Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros

Base de dados
Tipo de documento
Assunto da revista
País de afiliação
Intervalo de ano de publicação
1.
Gastroenterology ; 160(4): 1179-1193.e14, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32920015

RESUMO

BACKGROUND & AIMS: Streptococcus thermophilus was identified to be depleted in patients with colorectal cancer (CRC) by shotgun metagenomic sequencing of 526 multicohort fecal samples. Here, we aim to investigate whether this bacterium could act as a prophylactic for CRC prevention. METHODS: The antitumor effects of S thermophilus were assessed in cultured colonic epithelial cells and in 2 murine models of intestinal tumorigenesis. The tumor-suppressive protein produced by S thermophilus was identified by mass spectrometry and followed by ß-galactosidase activity assay. The mutant strain of S thermophilus was constructed by homologous recombination. The effect of S thermophilus on the gut microbiota composition was assessed by shotgun metagenomic sequencing. RESULTS: Oral gavage of S thermophilus significantly reduced tumor formation in both Apcmin/+ and azoxymethane-injected mice. Coincubation with S thermophilus or its conditioned medium decreased the proliferation of cultured CRC cells. ß-Galactosidase was identified as the critical protein produced by S thermophilus by mass spectrometry screening and ß-galactosidase activity assay. ß-Galactosidase secreted by S thermophilus inhibited cell proliferation, lowered colony formation, induced cell cycle arrest, and promoted apoptosis of cultured CRC cells and retarded the growth of CRC xenograft. The mutant S thermophilus without functional ß-galactosidase lost its tumor-suppressive effect. Also, S thermophilus increased the gut abundance of known probiotics, including Bifidobacterium and Lactobacillus via ß-galactosidase. ß-Galactosidase-dependent production of galactose interfered with energy homeostasis to activate oxidative phosphorylation and downregulate the Hippo pathway kinases, which partially mediated the anticancer effects of S thermophilus. CONCLUSION: S thermophilus is a novel prophylactic for CRC prevention in mice. The tumor-suppressive effect of S thermophilus is mediated at least by the secretion of ß-galactosidase.


Assuntos
Proteínas de Bactérias/metabolismo , Neoplasias Colorretais/prevenção & controle , Probióticos/administração & dosagem , Streptococcus thermophilus/enzimologia , beta-Galactosidase/metabolismo , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Azoximetano/administração & dosagem , Azoximetano/toxicidade , Proteínas de Bactérias/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/induzido quimicamente , Colo/microbiologia , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/genética , Neoplasias Colorretais/microbiologia , Humanos , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Camundongos Transgênicos , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/genética , Neoplasias Experimentais/microbiologia , Neoplasias Experimentais/prevenção & controle , Probióticos/metabolismo , Streptococcus thermophilus/genética , beta-Galactosidase/genética
2.
Pharmacol Res ; 149: 104352, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31323332

RESUMO

Mammalian / mechanistic target of rapamycin (mTOR) is a critical sensor of environmental cues that regulates cellular macromolecule synthesis and metabolism in eukaryotes. DNA methylation is the most well-studied epigenetic modification that is capable of regulating gene transcription and affecting genome stability. Both dysregulation of mTOR signaling and DNA methylation patterns have been shown to be closely linked to tumor progression and serve as promising targets for cancer therapy. Although their respective roles in tumorigenesis have been extensively studied, whether molecular interplay exists between them is still largely unknown. In this review, we provide a brief overview of mTOR signaling, DNA methylation as well as related serine and one-carbon metabolism, one of the most critical aspects of metabolic reprogramming in cancer. Based on the latest understanding regarding the regulation of metabolic processes by mTOR signaling as well as interaction between metabolism and epigenetics, we further discuss how serine and one-carbon metabolism may serve as a bridge that links mTOR signaling and DNA methylation to promote tumor growth. Elucidating their relationship may provide novel insight for cancer therapy in the future.


Assuntos
Metilação de DNA , Neoplasias/genética , Serina/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/metabolismo , Serina/genética , Serina-Treonina Quinases TOR/genética
3.
J Cancer ; 9(16): 2807-2816, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30123349

RESUMO

Using genome-wide screening and TCGA-based data analysis, we identified a DNA methylation-related gene named metallothionein-1G (MT1G), which may play an important role in hepatocellular carcinoma (HCC). In this study, we found that MT1G expression was silenced in 4/6 HCC cell lines and negatively related to aberrant promoter hypermethylation. Its mRNA level was restored with demethylation treatment. Moreover, MT1G downregulation at both the transcriptional and protein level was also detected in 8 pairs of clinical HCC samples compared with its expression in adjacent normal tissues. Ectopic expression of MT1G in silenced HCC cell lines inhibited colony formation, suppressed cell migration and invasion, and repressed xenograft tumor growth in nude mice. In contrast, knockdown of MT1G by short hairpin RNA showed the opposite effect on cell proliferation and the malignant phenotype. Moreover, our data showed that MT1G suppressed tumor invasion and metastasis mainly through regulating the expression of proteins in the matrix metalloproteinase family (MMP) and modulating the epithelial-mesenchymal transition (EMT) process. To our surprise, the data from TCGA showed that hypermethylation of MT1G is associated with good survival of HCC patients. In conclusion, our study demonstrated that MT1G acts as a tumor suppressor gene in HCC development, but its clinical potential in HCC requires further evaluation.

4.
Cell Cycle ; 16(18): 1673-1682, 2017 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-28841361

RESUMO

p53R2 is a p53-inducible ribonucleotide reductase subunit involved in deoxyribonucleotide biosynthesis and DNA repair. Although p53R2 has been linked to human cancer, its role in cervical cancer remains unknown. In this study, we investigated the expression and clinical significance of p53R2 in early-stage cervical cancer. p53R2 expression is significantly upregulated at both mRNA and protein levels in cervical cancer cells and tissues, compared with that in matched normal cervical cells and tissues, respectively. p53R2 overexpression is associated with increased risk of pelvic lymph node metastasis (PLNM, p = 0.001) and cancer relapse (p = 0.009). Patients with high p53R2 expression have a shorter overall survival (OS) and disease-free survival (DFS). p53R2 is an independent factor for predicting OS and DFS of cervical cancer patients. We further show that p53R2 is important for oncogenic growth, migration and invasion in cervical cancer cells. Mechanistically, p53R2 promotes Akt signaling and epithelial-mesenchymal transition (EMT). In conclusion, our study demonstrates for the first time that p53R2 protein is overexpressed in early-stage cervical cancer and unravels some unconventional oncogenic functions of p53R2. p53R2 may be a useful prognostic biomarker and therapeutic target for cervical cancer.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Progressão da Doença , Transição Epitelial-Mesenquimal , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ribonucleotídeo Redutases/metabolismo , Transdução de Sinais , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Metástase Neoplásica , Prognóstico , Análise de Sobrevida
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA