Cathepsin V is correlated with the prognosis and tumor microenvironment in liver cancer
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PROVIDER: PRJNA978045 | ENA |
REPOSITORIES: ENA
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Project description:Recent studies have shown that high cell cycle activity negatively correlates with antitumor immunity in certain cancer types. However, a similar correlation has not been proven in liver cancer.We downloaded transcriptomic profiles of TCGA-LIHC (the cancer genome atlas-liver hepatocellular carcinoma) and assessed the cell cycle distribution of samples using single sample gene set enrichment analysis (ssGSEA), termed the cell cycle score (CCS). We obtained cell cycle-related differentially expressed prognostic genes and identified CENPA, CDC20 and CTSV using LASSO regression. We studied the effect of CTSV on clinical features and immune alterations in liver cancer based on TCGA-LIHC data. In vitro and in vivo experiments were performed to validate the role of CTSV in liver cancer using liver cancer cell lines and tissues.We found that the CCS closely correlated with the clinical features and prognosis of patients in TCGA-LIHC. Analysis of differentially expressed genes (DEGs), univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression identified cathepsin V (CTSV) with prognostic significance in LIHC. Importantly, single-gene survival analysis of CTSV using microarray and sequencing data indicated that high levels of CTSV expression correlated with an unfavorable prognosis in various cancers. Gene set enrichment analysis (GSEA) revealed that high CTSV expression closely correlated with decreased expression of metabolic genes and increased expression of cell cycle genes. Furthermore, difference and correlation analyses of the relationship between CTSV expression and immune infiltrates, determined using CIBERSORT and TIMER algorithms, revealed that CTSV expression correlated with macrophages and CD4+ T cells. In vitro and in vivo experiments revealed that knockdown of CTSV inhibited liver cancer cells proliferation. Immunohistochemical staining showed that high CTSV expression correlated with macrophage infiltration in liver cancer tissues, predicted a poor prognosis, and may serve as a biomarker for HCC therapy.In conclusion, CTSV is a novel cell cycle prognostic gene that can affect HCC cells proliferation, and a potential biomarker for HCC therapy.
2023-07-18 | GSE233817 | GEO
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Project description:Tumor-associated macrophages (TAMs) have emerged as prominent cells within the tumor microenvironment playing critical roles in extracellular matrix remodeling, tumor cell proliferation and invasion, angiogenesis, and metastasis. Cathepsin proteases, produced by tumor cells and TAMs, have been demonstrated to mediate these processes, but it still remains unclear how these typically lysosomal enzymes are capable of executing their functions in the extracellular space. Here we identify a novel interaction between STAT6 and STAT3 that potently upregulates cathepsin secretion in macrophages in response to TH2 cytokine stimulation. Systematic gene expression analyses reveal that the TH2 cytokine IL-4 synergizes with IL-6 or IL-10 to activate the IRE1α/ XBP1 axis of the unfolded protein response. Pharmacological inhibition of the IRE1α axis blunts cathepsin secretion in macrophages and blocks macrophage-mediated tumor cell invasion. Finally, we show that genetic ablation of either STAT6 or STAT3 signaling impairs tumor development and invasion. Thus, these findings demonstrate that TH2 cytokine-mediated STAT6 and STAT3 activation in macrophages promotes a professional secretory phenotype capable of enhancing tumor cell invasion in a cathepsin-dependent manner.
2016-08-17 | GSE70626 | GEO
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Project description:Tumor-associated macrophages (TAMs) are known to be involved in progression, angiogenesis and motility of various cancers. We have previously reported the association between increased number of infiltrating TAMs with tumor progression and poor prognosis in esophageal squamous cell carcinomas (ESCCs). To study roles of TAMs in ESCC, we first exposed peripheral blood monocytes (PBMo) derived macrophages from healthy volunteers to conditioned media of TE series human ESCC cell line (TECM) and confirmed the induction of expression of M2 macrophage marker, CD204, and protumorigenic factors, interleukin (IL)-10, VEGFA and MMPs. Next, we compared gene expression profile between PBMo-derived macrophages and PBMo-derived macrophages stimulated with TECM by cDNA microarray. Based on the result, we focused on growth differentiation factor 15 (GDF15) among highly expressed genes including IL-6, IL-8 and CXCL1. Immunohistochemical study on 70 cases of surgically resected ESCCs revealed that GDF15 was detected not only in macrophages but also in cancer cells. High expression of GDF15 in ESCCs was significantly correlated with more malignant phenotypes including lymph and blood vessel invasion, lymph node metastasis as well as clinical stages. Patients with high expression of GDF15 showed poor disease-free survival (p = 0.011) and overall survival (p = 0.041). Furthermore, we found that recombinant human GDF15 promote cell proliferation and phosphorylation of both Akt and Erk1/2 in ESCC cell lines in vitro. These results indicate that GDF15 is secreted by both TAMs and cancer cells in tumor microenvironment and is associated with aberrant growth and poor prognosis of human ESCC. We exposed PBMo-derived macrophages from healthy volunteers to TECM and observed their acquisition of TAM-like characters in this study. We further investigated specific cancer-associated gene expression profile in TECM induced TAM-like macrophages by cDNA microarray analysis.
