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Cancer Cell Int ; 19: 282, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31728130


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.

J Exp Clin Cancer Res ; 38(1): 410, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533855


BACKGROUND: UFM1 has been found to be involved in the regulation of tumor development. This study aims to clarify the role and potential molecular mechanisms of UFM1 in the invasion and metastasis of gastric cancer. METHODS: Expression of UFM1 in gastric tumor and paired adjacent noncancerous tissues from 437 patients was analyzed by Western blotting, immunohistochemistry, and realtime PCR. Its correlation with the clinicopathological characteristics and prognosis of gastric cancer patients was analyzed. The effects of UFM1 on the invasion and migration of gastric cancer cells were determined by the wound and trans-well assays, and the effect of UFM1 on subcutaneous tumor formation was verified in nude mice. The potential downstream targets of UFM1 and related molecular mechanisms were clarified by the human protein kinase assay and co-immunoprecipitation technique. RESULTS: Compared with the corresponding adjacent tissues, the transcription level and protein expression level of UFM1 in gastric cancer tissues were significantly downregulated (P < 0.05). The 5-year survival rate of gastric cancer patients with low UFM1 expression was significantly lower than the patients with high UFM1 expression (42.1% vs 63.0%, P < 0.05). The invasion and migration abilities of gastric cancer cells with stable UFM1 overexpression were significantly decreased, and the gastric cancer cells with UFM1 stable knockdown showed the opposite results; similar results were also obtained in the nude mouse model. Further studies have revealed that UFM1 could increase the ubiquitination level of PDK1 and decrease the expression of PDK1 at protein level, thereby inhibiting the phosphorylation level of AKT at Ser473. Additionally, the effect of UFM1 on gastric cancer cell function is dependent on the expression of PDK1. The expression level of UFM1 can improve the poor prognosis of PDK1 in patients with gastric cancer. CONCLUSION: UFM1 suppresses the invasion and metastasis of gastric cancer by increasing the ubiquitination of PDK1 through negatively regulating PI3K/AKT signaling.

Oncol Rep ; 41(5): 2739-2752, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864700


Cyclin­dependent kinase 5 regulatory subunit­â€‹associated protein 3 (CDK5RAP3 or C53) is involved in the development of various types of tumor, and alternative splicing of C53 results in numerous transcription variants that encode different isoforms. The present study aimed to clone human C53 isoform d (IC53d) and explore its role in the proliferation of gastric cancer cells. Reverse transcription­quantitative polymerase chain reaction was used to detect the expression levels of IC53d in 80 primary gastric adenocarcinoma tissues and adjacent normal tissues. In addition, the association between IC53d and clinicopathological parameters was determined. Gastric cancer cell lines stably overexpressing IC53d were established to observe its effects on cell proliferation, invasion and migration, and on in vivo tumorigenicity, and the mechanism of action was explored. The results of the presen study demonstrated that IC53d was upregulated in gastric cancer tissues and was associated with tumor T­stage. Furthermore, overexpression of IC53d promoted the proliferation, colony formation and G1/S phase transition of gastric cancer cells, leading to enhancement of tumorigenesis in vitro and in vivo. Overexpression of IC53d also promoted phosphorylation of protein kinase B (AKT) and glycogen synthase kinase 3ß (GSK3ß), which increased the expression of cyclin D1. In addition, high cyclin D1 expression was associated with a significantly worse prognosis for patients compared with in patients with low cyclin D1 expression. These results indicated that IC53d may promote the phosphorylation of AKT and GSK3ß, which in turn may increase cyclin D1 expression, enhancing G1/S phase transition, accelerating cell cycle progression, promoting the proliferation of gastric cancer cells, and inducing a poor prognosis in patients with gastric cancer.

Adenocarcinoma/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neoplasias Gástricas/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Ciclina D1/metabolismo , Feminino , Seguimentos , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fosforilação , Prognóstico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno , Transdução de Sinais , Estômago/patologia , Neoplasias Gástricas/mortalidade , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto