Hepcidin Upregulation in Lung Cancer: A Potential Therapeutic Target Associated With Immune Infiltration.
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ABSTRACT:
SUBMITTER: Fan Y
PROVIDER: S-EPMC8047218 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe current study aimed to investigate the interrelation between P2RY14 and the prognosis of patients suffering from lung adenocarcinoma (LUAD) following surgery.MethodsThe differentially expressed gene (DEG) P2RY14 was screened by the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and Immunology Database and Analysis Portal (ImmPort) databases. The relationship between P2RY14 and clinical data of LUAD was analyzed in TCGA and Kaplan-Meier (KM)-plotter databases. The association of P2RY14 with immune cells and immune-related expressed genes was analyzed in the Tumor Immune Estimation Resource (TIMER) database. A retrospective analysis of the 100 patients clinical data undergoing pulmonary adenocarcinoma surgery admitted to Nanjing Chest Hospital. Immunohistochemistry (IHC) analysis was carried out to evaluate the P2RY14 expression in lung cancer tissues, and quantitative reverse transcription PCR (RT-qPCR) was used to confirm the mRNA expression of this gene in LUAD tissues. And their survival was evaluated. KM method and the log-rank test were used for univariate survival analysis, and the Cox regression method was employed for multivariate survival analysis.ResultsP2Y14 was the DEG identified by the database. P2Y14 expression was upregulated in para-cancer tissues in comparison to cancer tissues. Patients suffering from LUAD who have high P2RY14 expression had a better prognosis than those with low expression. P2RY14 expression was shown to be substantially linked with immune invasion in the TIMER database. Finally, the trial included 100 patients, of which 80 died and 20 survived with a mean overall survival (OS) of 48 months. Between the high and low expression groups of P2RY14, there were statistically significant variations in the clinical stage and differentiation degree (P<0.05). Cox regression analysis revealed that differentiation degree, smoking history, and P2RY14 expression were independent risk factors for the prognosis of LUAD patients (all P<0.05).ConclusionsP2RY14 can substantially prolong the OS of patients suffering from LUAD and can be utilized as a new LUAD predictive biomarker. P2RY14 may be related to LUAD immune invasion and have an essential role in inhibiting tumor cell immune escape within the LUAD microenvironment.
| S-EPMC8902120 | biostudies-literature
Project description:BackgroundBreast cancer (BC), a common malignant tumor originating from the terminal ductal lobular unit of the breast, poses a substantial health risk to women. Previous studies have associated cytochrome b561 (CYB561) with a poor prognosis in BC; however, its underlying mechanism of this association remains unclear.MethodsWe investigated the expression of CYB561 mRNA in BC using databases such as The Cancer Genome Atlas, Gene Expression Omnibus, Tumor-Normal-Metastatic plot, and Kaplan-Meier plotter databases. The prognostic value of CYB561 protein in BC was assessed in relation to its expression levels in tumor tissue samples from 158 patients with BC. The effect of CYB561 on BC progression was confirmed using in vivo and in vitro experiments. The biological functions and related signaling pathways of CYB561 in BC were explored using gene microarray, Innovative Pathway, Gene Ontology enrichment, and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. The correlation between CYB561 and the BC tumor immune microenvironment was evaluated using the CIBERSORT algorithm and single-cell analysis and further validated through immunohistochemistry of serial sections.ResultsOur study demonstrated that upregulation of CYB561 expression predicted poor prognosis in patients with BC and that CYB561 knockdown inhibited the proliferation, migration, and invasive ability of BC cells in vitro. CYB561 knockdown inhibited BC tumor formation in vivo.CYB561 was observed to modulate downstream tropomyosin 1 expression. Furthermore, CYB561 expression was associated with macrophage M2 polarization in the BC immune microenvironment.ConclusionsElevated CYB561 expression suggests a poor prognosis for patients with BC and is associated with macrophage M2 polarization in the BC microenvironment. Therefore, CYB561 could potentially serve as a therapeutic target for BC treatment.
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Project description:Ubiquitin-specific peptidase 10 (USP10) can sustain cellular functions and regulate cellular processes. It plays an essential role in cancer inhibition or facilitation by reversing ubiquitin-proteasome degradation. Studies have identified USP10 to be involved in tumor progression in various cancers. However, the pan-cancer expression pattern of USP10, its prognostic value, and the association between tumor immune cell infiltration and USP10 expression remain to be discussed and thus comprised the aims of the present study. Based on clinical samples and bioinformatic analyses, high USP10 expression was observed in most cancer tissues except for ovarian cancer. High USP10 expression correlated with pathological stage and node metastasis and predicted poor patient prognosis. In addition, further analyses at the TIMER and GEPIA databases showed that USP10 is involved in the infiltration of multiple immune cells and regulated the infiltration levels of specific immune cell subpopulations, particularly in pancreatic adenocarcinoma (PAAD) and liver hepatocellular carcinoma (LIHC). Importantly, USP10 might influence survival by modulating immune infiltration in patients with PAAD and LIHC. These results identified USP10 as a potential biomarker for pan-cancer prognosis, and in certain cancers, USP10 could identify clinical prognosis linked to tumor immune infiltration.
