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ADAM9 promotes lung cancer progression through vascular remodeling by VEGFA, ANGPT2, and PLAT.

ABSTRACT: Lung cancer has a very high prevalence of brain metastasis, which results in a poor clinical outcome. Up-regulation of a disintegrin and metalloproteinase 9 (ADAM9) in lung cancer cells is correlated with metastasis to the brain. However, the molecular mechanism underlying this correlation remains to be elucidated. Since angiogenesis is an essential step for brain metastasis, microarray experiments were used to explore ADAM9-regulated genes that function in vascular remodeling. The results showed that the expression levels of vascular endothelial growth factor A (VEGFA), angiopoietin-2 (ANGPT2), and tissue plasminogen activator (PLAT) were suppressed in ADAM9-silenced cells, which in turn leads to decreases in angiogenesis, vascular remodeling, and tumor growth in vivo. Furthermore, simultaneous high expression of ADAM9 and VEGFA or of ADAM9 and ANGPT2 was correlated with poor prognosis in a clinical dataset. These findings suggest that ADAM9 promotes tumorigenesis through vascular remodeling, particularly by increasing the function of VEGFA, ANGPT2, and PLAT.

SUBMITTER: Lin CY

PROVIDER: S-EPMC5678093 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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ADAM9 promotes lung cancer progression through vascular remodeling by VEGFA, ANGPT2, and PLAT.

Lin Chen-Yuan CY Cho Chia-Fong CF Bai Shih-Ting ST Liu Jing-Pei JP Kuo Ting-Ting TT Wang Li-Ju LJ Lin Yu-Sen YS Lin Ching-Chan CC Lai Liang-Chuan LC Lu Tzu-Pin TP Hsieh Chih-Ying CY Chu Chin-Nan CN Cheng Da-Chuan DC Sher Yuh-Pyng YP

Scientific reports 20171108 1

Lung cancer has a very high prevalence of brain metastasis, which results in a poor clinical outcome. Up-regulation of a disintegrin and metalloproteinase 9 (ADAM9) in lung cancer cells is correlated with metastasis to the brain. However, the molecular mechanism underlying this correlation remains to be elucidated. Since angiogenesis is an essential step for brain metastasis, microarray experiments were used to explore ADAM9-regulated genes that function in vascular remodeling. The results showe ...[more]

PMID: 29118335

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Project description:Background: Vascular endothelial growth factor A (VEGFA) and angiopoietin 2 (ANGPT2) are key mediators in angiogenesis. The expression and clinical significance of VEGFA and ANGPT2 have been investigated in lung cancer, but the results are controversial. The specific roles of VEGFA and ANGPT2 in adenocarcinoma (ADC) and squamous cell carcinoma (SQC) are still not fully understood. To characterize it, we conducted the current study. Materials and Methods: The relationships between clinic-pathological characteristics and the protein expressions of VEGFA and ANGPT2 were analyzed on tissue microarrays by immunohistochemistry (IHC) staining. Then public databases were used to evaluate the association of VEGFA and ANGPT2 mRNA expressions with clinic-pathological parameters and prognosis. Cobalt chloride (CoCl2) was adopted to mimic a hypoxic microenvironment and western blot was used to detect the expression of hypoxia inducible factor-1α (HIF-1α), VEGFA and ANGPT2 in lung cancer cell lines. Results: IHC staining revealed that the expressions of VEGFA and ANGPT2 were enriched in lung cancer tissues compared with normal tissues. Additionally, both VEGFA and ANGPT2 protein levels were significantly associated with the tumor size and lymph node metastasis only in ADC, not SQC. More importantly, increased VEGFA and ANGPT2 protein levels were negatively correlated with overall survival (OS) of ADC individuals. Meta-analyses of 22 gene expression omnibus (GEO) databases of lung cancer implicated that patients with higher VEGFA and ANGPT2 mRNA expressions tended to have advanced stage in ADC rather than SQC. Kaplan-Meier plot analyses further verified that high levels of VEGFA and ANGPT2 mRNA were associated with poor survival only in ADC. Moreover, the combination of VEGFA and ANGPT2 could more precisely predict prognosis in ADC. In hypoxia-mimicking conditions, induced expression of HIF-1α unregulated VEGFA and ANGPT2 proteins abundance. Conclusion: Our results showed hypoxia upregulated the protein levels of VEGFA and ANGPT2 in lung cancer cell lines, and the roles of VEGFA and ANGPT2 were distinct in ADC and SQC. Combined detections of VEGFA and ANGPT2 may be valuable prognostic biomarkers for ADC and double block of VEGFA and ANGPT2 may improve therapeutic outcome.

Project description:Legumain, a recently discovered cysteine protease, is increased in both carotid plaques and plasma of patients with carotid atherosclerosis. Legumain increases the migration of human monocytes and human umbilical vein endothelial cells (HUVECs). However, the causal relationship between legumain and atherosclerosis formation is not clear. We assessed the expression of legumain in aortic atheromatous plaques and after wire-injury-induced femoral artery neointimal thickening and investigated the effect of chronic legumain infusion on atherogenesis in Apoe-/- mice. We also investigated the associated cellular and molecular mechanisms in vitro, by assessing the effects of legumain on inflammatory responses in HUVECs and THP-1 monocyte-derived macrophages; macrophage foam cell formation; and migration, proliferation, and extracellular matrix protein expression in human aortic smooth muscle cells (HASMCs). Legumain was expressed at high levels in atheromatous plaques and wire injury-induced neointimal lesions in Apoe-/- mice. Legumain was also expressed abundantly in THP-1 monocytes, THP-1 monocyte-derived macrophages, HASMCs, and HUVECs. Legumain suppressed lipopolysaccharide-induced mRNA expression of vascular cell adhesion molecule-1 (VCAM1), but potentiated the expression of interleukin-6 (IL6) and E-selectin (SELE) in HUVECs. Legumain enhanced the inflammatory M1 phenotype and oxidized low-density lipoprotein-induced foam cell formation in macrophages. Legumain did not alter the proliferation or apoptosis of HASMCs, but it increased their migration. Moreover, legumain increased the expression of collagen-3, fibronectin, and elastin, but not collagen-1, in HASMCs. Chronic infusion of legumain into Apoe-/- mice potentiated the development of atherosclerotic lesions, accompanied by vascular remodeling, an increase in the number of macrophages and ASMCs, and increased collagen-3 expression in plaques. Our study provides the first evidence that legumain contributes to the induction of atherosclerotic vascular remodeling.

Dataset Information

ADAM9 promotes lung cancer progression through vascular remodeling by VEGFA, ANGPT2, and PLAT.

Publications

ADAM9 promotes lung cancer progression through vascular remodeling by VEGFA, ANGPT2, and PLAT.

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