HNF1α and CDX2 transcriptional factors bind to cadherin-17 (CDH17) gene promoter and modulate its expression in hepatocellular carcinoma. 2010

Rui Zhu, and Kwong-Fai Wong, and Nikki P Y Lee, and Kai-Fai Lee, and John M C Luk
Department of Surgery and Center for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China.

Cadherin-17 (CDH17) belongs to the cell adhesion cadherin family with a prominent role in tumorigenesis. It is highly expressed in human hepatocellular carcinoma (HCC) and is proposed to be a biomarker and therapeutic molecule for liver malignancy. The present study aims to identify the transcription factors which interact and regulate CDH17 promoter activity that might contribute to the up-regulation of CDH17 gene in human HCC. A 1-kb upstream sequence of CDH17 gene was cloned and the promoter activity was studied by luciferase reporter assay. By bioinformatics analysis, deletion and mutation assays, and chromatin immunoprecipitation studies, we identified hepatic nuclear factor 1α (HNF1α) and caudal-related homeobox 2 (CDX2) binding sites at the proximal promoter region which modulate the CDH17 promoter activities in two HCC cell lines (Hep3B and MHCC97L). A consistent down-regulation of CDH17 and the two transcriptional activators (HNF1α and CDX2) expression was found in the liver of mouse during development, as well as in human liver cancer cells with less metastatic potential. Suppression of HNF1α and CDX2 expression by small interfering RNA (siRNA) significantly down-regulated expressions of CDH17 and its downstream target cyclin D1 and the viability of HCC cells in vitro. In summary, we identified the minimal promoter region of CDH17 that is regulated by HNF1α and CDX2 transcriptional factors. The present findings enhance our understanding on the regulatory mechanisms of CDH17 oncogene in HCC, and may shed new insights into targeting CDH17 expression as potential therapeutic intervention for cancer treatment.

UI MeSH Term Description Entries
D008099 Liver A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances. Livers
D011401 Promoter Regions, Genetic DNA sequences which are recognized (directly or indirectly) and bound by a DNA-dependent RNA polymerase during the initiation of transcription. Highly conserved sequences within the promoter include the Pribnow box in bacteria and the TATA BOX in eukaryotes. rRNA Promoter,Early Promoters, Genetic,Late Promoters, Genetic,Middle Promoters, Genetic,Promoter Regions,Promoter, Genetic,Promotor Regions,Promotor, Genetic,Pseudopromoter, Genetic,Early Promoter, Genetic,Genetic Late Promoter,Genetic Middle Promoters,Genetic Promoter,Genetic Promoter Region,Genetic Promoter Regions,Genetic Promoters,Genetic Promotor,Genetic Promotors,Genetic Pseudopromoter,Genetic Pseudopromoters,Late Promoter, Genetic,Middle Promoter, Genetic,Promoter Region,Promoter Region, Genetic,Promoter, Genetic Early,Promoter, rRNA,Promoters, Genetic,Promoters, Genetic Middle,Promoters, rRNA,Promotor Region,Promotors, Genetic,Pseudopromoters, Genetic,Region, Genetic Promoter,Region, Promoter,Region, Promotor,Regions, Genetic Promoter,Regions, Promoter,Regions, Promotor,rRNA Promoters
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D002470 Cell Survival The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000071616 CDX2 Transcription Factor An antennapedia-like homeodomain transcription factor that regulates the expression of multiple genes in the INTESTINAL MUCOSA. It plays a critical role in many processes from early differentiation to maintenance of the intestinal epithelial lining of both the small and large intestine. CDX2 Protein,Caudal Type Homeo Box 2 Protein,Caudal Type Homeo Box Transcription Factor 2,Caudal Type Homeobox Transcription Factor 2,Cdx-2 Protein,Cdx-2-3 Protein,Cdx-3 Protein,Homeobox Protein CDX-2,Homeobox Protein CDX2,Transcription Factor CDX2,CDX-2, Homeobox Protein,CDX2, Homeobox Protein,CDX2, Transcription Factor,Cdx 2 3 Protein,Cdx 2 Protein,Cdx 3 Protein,Homeobox Protein CDX 2
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D014157 Transcription Factors Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. Transcription Factor,Factor, Transcription,Factors, Transcription
D014407 Tumor Cells, Cultured Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely. Cultured Tumor Cells,Neoplastic Cells, Cultured,Cultured Neoplastic Cells,Cell, Cultured Neoplastic,Cell, Cultured Tumor,Cells, Cultured Neoplastic,Cells, Cultured Tumor,Cultured Neoplastic Cell,Cultured Tumor Cell,Neoplastic Cell, Cultured,Tumor Cell, Cultured
D015534 Trans-Activators Diffusible gene products that act on homologous or heterologous molecules of viral or cellular DNA to regulate the expression of proteins. Nuclear Trans-Acting Factor,Trans-Acting Factors,Trans-Acting Factor,Trans-Activator,Transactivator,Transactivators,Factor, Nuclear Trans-Acting,Factor, Trans-Acting,Factors, Trans-Acting,Nuclear Trans Acting Factor,Trans Acting Factor,Trans Acting Factors,Trans Activator,Trans Activators,Trans-Acting Factor, Nuclear

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