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1.
Front Immunol ; 12: 647209, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841428

RESUMO

Background: Cholangiocarcinoma was a highly malignant liver cancer with poor prognosis, and immune infiltration status was considered an important factor in response to immunotherapy. In this investigation, we tried to locate immune infiltration related genes of cholangiocarcinoma through combination of bulk-sequencing and single-cell sequencing technology. Methods: Single sample gene set enrichment analysis was used to annotate immune infiltration status in datasets of TCGA CHOL, GSE32225, and GSE26566. Differentially expressed genes between high- and low-infiltrated groups in TCGA dataset were yielded and further compressed in other two datasets through backward stepwise regression in R environment. Single-cell sequencing data of GSE138709 was loaded by Seurat software and was used to examined the expression of infiltration-related gene set. Pathway changes in malignant cell populations were analyzed through scTPA web tool. Results: There were 43 genes differentially expressed between high- and low-immune infiltrated patients, and after further compression, PNOC and LAIR2 were significantly correlated with high immune infiltration status in cholangiocarcinoma. Through analysis of single-cell sequencing data, PNOC was mainly expressed by infiltrated B cells in tumor microenvironment, while LAIR2 was expressed by Treg cells and partial GZMB+ CD8 T cells, which were survival related and increased in tumor tissues. High B cell infiltration levels were related to better overall survival. Also, malignant cell populations demonstrated functionally different roles in tumor progression. Conclusion: PNOC and LAIR2 were biomarkers for immune infiltration evaluation in cholangiocarcinoma. PNOC, expressed by B cells, could predict better survival of patients, while LAIR2 was a potential marker for exhaustive T cell populations, correlating with worse survival of patients.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33839938

RESUMO

PURPOSE: Microvascular invasion (MVI) is a critical determinant of the early recurrence and poor prognosis of patients with hepatocellular carcinoma (HCC). Prediction of MVI status is clinically significant for the decision of treatment strategies and the assessment of patient's prognosis. A deep learning (DL) model was developed to predict the MVI status and grade in HCC patients based on preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and clinical parameters. METHODS: HCC patients with pathologically confirmed MVI status from January to December 2016 were enrolled and preoperative DCE-MRI of these patients were collected in this study. Then they were randomly divided into the training and testing cohorts. A DL model with eight conventional neural network (CNN) branches for eight MRI sequences was built to predict the presence of MVI, and further combined with clinical parameters for better prediction. RESULTS: Among 601 HCC patients, 376 patients were pathologically MVI absent, and 225 patients were MVI present. To predict the presence of MVI, the DL model based only on images achieved an area under curve (AUC) of 0.915 in the testing cohort as compared to the radiomics model with an AUC of 0.731. The DL combined with clinical parameters (DLC) model yielded the best predictive performance with an AUC of 0.931. For the MVI-grade stratification, the DLC models achieved an overall accuracy of 0.793. Survival analysis demonstrated that the patients with DLC-predicted MVI status were associated with the poor overall survival (OS) and recurrence-free survival (RFS). Further investigation showed that hepatectomy with the wide resection margin contributes to better OS and RFS in the DLC-predicted MVI present patients. CONCLUSION: The proposed DLC model can provide a non-invasive approach to evaluate MVI before surgery, which can help surgeons make decisions of surgical strategies and assess patient's prognosis.

3.
Pest Manag Sci ; 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33884743

RESUMO

BACKGROUND: With the rapid resistance development, new modes of action for pesticides are needed for insect control, such as RNAi-based biopesticides targeting essential genes. To explore the function of Argonaute-1 (Ago-1) and potential miRNAs in ovarian development of Bactrocera dorsalis, an important agricultural pest, and develop novel control stragety for the pest, the BdAgo-1 was first identified in B. dorsalis. RESULTS: Spatiotemporal expression analysis indicated that BdAgo-1 had a relatively high transcriptional level in the ovarian tissues of adult female B. dorsalis during the sexual maturation period. RNA interference (RNAi) experiment showed that BdAgo-1 knockdown significantly decreased the expression levels of ovarian development-related genes and delayed ovarian development. Although RNAi-mediated silencing of Ago-1 led to a reduced ovary surface area, a subsequent oviposition assay revealed that the influence was minimal over a longer time period. Small RNA libraries were constructed and sequenced from different ovarian developmental stages of B. dorsalis adults. Among identified 161 miRNAs, 84 miRNAs were differentially expressed during the three developmental stages of the B. dorsalis ovary. BdAgo-1 silencing caused significant down-regulation of 7 differentially expressed miRNAs (DEMs) showing relatively high expression levels (>1000 TPM (Transcripts per kilobase of exon model per million mapped reads)). The expression patterns of these 7 core DEMs and their putative target genes were analyzed in the ovaries of B. dorsalis. CONCLUSION: The results indicate that Ago-1 and Ago-1-dependent miRNAs are indispensable for normal ovarian development in B. dorsalis and help identify miRNA targets useful for control of this pest. This article is protected by copyright. All rights reserved.

