endothelin-1 and Carcinogenesis

Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is one of the four subtypes of gastric carcinoma and its unique clinicopathological mechanism is unclear. Herein, the expression of endothelin-1 (ET-1) in EBVaGC was lower than of Epstein-Barr virus-negative gastric carcinoma (EBVnGC) and associated with a low frequency of lymph node metastasis of EBVaGC. Functional studies showed that the activation of ET-1/endothelin receptor type A (ETAR) axis could promote cell growth, migration, and antiapoptosis. The expression of the ET-1 gene was unrelated to methylation of its promoter region and miRNAs (-1, -125a, -125b). After being treated with MEK1/2 inhibitor (PD0325901), the inactivation of ERK1/2 pathway resulted in downregulation of ET-1 and forkhead box O1 (FOXO1) expression. Further, FOXO1 knockdown decreased the ET-1 expression. These findings indicated that ET-1 could be involved in development of gastric cancer and EBV could suppress the expression of ET-1 via the regulation of the transcription factor FOXO1 through the MAPK/ERK pathway.

Topics: Carcinogenesis; Carcinoma; Endothelin-1; Epstein-Barr Virus Infections; Forkhead Box Protein O1; Herpesvirus 4, Human; Humans; MAP Kinase Signaling System; Stomach Neoplasms

Experimental study.. To examine the role of endothelin-1 (ET-1) and the Notch signaling pathway in giant cell tumor (GCT) of the spine.. Previously published studies have shown that the Notch signaling pathway has a role in tumor invasion and that ET-1 is involved in tumor invasion and angiogenesis. However, the roles of both Notch signaling and ET-1 in GCT of the spine remain unknown.. Expression of ET-1 in tissue samples from patients with spinal GCT, and adjacent normal tissue, were analyzed by immunohistochemistry and western blot. GCT stromal cells (GCTSCs) were isolated and ET-1 expression was demonstrated by immunofluorescence. Cell viability and cell migration of GCTSCs and human vascular endothelial cells following ET-1 treatment were assessed using the cell counting kit-8 assay and a transwell assay. Receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) mRNA expression was determined following ET-1 treatment of GCTSCs using quantitative real-time polymerase chain reaction. In GCTSCs treated with ET-1 and the ET-1 signaling antagonist, BQ-123, levels of cyclin D1, vascular endothelial growth factor, matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), Jagged1, Hes1, Hey2, and Notch intracellular domain were examined by western blot.. Compared with normal adjacent tissue, ET-1 was highly expressed in GCT tissue. In GCTSCs studied in vitro, treatment with ET-1 significantly increased GCTSC and human vascular endothelial cells growth and migration and increased the expression of RANKL and OPG, meanwhile the ratio of RANKL/OPG was increased, in GCTSCs, it upregulated the production of cyclin D1, vascular endothelial growth factor, MMP-2, MMP-9, Jagged1, Hes1, Hey2, and Notch intracellular domain expression in a dose-dependent manner. Treatment with BQ-123 reversed these effects.. In GCT of the spine, ET-1 showed increased expression. In cultured GCTSCs, ET-1 treatment activated the Notch signaling pathway.. 2.

Topics: Carcinogenesis; Endothelin-1; Giant Cell Tumors; Humans; Receptors, Notch; Signal Transduction; Spinal Neoplasms

Endothelin receptor A (ETAR) promotes tumorigenesis by stimulating cell proliferation, migration, and survival. However, the mechanism of ETAR in promoting tumor growth is largely unknown. In this study, we demonstrate that ETAR stimulates colon cell proliferation, migration, and tumorigenesis through the activation of YAP/TAZ, two transcription coactivators of the Hippo tumor suppressor pathway. Endothelin-1 treatment induced YAP/TAZ dephosphorylation, nuclear accumulation, and transcriptional activation in multiple colon cancer cells. ETAR stimulation acted via downstream G-protein Gαq/11 and Rho GTPase to suppress the Hippo pathway, thus leading to YAP/TAZ activation, which was required for ETAR-induced tumorigenesis. Overall, these results indicate a critical role of the YAP/TAZ axis in ETAR signaling.

Topics: Adaptor Proteins, Signal Transducing; Carcinogenesis; Cell Movement; Cell Proliferation; Colonic Neoplasms; Endothelin-1; Gene Expression Regulation, Neoplastic; GTP-Binding Protein alpha Subunits; HCT116 Cells; Humans; Intracellular Signaling Peptides and Proteins; Phosphoproteins; Receptor, Endothelin A; rho GTP-Binding Proteins; Trans-Activators; Transcription Factors; Transcriptional Coactivator with PDZ-Binding Motif Proteins; YAP-Signaling Proteins

The endothelin-1 (ET-1)/endothelin A receptor (ETAR, a G protein-coupled receptor) axis confers pleiotropic effects on both tumor cells and the tumor microenvironment, modulating chemo-resistance and other tumor-associated processes by activating Gαq- and β-arrestin-mediated pathways. While the precise mechanisms by which these effects occur remain to be elucidated, interference with ETAR signaling has emerged as a promising antitumor strategy in many cancers including ovarian cancer (OC). However, current clinical approaches using ETAR antagonists in the absence of a detailed knowledge of downstream signaling have resulted in multiple adverse side effects and limited therapeutic efficacy. To maximize the safety and efficacy of ETAR-targeted OC therapy, we investigated the role of other G protein subunits such as Gαs in the ETAR-mediated ovarian oncogenic signaling. In HEY (human metastatic OC) cells where the ET-1/ETAR axis is well-characterized, Gαs signaling inhibits ETAR-mediated OC cell migration, wound healing, proliferation and colony formation on soft agar while inducing OC cell apoptosis. Mechanistically, ET-1/ETAR is coupled to Gαs/cAMP signaling in the same ovarian carcinoma-derived cell line. Gαs/cAMP/PKA activation inhibits ETAR-mediated β-arrestin activation of angiogenic/metastatic Calcrl and Icam2 expression. Consistent with our findings, Gαs overexpression is associated with improved survival in OC patients in the analysis of the Cancer Genome Atlas data. In conclusion, our results indicate a novel function for Gαs signaling in ET-1/ETAR-mediated OC oncogenesis and may provide a rationale for a biased signaling mechanism, which selectively activates Gαs-coupled tumor suppressive pathways while blocking Gαq-/β-arrestin-mediated oncogenic pathways, to improve the targeting of the ETAR axis in OC.

Topics: Adenylyl Cyclases; Apoptosis; Arrestins; beta-Arrestins; Carcinogenesis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Colforsin; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Endothelin-1; Enzyme Activators; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; GTP-Binding Protein alpha Subunits, Gs; Humans; Models, Biological; Neoplasm Metastasis; Neovascularization, Pathologic; Ovarian Neoplasms; Receptor, Endothelin A; Signal Transduction; Survival Analysis