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Project description:Liver cancer is the fourth leading cause of cancer-related mortality worldwide and hepatocellular carcinoma (HCC) is the most common primary liver cancer. In the present study, it was demonstrated that translocated promoter region (TPR) was upregulated in tumor tissues and associated with prognosis and immune infiltration in HCC. The clinical outcome of patients with HCC with aberrant expression of TPR was examined using multiple databases, including Gene Expression Omnibus, The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression, Kaplan-Meier (KM) Plotter and Xiantao tool. The clinicopathologic characteristics of patients from TCGA database that were associated with overall survival were assessed using Cox regression and KM analysis. The potential hallmarks associated with TPR expression were further predicted by Metascape and Gene Set Enrichment Analysis, and the relationship between TPR and immune infiltration was explored using the Tumor-Immune System Interactions Database and the Tumor Immune Estimation Resource. The results demonstrated that TPR expression was higher in HCC and its overexpression was associated with a worse prognosis, alongside a correlation with several clinical features. Furthermore, cell differentiation, a prospective new hallmark of cancer, was differentially enriched in the high TPR expression phenotype pathway. Moreover, TPR may also modulate the tumor immune microenvironment as it was significantly associated with immunoregulators and chemokines, as well as different tumor infiltration immune cells. According to the in vitro experiments, TPR silencing inhibited the phosphorylation of AKT and the proliferation of HCC cells. In summary, TPR may be a new marker and target for HCC therapy.
| S-EPMC10895467 | biostudies-literature
Project description:Glioblastoma is highly enriched with macrophages, and osteopontin (OPN) expression levels correlate with glioma grade and the degree of macrophage infiltration; thus, we studied whether OPN plays a crucial role in immune modulation. Quantitative PCR, immunoblotting, and ELISA were used to determine OPN expression. Knockdown of OPN was achieved using complementary siRNA, shRNA, and CRISPR/Cas9 techniques, followed by a series of in vitro functional migration and immunological assays. OPN gene-deficient mice were used to examine the roles of non-tumor-derived OPN on survival of mice harboring intracranial gliomas. Patients with mesenchymal glioblastoma multiforme (GBM) show high OPN expression, a negative survival prognosticator. OPN is a potent chemokine for macrophages, and its blockade significantly impaired the ability of glioma cells to recruit macrophages. Integrin ?v?5 (ITG?v?5) is highly expressed on glioblastoma-infiltrating macrophages and constitutes a major OPN receptor. OPN maintains the M2 macrophage gene signature and phenotype. Both tumor-derived and host-derived OPN were critical for glioma development. OPN deficiency in either innate immune or glioma cells resulted in a marked reduction in M2 macrophages and elevated T cell effector activity infiltrating the glioma. Furthermore, OPN deficiency in the glioma cells sensitized them to direct CD8+ T cell cytotoxicity. Systemic administration in mice of 4-1BB-OPN bispecific aptamers was efficacious, increasing median survival time by 68% (P < 0.05). OPN is thus an important chemokine for recruiting macrophages to glioblastoma, mediates crosstalk between tumor cells and the innate immune system, and has the potential to be exploited as a therapeutic target.
| S-EPMC6307970 | biostudies-literature
Project description:In this study, we investigated whether proteins that are involved in cytokinesis are potential targets for therapy of lung cancer. We find that the microtubule-associated protein PRC1 (protein required for cytokinesis 1), which plays a key role in organizing anti-parallel microtubule in the central spindle in cytokinesis, is overexpressed in lung cancer cell lines compared to normal cells. Increased expression of PRC1 is correlated with a poor prognosis of human lung adenocarcinoma patients. Lentiviral delivered, inducible RNAi of PRC1 demonstrated that proliferation of lung cancer cell lines strongly depends on PRC1. Significantly, we also show that PRC1 is required for tumorigenesis in vivo using a mouse model for non-small cell lung cancer driven by oncogenic K-RAS and loss of p53. When PRC1 is depleted by in vivo RNA interference, lung tumor formation is significantly reduced. Although PRC1 has been suggested to regulate Wnt/ß-catenin signaling in cancer cells, we find no evidence for a role of PRC1 in this pathway in lung cancer. Instead, we show that the depletion of PRC1 results in a strong increase in bi- and multinuclear cells due to defects in cytokinesis. This ultimately leads to apoptosis and senescence. Together these data establish PRC1 as a potential target for therapy of lung cancer.