4.
Diagnostics (Basel) ; 11(4)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805513

RESUMO

OBJECTIVES: Intrahepatic cholangiocarcinoma (iCCA) is a highly malignant cancer. More than 70% of patients are diagnosed at an advanced stage. The aim of this study was to evaluate the diagnostic value of plasma miR-21, miR-122, and CA19-9, hoping to establish a novel model to improve the accuracy for diagnosing iCCA. MATERIALS AND METHODS: Plasma miR-21 and miR-122 were detected in 359 iCCA patients and 642 controls (healthy, benign liver lesions, other malignant liver tumors). All 1001 samples were allocated to training cohort (n = 668) and validation cohort (n = 333) in a chronological order. A logistic regression model was applied to combine these markers. Area under the receiver operating characteristic curve (AUC) was used as an accuracy index to evaluate the diagnostic performance. RESULTS: Plasma miR-21 and miR-122 were significantly higher in iCCA patients than those in controls. Higher plasma miR-21 level was significantly correlated with larger tumor size (p = 0.030). A three-marker model was constructed by using miR-21, miR-122 and CA19-9, which showed an AUC of 0.853 (95% CI: 0.824-0.879; sensitivity: 73.0%, specificity: 87.4%) to differentiate iCCA from controls. These results were subsequently confirmed in the validation cohort with an AUC of 0.866 (0.825-0.901). The results were similar for diagnosing early (stages 0-I) iCCA patients (AUC: 0.848) and CA19-9negative iCCA patients (AUC: 0.795). CONCLUSIONS: We established a novel three-marker model with a high accuracy based on a large number of participants to differentiate iCCA from controls. This model showed a great clinical value especially for the diagnosis of early iCCA and CA19-9negative iCCA.

5.
Sheng Li Xue Bao ; 73(1): 17-25, 2021 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-33665656

RESUMO

This study was aimed to determine the effect of acute cerebral ischemia on the protein expression level of silent mating type information regulator 2 homolog 3 (Sirt3) in the neurons and clarify the pathological role of Sirt3 in acute cerebral ischemia. The mice with middle cerebral artery occlusion (MCAO) and primary cultured rat hippocampal neurons with oxygen glucose deprivation (OGD) were used as acute cerebral ischemia models in vivo and in vitro, respectively. Sirt3 overexpression was induced in rat hippocampal neurons by lentivirus transfection. Western blot was utilized to measure the changes in Sirt3 protein expression level. CCK8 assay was used to detect cell viability. Immunofluorescent staining was used to detect mitochondrial function. Transmission electron microscope was used to detect mitochondrial autophagy. The results showed that, compared with the normoxia group, hippocampal neurons from OGD1 h/reoxygenation 2 h (R2 h) and OGD1 h/R12 h groups exhibited down-regulated Sirt3 protein expression levels. Compared with contralateral normal brain tissue, the ipsilateral penumbra region from MCAO1 h/reperfusion 24 h (R24 h) and MCAO1 h/R72 h groups exhibited down-regulated Sirt3 protein expression levels, while there was no significant difference between the Sirt3 protein levels on both sides of sham group. OGD1 h/R12 h treatment damaged mitochondrial function, activated mitochondrial autophagy and reduced cell viability in hippocampal neurons, whereas Sirt3 over-expression attenuated the above damage effects of OGD1 h/R12 h treatment. These results suggest that acute cerebral ischemia results in a decrease in Sirt3 protein level. Sirt3 overexpression can alleviate acute cerebral ischemia-induced neural injuries by improving the mitochondrial function. The current study sheds light on a novel strategy against neural injuries caused by acute cerebral ischemia.


Assuntos
Isquemia Encefálica , Traumatismo por Reperfusão , Sirtuína 3 , Animais , Regulação para Baixo , Infarto da Artéria Cerebral Média , Camundongos , Mitocôndrias , Neurônios/metabolismo , Ratos , Sirtuína 3/genética , Sirtuína 3/metabolismo , Sirtuínas
6.
Clin Transl Med ; 11(3): e313, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33783990

RESUMO

Lysine acetylation (Kac) as an important posttranslational modification of histones is essential for the regulation of gene expression in hepatocellular carcinoma (HCC). However, the atlas of whole acetylated proteins in HCC tissues and the difference in protein acetylation between normal human tissues and HCC tissues are unknown. In this report, we characterized the proteome and acetyl proteome (acetylome) profile of normal, paracancerous, and HCC liver tissues in human clinical samples by quantitative proteomics techniques. We identified 6781 acetylation sites of 2582 proteins and quantified 2492 acetylation sites of 1190 proteins in normal, paracancerous, and HCC liver tissues. Among them, 15 proteins were multiacetylated with more than 10 lysine residues. The histone acetyltransferases p300 and CBP were found to be hyperacetylated in hepatitis B virus pathway. Moreover, we found that 250 Kac sites of 214 proteins were upregulated and 662 Kac sites of 451 proteins were downregulated in HCC compared with normal liver tissues. Additionally, the acetylation levels of lysine 120 in histone H2B (H2BK120ac), lysine 18 in histone H3.3 (H3.3K18ac), and lysine 77 in histone H4 (H4K77ac) were increased in HCC. Interestingly, the higher levels of H2BK120ac, H3.3K18ac, and H4K77ac were significantly associated with worse prognosis, such as poorer survival and higher recurrence in an independent clinical cohort of HCC patients. Overall, this study lays a foundation for understanding the functions of acetylation in HCC and provides potential prognostic factors for the diagnosis and therapy of HCC.

9.
Pest Manag Sci ; 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33686750

RESUMO

BACKGROUND: Odorant-binding proteins (OBPs) in insects contribute to the sensitivity of the olfactory system and connect external odorants to olfactory receptor neurons. Determination of the chemosensory functions in Diaphorina citri, a vector of the citrus Huanglongbing pathogen, may help in developing a potential target for pest management. RESULTS: Diaphorina citri showed dose-dependent electroantennogram recording (EAG) responses to 12 host plant volatiles. A two-choice behavioral trap experiment showed that four compounds (methyl salicylate, linalool, citral and R-(+)-limonene) that elicited high EAG responses also had significant attraction to adults. The expression profiles induced by these compounds were detected in nine OBP genes, DcitOBP1-9. DcitOBP3, DcitOBP6 and DcitOBP7 commonly showed significant upregulation or downregulation compared with the control. Microscale thermophoresis (MST) showed that the recombinant protein DcitOBP7 had high in vitro binding affinities (Kd < 10 µm) to methyl salicylate, linalool and R-(+)-limonene, and moderate binding affinity to citral with a Kd value of 15.95 µm. Furthermore, RNA interference (RNAi)-suppressed messenger RNA (mRNA) expression of DcitOBP7 resulted in a significant reduction in EAG activity and in adult D. citri behavioral responses to tested volatiles and the preferred host, Murraya paniculata. The hydrophilic residue Arg107 of DcitOBP7 may have a key role in binding odorants via formation of hydrogen bonds. CONCLUSION: These results show that DcitOBP7 plays an important role in the olfactory response. This finding may provide new insight into the functions of OBP families in D. citri and aid in the development of safe strategies for managing D. citri populations.

10.
J Immunother Cancer ; 9(3)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33692217

RESUMO

BACKGROUND: Tumor-associated neutrophils (TANs) and macrophages (TAMs) can each influence cancer growth and metastasis, but their combined effects in intrahepatic cholangiocarcinoma (ICC) remain unclear. METHODS: We explored the distributions of TANs and TAMs in patient-derived ICC samples by multiplex immunofluorescent staining and tested their separate and combined effects on ICC in vitro and in vivo. We then investigated the mechanistic basis of the effects using PCR array, western blot analysis and ELISA experiments. Finally, we validated our results in a tissue microarray composed of primary tumor tissues from 359 patients with ICC. RESULTS: The spatial distributions of TANs and TAMs were correlated with each other in patient-derived ICC samples. Interaction between TANs and TAMs enhanced the proliferation and invasion abilities of ICC cells in vitro and tumor progression in a mouse xenograft model of ICC. TANs and TAMs produced higher levels of oncostatin M and interleukin-11, respectively, in co-culture than in monoculture. Both of those cytokines activated STAT3 signaling in ICC cells. Knockdown of STAT3 abolished the protumor effect of TANs and TAMs on ICC. In tumor samples from patients with ICC, increased TAN and TAM levels were correlated with elevated p-STAT3 expression. All three of those factors were independent predictors of patient outcomes. CONCLUSIONS: TANs and TAMs interact to promote ICC progression by activating STAT3.

