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BACKGROUND & AIMS: Metastases from gastric adenocarcinoma (GAC) lead to high morbidity and mortality. Developing innovative and effective therapies requires a comprehensive understanding of the tumor and immune biology of advanced GAC. Yet, collecting matched specimens from advanced, treatment-naïve patients with GAC poses a significant challenge, limiting the scope of current research, which has focused predominantly on localized tumors. This gap hinders deeper insight into the metastatic dynamics of GAC. METHODS: We performed in-depth single-cell transcriptome and immune profiling on 68 paired, treatment-naïve, primary metastatic tumors to delineate alterations in cancer cells and their tumor microenvironment during metastatic progression. To validate our observations, we conducted comprehensive functional studies both in vitro and in vivo, using cell lines and multiple patient-derived xenograft and novel mouse models of GAC. RESULTS: Liver and peritoneal metastases exhibited distinct properties in cancer cells and dynamics of tumor microenvironment phenotypes, supporting the notion that cancer cells and their local tumor microenvironments co-evolve at metastatic sites. Our study also revealed differential activation of cancer meta-programs across metastases. We observed evasion of cancer cell ferroptosis via GPX4 up-regulation during GAC progression. Conditional depletion of Gpx4 or pharmacologic inhibition of ferroptosis resistance significantly attenuated tumor growth and metastatic progression. In addition, ferroptosis-resensitizing treatments augmented the efficacy of chimeric antigen receptor T-cell therapy. CONCLUSIONS: This study represents the largest single-cell dataset of metastatic GACs to date. High-resolution mapping of the molecular and cellular dynamics of GAC metastasis has revealed a rationale for targeting ferroptosis defense in combination with chimeric antigen receptor T-cell therapy as a novel therapeutic strategy with potential immense clinical implications.
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Understanding tumor microenvironment (TME) reprogramming in gastric adenocarcinoma (GAC) progression may uncover novel therapeutic targets. Here, we performed single-cell profiling of precancerous lesions, localized and metastatic GACs, identifying alterations in TME cell states and compositions as GAC progresses. Abundant IgA+ plasma cells exist in the premalignant microenvironment, whereas immunosuppressive myeloid and stromal subsets dominate late-stage GACs. We identified six TME ecotypes (EC1-6). EC1 is exclusive to blood, while EC4, EC5, and EC2 are highly enriched in uninvolved tissues, premalignant lesions, and metastases, respectively. EC3 and EC6, two distinct ecotypes in primary GACs, associate with histopathological and genomic characteristics, and survival outcomes. Extensive stromal remodeling occurs in GAC progression. High SDC2 expression in cancer-associated fibroblasts (CAFs) is linked to aggressive phenotypes and poor survival, and SDC2 overexpression in CAFs contributes to tumor growth. Our study provides a high-resolution GAC TME atlas and underscores potential targets for further investigation.
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Adenocarcinoma , Fibroblastos Asociados al Cáncer , Lesiones Precancerosas , Neoplasias Gástricas , Humanos , Ecotipo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Adenocarcinoma/patología , Fibroblastos Asociados al Cáncer/patología , Lesiones Precancerosas/patología , Células del Estroma/patología , Microambiente TumoralRESUMEN
BACKGROUND: Lifelong premature ejaculation (LPE) is one of the most common ejaculatory dysfunctions in men. The serotonin (5-HT) synthesis rate-limiting enzyme (TPH2) and receptor (HTR1A) in the 5-HT regulatory system may play a key role in the pathogenesis of LPE. However, there are few studies on the effects of TPH2 and HTR1A polymorphisms on LPE risk. We speculated that TPH2 and HTR1A polymorphisms may affect the occurrence and development of LPE in the Chinese Han population. METHODS: In this study, 91 patients with LPE and 362 normal controls aged 18 to 64 years were enrolled in the male urology department of Hainan General Hospital in China from January 2016 to December 2018. The SNPs in HTR1A and TPH2, which are related to 5-HT regulation, were selected as indexes to genotype the collected blood samples of participants. Logistic regression was used to analyze the correlation between SNPs of HTR1A and TPH2 with LPE susceptibility, as well as the relationship with leptin, 5-HT and folic acid levels. RESULTS: The results revealed that HTR1A-rs6295 increased LPE risk in recessive model. Rs11178996 in TPH2 significantly reduced susceptibility to LPE in allelic (odds ratio (OR) = 0.68, 95% confidence interval (95% CI) = 0.49-0.96, p = 0.027), codominant (OR = 0.58, 95% CI = 0.35-0.98, p = 0.040), dominant (OR = 0.58, 95% CI = 0.36-0.92, p = 0.020), and additive (OR = 0.71, 95% CI = 0.52-0.98, p = 0.039) models. Grs11179041Trs10879352 could reduce the risk of LPE (OR = 0.44, 95% CI = 0.22-0.90, p = 0.024) by haplotype analysis. CONCLUSION: HTR1A-rs6295 and TPH2-rs11178996 are associated with LPE risk in the Chinese Han population based on the finding of this study.
