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1.
Oncogene ; 27(32): 4497-502, 2008 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-18372917

RESUMO

The homeobox gene Cdx1 is involved in anteroposterior patterning in embryos and its expression selectively persists in the intestinal epithelium throughout life. In human colon cancers, Cdx1 is overexpressed in few cases and lost in the majority of adenocarcinomas. We used mouse models of gain and loss-of-function to investigate the role of Cdx1 in intestinal development and cancers. Transgenic mice overexpressing Cdx1 and knockout mice exhibited a morphologically normal intestine. Cell proliferation, specification into the four differentiated lineages and migration along the crypt-villus axis were unchanged compared to wild-type mice. Changing Cdx1 caused an inverse and dose-dependent modification of the expression of the paralogous gene Cdx2, indicating that Cdx1 fine-tunes Cdx2 activity. Transgenenic and knockout mice failed to spontaneously develop tumours. Overexpressing Cdx1 was without incidence on the frequency of intestinal tumours induced chemically by azoxymethane treatment or genetically in Apc(Delta14/+) mice. However, it augmented the severity of the tumours in Apc(Delta14/+) mice. Inversely, the loss-of-function of Cdx1 in knockout mice was without incidence on the growth of tumours induced by azoxymethane. We conclude that Cdx1 is dispensable for intestinal development and that its overexpression could increase malignancy in early stages of tumourigenesis.


Assuntos
Genes Homeobox , Proteínas de Homeodomínio/fisiologia , Neoplasias Intestinais/etiologia , Intestinos/embriologia , Animais , Azoximetano/toxicidade , Fator de Transcrição CDX2 , Genes APC , Proteínas de Homeodomínio/genética , Neoplasias Intestinais/genética , Camundongos , Camundongos Transgênicos , Fatores de Transcrição/fisiologia
2.
Oncogene ; 27(1): 107-15, 2008 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-17599044

RESUMO

The gravity of colorectal cancer is mainly due to the capacity of tumor cells to migrate out of the tumor mass to invade the stroma and disseminate as metastases. The acquisition of a migratory phenotype also occurs during wound healing. Here, we show that several features characterizing invasive colon tumor cells are shared by migrating cells during wound repair in vitro. In particular, the expression of the intestine-specific transcription factor Cdx2, a key gene for intestinal identity downregulated in invasive cancer cells, is reduced during wound healing in vitro. Transcription factors involved in epithelial-mesenchymal transition such as Snail and Slug are upregulated during wound healing and are able to repress Cdx2 transcription. In vitro, forced expression of Cdx2 in human colon cancer cell lines retarded wound repair and reduced migration, whereas inhibition of Cdx2 expression by RNA interference enhanced migration. In vivo, forced expression of Cdx2 opposed tumor cells spreading in nude mice xenografted at three different sites. These data provide evidence that Cdx2 antagonizes the process of tumor cell dissemination, and they suggest that this homeobox gene might represent a new therapeutic target against metastatic spreading of colon cancer.


Assuntos
Inibição de Migração Celular , Movimento Celular/fisiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Proteínas de Homeodomínio/fisiologia , Metástase Neoplásica/prevenção & controle , Animais , Fator de Transcrição CDX2 , Células CACO-2 , Movimento Celular/genética , Neoplasias Colorretais/genética , Células HT29 , Proteínas de Homeodomínio/antagonistas & inibidores , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Nus , Invasividade Neoplásica/prevenção & controle , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Cicatrização/genética , Cicatrização/fisiologia
3.
Gut ; 56(12): 1688-95, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17595234

RESUMO

AIMS: The CDX1 and CDX2 homeoproteins are intestine-specific transcription factors regulating homeostasis. We investigated their relevance in experimentally-induced intestinal inflammation. METHODS: The response to intestinal inflammation induced by dextran sodium sulfate (DSS) was compared in wild type, Cdx1(-/-) and Cdx2(+/-) mice. Intestinal permeability was determined in wild type and Cdx2(+/-) mice. Protein-protein interactions were investigated by co-immunoprecipitation and GST-pulldown, and their functional consequences were assessed using Luciferase reporter systems. RESULTS: Heterozygous Cdx2(+/-) mice, but not Cdx1(-/-) mice, were hypersensitive to DSS-induced acute inflammation as all these mice showed blood in the stools at day 1 of DSS treatment. Hypersensitivity was associated to a 50% higher intestinal permeability. In Cdx2(+/-) mice, the colonic epithelium was repaired during the week after the end of DSS treatment, whereas two weeks were required for wild type animals. Subsequently, no colonic tumour was observed in Cdx2(+/-) mice subjected to 5 repeated cycles of DSS, in contrast to the 2.7 tumours found per wild type mouse. Based on the fact that Smad3(+/-) mice, like Cdx2(+/-) mice, better repair the damaged intestinal epithelium, we found that the CDX2 protein interacts with SMAD3, independently of SMAD4, resulting in a 5-fold stimulation of SMAD3 transcriptional activity. CDX1 also interacted with SMAD3 but it inhibited by 10-fold the SMAD3/SMAD4-dependent transcription. CONCLUSION: The Cdx1 and Cdx2 homeobox genes have distinct effects on the outcome of a pro-inflammatory challenge. This is mirrored by different functional interactions of the CDX1 and CDX2 proteins with SMAD3, a major element of the TGFbeta signalling pathway.