11.
Cell Death Dis ; 12(3): 260, 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33707417

RESUMO

Cancer-associated fibroblasts (CAFs) are commonly acquired activated extracellular matrix (ECM)-producing myofibroblasts, a phenotypes with multiple roles in hepatic fibrogenesis and carcinogenesis via crosstalk with cohabitating stromal/cancer cells. Here, we discovered a mechanism whereby CAF-derived cytokines enhance hepatocellular carcinoma (HCC) progression and metastasis by activating the circRNA-miRNA-mRNA axis in tumor cells. CAFs secreted significantly higher levels of CXCL11 than normal fibroblasts (NFs), and CXCL11 also had comparatively higher expressions in HCC tissues, particularly in metastatic tissues, than para-carcinoma tissues. Both CAF-derived and experimentally introduced CXCL11 promoted HCC cell migration. Likewise, CAFs promoted tumor migration in orthotopic models, as shown by an increased number of tumor nodules, whereas CXCL11 silencing triggered a decrease of it. CXCL11 stimulation upregulated circUBAP2 expression, which was significantly higher in HCC tissues than para-carcinoma tissues. Silencing circUBAP2 reversed the effects of CXCL11 on the expression of IL-1ß/IL-17 and HCC cell migration. Further downstream, the IFIT1 and IFIT3 levels were significantly upregulated in HCC cells upon CXCL11 stimulation, but downregulated upon circUBAP2 silencing. IFIT1 or IFIT3 silencing reduced the expression of IL-17 and IL-1ß, and attenuated the migration capability of HCC cells. Herein, circUBAP2 counteracted miR-4756-mediated inhibition on IFIT1/3 via sponging miR-4756. miR-4756 inhibition reversed the effects induced by circUBAP2 silencing on the IL-17 and IL-1ß levels and HCC cell migration. In orthotopic models, miR-4756 inhibition also reversed the effects on metastatic progression induced by silencing circUBAP2.

12.
Biomark Med ; 15(5): 359-371, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33666515

RESUMO

Aim: We aimed to identify novel exosomal circular RNAs for hepatocellular carcinoma (HCC) diagnosis. Materials & methods: Exosomes were extracted and characterized. The expression level of exosomal circRNAs were verified via quantitative real-time PCR. The diagnostic value of candidate circRNAs was evaluated according to the receiver operating characteristic curve analysis. Results: The exosomal circ_0070396 significantly elevated in HCC patients than other control groups and it performed better in distinguishing HCC patients from healthy donors than that of α-fetoprotein. Combination of two above markers exerted greater diagnostic performance. Exosomal circ_0070396 could discriminate HCC individuals from patients with chronic hepatitis B and liver cirrhosis. Intriguingly, exosomal circ_0070396 was positively correlated with HCC progression. Conclusion: Exosomal circ_0070396 may be a potential biomarker for HCC detection and management.

13.
Artigo em Inglês | MEDLINE | ID: mdl-33741523

RESUMO

The aim of this study was to identify novel gene and miRNA biomarkers of risk and prognostic factors for hepatocarcinogenesis using methods in systems biology. Differentially expressed genes (DEGs), microRNAs (miRNAs), and long non-coding RNA (lncRNAs) were compared between hepatocellular carcinoma (HCC) tumour tissue and normal liver tissues in the Cancer Genome Atlas (TCGA) database. Subsequently, the prognosis-associated gene co-expression network, mRNA-miRNA, and mRNA-miRNA-lncRNA regulatory networks were constructed to identify biomarkers of risk for HCC through Cox survival analysis. Seven prognosis-associated gene co-expression modules were obtained by analyzing these DEGs. An expression module including 120 genes significantly correlated with HCC patient survival. Combined with patient survival data, several mRNAs and miRNAs, including CHST4, SLC22A8, STC2, hsa-miR-326, and hsa-miR-21 were identified from the network to predict HCC patient prognosis. Clinical significance was investigated using tissue microarray analysis of samples from 258 patients with HCC. Functional annotation of hsa-miR-326 and hsa-miR-21-5p indicated specific associations with several cancer-related pathways. The present study provides a bioinformatics method for biomarker screening, which led to the identification of an integrated mRNA-miRNA-lncRNA regulatory network and their co-expression in relation to predicting HCC patient survival.

