MiR-200b Suppresses Gastric Cancer Cell Migration and Invasion by Inhibiting NRG1 through ERBB2/ERBB3 Signaling

Purpose. Accumulating evidence indicates that miRNAs (miRs) play crucial roles in the modulation of tumors development. However, the accurately mechanisms have not been entirely clarified. In this study, we aimed to explore the role of miR-200b in the development of gastric cancer (GC). Methods. Western blot and RT-PCR were applied to detect epithelial-mesenchymal transition (EMT) marker expression and mRNA expression. Transwell assay was used for measuring the metastasis and invasiveness of GC cells. TargetScan system, luciferase reporter assay, and rescue experiments were applied for validating the direct target of miR-200b. Results. MiR-200b was prominently decreased in GC tissues and cells, and its downregulation was an indicator of poor prognosis of GC patients. Reexpression of miR-200b suppressed EMT along with GC cell migration and invasion. Neuregulin 1 (NRG1) was validated as the target of miR-200b, and it rescued miR-200b inhibitory effect on GC progression. In GC tissues, the correlation of miR-200b with NRG1 was inverse. Conclusion. MiR-200b suppressed EMT-related migration and invasion of GC through the ERBB2/ERBB3 signaling pathway via targeting NRG1.

Abstract 341: Protective Role of Myeloid Cell-specific Erbb3 Signaling After Transverse Aortic Constriction

Introduction: Understanding molecular mechanisms underlying cardiac hypertrophy is crucial for protecting against cardiac remodeling, or slowing down its destined pathway to heart failure. Recent studies revealed that myeloid cells play an important role in the regulation of hypertrophic remodeling. Neuregulin-1 (NRG-1) has been shown to play an essential role in the regulation of tissue-protective and pro-survival processes in response to tissue injury in the cardiovascular system. We find that NRG-1 receptors, including ErbB2 and ErbB3, are expressed and functionally active in cardiac myeloid cells. We hypothesized that the NRG-1/ErbB3 signaling in myeloid cells plays a protective role in cardiac hypertrophic remodeling. To test this hypothesis, we examined the effect of Erbb3 gene ablation in mouse myeloid cells on cardiac hypertrophic remodeling induced by pressure overload. Methods and results: Myeloid-specific ErbB3-deficient mice (ErbB3 MyeKO ) were generated by crossing Erbb3 -floxed mice with LysM-Cre transgenic mice. Cardiac hypertrophic remodeling was established in mice by transverse aortic constriction (TAC). Five days after TAC, survival was dramatically reduced in male ErbB3 MyeKO mice (20% vs. 90%, p=0.021 , MyeKO vs. MyeWT). The post-mortem examination of lung weight to body weight ratio suggested that acute pulmonary edema was developed in ERBB3 MyeKO mice. In order to determine the cellular and molecular mechanisms involved in the increased mortality in ErbB3 MyeKO males, cardiac cell populations were examined at day 3 post-TAC using flow cytometry. A significant accumulation of myeloid cells was found in control but not in ErbB3 MyeKO males. This was accompanied by increased proliferation of Sca-1 positive non-immune cells (endothelial cells and cardiac progenitors) in control but not ErbB3 MyeKO males. An antibody-based protein array analysis revealed that IGF-1 expression was significantly downregulated only in ErbB3 MyeKO males after TAC. Conclusion: Our data highlight the important role of myeloid cell-specific ErbB3 signaling in the accumulation of myeloid cells that contributes to the development of compensatory hypertrophy and the prevention of acute heart failure in male mice.