Assuntos
Colite Ulcerativa/genética , Genes Homeobox , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Animais , Fator de Transcrição CDX2 , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/complicações , Colite Ulcerativa/patologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/genética , Sulfato de Dextrana , Modelos Animais de Doenças , Predisposição Genética para Doença , Proteínas de Homeodomínio/metabolismo , Absorção Intestinal/efeitos dos fármacos , Absorção Intestinal/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Permeabilidade/efeitos dos fármacos , Índice de Gravidade de Doença , Proteína Smad3/metabolismo , Fatores de Transcrição/metabolismo
4.
Gut ; 52(10): 1465-71, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12970140

RESUMO

BACKGROUND: During development, the homeobox gene Cdx2 exerts a homeotic function, providing the positional information necessary for correct specification of the midgut endoderm. This is illustrated by the non-neoplastic gastric-type heteroplasias present at birth in the pericaecal region of Cdx2(+/-) mice. Furthermore, intestinal expression of Cdx2 continues throughout life but diminishes in colorectal cancers compared with adjacent normal tissue, suggesting a role in tumorigenesis. AIM: To investigate the consequence of altered Cdx2 expression on colon tumour initiation and/or progression. METHODS: Heterozygous Cdx2(+/-) mice were analysed for spontaneous malignant tumours and for tumour development after treatment with a DNA mutagen, azoxymethane. RESULTS: Cdx2(+/-) mice did not spontaneously develop malignant tumours. After azoxymethane treatment, the gastric-like heteroplasias in the pericaecal region did not evolve into cancer indicating that they are not precancerous lesions. However, azoxymethane treated Cdx2(+/-) mice developed tumours specifically in the distal colon 12 weeks after azoxymethane treatment whereas no tumours were found in wild-type littermates at this stage. Histopathological and molecular analyses indicated that these tumours were invasive adenocarcinomas that recapitulated the malignant sequence observed in the majority of sporadic colorectal cancers in human. In addition, we found that the colonic epithelium was less sensitive to radiation induced apoptosis in Cdx2(+/-) than in wild-type mice. CONCLUSION: This study provides the first experimental evidence that Cdx2 is a tumour suppressor gene involved in cancer progression in the distal colon. This action in adults is functionally and geographically distinct from its homeotic role during gut development.


Assuntos
Adenocarcinoma/genética , Neoplasias do Colo/genética , Genes Supressores de Tumor/fisiologia , Proteínas de Homeodomínio/genética , Adenocarcinoma/induzido quimicamente , Adenocarcinoma/patologia , Animais , Apoptose , Azoximetano , Fator de Transcrição CDX2 , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutagênicos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transativadores
5.
Gut ; 50(4): 525-9, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11889074

RESUMO

BACKGROUND: The transcription factor encoded by the intestinal Cdx2 homeobox gene and treatment with sodium butyrate (NaB), a byproduct of fibre fermentation by colonic bacteria, exert similar effects on colon cancer cell lines as they both inhibit cell growth and stimulate cell differentiation and apoptosis. AIM: To investigate whether NaB regulates expression of the Cdx2 gene in colon cancer cell lines. METHODS: Human adenocarcinoma cell lines Caco2 and HT29 were grown in the presence or absence of NaB. Cells were analysed for Cdx2 mRNA expression by reverse transcription-polymerase chain reaction, for protein expression by western blotting and electromobility shift assays, and for transcriptional activity of the Cdx2 promoter by transfection with luciferase reporter plasmids. RESULTS: In HT29 and Caco2 cells, NaB stimulated Cdx2 mRNA and protein expression as well as transcriptional activity of the Cdx2 promoter. Stimulation of the activity of the Cdx2 promoter by NaB was dose and time dependent. The Cdx2 promoter contains discrete regions that participate in or inversely that blunt the stimulatory effect exerted by NaB. In addition, NaB stimulated the transcriptional activity of the Cdx2 promoter downregulated by oncogenic ras. CONCLUSION: This study is the first report of an intestine specific transcription factor, Cdx2, stimulated by butyrate. Thus it provides a new mechanism whereby butyrate controls proliferation and differentiation of colon cancer cells.


