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Suppression of IL-8-Src signalling axis by 17?-estradiol inhibits human mesenchymal stem cells-mediated gastric cancer invasion.

ABSTRACT: Epidemiologic data show the incidence of gastric cancer in men is twofold higher than in women worldwide. Oestrogen is reported to have the capacity against gastric cancer development. Endogenous oestrogen reduces gastric cancer incidence in women. Cancer patients treated with oestrogens have a lower subsequent risk of gastric cancer. Accumulating studies report that bone marrow mesenchymal stem cells (BMMSCs) might contribute to the progression of gastric cancer through paracrine effect of soluble factors. Here, we further explore the effect of oestrogen on BMMSCs-mediated human gastric cancer invasive motility. We founded that HBMMSCs notably secrete interleukin-8 (IL-8) protein. Administration of IL-8 specific neutralizing antibody significantly inhibits HBMMSCs-mediated gastric cancer motility. Treatment of recombinant IL-8 soluble protein confirmed the role of IL-8 in mediating HBMMSCs-up-regulated cell motility. IL-8 up-regulates motility activity through Src signalling pathway in human gastric cancer. We further observed that 17? -estradiol inhibit HBMMSCS-induced cell motility via suppressing activation of IL8-Src signalling in human gastric cancer cells. 17?-estradiol inhibits IL8-up-regulated Src downstream target proteins including p-Cas, p-paxillin, p-ERK1/2, p-JNK1/2, MMP9, tPA and uPA. These results suggest that 17?-estradiol significantly inhibits HBMMSCS-induced invasive motility through suppressing IL8-Src signalling axis in human gastric cancer cells.

SUBMITTER: Liu CJ

PROVIDER: S-EPMC4831355 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Suppression of IL-8-Src signalling axis by 17β-estradiol inhibits human mesenchymal stem cells-mediated gastric cancer invasion.

Liu Chung-Jung CJ Kuo Fu-Chen FC Wang Chiu-Lin CL Kuo Chao-Hung CH Wang Sophie S W SS Chen Chiao-Yun CY Huang Yaw-Bin YB Cheng Kuang-Hung KH Yokoyama Kazunari K KK Chen Chun-Lin CL Lu Chien-Yu CY Wu Deng-Chyang DC

Journal of cellular and molecular medicine 20160306 5

Epidemiologic data show the incidence of gastric cancer in men is twofold higher than in women worldwide. Oestrogen is reported to have the capacity against gastric cancer development. Endogenous oestrogen reduces gastric cancer incidence in women. Cancer patients treated with oestrogens have a lower subsequent risk of gastric cancer. Accumulating studies report that bone marrow mesenchymal stem cells (BMMSCs) might contribute to the progression of gastric cancer through paracrine effect of solu ...[more]

PMID: 26945908

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Project description:Estrogens play a protective role in coronary artery disease. The mechanisms of action are still poorly understood, although a role for estrogens in stimulation of angiogenesis has been suggested. In several cell types, estrogens modulate the Notch pathway, which is involved in controlling angiogenesis downstream of vascular endothelial growth factor A (VEGF-A). The goal of our study was to establish whether estrogens modulate Notch activity in endothelial cells and the possible consequences on angiogenesis. Human umbilical vein endothelial cells (HUVECs) were treated with 17?-estradiol (E2) and the effects on Notch signalling were evaluated. E2 increased Notch1 processing as indicated by i) decreased levels of Notch1 transmembrane subunit ii) increased amount of Notch1 in nuclei iii) unaffected level of mRNA. Similarly, E2 increased the levels of the active form of Notch4 without altering Notch4 mRNA. Conversely, protein and mRNA levels of Notch2 were both reduced suggesting transcriptional repression of Notch2 by E2. Under conditions where Notch was activated by upregulation of Delta-like ligand 4 (Dll4) following VEGF-A treatment, E2 caused a further increase of the active form of Notch1, of the number of cells with nuclear Notch1 and of Hey2 mRNA. Estrogen receptor antagonist ICI 182.780 antagonized these effects suggesting that E2 modulation of Notch1 is mediated by estrogen receptors. E2 treatment abolished the increase in endothelial cells sprouting caused by Notch inhibition in a tube formation assay on 3D Matrigel and in mouse aortic ring explants. In conclusion, E2 affects several Notch pathway components in HUVECs, leading to an activation of the VEGF-A-Dll4-Notch1 axis and to a modulation of vascular branching when Notch signalling is inhibited. These results contribute to our understanding of the molecular mechanisms of cardiovascular protection exerted by estrogens by uncovering a novel role of E2 in the Notch signalling-mediated modulation of angiogenesis.

Dataset Information

Suppression of IL-8-Src signalling axis by 17?-estradiol inhibits human mesenchymal stem cells-mediated gastric cancer invasion.

Publications

Suppression of IL-8-Src signalling axis by 17β-estradiol inhibits human mesenchymal stem cells-mediated gastric cancer invasion.

Similar Datasets

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