ADAMTS12 acts as a tumor microenvironment related cancer promoter in gastric cancer.
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ABSTRACT:
SUBMITTER: Hou Y
PROVIDER: S-EPMC8154915 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectivesThe present study aimed to develop a gene signature based on the ESTIMATE algorithm in hepatocellular carcinoma (HCC) and explore possible cancer promoters.MethodsThe ESTIMATE and CIBERSORT algorithms were applied to calculate the immune/stromal scores and the proportion of tumor-infiltrating immune cells (TICs) in a cohort of HCC patients. The differentially expressed genes (DEGs) were screened by Cox proportional hazards regression analysis and protein-protein interaction (PPI) network construction. Cyclin B1 (CCNB1) function was verified using experiments.ResultsThe stromal and immune scores were associated with clinicopathological factors and recurrence-free survival (RFS) in HCC patients. In total, 546 DEGs were up-regulated in low score groups, 127 of which were associated with RFS. CCNB1 was regarded as the most predictive factor closely related to prognosis of HCC and could be a cancer promoter. Gene Set Enrichment Analysis (GSEA) and CIBERSORT analyses indicated that CCNB1 levels influenced HCC tumor microenvironment (TME) immune activity.ConclusionsThe ESTIMATE signature can be used as a prognosis tool in HCC. CCNB1 is a tumor promoter and contributes to TME status conversion.
| S-EPMC8168034 | biostudies-literature
Project description:Background:ADAMTS12, a member of the ADAMTS family, is reported to be associated with the clinic outcome of colorectal cancer (CRC) patients. However, the functions and precise mechanism in CRC progression have yet to be fully understood. Methods:By analyzing The Cancer Genome Atlas (TCGA) database, we examined the mRNA level of ADAMTS12 and assessed the prognostic value of ADAMTS12 in CRC patients using a tissue microarray containing 41 CRC patient samples. Cell Counting Kit-8 (CCK-8), colony formation, and transwell assays were used to quantify the impact of ADAMTS12 on cell proliferation and migration in ADAMTS12-overexpressing and ADAMTS12-deficient cell lines. The signaling pathways that ADAMTS12 mediated were identified by dual-luciferase reporter assays, and confirmed by western blotting and quantitative teal-time polymerase chain reaction (qRT-PCR). Results:The ADAMTS12 mRNA level was upregulated in CRC tissues, and CRC patients with a high level of ADAMTS12 showed worse prognosis when compared with the patients with a low level of ADAMTS12. In vitro functional assays demonstrated that overexpression of ADAMTS12 significantly boosted cell proliferation and migration while ADAMTS12 deficiency remarkably impaired both tumor cell behaviors. Mechanical studies further verified that ADAMTS12 overexpression enhanced the transcriptional activity of ?-catenin in the Wnt/?-catenin signaling pathway. In the ADAMTS12-deficient context, the downstream gene expression of myc and cyclin D1 was significantly reduced compared with that in wild-type cancer cells. Conclusions:ADAMTS12 fulfills the tumor-promotor role by activating Wnt/?-catenin signaling pathway in colon cells and may represent a new option in CRC target treatment.
| S-EPMC7186627 | biostudies-literature
Project description:Background: Ferroptosis is a form of regulated cell death that occurs as a consequence of lethal lipid peroxidation. A wealth of studies has demonstrated that ferroptosis profoundly modulated numerous biological behaviors of tumor. However, its natural functions in gastric cancer (GC) remain to be explored. Methods: Firstly, a total of over 1,000 GC patients from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database were included in our study. Secondly, 32 ferroptosis-related genes were extracted from the ferrDb website. Then, unsupervised clustering was performed to classify patients into three distinct ferroptosis-related clusters. Subsequently, we systematically and comprehensively explored the biological characteristics of each cluster. Finally, we constructed a scoring system, named ferroptosis score, to quantify each cluster and also investigated the predictive therapeutic value of the ferroptosis score for chemotherapy and immunotherapy. Results: Based on the expressions of 32 ferroptosis-related genes, three distinct ferroptosis-related subtypes with various biological characteristics were determined. Integrated analysis showed that cluster 1 is a microsatellite instability (MSI)-like subtype, cluster 2 is an epithelial-mesenchymal transition (EMT)-like subtype, while cluster 3 tends to be a metabolic-like subtype. Prognostic analysis revealed that patients in cluster 2 had a worse overall survival and relapse-free survival. The distribution of the ferroptosis score was significantly different in clusters and gene clusters. The ferroptosis score could predict the biological characteristics of each cluster, the stromal activity, and progression of tumor. The low ferroptosis score group was characterized by the activation of antigen processing and presentation, DNA damage repair pathways, and metabolic pathways, while the high ferroptosis score group was characterized by stromal activation. In response to anticancer drugs, the ferroptosis score was highly negatively associated with drugs targeting MAPK signaling and PI3K/mTOR signaling, while it was positively correlated with drugs targeting the cell cycle, mitosis, and metabolism. Finally, we also proved that the ferroptosis score could serve as a reliable biomarker to predict response to immunotherapy. Conclusion: This work revealed that tumor cells and their surrounding microenvironment could be shaped by varying the activation degrees of ferroptosis. Establishing ferroptosis-related subtypes would guide in predicting the biological features of individual tumors and selecting appropriate treatment protocols for patients.
