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1.
Cancer Immunol Res ; 11(8): 1137-1155, 2023 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-37309673

RESUMO

Intraepithelial lymphocytes (IEL) expressing γδ T-cell receptors (γδTCR) play key roles in elimination of colon cancer. However, the precise mechanisms by which progressing cancer cells evade immunosurveillance by these innate T cells are unknown. Here, we investigated how loss of the Apc tumor suppressor in gut tissue could enable nascent cancer cells to escape immunosurveillance by cytotoxic γδIELs. In contrast with healthy intestinal or colonic tissue, we found that γδIELs were largely absent from the microenvironment of both mouse and human tumors, and that butyrophilin-like (BTNL) molecules, which can critically regulate γδIEL through direct γδTCR interactions, were also downregulated in tumors. We then demonstrated that ß-catenin activation through loss of Apc rapidly suppressed expression of the mRNA encoding the HNF4A and HNF4G transcription factors, preventing their binding to promoter regions of Btnl genes. Reexpression of BTNL1 and BTNL6 in cancer cells increased γδIEL survival and activation in coculture assays but failed to augment their cancer-killing ability in vitro or their recruitment to orthotopic tumors. However, inhibition of ß-catenin signaling via genetic deletion of Bcl9/Bcl9L in either Apc-deficient or mutant ß-catenin mouse models restored Hnf4a, Hnf4g, and Btnl gene expression and γδ T-cell infiltration into tumors. These observations highlight an immune-evasion mechanism specific to WNT-driven colon cancer cells that disrupts γδIEL immunosurveillance and furthers cancer progression.


Assuntos
Neoplasias do Colo , Linfócitos Intraepiteliais , Camundongos , Animais , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Linfócitos Intraepiteliais/metabolismo , Butirofilinas/genética , Butirofilinas/metabolismo , Neoplasias do Colo/genética , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Microambiente Tumoral
2.
Sci Rep ; 2: 515, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22808421

RESUMO

The interaction between human papillomavirus (HPV) and host cells is not well understood. We investigate the early stage of HPV infections by global expression profiling in a cell model, in which HaCaT cells were transfected with HPV11, HPV16 or HPV45 genomes. We report the differential expression of genes not previously implicated in HPV biology, such as the PSG family and ANKRD1, and of genes implicated in the biology of other viruses, e.g. MX1, IFI44 and DDX60. Carcinogenesis-related genes, e.g. ABL2, MGLL and CYR61, were upregulated by high-risk HPV16 and -45. The integrative analysis revealed the suppression of DNA repair by HPV11 and -16, and downregulation of cytoskeleton genes by all HPV types. Various signalling pathways were affected by the HPVs: IL-2 by HPV11; JAK-STAT by HPV16; and TGF-ß, NOTCH and tyrosine kinase signalling by HPV45. This study uncovered novel strategies employed by HPV to establish infection and promote uncontrolled growth.


Assuntos
Transformação Celular Viral/genética , Papillomavirus Humano 11/genética , Papillomavirus Humano 16/genética , Papillomaviridae/genética , Linhagem Celular , Biologia Computacional/métodos , Efeito Citopatogênico Viral , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Regulação Viral da Expressão Gênica , Redes Reguladoras de Genes , Interações Hospedeiro-Patógeno , Humanos , Mapas de Interação de Proteínas , Replicação Viral
3.
Biochem Biophys Res Commun ; 412(1): 20-5, 2011 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-21782796

RESUMO

Human papillomaviruses (HPVs) are highly prevalent giving rise to both benign and malignant lesions why they are classified as high- and low-risk viruses. In this study we selected one low-risk (HPV 11) and two high-risk (HPV 16 and -45) types for genomewide miRNA analysis to investigate possible common and distinct features in the expression profiles. For this purpose we developed a cell culture model system in HaCaT cells for expression of the viral genomes under standardized conditions. We identified 25 miRNAs which were differentially regulated in two or three HPV types where 13 miRNAs were in common for all three types. Among the miRNAs identified, miR-125a-5p, miR-129-3p, miR-363, and miR-145 are related to human cancers. Noteworthy, miR-145 is found upregulated in the miRNA profiles of both high-risk HPV types. For selected differentially expressed miRNAs in HPV 16 predicted miRNA target transcript involved in signal transduction, RNA splicing and tumor invasive growth were validated by qRT-PCR. In addition, our results imply that the early 3' untranslated region (3'UTR) of the three HPV genomes were not a target for miRNA regulation.


Assuntos
Regulação Viral da Expressão Gênica , Genoma Viral/genética , Papillomavirus Humano 11/genética , Papillomavirus Humano 16/genética , MicroRNAs/genética , Infecções Tumorais por Vírus/genética , Regiões 3' não Traduzidas/genética , Linhagem Celular , Humanos , Splicing de RNA , Transfecção , Infecções Tumorais por Vírus/virologia
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