ABSTRACT
BACKGROUND & AIMS: Human colorectal carcinomas display an infiltrative front of invasion where tumor cells undergo an epithelomesenchymal transition associated with low survival. Epithelomesenchymal transition is regulated by a nuclear beta-catenin accumulation, and subsequently, activation of beta-catenin/TCF4 target genes similar to CYCLIN D(1). Unexpectedly, these tumor cells are characterized by low proliferation, which correlates with the expression of the cell cycle inhibitor p16(INK4A). Therefore, we investigated the molecular mechanism of the transcriptional regulation of p16(INK4A) in colorectal cancer and its correlation with survival. METHODS: Molecular biological techniques were used for investigating the transcriptional mechanisms of the p16(INK4A) gene regulation. Moreover, p16(INK4A) expression was correlated with the 10-year survival of patients with colorectal carcinomas. RESULTS: In colorectal carcinomas, expression of the p16(INK4A) gene is regulated by beta-catenin/TCF4 and correlates with low survival rates of patients with tumors displaying an infiltrative front of invasion. CONCLUSIONS: beta-catenin/TCF4 regulates cell cycle promoting (c-MYC, CYCLIN D(1)) and inhibiting genes (p16(INK4A)) at the same time in the mesenchymally differentiated tumor cells at the front of invasion. The function of p16(INK4A) seems to supersede in this context thus leading to low proliferation. Moreover, these tumor cells seem to govern the outcome of colorectal cancer independently of their proliferation.
Subject(s)
Colorectal Neoplasms/mortality , Genes, p16 , beta Catenin/physiology , Adult , Aged , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Cell Line, Tumor , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , DNA-Binding Proteins/metabolism , Enhancer Elements, Genetic , Female , Gene Expression Regulation , Humans , Male , Middle Aged , Neoplasm Invasiveness , Promoter Regions, Genetic , Transcription Factor 4 , Transcription Factors/metabolismABSTRACT
Tenascin-C (TN-C) is a component of the extracellular matrix (ECM). It is expressed during development and re-expressed in many types of cancers, where it is involved in the modulation of adhesion and proliferation. TN-C expression is especially high at sites of epithelial mesenchymal transition (EMT), which are found frequently at the invasion front of well-differentiated human colorectal adenocarcinomas. Tumor cells in this compartment are characterized by a strong nuclear expression of the oncogenic transcription factor beta-catenin. Here, we demonstrate that TN-C is a beta-catenin target gene in human colorectal tumors. Thus, by far the most common mutations in colorectal tumors, found in the Wnt-signaling pathway and leading to the stabilizing of beta-catenin, might influence invasion by altering adhesive properties and EMT of tumor cells.
Subject(s)
Gene Expression Regulation, Neoplastic , Tenascin/genetics , beta Catenin/metabolism , Adenocarcinoma , Cell Differentiation , Cell Line, Tumor , Cell Nucleus/physiology , Colorectal Neoplasms , Epithelial Cells/pathology , Humans , Mesoderm/pathology , Neoplasm Invasiveness , beta Catenin/geneticsABSTRACT
Expression of the urokinase plasminogen activator (uPA) increases during the progression of colorectal tumors from adenomas to carcinomas. The highest amounts of uPA are found at the invasion front of carcinomas, which also displays a strong expression of nuclear beta-catenin and is therefore a region expressing beta-catenin target genes at high levels. Here we show that beta-catenin contributes to the transactivation of uPA. Therefore, beta-catenin might have an impact on the capacity of colorectal tumors for invasion and metastasis, as well as dormancy, which are hallmarks of cancer.
Subject(s)
Colorectal Neoplasms/enzymology , Cytoskeletal Proteins/physiology , Gene Expression Regulation, Enzymologic , Trans-Activators/physiology , Urokinase-Type Plasminogen Activator/genetics , Cell Line, Tumor , Enhancer Elements, Genetic , Humans , Promoter Regions, Genetic , Up-Regulation , beta CateninABSTRACT
Colorectal carcinomas with microsatellite instability accumulate errors in short repetitive DNA repeats, especially mono and dinucleotide repeats. One such error-prone A(9) monorepeat is found in exon 17 of the TCF-4 gene. TCF-4 and beta-catenin form a transcription complex, which is important for both maintenance of normal epithelium and development of colorectal tumors. To elucidate the relevance of frameshift mutations in the TCF-4 in colorectal carcinogenesis, a variety of investigations in human tumors and cell lines was performed. It was found that mutations in the TCF-4 A(9) repeat do not contribute to tumorigenesis and seem to be passenger mutations.