| S-EPMC8517126 | biostudies-literature
Project description:Immunotherapy is remarkably affected by the immune environment of the principal tumor. Nonetheless, the immune environment's clinical relevance in stage IV gastric cancer (GC) is largely unknown. The gene expression profiles of 403 stage IV GC patients in the three cohorts: GEO (Gene Expression Omnibus, GSE84437 (n=292) and GSE62254 (n=77), and TCGA (The Cancer Genome Atlas, n=34) were used in the present study. Using four publicly available stage IV GC expression datasets, 29 immune signatures were expression profiled, and on this basis, we classified stage IV GC. The classification was conducted using the hierarchical clustering method. Three stage IV GC subtypes L, M, and H were identified representing low, medium, and high immunity, respectively. Immune correlation analysis of these three types revealed that Immune H exhibited a better prognostic outcome as well as a higher immune score compared with other subtypes. There was a noticeable difference in the three subgroups of HLA genes. Further, on comparing with other subtypes, CD86, CD80, CD274, CTLA4, PDCD1, and PDCD1LG2 had higher expression in the Immunity H subtype. In stage IV GC, potentially positive associations between immune and pathway activities were displayed, due to the enrichment of pathways including TNF signaling, Th-17 cell differentiation, and JAK-STAT signaling pathways in Immunity H vs Immunity L subtypes. External cohorts from TCGA cohort ratified these results. The identification of stage IV GC subtypes has potential clinical implications in stage IV GC treatment.
| S-EPMC7796192 | biostudies-literature
Project description:BackgroundGastric cancer (GC) is an important disease and the fifth most common malignancy worldwide. Autophagy is an important process for the turnover of intracellular substances. Autophagy-related genes (ARGs) are crucial in cancer. Accumulating evidence indicates the clinicopathological significance of the tumor microenvironment (TME) in predicting prognosis and treatment efficacy.MethodsClinical and gene expression data of GC were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. A total of 22 genes with differences in expression and prognosis were screened from 232 ARGs. Three autophagy patterns were identified using an unsupervised clustering algorithm and scored using principal component analysis to predict the value of autophagy in the prognosis of GC patients. Finally, the relationship between autophagy and ferroptosis was validated in gastric cancer cells.ResultsThe expression of ARGs showed obvious heterogeneity in GC patients. Three autophagy patterns were identified and used to predict the overall survival of GC patients. These three patterns were well-matched with the immunophenotype. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analyses showed that the biological functions of the three autophagy patterns were different. A scoring system was then set up to quantify the autophagy model and further evaluate the response of the patients to the immunotherapy. Patients with high autophagy scores had a more severe tumor mutation burden and better prognosis. High autophagy scores were accompanied by high microsatellite instability. Patients with high autophagy scores had significantly higher PD-L1 expression and increased survival. The experimental results confirmed that the expression of ferroptosis genes was positively correlated with the expression of autophagy genes in different autophagy clusters, and inhibition of autophagy dramatically reversed the decrease in ferroptotic cell death and lipid accumulation.ConclusionsAutophagy patterns are involved in TME diversity and complexity. Autophagy score can be used as an independent prognostic biomarker in GC patients and to predict the effect of immunotherapy and ferroptosis-based therapy. This might benefit individualized treatment for GC.
