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

journal_name

Cancer Cell Int

journal_title

Cancer cell international

authors

Lin JX,Weng XF,Xie XS,Lian NZ,Qiu SL,Wang JB,Lu J,Chen QY,Cao LL,Lin M,Tu RH,Yang YH,Liu SJ,Hu M,Lin YK,Huang CM,Zheng CH,Li P,Xie JW

doi

10.1186/s12935-019-0997-5

subject

Has Abstract

pub_date

2019-11-07 00:00:00

pages

282

issn

1475-2867

pii

997

journal_volume

pub_type

杂志文章

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