNA is up-regulated in the population of cancer stem cells [6]
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