RESUMO
BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) constitutes a group of heterogeneous malignancies within the liver. We sought to subtype ICC based on anatomical origin of tumors, as well as propose modifications of the current classification system. METHODS: Patients undergoing curative-intent resection for ICC, hilar cholangiocarcinoma (CCA), or hepatocellular carcinoma (HCC) were identified from three international multi-institutional consortia of databases. Clinicopathological characteristics and survival outcomes were assessed. RESULTS: Among 1264 patients with ICC, 1066 (84.3%) were classified as ICC-peripheral subtype, whereas 198 (15.7%) were categorized as ICC-perihilar subtype. Compared with ICC-peripheral subtype, ICC-perihilar subtype was more often associated with aggressive tumor characteristics, including a higher incidence of nodal metastasis, macro- and microvascular invasion, perineural invasion, as well as worse overall survival (OS) (median: ICC-perihilar 19.8 vs. ICC-peripheral 37.1 months; p < 0.001) and disease-free survival (DFS) (median: ICC-perihilar 12.8 vs. ICC-peripheral 15.2 months; p = 0.019). ICC-perihilar subtype and hilar CCA had comparable OS (19.8 vs. 21.4 months; p = 0.581) and DFS (12.8 vs. 16.8 months; p = 0.140). ICC-peripheral subtype tumors were associated with more advanced tumor features, as well as worse survival outcomes versus HCC (OS, median: ICC-peripheral 37.1 vs. HCC 74.3 months; p < 0.001; DFS, median: ICC-peripheral 15.2 vs. HCC 45.5 months; p < 0.001). CONCLUSIONS: ICC should be classified as ICC-perihilar and ICC-peripheral subtype based on distinct clinicopathological features and survival outcomes. ICC-perihilar subtype behaved more like carcinoma of the bile duct (i.e., hilar CCA), whereas ICC-peripheral subtype had features and a prognosis more akin to a primary liver malignancy.
Assuntos
Neoplasias dos Ductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/patologia , Colangiocarcinoma/patologia , Prognóstico , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologiaRESUMO
The intimate interaction between redox signaling and immunity has been widely revealed. However, the clinical application of relevant therapeutic is unavailable due to the absence of validated markers that stratify patients. Here, we identified novel biomarkers for prognosis prediction in hepatocellular carcinoma (HCC). Prognostic redox-immune-related genes for predicting overall survival (OS) of HCC were identified using datasets from TCGA, LIRI-JP, and GSE14520. LASSO Cox regression was employed to construct the signature model and generate a risk score in the TCGA cohort. The signature contained CDO1, G6PD, LDHA, GPD1L, PPARG, FABP4, CCL20, SPP1, RORC, HDAC1, STC2, HDGF, EPO, and IL18RAP. Patients in the high-risk group had a poor prognosis compared to the low-risk group. Univariate and multivariate Cox regressions identified this signature as an independent factor for predicting OS. Nomogram constructed by multiple clinical parameters showed good performance for predicting OS indicated by the c-index, the calibration curve, and AUC. GSEA showed that oxidoreductase activity and peroxisome-related metabolic pathways were enriched in the low-risk group, while glycolysis activity and hypoxia were higher in the high-risk group. Furthermore, immune profiles analysis showed that the immune score and stromal score were significantly decreased in the high-risk group in the TCGA cohort. There was a considerably lower infiltration of anti-tumor immune cells while a higher proportion of pro-tumor immune cells in silico. Immune markers were distinctly expressed between the subgroups, and redox-sensitive immunoregulatory biomarkers were at higher levels in the high-risk group. Altogether, we identified a redox-immune prognostic signature. A more severe redox perturbation-driven immunosuppressive environment in the high-risk group stratified by the signature may account for poor survival. This may provide a clue to the combined therapy targeting redox and immune in HCC.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/mortalidade , Regulação Neoplásica da Expressão Gênica/imunologia , Neoplasias Hepáticas/mortalidade , Nomogramas , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Estudos de Coortes , Conjuntos de Dados como Assunto , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Oxirredução , Prognóstico , Curva ROC , Medição de Risco/métodos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: Chemo-resistance in hepatocellular carcinoma (HCC) is a major problem, and acquired drug resistance prevents cancer therapies from achieving complete responses. Molecular targeting therapy presents an opportunity to impede tumor through combination or sequential therapy, while the accurate effect is vague. METHODS: The efficacy of combinations between oxaliplatin and anti-cancer molecular targeting drugs was screened. Strangely, the combined chemotherapy with oxaliplatin and