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Clin Cancer Res ; 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34526363


PURPOSE: Targeted therapy and immunotherapy are transforming the treatment approach for intrahepatic cholangiocarcinoma(ICC). However, little is known about the intertumor heterogeneity(ITH) of multifocal ICC and its impacts on patient response to these treatments. We aimed to characterize the immunogenomic and epigenomic heterogeneity of multifocal ICC to guide treatment decision making. EXPERIMENTAL DESIGN: We obtained 66 tumor samples from sixteen multifocal ICC patients and characterized the tumor and immune heterogeneity using whole-exome sequencing, bulk and single-cell RNA-sequencing, methylation-microarray and multiplex immunostaining. Patients were divided into high or low ITH groups according to the median ITH index. Two independent cohorts were used to validate findings. Responses to anti-PD-1 therapy were assessed. RESULTS: Multifocal ICC presented considerable intertumor genomic, transcriptional and epigenomic heterogeneity within a patient in high ITH group. The immune profile among multiple tumors within a patient was relatively less heterogeneous in high- or low-ITH group, and consistent responses of multiple tumors to anti-PD-1 immunotherapy were observed. Unsupervised clustering of immune markers identified one low and one high immune subtype, with higher immune cell infiltration, closer tumor-immune cell interactions and upregulated IFN-signature expression in high immune subtype. Determining expression levels of CD8B and ICOS facilitated this immune classification and prediction of patient prognosis. Finally, promoter DNA-methylation contributed to different immune profiles of two subtypes by regulating immune-gene expression. CONCLUSIONS: There is comprehensive heterogeneity in the genome, transcriptome and epigenome of multifocal ICC. Based on the less heterogeneous immune profile of ICC, we suggest an immune classification that stratifies patients' prognosis and may support personalized immunotherapy.

Mol Cell ; 81(16): 3339-3355.e8, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34352206


Cancer cells selectively promote translation of specific oncogenic transcripts to facilitate cancer survival and progression, but the underlying mechanisms are poorly understood. Here, we find that N7-methylguanosine (m7G) tRNA modification and its methyltransferase complex components, METTL1 and WDR4, are significantly upregulated in intrahepatic cholangiocarcinoma (ICC) and associated with poor prognosis. We further reveal the critical role of METTL1/WDR4 in promoting ICC cell survival and progression using loss- and gain-of-function assays in vitro and in vivo. Mechanistically, m7G tRNA modification selectively regulates the translation of oncogenic transcripts, including cell-cycle and epidermal growth factor receptor (EGFR) pathway genes, in m7G-tRNA-decoded codon-frequency-dependent mechanisms. Moreover, using overexpression and knockout mouse models, we demonstrate the crucial oncogenic function of Mettl1-mediated m7G tRNA modification in promoting ICC tumorigenesis and progression in vivo. Our study uncovers the important physiological function and mechanism of METTL1-mediated m7G tRNA modification in the regulation of oncogenic mRNA translation and cancer progression.

Colangiocarcinoma/genética , Proteínas de Ligação ao GTP/genética , Metiltransferases/genética , Biossíntese de Proteínas , Animais , Carcinogênese/genética , Colangiocarcinoma/patologia , Progressão da Doença , Receptores ErbB/genética , Guanosina/análogos & derivados , Guanosina/genética , Humanos , Camundongos , Processamento Pós-Transcricional do RNA/genética , RNA Mensageiro/genética , RNA de Transferência/genética
J Nanosci Nanotechnol ; 19(4): 2269-2275, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30486980


Phenotype conversion of smooth muscle cells (SMCs) plays a key role in the formation of atherosclerosis. Understanding how SMCs respond to a micro/nano-topology and elucidating the cellular mechanism of phenotype conversion is critical to the atherosclerosis treatment. Herein, we prepared poly(ɛ-caprolactone) (PCL) spherulites with a radius more than 350 µm for the studying of radial microstructure influence on SMCs behaviors. We found that on the PCL spherulitic films, SMCs grew aligning the radial direction of PCL spherulites, overexpressed α-SMA gene than OPN gene, and preferred contractile phenotype. FAK signaling pathway and ROCK1 signaling pathway both contributed to the contractile phenotype maintenance of SMCs. This work illustrated the feasibility of spherulites in regulating SMCs behaviors, and elucidated the mechanism how SMCs respond to a radial micro/nano-topology. This research may provide theoretical basis for the atherosclerosis formation and treatment.

Caproatos , Miócitos de Músculo Liso , Cristalização , Lactonas , Fenótipo
Talanta ; 184: 50-57, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29674075


It is a great challenge to develop multifunctional nanocarriers for cancer diagnosis and therapy. Herein, versatile CDs/ICG-uLDHs nanovehicles for triple-modal fluorescence/photoacoustic/two-photon bioimaging and effective photothermal therapy were prepared via a facile self-assembly of red emission carbon dots (CDs), indocyanine green (ICG) with the ultrathin layered double hydroxides (uLDHs). Due to the J-aggregates of ICG constructed in the self-assembly process, CDs/ICG-uLDHs was able to stabilize the photothermal agent ICG and enhanced its photothermal efficiency. Furthermore, the unique confinement effect of uLDHs has extended the fluorescence lifetime of CDs in favor of bioimaging. Considering the excellent in vitro and in vivo phototherapeutics and multimodal imaging effects, this work provides a promising platform for the construction of multifunctional theranostic nanocarrier system for the cancer treatment.

Carbono/química , Corantes Fluorescentes/química , Hidróxidos/química , Neoplasias/diagnóstico por imagem , Imagem Óptica , Fototerapia , Pontos Quânticos/química , Fluorescência , Humanos , Hidróxidos/síntese química , Neoplasias/terapia