| S-EPMC9424910 | biostudies-literature
Project description:BackgroundN6-methyladenosine (m6A) modification and long non-coding RNAs (lncRNAs) play pivotal roles in gastric cancer (GC) progression. The emergence of immunotherapy in GC has created a paradigm shift in the approaches of treatment, whereas there is significant heterogeneity with regard to degree of treatment responses, which results from the variability of tumor immune microenvironment (TIME). How the interplay between m6A and lncRNAs enrolling in the shaping of TIME remains unclear.MethodsThe RNA sequencing and clinical data of GC patients were collected from TCGA database. Pearson correlation test and univariate Cox analysis were used to screen out m6A-related lncRNAs. Consensus clustering method was implemented to classify GC patients into two clusters. Survival analysis, the infiltration level of immune cells, Gene set enrichment analysis (GSEA) and the mutation profiles were analyzed and compared between two clusters. A competing endogenous RNA (ceRNA) network and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied for the identification of pathways in which m6A-related lncRNAs enriched. Then least absolute shrinkage and selection operator (LASSO) COX regression was implemented to select pivotal lncRNAs, and risk model was constructed accordingly. The prognosis value of the risk model was explored. In addition, the response to immune checkpoint inhibitors (ICIs) therapy were compared between different risk groups. Finally, we performed qRT-PCR to detect expression patterns of the selected lncRNAs in the 35 tumor tissues and their paired adjacent normal tissues, and validated the prognostic value of risk model in our cohort (N = 35).ResultsThe expression profiles of 15 lncRNAs were included to cluster patients into 2 subtypes. Cluster1 with worse prognosis harbored higher immune score, stromal score, ESTIMATE score and lower mutation rates of the genes. Different immune cell infiltration patterns were also displayed between the two clusters. GSEA showed that cluster1 preferentially enriched in tumor hallmarks and tumor-related biological pathways. KEGG pathway analysis found that the target mRNAs which m6A-related lncRNAs regulated by sponging miRNAs mainly enriched in vascular smooth muscle contraction, cAMP signaling pathway and cGMP-PKG signaling pathway. Next, eight lncRNAs were selected by LASSO regression algorithm to construct risk model. Patients in the high-risk group had poor prognoses, which were consistent in our cohort. As for predicting responses to ICIs therapy, patients from high-risk group were found to have lower tumor mutation burden (TMB) scores and account for large proportion in the Microsatellite Instability-Low (MSI-L) subtype. Moreover, patients had distinct immunophenoscores in different risk groups.ConclusionOur study revealed that the interplay between m6A modification and lncRNAs might have critical role in predicting GC prognosis, sculpting TIME landscape and predicting the responses to ICIs therapy.
| S-EPMC8943990 | biostudies-literature
Project description:The tumor microenvironment is closely related to the progression and immune escape of tumor cells. Tumor-infiltrating immune cells (TIICs) and immune-related genes (IRGs) are indispensable components of the tumor microenvironment and have been demonstrated to be highly valuable in determining the prognosis of multiple cancers. To elucidate the prognostic value of TIICs and IRGs in gastric cancer, we conducted a comprehensive analysis focusing on the abundances of 22 types of TIICs and differentially expressed IRGs based on a dataset from The Cancer Genome Atlas (TCGA). The results showed that great composition differences in TIICs and immune cell subfractions were associated with survival outcomes in different stages. Additionally, 29 hub genes were characterized from 345 differentially expressed IRGs and found to be significantly associated with survival outcomes. Then, an independent prognostic indicator based on ten IRGs was successfully constructed after multivariate adjustment for some clinical parameters. Further validation revealed that these hub IRGs could reflect the infiltration levels of immune cells. Thus, our results confirmed the clinical significance of TIICs and IRGs in gastric cancer and may establish a foundation for further exploring immune cell and gene targets for personalized treatment.
| S-EPMC7585095 | biostudies-literature
Project description:Gastric cancer is one of the major causes of cancer mortality. Several microRNAs play a role in the tumor growth and invasion. However, the underlying molecular mechanism remains poorly understood. We detected the miR-638 expression levels in tumor samples and adjacent noncancerous tissues from 68 patients with gastric cancer as well as in the gastric cancer cell line SGC-7901 and SC-M1. The cell cycle was analyzed by flow cytometry, cell proliferation was observed by CCK-8 assay and cell invasion was detected using Transwell assay. MiR-638 was down-regulated in human GC tissues and its expression level was negatively correlated to TNM stage and lymph metastasis. In the cell lines, aberrant expression of miR-638 was related to the cell proliferation, cell cycle and invasion. We also found that SOX2 had a negative correlation with miR-638 in GC tissues, and miR-638 overexpression could decrease SOX2 expression level by directly binding the 3'-UTR of SOX2. in vitro, down-regulating SOX2 by siRNA could counteract the effect of miR-638 inhibitor on GC cells proliferation and invasion. Our results demonstrate that miR-638 may play a pivotal role in the growth and invasion of GC.