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Pueblos del Este de Asia , Eyaculación Prematura , Adolescente , Adulto , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Pueblo Asiatico/genética , Polimorfismo de Nucleótido Simple/genética , Eyaculación Prematura/genética , Receptor de Serotonina 5-HT1A/genética , Serotonina , Triptófano Hidroxilasa/genéticaRESUMEN
Premature ejaculation (PE) is a common male sexual dysfunction disorder, and is considered to have the genetic predisposition. However, the internal regulation mechanisms is still unclear. Hence, this study intended to explore the effects of genetic polymorphisms of CYP24A1 on the risk of PE. This case-control study genotyped three SNPs of CYP24A1 (rs2762934, rs1570669 and rs6068816) from 139 PE patients and 372 healthy men using Agena MassARRAY platform. Collected data was then processed in SPSS 18.0. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in logistic regression analysis to evaluate the associations between CYP24A1 polymorphisms and the PE risk. The results suggested that allele A of rs1570669 was significantly associated with the increased PE risk (OR=1.38, 95% CI=1.04-1.84, P=0.026). Meanwhile, we also identified rs1570669 as a risk factor of PE under the additive model (OR=1.47, 95% CI=1.02-2.11, P=0.039) by comparing the genotypic distributions between cases and controls, and genotype AA of rs1570669 was detected to be significantly related with an increased risk of PE under the codominant model (OR=2.26, 95% CI=1.06-4.83, P=0.036). This study is the first to proved that the genetic variants of CYP24A1 played essential role in affecting the susceptibility to PE in Chinese Han.
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Eyaculación Prematura , Estudios de Casos y Controles , China , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Eyaculación Prematura/genética , Vitamina D3 24-Hidroxilasa/genéticaRESUMEN
Breast cancer is the most prevalent cancer diagnosed in women and the major malignancy that threatens women health, thus we explored the role of long noncoding RNA LINC01605 in triple-negative breast cancer (TNBC). We collected tissue samples from TNBC patients and cultured breast cancer cells to detect LINC01605 levels by RT-PCR. We then constructed LINC01605 knockdown and LINC01605 overexpressed TNBC cell lines, cell proliferation was measured by CCK-8 and colony formation assays, cell migration and invasion were measured by Transwell assay, and aerobic glycolysis of cells was detected. Furthermore, a downstream target gene was found, and its role was confirmed by mouse allogeneic tumor formation. It discovered that LINC01605 expression was significantly increased in TNBC patients, and its high expression predicted a low survival prognosis for TNBC patients. Stable knockdown of LINC01605 remarkably inhibited cell proliferation, migration, and invasion, as well as aerobic glycolysis by inhibiting lactate dehydrogenase A in TNBC cell lines. Notably, knockdown of LINC01605 suppressed in vivo tumor formation and migration in TNBC transplanted mice. In conclusion, targeting long noncoding RNA LINC01605 might serve as a therapeutic candidate strategy to treat patients with TNBC.
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Lactato Deshidrogenasa 5 , ARN Largo no Codificante , Neoplasias de la Mama Triple Negativas , Animales , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Glucólisis/genética , Humanos , Lactato Deshidrogenasa 5/metabolismo , Ratones , ARN Largo no Codificante/genética , Neoplasias de la Mama Triple Negativas/metabolismoRESUMEN
Gastric cancer (GC) is one of the most common types of cancer. The n-butanol extract of Huaier (NEH) is the alcohol-soluble part extracted by the systematic solvent method, which is effective against gastric cancer (GC). However, the mechanism of action of NEH remains unclear. In this study, we aim to evaluate the clinical relevance of GPR30 expression in GC patients and the role of the GPR30/PI3K/AKT signalling pathway in the anti-GC effect of NEH. The expression of GPR30 was examined using immunohistochemistry. Cell counting kit 8 (CCK-8) assay, wound healing, and transwell experiments were used to investigate the viability, migration, and invasion of gastric cancer cells. Western blotting was used to detect the expression of GPR30 and its downstream signalling molecules of the PI3K/AKT signalling pathway. Gastric cancer patient-derived xenografts (PDX) mouse model was used to evaluate the antitumor effect of NEH in vivo. In addition, the graded doses and the maximum tolerated dose of NEH were administered intraperitoneally into the mice for acute toxicity test. We demonstrate that GPR30 expression in GC tissues was significantly higher than that in corresponding adjacent noncancerous tissues and the expression of GPR30 was correlated with a poor prognosis in GC patients. Moreover, GPR30 expression was involved in the migration and invasion of GC cells in vitro. Additionally, we found that NEH can suppress the growth of GC in patient-derived xenograft tumors in vivo. Furthermore, NEH inhibited the proliferation, migration, and invasion in GC cells in a concentration-dependent manner through inhibiting the GPR30-mediated PI3K/AKT signalling pathway in vitro. Acute toxicity test showed that NEH caused no toxic reaction or death and the maximum tolerated dose of NEH in mice was greater than 1600 mg/kg. Our results demonstrate that the high expression of GPR30 is an independent factor of poor prognosis in patients with GC and NEH could be a new agent for the treatment of gastric cancer.
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PURPOSE: Genetic factors play an indispensable role in the pathogenesis of lifelong premature ejaculation (LPE). The susceptibility genes/SNPs that have been discovered are very limited and can only explain part of the genetic effects of LPE. Therefore, discovering more genetic polymorphisms associated with the occurrence and development of LPE will help reveal the pathogenesis of LPE. MATERIALS AND METHODS: We conducted a genome-wide association study of LPE in 486 Chinese male Han people (cases and controls). We used Gene Titan multi-channel instrument and Axiom Analysis Suite 6.0 software for genotyping. Imputation was performed by IMPUTE2 software and the 1000 Genomes Project (Phase3) was used as reference for haplotype. Finally, logistic regression analysis was performed on all loci that passed the quality control. The odds ratio and 95% confidence interval were calculated to determine the association between each SNPs and Chinese male Han population LPE risk. RESULTS: The results showed that a total of 33 genetic variants in 13 genes (LACTBL1, SSBP3, ACOT11, LINC02486, TMEM154, LINC01098, NONE, HCG27, HLA-C, TNFSF8, TNC, FAM53B, SULF2) have a suggestively significant genome-wide association with LPE risk (p<5×10-6). CONCLUSIONS: This study is the first to conduct a GWAS on LPE in Chinese male Han population 33 genetic polymorphisms have a suggestive genome-wide association with LPE risk. This study have provided data supplement for the genetic loci of LPE risk, and laid a scientific foundation for the pathogenesis and the targeted therapy of LPE.
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The incidence rate of adenocarcinoma of the esophagogastric junction (AEG) is increasing worldwide with poor prognosis and unclear pathogenesis. Trametes robiniophila Murr. (Huaier), a traditional Chinese medicine has been used in the clinical treatment of a variety of solid tumors, including AEG. However, its anticancer components and molecular mechanisms are still unclear. In our previous studies, we have found that Huaier n-butanol extract (HBE) shows the most potent anticancer activity among different extracts. In the present study, we aimed to investigate the clinical relevance of p-MEK expression in AEG patients and the role of the MEK/ERK signaling pathway in the anti-AEG efficacy of HBE in vitro and in vivo. We herein demonstrate that p-MEK expression in AEG tissues was significantly higher than that in paracancerous tissues and correlated with a poor prognosis in AEG patients. We further found that HBE inhibited the colony formation, migration, and invasion in AEG cell lines in a concentration-dependent manner in vitro. HBE also suppressed the growth of AEG xenograft tumors without causing any host toxicity in vivo. Mechanistically, HBE caused the inactivation of the MEK/ERK signaling pathway by dephosphorylating MEK1 at S298, ERK1 at T202, and ERK2 at T185 and modulating the expression of EMT-related proteins. In summary, our results demonstrate that the high expression of p-MEK may be an independent factor of poor prognosis in patients with AEG. The clinically used anticancer drug Huaier may exert its anti-AEG efficacy by inhibiting the MEK/ERK signaling pathway.