14.
Biosens Bioelectron ; 179: 113058, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33592557

RESUMO

Extracellular vesicles (EVs) can represent a novel source of disease biomarkers, and are under intensive study for their clinical potential. Most EV-based cancer diagnostic studies have focused on establishing EV assays that detect increased expression of a single cancer-associated marker or marker signatures based on multiplex detection of these biomarkers. EV biomarker readouts can be obscured by high background signal leading to false positives, and may markedly differ between analyses due to variation in sample purity during EV isolation. This can obstruct the comparisons among studies and lead to conflicting conclusions. This work reports that the nucleic acid to protein UV absorption ratio of an EV is a cell-specific EV characteristic. This EV collective attribute can be measured at low-cost to discriminate EVs derived from malignant and non-malignant cells rather than employing single markers that may be cancer- or subtype-specific. Our work also highlighted the application for accessing purity in EV preparations irrelevant to EV yield. It can be employed to distinguish from patients with and without malignant disease upon analysis of EVs isolated from their serum samples.

15.
Clin Transl Med ; 11(2): e335, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33634982

RESUMO

OBJECTIVE: Differentiation-inducing therapy for tumors is a strategy that aims to induce the differentiation and maturation of cancer stem cells (CSCs). The differentiation-inducing capacity of arsenic trioxide (ATO) in hepatocellular carcinoma (HCC) and the underlying mechanism were previously unknown. METHODS: In the present study, we explored the ATO-induced differentiation of CSCs in HCC by detecting the expression of CSC-related markers and tumorigenicity variation in vivo and in vitro. We developed a combined chemotherapeutic approach to HCC by characterizing the effects of combinatorial treatment with 5-fluorouracil (5-FU)/cisplatin and ATO in vitro and in patient-derived xenograft models. Changes in gene expression patterns were investigated by gene microarray analysis. RESULTS: ATO effectively induced differentiation of CSCs by downregulation of CSC-related genes and suppression of tumorigenicity capability. Combinatorial treatment with ATO and 5-FU/cisplatin significantly enhanced therapeutic effects in HCC cells compared with the treatment with 5-FU/cisplatin alone. Synergistic inhibition of the LIF/JAK1/STAT3 and NF-kB signaling pathways by ATO and 5-FU/cisplatin is a potential molecular mechanism underlying the differentiation effect. CONCLUSIONS: ATO induced the differentiation of HCC CSCs and potentiated the cytotoxic effects of 5-FU/cisplatin through synergistic inhibition of the LIF/JAK1/STAT3 and NF-kB signaling pathways. These results offer new insights for the clinical treatment of HCC.

16.
Arthroscopy ; 37(3): 862-870, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33524479

RESUMO

PURPOSE: To investigate the change in muscle volume around the hip in patients with femoroacetabular impingement (FAI) after arthroscopy and evaluate other factors related to muscle change. METHODS: We performed a retrospective review of magnetic resonance imaging data of patients with FAI who underwent hip arthroscopy. Magnetic resonance imaging was obtained pre- and postoperatively. The cross-sectional area (CSA) of muscles were determined on axial images. The Wilcoxon signed-rank test was used to determine the differences between pre- and postoperative hip muscle CSA. The correlations of change in muscle CSA with age, sex, body mass index, pain level, preoperative symptom duration, follow-up time, and multiple validated patient-reported outcomes were also analyzed with a Spearman rank correlation test. RESULTS: Fifty-one patients with a mean age of 36.5 ± 5.6 years were included and analyzed. The follow-up was 26.6 ± 0.5 months (range, 24-40 months), and 27 (52.9%) were women. Patients with FAI showed increased hip muscle CSA of gluteus maximus (P = .002) and gluteus minimus (P = .001). Post- compared with preoperative, the value for the change in medius CSA was underpowered, and no differences in other hip muscle CSAs were observed. The increased muscle CSA of the gluteus maximus was significantly correlated with the improvement of modified Harris Hip Score (ρ = 0.404; P = .003). The increased muscle CSA of the gluteus minimus was significantly correlated with the improvement of pain Visual Analog Scale (ρ = 0.452; P = .001). Age, body mass index, sex, symptom duration, and follow-up time were not significantly correlated with change in muscle CSA. CONCLUSIONS: Patients with FAI have a significantly increased postoperative muscle CSA of the gluteus maximus (7.8%) and the gluteus minimus (11.6%) compared with preoperative values. The increased muscle CSA of the gluteus maximus and gluteus minimus was significantly correlated with improvement in modified Harris Hip Score and pain Visual Analog Scale, respectively. The increase of muscle volume may be associated with the improvement of subjective function and pain relief. LEVELS OF EVIDENCE: Level IV, therapeutic case series.

