RESUMO
N6-methyladenosine (m6A) is the most abundant internal RNA modification and plays a critical role in carcinogenesis and tumor progression. As a powerful m6A reader, YTHDF1 is implicated in multiple malignancies. However, the functions and underlying mechanisms of YTHDF1 in esophageal cancer (ESCA) are elusive. Here, we revealed that YTHDF1 expression was remarkably up-regulated in ESCA and linked with poor prognosis. Functionally, YTHDF1 promoted ESCA cell proliferation, migration, and metastasis in vitro and in vivo. Mechanistically, we demonstrated that TINAGL1 might be a potential target of YTHDF1. We revealed that YTHDF1 recognized and bound to m6A-modified sites of TINAGL1 mRNA, resulting in enhanced translation of TINAGL1. Furthermore, TINAGL1 knockdown partially rescued tumor-promoting effects of YTHDF1 overexpression. Therefore, we unveil that YTHDF1 facilitates ESCA progression by promoting TINAGL1 translation in an m6A-dependent manner, which offers an attractive therapeutic target for ESCA.
Assuntos
Adenosina , Proliferação de Células , Neoplasias Esofágicas , Proteínas de Ligação a RNA , Animais , Feminino , Humanos , Masculino , Camundongos , Adenosina/análogos & derivados , Adenosina/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/genética , Regulação Neoplásica da Expressão Gênica , Camundongos Nus , Biossíntese de Proteínas , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/genética , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Proteínas de Ligação a RNA/metabolismoRESUMO
BACKGROUND: Tetraspanin 8 (TSPAN8), a transmembrane glycoprotein, is implicated in various pathological conditions including human malignancies. However, the roles and underlying mechanisms of TSPAN8 in promoting gastric cancer(GC) progression are yet to be fully understood. METHODS AND RESULTS: Our study found that TSPAN8 expression was significantly elevated in GC tissues. We also observed a positive correlation between high TSPAN8 expression and various clinicopathological characteristics of GC, including tumor differentiation, invasion depth, lymph node metastasis, and clinical stage. Moreover, the elevated TSPAN8 expression was indicative of poor prognosis. Functionally, we observed that knockdown of TSPAN8 significantly attenuated while overexpression of TSPAN8 promoted GC cell migration and invasion. In vivo experiments, knockdown of TSPAN8 suppressed lung metastasis in nude mice. We further explored the underlying mechanisms of TSPAN8 and found that it regulated EGFR expression in GC cells by accelerating phosphorylation of EGFR and AKT. CONCLUSIONS: Our study reveals that TSPAN8 plays a significant role in promoting tumor metastasis by activating the EGFR/AKT pathway, indicating that it may serve as a promising therapeutic target of gastric cancer.