ABSTRACT
The transcription factor Forkhead box protein M1 (FOXM1) plays critical roles in cancer development and progression, including human hepatocellular carcinoma (HCC). However, the regulatory role and underlying mechanisms of FOXM1 is still limited. Here, we found that the high level expression of FOXM1 and CCNB1 is closely associated with poor prognosis in HCC patients. And FOXM1 and CCNB1 were overexpressed concomitantly in liver tumor tissues. Knockdown of FOXM1 significantly inhibited the expression levels of CCNB1 in HCC cell lines at both the mRNA and protein levels. Mechanistic studies revealed that FOXM1 binds directly to the promoter region of CCNB1 and regulates the expression levels of the CCNB1 gene in the transcriptional level. Furthermore, the loss of functional and rescue experiments showed that CCNB1 is essential for FOXM1-driven proliferation in HCC cells. In the present study, our results partially explained the dysregulated expression of FOXM1 play an important role in proliferation of human hepatocellular carcinoma cells via transcriptional activation of CCNB1 expression. And it also highlights a FOXM1/CCNB1 axis could be a potential target for the treatment of HCCs.
Subject(s)
Carcinoma, Hepatocellular/genetics , Cyclin B1/genetics , Forkhead Box Protein M1/genetics , Gene Expression Regulation, Neoplastic , Liver Neoplasms/genetics , RNA, Messenger/genetics , Binding Sites , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/mortality , Cell Line, Tumor , Cyclin B1/antagonists & inhibitors , Cyclin B1/metabolism , Forkhead Box Protein M1/metabolism , Hep G2 Cells , Humans , Liver Neoplasms/diagnosis , Liver Neoplasms/metabolism , Liver Neoplasms/mortality , Prognosis , Promoter Regions, Genetic , Protein Binding , RNA, Messenger/antagonists & inhibitors , RNA, Messenger/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Signal Transduction , Survival Analysis , Transcriptional ActivationABSTRACT
BACKGROUND AND AIMS: Aberrant upregulation of POU2F2 expression has been discovered in metastatic gastric cancer (GC). However, the mechanisms underlying the aberrant upregulation and the potential functions of POU2F2 remain uncertain. DESIGN: The role and mechanism of POU2F2 in GC metastasis were investigated in gastric epithelial cells, GC cell lines and an experimental metastasis animal model by gain of function and loss of function. Upstream and downstream targets of POU2F2 were selected by bioinformatics and identified by luciferase reporter assay, electrophoretic mobility shift assay and chromatin immunoprecipitation PCR. The influence of miR-218 on its putative target genes (POU2F2, ROBO1 and IKK-ß) and GC metastasis was further explored via in vitro and in vivo approaches. RESULTS: Increased POU2F2 expression was detected in metastatic GC cell lines and patient samples. POU2F2 was induced by the activation of nuclear factor (NF)-κB and, in turn, regulated ROBO1 transcription, thus functionally contributing to GC metastasis. Finally, miR-218 was found to suppress GC metastasis by simultaneously mediating multiple molecules in the POU2F2-oriented network. CONCLUSIONS: This study demonstrated that NF-κB and the SLIT2/ROBO1 interaction network with POU2F2 as the central part may exert critical effects on tumour metastasis. Blocking the activation of the POU2F2-oriented metastasis network using miR-218 precursors exemplified a promising approach that sheds light on new strategies for GC treatment.
Subject(s)
Intercellular Signaling Peptides and Proteins/metabolism , MicroRNAs , Neoplasm Metastasis/genetics , Nerve Tissue Proteins/metabolism , Octamer Transcription Factor-2/genetics , Receptors, Immunologic/metabolism , Stomach Neoplasms , Animals , Cell Line, Tumor , Cell Movement , Disease Models, Animal , Gene Expression Regulation, Neoplastic , Humans , Mice , MicroRNAs/genetics , MicroRNAs/metabolism , NF-kappa B/metabolism , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Up-Regulation , Roundabout ProteinsABSTRACT
AIM: To establish a hepatocellular carcinoma model of BALB/c mouse and to study the expression and potential role of metastasis-associated protein 1 (MTA1) in the carcinogenesis process. METHODS: Normal adult male BALB/c mice were induced by the combined dimethylnitrosamine (DEN)/carbon tetrachloride (CCl(4);)/alcohol for 150 d. The morphological changes in liver cells and the expression of MTA1 in the liver lesions were observed by HE and immunohistochemical stainings, respectively. RESULTS: The pathological changes of the survivals' livers in experimental group were liver inflammation, fibrosis and cancer in sequence. The level of MTA1 increased in the carcinogenesis process, and MTA1 was mainly expressed in the cytoplasm of the cells suffering cirrhosis. CONCLUSION: The changes of the expression sites and quantity of MTA1 in the DEN-induced carcinogenesis of mouse liver indicate that MTA1 may play an important role in the whole process of liver carcinogenesis.
