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

Abstract

BackgroundAngiogenesis 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.MethodsImmunohistochemistry 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.ResultsCompared 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.ConclusionsThis 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.

Extrapulmonary poorly differentiated NECs, including molecular and immune aspects

“…Gastric NEC is rich in blood vessels and has highly malignant biological behaviour (Lin et al 2019). In Lin et al, immunohistochemistry was used to assess expression of CDK5RAP3 in tumour tissue and adjacent non-tumour tissue from gastric NEC.…”

“…Cell lines with stable overexpression or knockdown of CDK5RAP3 were developed using lentiviral transfection; protein levels of CDK5RAP3 were reduced in tissue from gastric NEC and low expression correlated with more advanced stage, increased tumour micro-vessel density and poor prognosis. The authors reported that CDK5RAP3 inhibited angiogenesis and thus could be a potential therapeutic target in gastric NEC (Lin et al 2019).…”

Inhibition of Nrf2/HO-1 signaling pathway by Dextran Sulfate suppresses angiogenesis of Gastric Cancer

“…In vivo studies have found that DS reduced the number and volume of tumor nodules in nude mice with gastric cancer 10 . Angiogenesis is the core event of solid tumor growth and metastasis in the hypoxic microenvironment 3 . Is the pharmacological effect of DS on tumor nodules in tumor-bearing mice achieved by suppressing angiogenesis?…”

“…Metastasis is the leading cause of death in patients with gastric cancer 2 . Gastric cancer metastasis is a complex process involving numerous factors and multiple stages, and angiogenesis plays a central role in the growth and spread of tumor cells 3 . It not only provides necessary nutrients for tumor cells, removes metabolites produced by tumor cell growth, but also provides channels for distant metastasis of tumor cells, enabling the tumor to acquire the ability to further grow and metastasize.…”

Cyclin-Dependent Kinase 5 Regulatory Subunit Associated Protein 3: Potential Functions and Implications for Development and Disease

“…CDK5RAP3 was initially considered as a putative tumor suppressor since it is found to be markedly reduced in 32% of primary head and neck squamous cell carcinoma (HNSCC), and inhibits cellular transformation and tumor growth in vitro and in vivo (5). Hereafter, it displays a tumor suppressor activity in hepatocellular carcinoma (23), gastric cancer (16,(24)(25)(26)(27), and renal cancer (28) as well. In contrast, additional studies indicate that CDK5RAP3 appears to promote tumorigenesis because it is overexpressed in lung adenocarcinoma (29), hepatocellular carcinoma (11,14), breast cancer (17) and cervical carcinoma (30), and has an oncogenic roles in these cancers.…”