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Adenocarcinoma/diagnóstico , Antineoplásicos/uso terapéutico , Mezclas Complejas/uso terapéutico , Neoplasias Esofágicas/diagnóstico , Unión Esofagogástrica , Quinasas Quinasa Quinasa PAM/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neoplasias Gástricas/diagnóstico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/metabolismo , Unión Esofagogástrica/metabolismo , Humanos , Masculino , Pronóstico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Análisis de Matrices Tisulares , Trametes , Resultado del TratamientoRESUMEN
The purpose of this study was to investigate whether the polymorphisms of SLC6A4 gene affect the occurrence of lifelong premature ejaculation (LPE). In this case-control study, Agena MassARRAY was used to genotype SLC6A4 polymorphisms of 91 LPE patients and 362 controls. Then, genetic model and haplotype analysis were utilised to explore the correlation between SLC6A4 polymorphisms and LPE risk. The results showed that allele T, genotype T/T and C/T-T/T of rs9303628 were significantly correlated with a decreased risk of LPE in allele (p = .009), co-dominant (p = .025) and dominant (p = .014) model respectively. Allele T and genotype C/T-T/T of rs2054847 reduced the risk of LPE in co-dominant (p = .015) and dominant (p = .030) models respectively. Furthermore, there was a significant correlation between Ars9303628 Crs2054847 haplotype and the decreased the risk of LPE (p = .010). In conclusion, this study firstly proved that the presence of rs9303628 and rs2054847 in SLC6A4 gene was a protective factor for the occurrence of LPE in the Chinese Han population.
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Eyaculación Prematura , Pueblo Asiatico/genética , Estudios de Casos y Controles , China/epidemiología , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Masculino , Polimorfismo Genético , Polimorfismo de Nucleótido Simple , Eyaculación Prematura/epidemiología , Eyaculación Prematura/genética , Factores Protectores , Proteínas de Transporte de Serotonina en la Membrana PlasmáticaRESUMEN
Hepatocellular carcinoma (HCC) accounts for approximately 85-90% of all liver cancer cases and has poor relapse-free survival. There are many gene expression studies that have been performed to elucidate the genetic landscape and driver pathways leading to HCC. However, existing studies have been limited by the sample size and thus the pathogenesis of HCC is still unclear. In this study, we performed an integrated characterization using four independent datasets including 320 HCC samples and 270 normal liver tissues to identify the candidate genes and pathways in the progression of HCC. A total of 89 consistent differentially expression genes (DEGs) were identified. Gene-set enrichment analysis revealed that these genes were significantly enriched for cellular response to zinc ion in biological process group, collagen trimer in the cellular component group, extracellular matrix (ECM) structural constituent conferring tensile strength in the molecular function group, protein digestion and absorption, mineral absorption and ECM-receptor interaction. Network system biology based on the protein-protein interaction (PPI) network was also performed to identify the most connected and important genes based on our DEGs. The top five hub genes including osteopontin (SPP1), Collagen alpha-2(I) chain (COL1A2), Insulin-like growth factor I (IGF1), lipoprotein A (LPA), and Galectin-3 (LGALS3) were identified. Western blot and immunohistochemistry analysis were employed to verify the differential protein expression of hub genes in HCC patients. More importantly, we identified that these five hub genes were significantly associated with poor disease-free survival and overall survival. In summary, we have identified a potential clinical significance of these genes as prognostic biomarkers for HCC patients who would benefit from experimental approaches to obtain optimal outcome.