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Project description:Targeted therapeutics, such as those abrogating hypoxia inducible factor (HIF)/vascular endothelial growth factor signaling, are initially effective against kidney cancer (or renal cell carcinoma, RCC); however, drug resistance frequently occurs via subsequent activation of alternative pathways. Through genome-scale integrated analysis of the HIF-? network, we identified the major protein kinase C substrate MARCKS (myristoylated alanine-rich C kinase substrate) as a potential target molecule for kidney cancer. In a screen of nephrectomy samples from 56 patients with RCC, we found that MARCKS expression and its phosphorylation are increased and positively correlate with tumor grade. Genetic and pharmacologic suppression of MARCKS in high-grade RCC cell lines in vitro led to a decrease in cell proliferation and migration. We further demonstrated that higher MARCKS expression promotes growth and angiogenesis in vivo in an RCC xenograft tumor. MARCKS acted upstream of the AKT/mTOR pathway, activating HIF-target genes, notably vascular endothelial growth factor-A. Following knockdown of MARCKS in RCC cells, the IC50 of the multikinase inhibitor regorafenib was reduced. Surprisingly, attenuation of MARCKS using the MPS (MARCKS phosphorylation site domain) peptide synergistically interacted with regorafenib treatment and decreased survival of kidney cancer cells through inactivation of AKT and mTOR. Our data suggest a major contribution of MARCKS to kidney cancer growth and provide an alternative therapeutic strategy of improving the efficacy of multikinase inhibitors.
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Project description:Lung cancer remains one of the leading causes of cancer-related deaths worldwide with a 5-year survival rate of less than 20%. One approach to improving survival is the identification of biomarkers to detect early stage disease. In this study, we investigated the potential of the stem cell and progenitor cell marker, Musashi1 (Msi1), as a diagnostic marker and potential therapeutic target for lung cancer. Functional studies in A549 bronchioalveolar carcinoma and NCI-H520 squamous cell carcinoma cells revealed that Msi1 was enriched in spheroid cultures of tumor cells and in the CD133+ cell population. Downregulation of Msi1 by lentivirus-mediated expression of an Msi1 shRNA reduced spheroid colony proliferation. Growth inhibition was associated with reduced nuclear localization of ?-catenin and inhibition of the processing of intracellular Notch. In primary lung cancer, Msi1 protein expression was elevated in 86% of 202 tissue microarray specimens, and Msi1 mRNA was increased in 80% of 118 bronchoscopic biopsies, including metastatic disease, but was rarely detected in adjacent normal lung tissue and in non-malignant diseased tissue. Msi1 was expressed in a diffuse pattern in most tumor subtypes, except in squamous cell carcinomas, where it appeared in a focal pattern in 50% of specimens. Thus, Msi1 is a sensitive and specific diagnostic marker for all lung cancer subtypes.
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Project description:The underlying role of pyroptosis in breast cancer (BC) remains unknown. Herein, we investigated the correlations of 33 pyroptosis-related genes (PRGs) with immune checkpoints and immune cell infiltrations in BC patients based on The Cancer Genome Atlas cohort (n = 996) and Gene Expression Omnibus cohort (n = 3,262). Enrichment analysis revealed that these PRGs mainly functioned in pyroptosis, inflammasomes and regulation of autophagy pathway. Four prognostic independent PRGs (CASP9, TIRAP, GSDMC and IL18) were identified. Then, cluster 1/2 was recognized using consensus clustering for these four PRGs. Patients from cluster 1 had a favourable prognosis and diverse immune cell infiltrations. A nomogram was developed based on age, TNM stage, tumour subtype and pyroptosis score. Patients with the high-risk group exhibited worse 5-year OS, and the result was consistent in the external cohort. Additionally, high-risk group patients were associated with downregulated immune checkpoint expression. Further analysis suggested that the high-risk group patients were associated with a higher IC50 of paclitaxel, doxorubicin, cisplatin, methotrexate and vinorelbine. In summarizing, the pyroptosis score-based nomogram might serve as an independent prognostic predictor and could guide medication for chemotherapy. Additionally, it may bring novel insight into the regulation of tumour immune microenvironment in BC and help to achieve precision immunotherapy.
| S-EPMC8995442 | biostudies-literature
Project description:Approaches to vaccine-based immunotherapy of human cancer may ultimately require targets that are both tumour-specific and immunogenic. In order to generate specific antitumour immune responses to lung cancer, we have sought lung cancer-specific proteins that can be targeted for adjuvant vaccine therapy. By using a combination of cDNA subtraction and microarray analysis, we previously reported the identification of an RNA-binding protein within the KOC family, L523S, to be overexpressed in squamous cell cancers of the lung. We show here that L523S exhibits significant potential for vaccine immunotherapy of lung cancer. As an oncofetal protein, L523S is normally expressed in early embryonic tissues, yet it is re-expressed in a high percentage of nonsmall cell lung carcinoma. The specificity of L523S expression in lung cancer was demonstrated by both mRNA and protein measurements using real-time PCR, Western blot, and immunohistochemistry analyses. Furthermore, we show that immunological tolerance of L523S is naturally broken in lung cancer patients, as evidenced by detectable antibody responses to recombinant L523S protein in eight of 17 lung pleural effusions from lung cancer patients. Collectively, our studies suggest that L523S may be an important marker of malignant progression in human lung cancer, and further suggest that treatment approaches based on L523S as an immunogenic target are worthy of pursuit.
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