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2021-09-08 | PXD015209 | Pride
Project description:Tumor cells can induce their own advantageous microenvironment. Here, we describe aberrant cathepsin S (CTSS) activity to modulate T-cell activation in follicular lymphoma (FL). In donor-derived FLs following bone marrow transplantation, we identified independent acquisition of CTSS mutations at Y132 in the donor´s and recipient's tumors. In a larger cohort, 6% of FL (20/312) harbored CTSS mutations, mostly Y132D, another 14% had CTSS amplification (40/280). Y132D leads to accelerated conversion from pro-CTSS to active CTSS and increased substrate cleavage, including CD74, which regulates MHC-II restricted antigen-presentation. In co-culture experiments, CTSS mutant lymphoma cells induced increased antigen-specific CD4+ T-cell activation. Moreover, antigen-processing was the top upregulated pathway in CTSS mutant primary FL biopsies. Thus, aberrant CTSS activity is a promising target in lymphoma.
2021-01-07 | PXD014612 | Pride
Project description:Background: The tumor suppressor gene TP53 is frequently mutated or inactivated in bladder cancer (BLCA), which is implicated in the pathogenesis of tumor. However, the cellular mechanisms of TP53 mutations are complicated, yet well-defined, but their clinical prognostic value in the management of BLCA remains controversial. This study aimed to explore the role of TP53 mutation in regulating the tumor microenvironment (TME), elucidate the effects of TP53 activity on BLCA prognosis and immunotherapy response. Methods: A TP53-related signature based on TP53-induced and TP53-repressed genes was used to construct a TP53 activity-related score and classifier. The abundance of different immune cell types was determined using CIBERSORT to estimate immune cell infiltration. Moreover, the heterogeneity of the tumor immune microenvironment between the high and low TP53 score groups was further evaluated using single-cell mass cytometry (CyTOF) and imaging mass cytometry (IMC). Moreover, pathway enrichment analysis was performed to explore the differential biological functions between tumor epithelial cells with high and low TP53 activity scores. Finally, the receptor–ligand interactions between immune cells and tumor epithelial cells harboring distinct TP53 activity were analyzed by single-cell RNA-sequencing. Results: The TP53 activity-related gene signature differentiated well between TP53 functional retention and inactivation in BLCA. BLCA patients with low TP53 scores had worse survival prognosis, more TP53 mutations, higher grade, and stronger lymph node metastasis than those with high TP53 scores. Additionally, CyTOF and IMC analyses revealed that BLCA patients with low TP53 scores exhibited a potent immunosuppressive TME. Consistently, single-cell sequencing results showed that tumor epithelial cells with low TP53 scores were significantly associated with high cell proliferation and stemness abilities and strongly interacted with immunosuppressive receptor–ligand pairs. Conclusions: Patients with BLCA with low TP53 scores have a worse prognosis and a more immunosuppressive TME. This TP53 activity-related signature can serve as a potential prognostic signature for predicting the immune response, which may facilitate the development of new strategies for immunotherapy in BLCA. Keywords: bladder cancer, TP53, immunosuppression, tumor microenvironment
2022-10-24 | GSE216037 | GEO
Project description:TP53-related signature for predicting prognosis and tumor microenvironment characteristics in bladder cancer: a multi-omics study 1 microenvironment characteristic
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Project description:Cathepsin L is a lysosomal protease that is secreted by several cancer cells. Cathepsin L upregulation has been widely associated with poor clinical outcome and increased metastatic incidence. However, whether Cathepsin L participates in tumor angiogenesis remains less studied. Our study showed a significant activation of angiogenic capacity of endothelial cells in presence of purified or tumor derived Cathepsin L. In addition, Cathepsin L exposure led to a significant increase in the proliferative capacity of endothelial cells. While the ability of Cathepsin L to promote endothelial cell sprouting, migration, invasion and tube formation can be attributed to its proteolytic effects on extracellular matrix, how it promotes endothelial cell proliferation remains obscure. The objective of this study was to test if Cathepsin L exposure can activate signaling cascades and gene expression leading to proliferation of endothelial cells.
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