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Cancer Cell International
Published in: Cancer Cell International 1/2019

Open Access 01-12-2019 | Primary research

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

Authors: Jian-Xian Lin, Xiong-Feng Weng, Xin-Sheng Xie, Ning-Zi Lian, Sheng-Liang Qiu, Jia-Bin Wang, Jun Lu, Qi-Yue Chen, Long-Long Cao, Mi Lin, Ru-Hong Tu, Ying-Hong Yang, Si-Jia Liu, Min Hu, Yi-Ke Lin, Chang-Ming Huang, Chao-Hui Zheng, Ping Li, Jian-Wei Xie

Published in: Cancer Cell International | Issue 1/2019

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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-1α/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-1α/VEGFA signaling in GNEC and improves patient prognosis, suggesting that CDK5RAP3 could be a potential therapeutic target for GNEC.
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Metadata
Title
CDK5RAP3 inhibits angiogenesis in gastric neuroendocrine carcinoma by modulating AKT/HIF-1α/VEGFA signaling
Authors
Jian-Xian Lin
Xiong-Feng Weng
Xin-Sheng Xie
Ning-Zi Lian
Sheng-Liang Qiu
Jia-Bin Wang
Jun Lu
Qi-Yue Chen
Long-Long Cao
Mi Lin
Ru-Hong Tu
Ying-Hong Yang
Si-Jia Liu
Min Hu
Yi-Ke Lin
Chang-Ming Huang
Chao-Hui Zheng
Ping Li
Jian-Wei Xie
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2019
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-019-0997-5

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