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The oncogene MDMX, also known as MDM4 is a critical negative regulator of the tumor suppressor p53 and has been implicated in the initiation and progression of human cancers. Increasing evidence indicates that MDMX is often amplified and highly expressed in human cancers, promotes cancer cell growth, and inhibits apoptosis by dampening p53-mediated transcription of its target genes. Inhibiting MDMX-p53 interaction has been found to be effective for restoring the tumor suppressor activity of p53. Therefore, MDMX is becoming one of the most promising molecular targets for developing anticancer therapeutics. In the present review, we mainly focus on the current MDMX-targeting strategies and known MDMX inhibitors, as well as their mechanisms of action and in vitro and in vivo anticancer activities. We also propose other potential targeting strategies for developing more specific and effective MDMX inhibitors for cancer therapy.
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The mutations and deregulation of Wnt signaling pathway occur commonly in human cancer and cause the aberrant activation of ß-catenin and ß-catenin-dependent transcription, thus contributing to cancer development and progression. Therefore, ß-catenin has been demonstrated as a promising target for cancer prevention and therapy. Many natural products have been characterized as inhibitors of the ß-catenin signaling through down-regulating ß-catenin expression, modulating its phosphorylation, promoting its ubiquitination and proteasomal degradation, inhibiting its nuclear translocation, or other molecular mechanisms. These natural product inhibitors have shown preventive and therapeutic efficacy in various cancer models in vitro and in vivo. In the present review, we comprehensively discuss the natural product ß-catenin inhibitors, their in vitro and in vivo anticancer activities, and underlying molecular mechanisms. We also discuss the current ß-catenin-targeting strategies and other potential strategies that may be examined for identifying new ß-catenin inhibitors as cancer preventive and therapeutic drugs.
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The tumor microenvironment (TME) has attracted attention owing to its essential role in tumor initiation, progression, and metastasis. With the emergence of immunotherapies for various cancers, and their high efficacy, an understanding of the TME in gastric cancer (GC) is critical. The aim of this study was to investigate the effect of various components within the GC TME, and to identify mechanisms that exhibit potential as therapeutic targets. The ESTIMATE algorithm was used to quantify immune and stromal components in GC samples, whose clinicopathological significance and relationship with predicted outcomes were explored. Low tumor mutational burden and high M2 macrophage infiltration, which are considered immune suppressive characteristics and may be responsible for unfavorable prognoses in GC, were observed in the high stromal group (HR = 1.585; 95% CI, 1.112-2.259; P = 0.009). Furthermore, weighted correlation network, differential expression, and univariate Cox analyses were used, along with machine learning methods (LASSO and SVM-RFE), to reveal genome-wide immune phenotypic correlations. Eight stromal-relevant genes cluster (FSTL1, RAB31, FBN1, ANTXR1, LRRC32, CTSK, COL5A2, and ENG) were identified as adverse prognostic factors in GC. Finally, using a combination of TIMER database and single-sample gene set enrichment analyses, we found that the identified genes potentially contribute to macrophage recruitment and polarization of tumor-associated macrophages. These findings provide a different perspective into the immune microenvironment and indicate potential prognostic and therapeutic targets for GC immunotherapies.
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A new dihydrobenzofuran-phenyl acrylate hybrid, aspeterreurone A (1), was obtained from the culture of the deep-sea-derived fungus Aspergillus terreus CC-S06-18. The relative configuration of 1 was elucidated by HSQMBC NMR, calculated NMR chemical shifts coupled with a statistical procedure (DP4+), and the absolute configuration was established by ECD calculations. 1 exhibited cytotoxicities against the gastric cancer cell lines HGC27, MGC803, BGC823, and AGS, with minimal effects on normal gastric epithelial cell line GES-1. Further studies showed that 1 inhibited cell cycle progression and induced apoptosis of gastric cancer MGC803 cells in a concentration-dependent manner. Western blot analysis indicated that 1 inhibited the phosphorylation of STAT3, which might contribute to its cytotoxic activity.