saracatinib induced significantly antagonistic effects. Then the antitumor effects of combined treatment with saracatinib and oxaliplatin were confirmed in wide type HCC as well as in saracatinib- and oxaliplatin-resistant HCC. RNA sequencing was used to explore the resistance mechanism, and the roles of ATP-binding cassette transporter G1 (ABCG1) and Wnt signaling in oxaliplatin resistance were confirmed. RESULTS: Chemotherapy with oxaliplatin and saracatinib individually induced strong anti-HCC effects, while combined or sequential treatment of HCC cells with these two drugs exhibited reduced efficacy compared to treatment with the single drugs. And it was saracatinib treatment caused oxaliplatin resistance. RNA sequencing revealed 458 genes that were altered by treatment with saracatinib and oxaliplatin. Of these, the gene encoding ABCG1 and Wnt-associated genes were significantly upregulated. Upregulation of ABCG1 and oxaliplatin resistance were associated with activation of Wnt signaling. Interference with ABCG1 expression or inhibition of Wnt signaling resulted in reversal of the saracatinib-induced oxaliplatin resistance in HCC. CONCLUSIONS: These studies demonstrated that combined or sequential chemotherapy with oxaliplatin and saracatinib reduced antitumor efficacy, and this antagonism was attributed to the activation of Wnt signaling and upregulation of ABCG1 by saracatinib.
Assuntos
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Benzodioxóis/farmacologia , Carcinoma Hepatocelular/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hepáticas/metabolismo , Oxaliplatina/farmacologia , Quinazolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Wnt/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Biologia Computacional/métodos , Modelos Animais de Doenças , Antagonismo de Drogas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Hepatic stellate cells (HSCs) have a key role in fibrogenesis and in the filtrates of the hepatocellular carcinoma (HCC) stroma, in which they are remodeled and play a critical role in HCC progression. However, the precise role of HSCs trending, infiltration and paracrine in orchestrating the stroma-derived oxaliplatin-resistance in HCC is still vague. METHODS: The chemo-resistant models were established to explore the correlation between HSC cells and the condition of chemoresistance. The HCC clinical samples were collected to confirm this phenomenon. Then, the relationship between secretory CCN3 from oxaliplatin-resistant HCC and the infiltration of HSCs in associated HCC microenvironment was evaluated. Finally, the role and mechanism of HSCs remodeling in the orchestration of oxaliplatin-resistant HCC were explored. RESULTS: The increased infiltration of HSCs and collagen accumulation were found in the microenvironment of oxaliplatin-resistant HCC. The cDNA profiles of the oxaliplatin-resistant HCC was reanalyzed, and CCN3 was one of the significantly increased genes. In HCC clinical samples, the levels of CCN3 and α-SMA are positively correlated, and high expression of CCN3 and α-SMA are positively associated with malignant phenotype and poor prognosis. Then the enhanced abilities of migration and proliferation of HSCs, and elevation of the cytokines paracrine from HSCs relating to HCC malignancy were proved in vitro and in vivo, and which were related to CCN3-ERK signaling pathway activation. CONCLUSIONS: HSCs remodeling are positively related to CCN3 paracrine in hepatocellular carcinoma, which orchestrated the stroma-derived resistance to chemotherapy in HCC.
Assuntos
Carcinoma Hepatocelular/patologia , Resistencia a Medicamentos Antineoplásicos , Células Estreladas do Fígado/patologia , Neoplasias Hepáticas/patologia , Proteína Sobre-Expressa em Nefroblastoma/genética , Proteína Sobre-Expressa em Nefroblastoma/metabolismo , Actinas/genética , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Colágeno/metabolismo , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Células Estreladas do Fígado/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Transplante de Neoplasias , Oxaliplatina , Comunicação Parácrina , Prognóstico , Microambiente Tumoral , Regulação para CimaRESUMO
OBJECTIVE: To investigate the roles of miR-145 in lung adenocarcinoma (LAC) and to clarify the regulation of N-cadherin by miR-145. RESULTS: In 57 paired clinical LAC tissues, diminished miR-145 was significantly correlated with the lymph node metastasis and was negatively correlated with N-cadherin mRNA level expression. Wound healing and transwell assays revealed a reduced capability of tumor metastasis induced by miR-145 in LAC. miR-145 negatively regulated the invasion of cell lines through targeting N-cadherin by directly binding to its 3'-untranslated region. Silencing of N-cadherin inhibited invasion and migration of LAC cell lines similar to miR-145 overexpression. CONCLUSIONS: MiR-145 could inhibit invasion and migration of lung adenocarcinoma cell lines by directly targeting N-cadherin.
Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Antígenos CD/genética , Antígenos CD/metabolismo , Caderinas/genética , Caderinas/metabolismo , Movimento Celular/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , MicroRNAs/metabolismo , Células A549 , Adenocarcinoma/epidemiologia , Adenocarcinoma/genética , Adenocarcinoma de Pulmão , Estudos de Coortes , Feminino , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Masculino , MicroRNAs/análise , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica/genéticaRESUMO
Pectin-nanoscale zerovalent iron (PNZVI) has been studied as an effective phosphate adsorption material to remove highly concentrated phosphate from aqueous solution. Batch phosphate removal and equilibrium experiments were conducted in order to evaluate the effects of environmental factors such as pH, coexisting anions and ionic strengths on phosphate removal by PNZVI. The scanning electron microscope images of nanoscale zerovalent iron (NZVI) and PNZVI demonstrated that PNZVI exhibited larger specific surface areas than NZVI so that PNZVI had higher phosphate removal efficiency than NZVI. Equilibrium experiments showed that phosphate adsorption by PNZVI was well fitted with the Freundlich and Langmuir models. In addition, the maximum adsorption capacity reached 277.38 mgP/gPNZVI. The ionic strengths and common anions showed no significant effects on the process of phosphate adsorption by PNZVI. The phosphate removal efficiency increased to a peak value with pH increased from 2.0 to 5.0, then decreased with pH further increased from 5.0 to 10.0. The Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy analyses of PNZVI and P-loaded PNZVI indicated that adsorption, rather than redox reaction, was the dominant mechanism for the removal of phosphate by PNZVI.
Assuntos
Ferro/química , Nanopartículas Metálicas/química , Pectinas/química , Fosfatos/isolamento & purificação , Poluentes Químicos da Água/isolamento & purificação , Adsorção , Concentração Osmolar , Espectroscopia FotoeletrônicaRESUMO
INTRODUCTION: Methylation assays have demonstrated potential as dependable and high-precision approaches for identifying or triaging individuals with cervical cancer (CA) or cervical intraepithelial neoplasia (CIN). Our investigation aimed to assess the efficacy of the diagnosis and triage of the PAX1/SOX1 methylation panel in detecting CIN or CA. METHODS: A total of 461 patients with abnormal high-risk human papillomavirus (hrHPV) or cytology test results were recruited for this study. Each patient underwent an assortment of assessments, comprising a cytology test, hrHPV test, colposcopy examination, and PAX1 and SOX1 methylation tests. RESULTS: The extent of methylation of both genes demonstrates a positive correlation with the severity of CIN lesions and CA. To determine the correlation for patients with CIN2 or worse (CIN2+), the area under curve was 0.821 (95% CI: 0.782-0.853) for PAX1 and 0.800 (95% CI: 0.766-0.838) for SOX1, while for CIN3 or worse (CIN3+), 0.881 (95% CI: 0.839-0.908) for PAX1 and 0.867 (95% CI: 0.830-0.901) for SOX1. The PAX1/SOX1 methylation marker panel performed sensitivity and specificity of 77.16% and 91.67% for CIN2+, 84.76% and 90.50% for CIN3+, respectively. Regarding triaging hrHPV+ patients, the PAX1/SOX1 methylation test only referred 11.83% of the patients who are unnecessary for colonoscopy examination, which is comparatively lower than cytology, thereby signifying a promising triage strategy for hrHPV-positive women. Furthermore, we observed that the positive PAX1/SOX1 methylation test result for untreated CIN1 or fewer patients would result in a higher likelihood of progression upon a 24-month follow-up visit. CONCLUSION: The present investigation demonstrates that the PAX1/SOX1 methylation marker panel exhibits favorable diagnostic performance in CIN detection and holds the potential to be employed for individual CIN tests or hrHPV-positive triage.
