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Supervillin promotes tumor angiogenesis in liver cancer.

ABSTRACT: Tumor angiogenesis is a hallmark of liver cancer and is necessary for tumor growth and progression. Supervillin (SVIL) is highly expressed and implicated in several malignant processes of liver cancer. However, the functional relationships between SVIL and tumor angiogenesis in liver cancer have not yet been fully elucidated. The present study was based on bioinformatics analysis, patient tissue sample detection, three?dimensional simulated blood vessel formation, a series of cytological experiments and mouse models. The results demonstrated the important role of SVIL in the progression of malignant liver cancer and tumor angiogenesis, both in terms of vasculogenic mimicry (VM) and endothelium?dependent vessel (EDV) development. SVIL knockdown inhibited VM formation and induced tumor cell apoptosis via the VEGF?p38 signaling axis and through various VM?associated transcriptional factors, including vascular endothelial?cadherin, matrix metalloproteinase 9/12 and migration?inducing protein 7. SVIL may therefore be considered a potential tumor vascular biomarker and a promising therapeutic target for patients with liver cancer.

SUBMITTER: Zhao C

PROVIDER: S-EPMC7336518 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Supervillin promotes tumor angiogenesis in liver cancer.

Zhao Chenggang C Zhao Zhiyang Z Wang Zhen Z Hu Lizhu L Wang Hongzhi H Fang Zhiyou Z

Oncology reports 20200525 2

Tumor angiogenesis is a hallmark of liver cancer and is necessary for tumor growth and progression. Supervillin (SVIL) is highly expressed and implicated in several malignant processes of liver cancer. However, the functional relationships between SVIL and tumor angiogenesis in liver cancer have not yet been fully elucidated. The present study was based on bioinformatics analysis, patient tissue sample detection, three‑dimensional simulated blood vessel formation, a series of cytological experim ...[more]

PMID: 32468064

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Project description:PurposeIntegrins are critical to cancer progression. Integrin alpha 5 (ITGA5) is correlated with the prognosis of cervical cancer patients. However, whether ITGA5 plays an active role in cervical cancer progression or not remains unknown.MethodsITGA5 protein expression was detected in 155 human cervical cancer tissues by immunohistochemistry. Data from The Cancer Genome Atlas were utilized to identify risk factors for the overall survival of cervical cancer patients and ITGA5-associated differentially expressed genes. Analyses of single-cell RNA-seq based on Gene Expression Omnibus datasets were performed to show the coexpression of ITGA5 and angiogenesis factors. Tube formation assay, 3D spheroid sprout assay, qRT-PCR, Western Blotting, ELISA, and immunofluorescence were conducted to explore the angiogenic function of ITGA5 in vitro and underlying mechanisms.ResultsHigh ITGA5 level was significantly correlated with increased risk in terms of overall survival and advanced disease stage in cervical cancer patients. ITGA5-associated differentially expressed genes linked ITGA5 to angiogenesis, and immunohistochemistry showed a positive correlation between ITGA5 and microvascular density in cervical cancer tissues. Moreover, tumor cells transfected with ITGA5-targeting siRNA decreased ability to promote endothelial tube formation in vitro. ITGA5/VEGFA coexpression was observed in a tumor cell subpopulation and the decreased endothelial angiogenesis by downregulating ITGA5 could be reversed by VEGFA. Bioinformatics analysis highlighted the PI3K-Akt signaling pathway as downstream of ITGA5. Downregulation of ITGA5 in tumor cells significantly decreased p-AKT and VEGFA levels. Fibronectin (FN1) coated cells or transfected with FN1-targeting siRNA showed fibronectin may play a critical role on ITGA5-mediated angiogenesis.ConclusionITGA5 promotes angiogenesis and possibly be a potential predictive biomarker for poor survival of patients in cervical cancer.

Project description:Angiogenesis is a fundamental process that involves in tumor progression and metastasis. Vascular endothelial growth factor (VEGF) family and their receptors are identified as the most prominent regulators of angiogenesis. However, the clinical efficacy of anti-VEGF/VEGFR therapy is not ideal, prompting the needs to further understand mechanisms behind tumor angiogenesis. Here, we found that Dickkopf associated protein 2 (DKK2), a secretory protein highly expressed in metastatic colorectal cancer tissues, could stimulate angiogenesis via a classic VEGF/VEGFR independent pathway. Methods: DKK2 was screened out from microarray data analyzing gene expression profiles of eight pairs of non-metastatic and metastatic human colorectal cancer (CRC) tissues. Immunofluorescence histochemical staining (IHC) was used to detect the expression of DKK2 and angiogenesis in CRC tissues. Chicken chorioallantoic membrane (CAM) assay and Human umbilical vein endothelial cells (HUVEC) tubule formation assay was used for in vitro and in vivo angiogenesis study, respectively. Lactate and glucose concentration in the culture medium was measured by enzyme-linked immunosorbent assay (ELISA). Luciferase reporter assay was used to verify the interaction between miR-493-5p and the 3'UTR of DKK2. Results: DKK2 could stimulate angiogenesis via accelerating the aerobic glycolysis of CRC cells, through which lactate is produced from glucose and accumulated in tumor microenvironment. Lactate functions as the final executor of DDK2 to stimulate tube formation of endothelial cells, and blockage of lactate secretion by lactate transporter (MCT) inhibitors dramatically neutralize the progression and metastasis of CRC both in vitro and in vivo. DKK2 could cooperate with lipoprotein receptor-related protein 6, which is required for glucose uptake, and activated the downstream mTOR signal pathway to accelerate lactate secretion. In addition, the expression of DKK2 is switched on via the demethylation of miR-493-5p, which allows the dissociated of miR-493-5p from the 3'-UTRs of DKK2 and initiates its stimulatory role on CRC progression in an autocrine or paracrine manner. Conclusion: DKK2 promotes tumor metastasis and angiogenesis through a novel VEGF-independent, but energy metabolism related pathway. DKK2 might be a potential anti-angiogenic target in clinical treatment for the advanced CRC patients.

Dataset Information

Supervillin promotes tumor angiogenesis in liver cancer.

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Supervillin promotes tumor angiogenesis in liver cancer.

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