RESUMO
The expression levels of the SOX9 gene in fetal, postnatal, and neoplastic pancreatic tissues were compared. In the fetal pancreatic samples, the mean relative level of the SOX9 gene expression was 8 times greater than the normal level. The tumor samples were divided into three groups depending on the SOX9 expression level. The first group showed a 6.5-fold increased expression level of SOX9 with respect to the normal one. The second and normal groups had approximately equal levels expression. The third group showed a 25-fold decreased expression level of SOX9. The discrepancy in the SOX9 expression, associated with the predominance of different functions of this master gene, depends on the poorly predictable individual factors and indicates that SOX9 should be excluded from the potential diagnostic biomarkers of pancreatic cancer.
Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/genética , Fatores de Transcrição SOX9/genética , Desenvolvimento Embrionário/genética , Feto/metabolismo , HumanosRESUMO
The mRNA content of the transcription factors KLF5 and ZEB1 was studied in pancreatic tumor tissues and in fetal and normal pancreas. Transcription of these factors was not high and similar in normal and fetal pancreatic tissues but greatly increased in the pancreatic ductal adenocarcinoma tissues. A significant positive correlation between the KLF5 and ZEB1 transcription levels in the pancreatic tumor tissues was observed.
Assuntos
Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição Kruppel-Like/genética , Neoplasias Pancreáticas/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Adulto , Humanos , Masculino , Neoplasias Pancreáticas/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias PancreáticasRESUMO
Exogenous expression of the gene encoding the pancreatic master regulator PDX1 in cell lines with different degrees of differentiation of pancreatic cancer cells is accompanied by changes in the expression of known master genes involved in cancer progression. In BxPC3PDX+ cells, as compared to BxPC3PDX-, we detected an increased expression of the following genes: NKX6.1 (2 times), NR5A2 (2.5 times), KLF5 (1.8 times), ZEB1 (3 times), and ONECUT1 (1.3 times), as well as a decreased expression of MUC1 and SLUG genes (3 and 2 times, respectively). In PANC1PDX+ cells, as compared to the control PANC1PDX- cells, we detected a decreased expression of ISL1 (2 times) and an increased expressed of KRT8 (2 times) and MUC1 (by 30%). In the high-grade cell lines (including the BxPC3 line studied), the total content of sites containing the marks of active enhancers was higher than that in the low-grade cell lines (PANC1).
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Espaço Intracelular/metabolismo , Neoplasias Pancreáticas/patologia , Transativadores/genética , Transativadores/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Progressão da Doença , HumanosRESUMO
The expression level of some important master regulators of embryonic development of the pancreas in the tumor samples of this human organ was determined. We found that the transcription of SOX9, GATA4, PDX1, PTF1a, and HNF1b genes in the tumor samples was reduced as compared to the samples of normal pancreatic tissues, and the KLF5 gene expression in the tumor cells was elevated. We assume that all the studied genes, except KLF5, form a single regulatory module that supports the identity of tumor progenitor cells. A simultaneous suppression of expression of these master factors may be critical for the neoplastic transformation of pancreatic cells.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Neoplasias Pancreáticas/embriologia , Neoplasias Pancreáticas/genética , Humanos , Pâncreas/embriologia , Neoplasias Pancreáticas/patologiaRESUMO
We show characteristic morphological changes corresponding to epithelial-mesenchymal transition (EMT) program fulfillment in PANC1 cell line stimulated with TGFß1. Our results support downregulation of E-cadherin protein. We show 5- and 28-fold increase in SNAI1 and SNAI2 expression levels and 25- and 15-fold decrease in CDH1 and KRT8 expression levels, respectively, which confirms the EMT-program fulfillment. We demonstrate downregulation of expression of pancreatic master genes SOX9, FOXA2, and GATA4 (2-, 5-, and 4-fold, respectively) and absence of significant changes in HES1, NR5A2, and GATA6 expression levels in the cells stimulated with TGFß1. Our results indicate the absence of induction of expression of PTF1A, PDX1, HNF1b, NEUROG3, RPBJL, NKX6.1, and ONECUT1 genes, which are inactive in PANC1 cell line after the EMT stimulated by TGFß1.
Assuntos
Adenocarcinoma/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Fator de Transcrição GATA4/metabolismo , Fator 3-beta Nuclear de Hepatócito/metabolismo , Neoplasias Pancreáticas/metabolismo , Fatores de Transcrição SOX9/metabolismo , Adenocarcinoma/patologia , Antígenos CD , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/genética , Fator de Transcrição GATA4/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Fator 3-beta Nuclear de Hepatócito/genética , Humanos , Queratina-8/genética , Queratina-8/metabolismo , Mesoderma/metabolismo , Mesoderma/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fatores de Transcrição SOX9/genética , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta1/administração & dosagem , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Great successes in identification and deciphering of mechanisms of the adult stem cells regulation have given rise to the idea that stem cells can also function in tumors as central elements of their development, starting from the initial stage and continuing until metastasis. Such cells were called cancer stem cells (CSCs). Over the course of intense discussion, the CSCs hypothesis gradually began to be perceived as an obvious fact. Recently, the existence of CSCs has been indeed confirmed in a number of works. However, when are CSCs universal prerequisites of tumors and to what extent their role is essential for tumor evolution remains an issue far from resolved. Likewise, the problem of potential use of CSCs as therapeutic targets remains unsolved. The present review attempts to analyze the issue of cancer stem cells and the potential of targeting them in tumor therapy.
RESUMO
The transformation of normal precursors into cancer cells is an intricately regulated, multistep process. The master regulatory genes that play a crucial role in the process of organism development may also play a key role in carcinogenesis. From such a point of view, cancer is not simply a genetic disease that is due to a progressive accumulation of mutation--it is also a disorder of the developmental system of the tissue in which cancer emerges. Master regulators and their genes disturb stem cell differentiation upon mutation and thus may serve as targets for cancer therapy, in addition to the classic oncogenes and suppressors of tumor formation. This review is an attempt to give a modern concept of master genes and their functions in adult stem cells of the organism and in carcinogenesis, with pancreatic cancer as an example.