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Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacología , Aspergillus/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Células Epiteliales/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Fosforilación , Factor de Transcripción STAT3/metabolismo , Agua de Mar , Neoplasias Gástricas/tratamiento farmacológicoRESUMEN
Gastric cancer is a deadly disease and remains the third leading cause of cancer-related death worldwide. The 5-year overall survival rate of patients with early-stage localized gastric cancer is more than 60%, whereas that of patients with distant metastasis is less than 5%. Surgical resection is the best option for early-stage gastric cancer, while chemotherapy is mainly used in the middle and advanced stages of this disease, despite the frequently reported treatment failure due to chemotherapy resistance. Therefore, there is an unmet medical need for identifying new biomarkers for the early diagnosis and proper management of patients, to achieve the best response to treatment. Long non-coding RNAs (lncRNAs) in body fluids have attracted widespread attention as biomarkers for early screening, diagnosis, treatment, prognosis, and responses to drugs due to the high specificity and sensitivity. In the present review, we focus on the clinical potential of lncRNAs as biomarkers in liquid biopsies in the diagnosis and prognosis of gastric cancer. We also comprehensively discuss the roles of lncRNAs and their molecular mechanisms in gastric cancer chemoresistance as well as their potential as therapeutic targets for gastric cancer precision medicine.
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Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Resistencia a Antineoplásicos/genética , ARN no Traducido/metabolismo , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/tratamiento farmacológico , Animales , Progresión de la Enfermedad , Humanos , Medicina de Precisión , ARN no Traducido/genética , Neoplasias Gástricas/genéticaRESUMEN
Metastasis and recurrence are major causes of death in gastric cancer patients. Because there are no obvious clinical symptoms during the early stages of metastasis, we sought to isolate highly invasive metastatic gastric cancer cells for future drug screening. We first established a mouse model to observe gastric cancer metastasis in vivo. The incidence of peritoneal metastasis of gastric cancer was much higher than liver or lymph metastasis. Peritoneal metastatic and non-metastatic NUGC-4 cells were isolated from the mouse model. Cell proliferation was measured using CCK-8 assays, while migration and invasion were investigated in Transwell assays. Proteins involved in epithelial-mesenchymal transition were detected by Western blotting. Metastatic gastric carcinoma cells were more proliferative and invasive than primary NUGC-4 cells. The supernatants of metastatic gastric carcinoma cells notably altered the morphology of HMrSV5 peritoneal mesothelial cells and promoted their epithelial-mesenchymal transition. Moreover, primary or metastatic gastric cancer cells co-cultured with HMrSV5 cells markedly increased cancer cell proliferation and invasiveness. Moreover, peritoneal metastatic gastric carcinoma cells in the presence of HMrSV5 cells exhibited most malignant behaviors. Thus, peritoneal metastatic gastric carcinoma cells exhibited high capacities for proliferation and invasion, and could be used as a new drug screening tool for the treatment of advanced gastric cancer and peritoneal metastatic gastric cancer.
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Gastric cancer (GC) is a common malignancy with low 5-year overall survival (OS). Recently, immune therapy has been used to treat cancer. B7H5 and CD28H are novel immune checkpoint molecules. However, the prognostic value of B7H5/CD28H expression in patients with GC remains unclear. In this study, seventy-one patients diagnosed with GC were included in this study. Patients' GC tissues and matched adjacent tissue constructed a tissue microarray. The expression levels of B7H5 and CD28H were examined using immunohistochemistry. Correlations between the expression of B7H5 and CD28H and the clinical data were evaluated. We found that the expression of B7H5 and CD28H (both P = .001) were higher in GC tumour tissues than in adjacent noncancerous tissues. B7H5/CD28H expression acted as an independent predictive factor in the OS of patients with GC. High expression of B7H5 and CD28H predicted poor outcome. Patients in the B7H5+CD28H+ group had a lower 5-year OS compared with patients in the B7H5-CD28- group (4.5% vs 55.6%, P = .001). A significant difference was found in the 5-year OS between patients in the B7H5+CD28H- and B7H5+CD28H+ groups (33.5% vs 4.5%, P = .006). However, there was no correlation between B7H5 and CD28H expression (P = .844). Therefore, B7H5 and CD28H expression are up-regulated in GC and are independent prognostic factors for overall survival in patients with GC. Although there was no correlation between B7H5 and CD28H expression, high expression of B7H5 and CD28H predicts poor prognosis, especially when both are highly expressed.
