RESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Extensive research is currently directed at identifying novel targets for its diagnosis and treatment. AIMS: We investigated the biological functions and clinical significance of mucin-type N-acetylglucosaminyltransferase 3 (GCNT3) in HCC. METHODS: Variations in the mRNA expression of GCNT3 were examined in normal and HCC tissues. Cell function assays and animal models characterized the effects of GCNT3 on the proliferation, invasion, and migration abilities of HCC cells. Western blot and immunofluorescence analyses were performed to explore further the specific mechanisms whereby GCNT3 affects HCC progression. RESULTS: There is a strong correlation between GCNT3 overexpression and tumor formation and metastasis in vivo and in vitro. GCNT3 acted as a regulator of the synthesis of mucin-type O-glycans by interacting with mucin 13 (MUC13) to regulate its expression levels, activating the GSK3ß/ß-catenin signaling pathway. The activation of GSK3ß/ß-catenin signaling by GCNT3 was mitigated by MUC13 knockdown. In clinical HCC specimens, GCNT3 expression was upregulated in HCC tissues compared to non-tumor tissues. Further, there was a significant correlation between high GCNT3 expression and poor patient survival. CONCLUSIONS: GCNT3 regulated tumor progression in HCC through the MUC13/GSK3-ß/ß-catenin signaling pathway.
Asunto(s)
Carcinoma Hepatocelular , Glucógeno Sintasa Quinasa 3 beta , Neoplasias Hepáticas , N-Acetilglucosaminiltransferasas , beta Catenina , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Humanos , N-Acetilglucosaminiltransferasas/metabolismo , N-Acetilglucosaminiltransferasas/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Glucógeno Sintasa Quinasa 3 beta/genética , Animales , Línea Celular Tumoral , beta Catenina/metabolismo , beta Catenina/genética , Ratones , Masculino , Mucinas/metabolismo , Mucinas/genética , Proliferación Celular/genética , Ratones Desnudos , Movimiento Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Persona de Mediana Edad , Transducción de Señal , Ratones Endogámicos BALB CRESUMEN
PURPOSE: Cholangiocarcinoma (CHOL) comprises a cluster of highly heterogeneous malignant biliary tumors. Flap endonuclease-1 (FEN1) is a member of the Rad2 structure-specific nuclease family. This study aimed to explore the biological functions and mechanisms of FEN1 in CHOL. METHODS: FEN1 expression was analyzed in tissues of patients with CHOL and FEN1 mutations. We observe the influence of FEN1 on cellular proliferation, migration, and invasion, as well as on DNA damage repair and glycolysis. Western blotting was performed to determine the regulatory mechanism of FEN1 in CHOL progression. RESULTS: FEN1 was highly expressed in the cancer tissues of CHOL patients. The high mutation rate of FEN1 in CHOL tissues was mainly due to the amplified repeats. FEN1 promotes the proliferation, migration, and invasion of HUCCT1 and QBC939 cells. In addition, FEN1 induced DNA damage repair and aerobic glycolysis in CHOL cells. FEN1 also promoted xenograft tumor growth in vivo. Moreover, we showed that FEN1 mediated the epithelial-mesenchymal transition (EMT) of CHOL. FEN1-mediated EMT was found to be transduced by the Wnt/ß-catenin signaling pathway. CONCLUSION: FEN1 was significantly overexpressed in CHOL tissues, and FEN1 regulates the progression of CHOL through the Wnt/ß-catenin signaling pathway.