Assuntos
Adenocarcinoma/genética , Butiratos/farmacologia , Neoplasias do Colo/genética , Genes Homeobox/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Adenocarcinoma/metabolismo , Fator de Transcrição CDX2 , Células CACO-2/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Regulação para Baixo , Genes ras , Células HT29/efeitos dos fármacos , Proteínas de Homeodomínio/metabolismo , Humanos , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transativadores
6.
Mol Cell Biol ; 21(14): 4761-72, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11416151

RESUMO

Thyroid hormone is known to participate in the control of intestine maturation at weaning. Its action is mediated by the thyroid hormone nuclear receptors, encoded by the TRalpha and TRbeta genes. Since previous studies have shown that TRbeta plays a minor role in the gut, we focused here our analysis on the TRalpha gene. The TRalpha locus generates the TRalpha1 receptor together with the splicing variant TRalpha2 and the truncated products TRDeltaalpha1 and TRDeltaalpha2, which all lack an intact ligand binding domain. The TRDeltaalpha isoforms are transcribed from an internal promoter located in intron 7, and their distribution is restricted to a few tissues including those of the intestine. In order to define the functions of the different isoforms encoded by the TRalpha locus in the intestinal mucosa, we produced mice either lacking all known TRalpha products or harboring a mutation which inactivates the intronic promoter. We performed a detailed analysis of the intestinal phenotypes in these mice and compared it to that of the previously described TRalpha(-/-) mice, in which TRalpha isoforms are abolished but the TRDeltaalpha isoforms remain. This comparative analysis leads us to the following conclusions: (i) the TRalpha1 receptor mediates the T3-dependent functions in the intestine at weaning time and (ii) the TRDeltaalpha products negatively control the responsiveness of the epithelial cells to T3. Moreover, we show that TRDeltaalpha proteins can interfere with the transcription of the intestine-specific homeobox genes cdx1 and cdx2 and that their activity is regulated by TRalpha1. Altogether these data demonstrate that cooperation of TRalpha and TRDeltaalpha products is essential to ensure the normal postnatal development of the intestine and that mutations in the TRalpha locus can generate different phenotypes caused by the disruption of the equilibrium between these products.


Assuntos
Proteínas Aviárias , Intestino Delgado/crescimento & desenvolvimento , Receptores dos Hormônios Tireóideos/fisiologia , Animais , Fator de Transcrição CDX2 , Diferenciação Celular , Divisão Celular , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Marcação de Genes , Proteínas de Homeodomínio/genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Intestino Delgado/patologia , Intestino Delgado/fisiologia , Camundongos , Camundongos Knockout , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/fisiologia , RNA Mensageiro , Receptores dos Hormônios Tireóideos/biossíntese , Receptores dos Hormônios Tireóideos/genética , Receptores dos Hormônios Tireóideos/metabolismo , Transativadores , Tri-Iodotironina/metabolismo
7.
Biochem Cell Biol ; 76(6): 957-69, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-10392709

RESUMO

The past years have witnessed an increasing number of reports relative to homeobox genes in endoderm-derived tissues. In this review, we focus on the caudal-related Cdx-1 and Cdx-2 homeobox genes to give an overview of the in vivo, in vitro, and ex vivo approaches that emphasize their primary role in intestinal development and in the control of intestinal cell proliferation, differentiation, and identity. The participation of these genes in colon tumorigenesis and their identification as important actors of the oncogenic process are also discussed.


Assuntos
Proteínas Aviárias , Genes Homeobox/fisiologia , Proteínas de Homeodomínio/genética , Intestinos/embriologia , Animais , Fator de Transcrição CDX2 , Diferenciação Celular , Divisão Celular , Embrião de Galinha , Proteínas de Drosophila , Drosophila melanogaster/genética , Epitélio/embriologia , Neoplasias Gastrointestinais/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/fisiologia , Humanos , Camundongos , Modelos Biológicos , Transativadores , Fatores de Transcrição
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