| S-EPMC5746134 | biostudies-literature
Project description:BackgroundWe recently reported that miR-1 was one of the most significantly downregulated microRNAs in gastric cancer (GC) patients from The Cancer Genome Atlas microRNA sequencing data. Here we aim to elucidate the role of miR-1 in gastric carcinogenesis.MethodsWe measured miR-1 expression in human GC cell lines and 90 paired primary GC samples, and analyzed the association of its status with clinicopathological features. The effect of miR-1 on GC cells was evaluated by proliferation and migration assay. To identify the target genes of miR-1, bioinformatic analysis and protein array analysis were performed. Moreover, the regulation mechanism of miR-1 with regard to these predicted targets was investigated by quantitative PCR (qPCR), Western blot, ELISA, and endothelial cell tube formation. The putative binding site of miR-1 on target genes was assessed by a reporter assay.ResultsExpression of miR-1 was obviously decreased in GC cell lines and primary tissues. Patients with low miR-1 expression had significantly shorter overall survival compared with those with high miR-1 expression (P = 0.0027). Overexpression of miR-1 in GC cells inhibited proliferation, migration, and tube formation of endothelial cells by suppressing expression of vascular endothelial growth factor A (VEGF-A) and endothelin 1 (EDN1). Conversely, inhibition of miR-1 with use of antago-miR-1 caused an increase in expression of VEGF-A and EDN1 in nonmalignant GC cells or low-malignancy GC cells.ConclusionsMiR-1 acts as a tumor suppressor by inhibiting angiogenesis-related growth factors in human gastric cancer. Downregulated miR-1 not only promotes cellular proliferation and migration of GC cells, but may activates proangiogenesis signaling and stimulates the proliferation and migration of endothelial cells, indicating the possibility of new strategies for GC therapy.
| S-EPMC5741792 | biostudies-literature
Project description:The tumor microenvironment (TME) plays an important role in the pathogenesis of many cancers. We aimed to screen the TME-related hub genes of colorectal adenoma (CRAD) and identify possible prognostic biomarkers. The gene expression profiles and clinical data of 464 CRAD patients in The Cancer Genome Atlas (TCGA) database were downloaded. The Estimation of STromal and Immune cells in MAlignant Tumours using Expression data (ESTIMATE) algorithm was performed to calculate the ImmuneScore, StromalScore, and EstimateScore. Thereafter, differentially expressed genes (DEGs) were screened. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) analysis were performed to explore the roles of DEGs. Furthermore, univariate and multivariate Cox analyses were accomplished to identify independent prognostic factors of CRAD. CX3CR1 was selected as a hub gene, and the expression was confirmed in colorectal cancer (CRC) patients and cell lines. The correlations between CX3CR1 and tumor-infiltrating immune cells were estimated by Tumor IMmune Estimation Resource database (TIMER) and CIBERSORT analysis. Besides, we investigated the effects of coculture with THP-1-derived macrophages with HCT8 cells with low CX3CR1 expression on immune marker expression, cell viability, and migration. There were significant differences in the ImmuneScore and EstimateScore among different stages. Patients with low scores presented significantly lower lifetimes than those in the high-score group. Moreover, we recognized 1,578 intersection genes in ImmuneScore and StromalScore, and these genes were mainly enriched in numerous immune-related biological processes. CX3CR1 was found to be associated with immune cell infiltration levels, immune marker expression, and macrophage polarization. Simultaneous silencing of CX3CR1 and coculture with THP-1 cells further regulated macrophage polarization and promoted the cell proliferation and migration of CRC cells. CX3CR1 was decreased in CRAD tissues and cell lines and was related to T and N stages, tumor differentiation, and prognosis. Our results suggest that CX3CR1 contributes to the recruitment and regulation of immune-infiltrating cells and macrophage polarization in CRC and TAM-induced CRC progression. CX3CR1 may act as a prognostic biomarker in CRC.
| S-EPMC8818863 | biostudies-literature