Assuntos
Biomarcadores Tumorais , Metilação de DNA , Fatores de Transcrição Box Pareados , Fatores de Transcrição SOXB1 , Triagem , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Humanos , Feminino , Displasia do Colo do Útero/diagnóstico , Displasia do Colo do Útero/genética , Displasia do Colo do Útero/virologia , Displasia do Colo do Útero/patologia , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/patologia , Adulto , Fatores de Transcrição Box Pareados/genética , Biomarcadores Tumorais/genética , Pessoa de Meia-Idade , Fatores de Transcrição SOXB1/genética , Triagem/métodos , Colposcopia , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/genética , Idoso , Adulto Jovem , Esfregaço Vaginal/métodos , Valor Preditivo dos TestesRESUMO
BACKGROUND: Deubiquitinating enzymes (DUBs) cleave ubiquitin on substrate molecules to maintain protein stability. DUBs reportedly participate in the tumorigenesis and tumour progression of hepatocellular carcinoma (HCC). OTU deubiquitinase 5 (OTUD5), a DUB family member, has been recognized as a critical regulator in bladder cancer, breast cancer and HCC. However, the expression and biological function of OTUD5 in HCC are still controversial. RESULTS: We determined that the expression of OTUD5 was significantly upregulated in HCC tissues. High levels of OTUD5 were also detected in most HCC cell lines. TCGA data analysis demonstrated that high OTUD5 expression indicated poorer overall survival in HCC patients. OTUD5 silencing prominently suppressed HCC cell proliferation, while its overexpression markedly enhanced the proliferation of HCC cells. Mass spectrometry analysis revealed solute carrier family 38 member 1 (SLC38A1) as a candidate downstream target protein of OTUD5. Coimmunoprecipitation analysis confirmed the interaction between OTUD5 and SLC38A1. OTUD5 knockdown reduced and OTUD5 overexpression increased SLC38A1 protein levels in HCC cells. However, OTUD5 alteration had no effect on SLC38A1 mRNA expression. OTUD5 maintained SLC38A1 stability by preventing its ubiquitin-mediated proteasomal degradation. SLC38A1 silencing prominently attenuated the OTUD5-induced increase in HCC cell proliferation. Finally, OTUD5 knockdown markedly suppressed the growth of HCC cells in vivo. CONCLUSIONS: OTUD5 is an oncogene in HCC. OTUD5 contributes to HCC cell proliferation by deubiquitinating and stabilizing SLC38A1. These results may provide a theoretical basis for the development of new anti-HCC drugs.
Assuntos
Carcinoma Hepatocelular , Proliferação de Células , Neoplasias Hepáticas , Animais , Humanos , Camundongos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Enzimas Desubiquitinantes/metabolismo , Enzimas Desubiquitinantes/genética , Endopeptidases/genética , Endopeptidases/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , UbiquitinaçãoRESUMO
Yes-associated protein (YAP) is an essential driver of hepatocellular carcinoma (HCC) progression and the ubiquitin-proteasome system controls its abundance. However, the role of ubiquitin-specific protease 40 (USP40) in YAP stability remains unclear. Here, USP40 was first identified as a novel regulator of YAP abundance and its target genes in HCC cells. USP40 interacted with YAP to remove the lysine 48 (K48)-linked polyubiquitination of YAP at K252 and K315 sites, thereby maintaining YAP stability. USP40 facilitated the proliferation, colony formation, migration and spheroid formation of HCC cells in vitro and promoted HCC growth in vivo in a YAP-dependent manner. In turn, YAP transcriptionally activated USP40 expression in HCC cells. RNA sequencing analysis showed that about 37% of USP40-regulated genes overlapped with YAP-regulated genes. Interestingly, stiffness-induced USP40 upregulation was abolished by YAP knockdown, and USP40 knockdown attenuated stiffness-induced YAP accumulation in HCC cells. Clinical data demonstrated that USP40 was positively associated with YAP expression in HCC tissues and its high expression indicated a poor prognosis. In conclusion, the USP40/YAP positive feedback loop contributes to HCC progression, suggesting that USP40 may be a promising drug target for anti-HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Retroalimentação , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAPRESUMO
Matrix stiffness is a central modulator of hepatic stellate cells (HSCs) activation and hepatic fibrogenesis. However, the long non-coding RNAs (lncRNAs)-regulated transcriptional factors linking matrix stiffness to alterations in HSCs phenotype are not completely understood. In this study, we investigated the effects of matrix stiffness on HSCs activation and its potential mechanism. Through analysis the RNA-seq data with human primary HSCs cultured on 0.4 kPa and 25.6 kPa hydrogel, we identified that forkhead box protein C2 (FOXC2) and its antisense lncRNA FXOC2-AS1 as the new mechanosensing transcriptional regulators that coordinate HSCs responses to the matrix stiffness, moreover, FOXC2 and FOXC2-AS1 expression were also elevated in human fibrosis and cirrhosis tissues. The matrix stiffness was sufficient