17.
Dalton Trans ; 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33527956

RESUMO

Two-dimensional (2D) organometallic halide perovskites (OHPs) are promising optoelectronic materials because of their excellent stability and tunable band gaps. Herein, we report the optical and elastic properties of a newly synthesized 2D lead halide perovskite, (C9H14ON)2PbI4 (C9H14ON+ = 4-methoxyphenethylammonium), by a combined experimental and theoretical approach. Our experiments demonstrate that (C9H14ON)2PbI4 shows a strong green emission under ambient conditions which is ascribed to its band gap of 2.4 eV. Moreover, our temperature-dependent photoluminescence (PL) experiments in the temperature range of 143-283 K reveal that the green emission red-shifts with increasing temperature, which is primarily attributed to the synergistic effect of thermal expansion and electron-phonon interactions. The elastic properties, obtained from density functional theory calculations, reveal that (C9H14ON)2PbI4 has relatively low modulus and anisotropy compared with other 2D materials.

18.
Cancer Sci ; 112(3): 1235-1250, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33393145

RESUMO

Acute lymphoblastic leukemia (ALL) is an aggressive hematological cancer that mainly affects children. Relapse and chemoresistance result in treatment failure, underlining the need for improved therapies. BTB and CNC homology 2 (BACH2) is a lymphoid-specific transcription repressor recognized as a tumor suppressor in lymphomas, but little is known about its function and regulatory network in pediatric ALL (p-ALL). Herein, we found aberrant BACH2 expression at new diagnosis not only facilitated risk stratification of p-ALL but also served as a sensitive predictor of early treatment response and clinical outcome. Silencing BACH2 in ALL cells increased cell proliferation and accelerated cell cycle progression. BACH2 blockade also promoted cell adhesion to bone marrow stromal cells and conferred cytarabine (Ara-C)-resistant properties to leukemia cells by altering stromal microenvironment. Strikingly, we identified FOS, a transcriptional activator competing with BACH2, as a novel downstream target repressed by BACH2. Blocking FOS by chemical compounds enhanced the effect of Ara-C treatment in both primary p-ALL cells and pre-B-ALL-driven leukemia xenografts and prolonged the survival of tumor-bearing mice. These data highlight an interconnected network of BACH2-FOS, disruption of which could render current chemotherapies more effective and offer a promising therapeutic strategy to overcome Ara-C resistance in p-ALL.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Fatores de Transcrição de Zíper de Leucina Básica/genética , Proliferação de Células/genética , Criança , Pré-Escolar , Citarabina/farmacologia , Citarabina/uso terapêutico , Feminino , Regulação Leucêmica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Lactente , Masculino , Células-Tronco Mesenquimais , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Cultura Primária de Células , Células Tumorais Cultivadas , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Cell ; 184(2): 404-421.e16, 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33357445

RESUMO

Hepatocellular carcinoma (HCC) has high relapse and low 5-year survival rates. Single-cell profiling in relapsed HCC may aid in the design of effective anticancer therapies, including immunotherapies. We profiled the transcriptomes of ∼17,000 cells from 18 primary or early-relapse HCC cases. Early-relapse tumors have reduced levels of regulatory T cells, increased dendritic cells (DCs), and increased infiltrated CD8+ T cells, compared with primary tumors, in two independent cohorts. Remarkably, CD8+ T cells in recurrent tumors overexpressed KLRB1 (CD161) and displayed an innate-like low cytotoxic state, with low clonal expansion, unlike the classical exhausted state observed in primary HCC. The enrichment of these cells was associated with a worse prognosis. Differential gene expression and interaction analyses revealed potential immune evasion mechanisms in recurrent tumor cells that dampen DC antigen presentation and recruit innate-like CD8+ T cells. Our comprehensive picture of the HCC ecosystem provides deeper insights into immune evasion mechanisms associated with tumor relapse.

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