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Antígenos B7/metabolismo , Biomarcadores de Tumor/metabolismo , Antígenos CD28/metabolismo , Neoplasias Gástricas/mortalidad , Anciano , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Masculino , Pronóstico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Tasa de SupervivenciaRESUMEN
BACKGROUND: Resistance to trastuzumab has become a leading cause of mortality in breast cancer patients and is one of the major obstacles for improving the clinical outcome. Cell behavior can be modulated by long non-coding RNAs (lncRNAs), but the contribution of lncRNAs in trastuzumab resistance to breast cancer is largely unknown. To this end, the involvement and regulatory function of lncRNA AGAP2-AS1 in human breast cancer are yet to be investigated. METHODS: Trastuzumab-resistant SKBR-3 and BT474 cells were obtained by continuous culture with 5 mg/mL trastuzumab for 6 months. RT-qPCR assay was used to determine the expression of AGAP2-AS1 in tissues and cells. RNA fluorescence in situ hybridization was used to investigate the subcellular location of AGAP2-AS1 in breast cancer cells. Bioinformatic analysis, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), western blotting, and immunofluorescence were carried out to verify the regulatory interaction of AGAP2-AS1, CREB-binding protein (CBP), and MyD88. In addition, a series of in vitro assays and a xenograft tumor model were used to analyze the functions of AGAP2-AS1 in breast cancer cells. RESULTS: AGAP2-AS1 was upregulated and transcriptionally induced by SP1 in breast cancer. Overexpression of AGAP2-AS1 promoted cell growth, suppressed apoptosis, and caused trastuzumab resistance, whereas knockdown of AGAP2-AS1 showed an opposite effect. MyD88 was identified as a downstream target of AGAP2-AS1 and mediated the AGAP2-AS1-induced oncogenic effects. Mechanistically, the RIP assay revealed that AGAP2-AS1 could bind to CBP, a transcriptional co-activator. ChIP assays showed that AGAP2-AS1-bound CBP increased the enrichment of H3K27ac at the promoter region of MyD88, thus resulting in the upregulation of MyD88. Gain- and loss-of-function assays confirmed that the NF-κB pathway was activated by MyD88 and AGAP2-AS1. Furthermore, high AGAP2-AS1 expression was associated with poor clinical response to trastuzumab therapy in breast cancer patients. CONCLUSION: AGAP2-AS1 could promote breast cancer growth and trastuzumab resistance by activating the NF-κB signaling pathway and upregulating MyD88 expression. Therefore, AGAP2-AS1 may serve as a novel biomarker for prognosis and act as a therapeutic target for the trastuzumab treatment.
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Neoplasias de la Mama/tratamiento farmacológico , Factor 88 de Diferenciación Mieloide/genética , ARN Largo no Codificante/genética , Factor de Transcripción Sp1/genética , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Epigénesis Genética/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Pronóstico , Transducción de Señal/efectos de los fármacos , Trastuzumab/administración & dosificaciónRESUMEN
Currently, resistance to trastuzumab, a human epidermal growth factor receptor 2 (HER2) inhibitor, has become one major obstacle for improving the clinical outcome of patients with advanced HER2+ breast cancer. While cell behaviour can be modulated by long non-coding RNAs (lncRNAs), the contributions of lncRNAs in progression and trastuzumab resistance of breast cancer are largely unknown. To this end, the involvement and regulatory functions of lncRNA SNHG14 in human breast cancer were investigated. RT-qPCR assay showed that SNHG14 was up-regulated in breast cancer tissues and associated with trastuzumab response. Gain- and loss-of-function experiments revealed that overexpression of SNHG14 promotes cell proliferation, invasion and trastuzumab resistance, whereas knockdown of SNHG14 showed an opposite effect. PABPC1 gene was identified as a downstream target of SNHG14, and PABPC1 mediates the SNHG14-induced oncogenic effects. More importantly, ChIP assays demonstrated that lncRNA SNHG14 may induce PABPC1 expression through modulating H3K27 acetylation in the promoter of PABPC1 gene, thus resulting in the activation of Nrf2 signalling pathway. These data suggest that lncRNA SNHG14 promotes breast cancer tumorigenesis and trastuzumab resistance through regulating PABPC1 expression through H3K27 acetylation. Therefore, SNHG14 may serve as a novel diagnostic and therapeutic target for breast cancer patients.