to activate HSCs into myofibroblasts, resulting in nuclear accumulation of FOXC2. Disrupting FOXC2 and FOXC2-AS1 level abrogated stiffness-induced activation of HSCs. Further mechanistic studies displayed that stiffness-upregulated lncRNA FOXC2-AS1 had no influence on transcription of FOXC2. FOXC2-AS1 exerted its biological function through maintaining the RNA stability of FOXC2, and protecting FOXC2 mRNA from degradation by RNA exosome complex. Additionally, rescue assays confirmed that reintroduction of FOXC2 in FOXC2-AS1-depleted HSCs reversed the repression of FOXC2-AS1 knockdown on stiffness-induced HSCs activation. In AAV6-treated mice fibrotic models, targeting FOXC2 in vivo lead to a reduced degree of liver fibrosis. In sum, our study uncovers a reciprocal crosstalk between matrix stiffness and FOXC2-AS1/FOXC2 axis leading to modulation of HSCs mechanoactivation and liver fibrosis, and present AAV6 shRNA as an effective strategy that targets FOXC2 leading to the resolution of liver fibrosis.
Assuntos
Células Estreladas do Fígado , RNA Longo não Codificante , Animais , Humanos , Camundongos , Transdiferenciação Celular/genética , Modelos Animais de Doenças , Cirrose Hepática/genética , Miofibroblastos , RNA Longo não Codificante/genéticaRESUMO
Ubiquitination, a crucial post-translational modification, controls substrate degradation and can be reversed by deubiquitinases (DUBs). An increasing number of studies are showing that DUBs regulate the malignant behavior and chemotherapy resistance of gastric cancer (GC) by stabilizing various proteins. However, the expression level and biological function of the DUB, proteasome 26S subunit, non-ATPase 7 (PSMD7), in GC remains unknown. Herein, we report for the first time that PSMD7 is frequently overexpressed in GC tissues. Elevated levels of PSMD7 were also detected in GC cell lines. Notably, the upregulation of PSMD7 closely correlated with malignant clinical parameters and reduced the survival of GC patients. Functionally, we found that PSMD7 knockdown consistently suppressed the proliferation, migration, and invasion of AGS and SGC-7901 cells. Ectopic expression of PSMD7 facilitated GC cell proliferation and mobility. Based on protein-protein interaction prediction, RAD23 homolog B (RAD23B) protein was identified as a candidate substrate of PSMD7. PSMD7 positively regulated the abundance of RAD23B and xeroderma pigmentosum, complementation group C (XPC) protein in GC cells. The interaction between PSMD7 and RAD23B was confirmed using protein immunoprecipitation. PSMD7 knockdown enhanced the ubiquitination and degradation of RAD23B protein in GC cells. PSMD7 promoted cell viability, apoptosis resistance, and DNA damage repair in GC cells upon cisplatin (DDP) treatment. Moreover, PSMD7 silencing inhibited tumor growth and enhanced the sensitivity of GC cells to DDP treatment in mice. In summary, PSMD7 was highly expressed in GC and contributed to the malignant behavior and DDP resistance of tumor cells by stabilizing RAD23B.
Assuntos
Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Gástricas/enzimologia , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , China/epidemiologia , Cisplatino/uso terapêutico , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Mutations in the CTNNB1 gene in hepatocellular carcinoma (HCC) are related to immune exclusion, and HCC patients with CTNNB1 mutations tend to be primarily resistant to anti-PD1 therapy. However, systemic evaluation of immune cell infiltration in HCC with mutant CTNNB1 is lacking, and the mechanism of immune exclusion resulting from CTNNB1 mutations remains unclear. Based on CTNNB1 mutation status in HCC, we investigated RNA and miRNA expression and infiltration of immune cells. Data downloaded from TCGA showed that HCC with CTNNB1 mutation had an increased expression of CTNNB1. HCC with CTNNB1 mutation showed a reduction in infiltration score as well as in abundance of certain kinds of immune cells, including CD4 naïve T cells, CD4+ T cells, Tex cells, Th2 cells, Tfh cells, B cells, macrophages, and NK cells. Furthermore, there were 13 chemokines downregulated among all the 14 differentially expressed chemokines (DE-CKs) in CTNNB1 mutants compared to those in the wild type. A positive correlation was found between the expression of DE-CKs and infiltration score, as well as infiltration level of 6 types of immune cells, namely B cells, CD8+ cells, CD4+ cells, macrophages, neutrophils, and dendritic cells. Additionally, 302 differentially expressed immune-related genes (DE-IRGs) were involved mainly in the human immune response and cytokine-cytokine receptor interaction. The target DE-IRGs of differentially expressed miRNAs (DE-miRNAs) were identified and used to construct a network with DE-miRNAs and DE-CKs. Overall, CTNNB1 mutation in HCC led to a decrease in chemokine expression and subsequent suppression of immune cell infiltration partly through regulating specific miRNA-IRG-CK axes, pointing to a potential combination of interference of Wnt/ß-catenin signaling with immunotherapy in HCC with CTNNB1 mutation.
Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , MicroRNAs/metabolismo , beta Catenina/genética , Quimiocinas/genética , Quimiocinas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Mutação , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Chemotherapy is an alternative treatment for advanced HCCs, but chemo-resistance prevents cancer therapies from achieving stable and complete responses. Understanding the underlying mechanisms in chemo-resistance is critical to improve the efficacy of HCC. METHODS: The expression levels of Id-1 and CCN2 were detected in large cohorts of HCCs, and functional analyses of Id-1 and CCN2 were performed both in vitro and in vivo. cDNA microarrays were performed to evaluate the alterations of expression profiling of HCC cells with overexpression of CCN2. Finally, the role of downstream signaling of MAPK/Id-1 signaling pathway in oxaliplatin resistance were also explored. RESULTS: The increased expression of Id-1 and CCN2 were closely related to oxaliplatin resistance in HCC. Upregulation of CCN2 and Id-1 was independently associated with shorter survival and increased recurrence in HCC patients, and significantly enhanced oxaliplatin resistance and promoted lung metastasis in vivo, whereas knock-down of their expression significantly reversed the chemo-resistance and inhibited HCC cell stemness. cDNA microarrays and PCR revealed that Id-1 and MAPK pathway were the downstream signaling of CCN2. CCN2 significantly enhanced oxaliplatin resistance by activating the MAPK/Id-1 signaling pathway, and Id-1 could upregulate CCN2 in a positive feedback manner. CONCLUSIONS: CCN2/MAPK/Id-1 loop feedback amplification is involved in oxaliplatin resistance, and the combination of oxaliplatin with inhibitor of CCN2 or MAPK signaling could provide a promising approach to ameliorating oxaliplatin resistance in HCC.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Oxaliplatina/uso terapêutico , Adulto , Idoso , Animais , Biomarcadores Tumorais/metabolismo , Butadienos/farmacologia , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Retroalimentação/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/fisiologia , Xenoenxertos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Recidiva Local de Neoplasia , Transplante de Neoplasias , Células-Tronco Neoplásicas/efeitos dos fármacos , Nitrilas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro/metabolismo , Sorafenibe/farmacologia , Regulação para Cima/efeitos dos fármacosRESUMO
MicroRNAs (miRNAs) are small noncoding, single-stranded RNAs consisting of 20-24 nucleotides (Bartel, Cell 116:281-297, 2004), which regulate target genes expression by interacting with 3'-untranslated regions (3'-UTRs) of target mRNAs, leading to translation repression or mRNA degradation (Filipowicz et al., Nat Rev Genet 9:102-114, 2008; Nilsen, Trends Genet 23:243-249, 2007). Accumulating evidence has elucidated them as oncogenes or tumor suppressors in cancers such as hepatocellular carcinoma, breast cancer, and lung cancer (Liu et al., Gastroenterology 136:683-693, 2009; Yu et al., Cell 131:1109-1123, 2007; Zhou et al., Sci Rep 7:42680, 2017; Iorio and Croce, Carcinogenesis 33:1126-1133, 2012). MiRNAs are involved in various biological processes, including cell proliferation (Liu et al., Mol Cancer Res 11:1314-1325, 2013), differentiation (Liu et al., Mol Cancer Res 11:1314-1325, 2013), apoptosis (Pan et al., Oncol Res 24:429-435, 2016), invasion and metastasis (Liu et al., Nat Commun 8:14270, 2017). Understanding the role of miRNAs in tumor gives new perspective on cancer diagnosis and therapy (Rupaimoole and Slack, Nat Rev Drug Discov 16:203-222, 2017; Berindan-Neagoe et al., CA Cancer J Clin 64:311-336, 2014). This chapter will focus on the in vitro methods for identifying miRNAs roles in cell proliferation, invasion, and metastasis in tumor development, which includes CCK-8 assay, Wound Healing assay, and Transwell assay.
Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias/genética , Movimento Celular/genética , Proliferação de Células , Humanos , Metástase Neoplásica , Neoplasias/patologia , Reação em Cadeia da Polimerase em Tempo Real , TransfecçãoRESUMO
miRNAs play important roles in lung adenocarcioma (LADC) progression. We previously found that miR-1290 expression was upregulated in LADC tissue and serum samples from patients with LADC, and correlated with prognosis. However, the biological role of miR-1290 in LADC and mechanism of such role are poorly understood. Here, we found that miR-1290 overexpression promoted LADC cell proliferation, cell cycle progression and invasion, while suppressing cell apoptosis in vitro. Furthermore, miR-1290 promoted tumor growth, invasion and metastasis in vivo. miR-1290 downregulated suppressor of cytokine signaling 4 (SOCS4) at both the mRNA and protein levels by targeting SOCS4. Reduced SOCS4 level reversed the inhibitory effect of miR-1290 downregulation on cell proliferation and invasion. miR-1290 activated the JAK/STAT3 and PI3K/AKT signaling pathways by targeting SOCS4. An inverse correlation was observed between miR-1290 and SOCS4 expression in LADC tissues. Clinicopathological characteristics analysis showed that SOCS4 expression was negatively associated with higher clinical stage and lymph node metastasis. These observations suggest that miR-1290 promotes LADC cell proliferation and invasion by targeting SOCS4.
RESUMO
SP70 is a novel tumor biomarker in patients with nonsmall cell lung cancer (NSCLC). However, its role as a marker for predicting the response to chemotherapy for patients with advanced NSCLC has not been investigated. A total of 152 patients were enrolled. Serum SP70, carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA21-1), and neuron-specific enolase (NSE) were detected before and after 2 cycles of chemotherapy. The correlation between serum tumor biomarker levels and chemotherapy responses and their association with epidermal growth factor receptor (EGFR) mutation status and progression-free survival (PFS) were analyzed. Serum SP70 levels were significantly decreased after chemotherapy in the partial remission (PR) group (P < .001) and increased in the progressive disease (PD) group (P < .001), but not significantly changed in the stable disease (SD) group (P = .114). Although similar changes were observed on CEA and CYFRA21-1 levels but not NSE, ROC analysis demonstrated that SP70 is superior to the others. Additionally, patients with EGFR mutation had higher serum SP70 levels and tissue SP70 expression than patients without EGFR mutation (P = .014 and P = .002, respectively). The median PFS of patients with decreased SP70 levels after chemotherapy was longer than that of patients with stable or increased serum SP70 level (24 months vs 12 months vs 2 months, P < .001), and the differences of all other 3 tumor markers were not obvious. Serum SP70 is a sensitive and real-time indicator of chemotherapeutic efficacy in patients with advanced NSCLC and related to PFS.
RESUMO
BACKGROUND: High level of red blood cell distribution width (RDW) has been associated with adverse outcomes in coronary artery disease patients. We aimed to investigate the relationship between RDW and the risk of myocardial injury in chest pain patients. METHODS AND RESULTS: We retrospectively reviewed 2078 chest pain patients with suspected acute myocardial infarction. Myocardial injury was defined as high-sensitivity cardiac troponin T (hs-cTnT) >14â¯ng/L. RDW was associated with hs-cTnT (râ¯=â¯0.607) and the risk of myocardial injury stepwise increased across increasing RDW quartiles in all subgroups based on age and sex. The receiver operating characteristic curve analysis was calculated to assess the elevated RDW to predict myocardial injury, with the cutoff value of 13.25%. RDW had a high sensitivity (78.10%), specificity (87.44%), as well as positive predictive value (77.48%). The area under the curve (AUC) for all patients was 0.88 (95%CI 0.87, 0.90) and there is no statistical significant in AUCs for all subgroups. CONCLUSIONS: Elevated RDW was significantly associated with a higher risk of myocardial injury in chest pain patients with potential acute myocardial infarction. The RDW may be helpful to identify myocardial injury in such patients.