RESUMO
AIM: To explore the correlation between Twist-related protein (Twist)1, fibroblast growth factor receptor (FGFR)2 and gastric adenocarcinoma differentiation and progression. METHODS: We evaluated Twist1 and FGFR2 in 52 gastric adenocarcinoma samples by immunohistochemistry and quantitative real time polymerase chain reaction, and analyzed the correlation between Twist1, FGFR2 and cancer differentiation. We also detected Twist1 and FGFR2 expression in gastric adenocarcinoma cell lines, and evaluated Twist1 influence on FGFR2 expression. In addition, we studied the role of FGFR2 in Twist1-promoted cancer progression, including proliferation, invasion and epithelial-mesenchymal transition (EMT). RESULTS: Twist1 and FGFR2 were detected in almost all the gastric adenocarcinoma samples. Twist1 (P = 0.0213) and FGFR2 (P = 0.0310) mRNA levels had a significant association with gastric adenocarcinoma differentiation. Moreover, Twist1 and FGFR2 expression in poorly differentiated cells (SNU-1 and SNU-16) was notably higher than in well-differentiated cells (MKN-7 and MKN-28). In poorly differentiated gastric adenocarcinomas, FGFR2 mRNA level was significantly positively correlated with Twist1 mRNA level (P = 0.004). Twist1 was proved to promote FGFR2 by regulating Twist1 expression by knockdown and overexpression. Additionally, Twist1 could induce proliferation, invasion and EMT in gastric cancer; of these, FGFR2 was required for invasion and EMT, rather than proliferation. CONCLUSION: Twist1 and FGFR2 are highly associated with differentiation of gastric adenocarcinoma; Twist1 can facilitate invasion and EMT in gastric adenocarcinoma via promotion of FGFR2 expression.
Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Diferenciação Celular , Proteínas Nucleares/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Neoplasias Gástricas/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patologia , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Invasividade Neoplásica , Proteínas Nucleares/genética , Prognóstico , Interferência de RNA , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Transfecção , Proteína 1 Relacionada a Twist/genética , Regulação para CimaRESUMO
In this study, we investigated the anti-vasculature effects and the antitumor effects of combining attenuated Salmonella typhimurium vaccine strain encoding murine vascular endothelial growth factor (VEGF) receptor-2 (flk1) with plasmid DNA vector encoding the murine interleukin-12 (mIL-12) gene. In combination, flk1 based DNA vaccine and mIL-12 slowed down tumor growth more effectively than either one alone. Splenocytes from the combined group were showed a strong CTL response against both the flk1 and tumor cells. Automated image analysis revealed that the mean microvessel density was significantly reduced after administering either flk1 based DNA vaccine or mIL-12. In addition, the combination of flk1 based DNA vaccine and mIL-12 appeared more effective at reducing the microvessel density of tumor (P<0.01, both comparisons). In summary, the antivasculature effect and the anti-tumor effect were better when the combination of flk1 based DNA vaccine and IL-12 was administered in comparison to the individual treatment groups, suggesting the synergistic action of flk1 based DNA vaccine and mIL-12.