RESUMO
Childhood onset of colorectal signet-ring cell carcinoma (CR-SRCC) is extremely rare and featured as highly malignant with poor prognosis. Here we reported a CR-SRCC case of 11-year-old boy with a novel inherited X-linked KDM6AA694T mutation. The H3K27me3 demethylase KDM6A was frequently mutated in varieties of tumors and acts as a tumor suppressor. In vivo H3K27me3 demethylation assay demonstrated that KDM6AA694T had dampened H3K27me3 demethylase activity. Overexpression of KDM6AA694T in SRCC cell line KATO3 promoted cell proliferation, invasion and migration, which were further confirmed in vivo by constructing orthotopic tumor growth and lung metastasis model. Besides, expression of KDM6AA694T in immune cells suppresses inflammatory macrophage response and effector T cell response. In conclusion, we characterized a novel inherited KDM6AA694T mutant from a childhood-onset SRCC case and demonstrated that the mutant with impaired H3K27me3 demethylase activity could potentiate tumor malignancy and suppress antitumor immunity.
Assuntos
Carcinoma de Células em Anel de Sinete , Neoplasias Colorretais , Histona Desmetilases , Criança , Humanos , Masculino , Carcinoma de Células em Anel de Sinete/genética , Carcinoma de Células em Anel de Sinete/patologia , Carcinoma de Células em Anel de Sinete/imunologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/imunologia , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Mutação , Evasão Tumoral/genéticaRESUMO
Chronic lung diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), involve progressive and irreversible destruction and pathogenic remodeling of airways and have become the leading health care burden worldwide. Pulmonary tissue has extensive capacities to launch injury-responsive repairing programs (IRRPs) to replace the damaged or dead cells upon acute lung injuries. However, the IRRPs are frequently compromised in chronic lung diseases. In this review, we aim to provide an overview of somatic stem cell subpopulations within distal airway epithelium and the underlying mechanisms mediating their self-renewal and trans-differentiation under both physiological and pathological circumstances. We also compared the differences between humans and mice on distal airway structure and stem cell composition. At last, we reviewed the current status and future directions for the development of targeted therapeutics on defective distal airway regeneration and repairment in chronic lung diseases.
Assuntos
Fibrose Pulmonar Idiopática , Doença Pulmonar Obstrutiva Crônica , Humanos , Animais , Camundongos , Pulmão/patologia , Doença Pulmonar Obstrutiva Crônica/terapia , Doença Pulmonar Obstrutiva Crônica/patologia , Fibrose Pulmonar Idiopática/terapia , Fibrose Pulmonar Idiopática/patologia , Diferenciação Celular , Epitélio/patologiaRESUMO
Fusion of the E-26 transformation-specific (ETS)-related gene (ERG) with transmembrane serine protease 2 (TMPRSS2) is a crucial step in the occurrence and progression of approximately 50% of prostate cancers. Despite significant progress in drug discovery, ERG inhibitors have yet to be approved for the clinical treatment of prostate cancer. In this study, we used computer-aided drug design (CADD)-based virtual screening to screen for potential inhibitors of ERG. In vivo and in vitro methods revealed that nifuroxazide (NFZ) inhibited the proliferation of a TMPRSS2:ERG fusion-positive prostate cancer cell line (VCaP) with an IC50 lower than that of ERG-negative prostate cancer cell lines (LNCaP, DU145, and WPMY cells). Poly [ADP-ribose] polymerase 1, the critical mediator of parthanatos, is known to bind ERG and is required for ERG-mediated transcription. NFZ blocked this interaction and overly activated PARP1, leading to cell death that was reduced by olaparib, a PARP1 inhibitor. These results show that NFZ inhibits ERG, leading to parthanatic cell death.
Assuntos
Nitrofuranos , Proteínas de Fusão Oncogênica , Parthanatos , Neoplasias da Próstata , Humanos , Masculino , Linhagem Celular Tumoral , Proteínas de Fusão Oncogênica/genética , Parthanatos/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Transativadores/genética , Regulador Transcricional ERG/genética , Regulador Transcricional ERG/metabolismo , Nitrofuranos/farmacologia , Nitrofuranos/uso terapêuticoRESUMO
The aim of the present study was to explore the differentially expressed genes in the blood vessel endothelial cells (BVECs) between diffuse large B-cell lymphoma (DLBCL) and reactive lymph node hyperplasia (RLNH), and to perform an initial bioinformatics analysis on a novel gene, C20orf14, which is highly expressed in lymph node of lymphoma. The mRNA of the tissue from the BVECs of DLBCL and RLNH tissues was labeled with biotin respectively and hybridized with expression profile microarray, and the differentially expressed genes were obtained. Initial bioinformatics analysis was performed on a novel gene named C20orf14. Its gene structure, genomic localization, the physical and chemical characteristics of the putative protein, subcellular localization, functional domain etc. were predicted, and the systematic evolution analysis was performed on the similar proteins among several species. By using expression profile microarray, many differentially expressed genes were uncovered. The efficient bioinformatics analysis have fundamentally identified that C20orf14 was a nuclear protein, and may be involved in the post-transcription modification of mRNA. Therefore, microarray is an efficient and high throughout strategy for the detection of differentially expressed genes, and C20orf14 is thought to be a potential target for tumor metastasis researches by bioinformatics analysis.