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CDK5RAP3 inhibits angiogenesis in gastric neuroendocrine carcinoma by modulating AKT/HIF-1?/VEGFA signaling.

ABSTRACT: Background:Angiogenesis plays critical roles in the progression and metastasis of malignant tumors. Gastric neuroendocrine carcinoma is an uncommon stomach cancer that is rich in blood vessels and exhibits highly malignant biological behavior with a poor prognosis. The role of CDK5RAP3 in GNEC has not been reported to date. Methods:Immunohistochemistry was used to assess the expression of CDK5RAP3 in GNEC tissues and adjacent non-tumor tissues. Cell lines with stable overexpression or knockdown of CDK5RAP3 were constructed using lentiviral transfection. Wound-healing assays, invasion and metastasis assays, tube formation assays, and tumor xenograft transplantation assays were performed to evaluate the effect of CDK5RAP3 on GNEC angiogenesis in vitro and in vivo. Real-time PCR, ELISA, western blot analysis, and confocal-immunofluorescence staining were used to explore the molecular mechanism of CDK5RAP3's effect on angiogenesis. Results:Compared with their respective adjacent non-tumor tissues, protein levels of CDK5RAP3 were significantly decreased in GNEC tissues. Furthermore, low expression of CDK5RAP3 was correlated with more advanced TNM stage, increased tumor microvessel density, and poor prognosis. Functionally, we found that GNEC cells with CDK5RAP3 knockdown promoted human umbilical vein endothelial cells migration and tube formation via activation of AKT/HIF-1?/VEGFA signaling, resulting in increased levels of VEGFA in GNEC cell supernatant. In addition, CDK5RAP3 overexpression in GNEC cells caused the opposing effect. Consistent with these results, nude mouse tumorigenicity assays showed that CDK5RAP3 expression downregulated angiogenesis in vivo. Lastly, patients with low CDK5RAP3 expression and high VEGFA expression exhibited the worst prognosis. Conclusions:This study demonstrated that CDK5RAP3 inhibits angiogenesis by downregulating AKT/HIF-1?/VEGFA signaling in GNEC and improves patient prognosis, suggesting that CDK5RAP3 could be a potential therapeutic target for GNEC.

SUBMITTER: Lin JX

PROVIDER: S-EPMC6839262 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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CDK5RAP3 inhibits angiogenesis in gastric neuroendocrine carcinoma by modulating AKT/HIF-1α/VEGFA signaling.

Lin Jian-Xian JX Weng Xiong-Feng XF Xie Xin-Sheng XS Lian Ning-Zi NZ Qiu Sheng-Liang SL Wang Jia-Bin JB Lu Jun J Chen Qi-Yue QY Cao Long-Long LL Lin Mi M Tu Ru-Hong RH Yang Ying-Hong YH Liu Si-Jia SJ Hu Min M Lin Yi-Ke YK Huang Chang-Ming CM Zheng Chao-Hui CH Li Ping P Xie Jian-Wei JW

Cancer cell international 20191107

<h4>Background</h4>Angiogenesis plays critical roles in the progression and metastasis of malignant tumors. Gastric neuroendocrine carcinoma is an uncommon stomach cancer that is rich in blood vessels and exhibits highly malignant biological behavior with a poor prognosis. The role of CDK5RAP3 in GNEC has not been reported to date.<h4>Methods</h4>Immunohistochemistry was used to assess the expression of CDK5RAP3 in GNEC tissues and adjacent non-tumor tissues. Cell lines with stable overexpressio ...[more]

PMID: 31728130

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Dataset Information

CDK5RAP3 inhibits angiogenesis in gastric neuroendocrine carcinoma by modulating AKT/HIF-1?/VEGFA signaling.

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CDK5RAP3 inhibits angiogenesis in gastric neuroendocrine carcinoma by modulating AKT/HIF-1α/VEGFA signaling.

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