Integrated analysis identifies TfR1 as a prognostic biomarker which correlates with immune infiltration in breast cancer.
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ABSTRACT:
SUBMITTER: Chen F
PROVIDER: S-EPMC8457555 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Breast-invasive carcinoma (BRCA) is the most frequent and malignant tumor in females. Ceruloplasmin (CP) is a multifunctional molecule involved in iron metabolism, but its expression profile, prognostic potential and relationship with immune cell infiltration in BRCA are unknown. Ceruloplasmin mRNA and protein expression was significantly decreased in BRCA patients according to the Oncomine, UALCAN, GEPIA and TCGA databases. Ceruloplasmin expression was strongly correlated with various clinicopathological features of BRCA patients. BRCA patients with high ceruloplasmin expression exhibited shorter survival times than those with low ceruloplasmin expression based on the Kaplan-Meier plotter and PrognoScan databases. GO and KEGG analyses and GSEA revealed a strong correlation between ceruloplasmin and various immune-related pathways. Ceruloplasmin expression was significantly associated with the infiltration of immune cells into tumor sites by analyzing the TIMER and CIBERSORT. Additionally, ceruloplasmin was positively correlated with immune checkpoints in BRCA. These findings suggest that low ceruloplasmin expression correlates with a favorable prognosis and tumor immune cell infiltration in BRCA patients. Ceruloplasmin may serve as a therapeutic target and predict the efficacy of immunotherapy for BRCA.
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Project description:Several diseases have been linked to the dysfunction of anoctamins. Anoctamins play a wide range of physiological roles, including cell proliferation, migration, epithelial secretion, and calcium-activated chloride channel activity. However, the function of anoctamin 10 (ANO10) in breast cancer is still unclear. ANO10 was highly expressed in bone marrow, blood, skin, adipose tissue, thyroid gland and salivary gland, while ANO10 was expressed at low levels in liver and skeletal muscle. Compared to benign breast lesions, the protein level of ANO10 was lower in malignant breast tumors. However, breast cancer patients with low ANO10 expression have favorable survival outcomes. ANO10 was negatively correlated with the infiltration of memory CD4 T cells, naïve B cells, CD8 T cells, chemokines and chemokine receptors. Furthermore, the ANO10 low expression group was more sensitive to certain chemotherapy drugs, including bleomycin, doxorubicin, gemcitabine, mitomycin and etoposide. Altogether, ANO10 is a potential biomarker that can effectively predict the prognosis of breast cancer. Our findings highlight the promising prognostic value and therapeutic target of ANO10 in breast cancer.
| S-EPMC10244099 | biostudies-literature
Project description:Mesothelin (MSLN) is a glycoprotein with various expression degrees in different tumors including mesothelioma, ovarian cancer, pancreatic cancer, etc. MSLN is considered to play an important role in cell survival, proliferation, and tumor progression. Although the expression of MSLN in tumors makes it a potential therapeutic target, its mechanism of action is still unclear, especially its correlation with immune cells infiltration in the tumor microenvironment has not been investigated. In this study, we detected the overexpression of MSLN in ovarian cancer using database analysis and tissue-array staining. We further evaluated the diagnostic value of MSLN and found it was associated with poor overall survival in ovarian cancer. In addition, the high expression of MSLN was significantly related to the immune-related genes and chemoresistant genes. We confirmed the overexpression of MSLN in the chemoresistant ovarian cancer cell lines. Our research suggests that MSLN participates in a variety of pathways related to the suppression of immune activation and promotion of chemoresistance, leading to a poor prognosis in ovarian cancer.
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Project description:BackgroundCurrent studies on the role of ARHGAP39 mainly focused on its effect on neurodevelopment. However, there are few studies on the comprehensive analysis of ARHGAP39 in breast cancer.MethodsARHGAP39 expression level was analyzed based on the Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression Project (GTEx), and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database and validated by qPCR in various cell lines and tumor tissues. The prognostic value was analyzed using Kaplan-Meier curve analysis. CCK-8 and transwell assays were conducted to identify the biological function of ARHGAP39 in tumorigenesis. Signaling pathways related to ARHGAP39 expression were identified by the GO and KEGG enrichment analysis and gene set enrichment analysis (GSEA). The correlations between ARHGAP39 and cancer immune infiltrates were investigated via TIMER, CIBERSORT, ESTIMATE and tumor-immune system interactions database (TISIDB).ResultsARHGAP39 was overexpressed in breast cancer and associated with poor survival outcomes. In vitro experiments revealed that ARHGAP39 could facilitate the proliferation, migration, and invasion capability of breast cancer cells. GSEA analysis showed that the main enrichment pathways of ARHGAP39 was immunity-related pathways. Considering the immune infiltration level, ARHGAP39 was negatively associated with infiltrating levels of CD8 + T cell and macrophage, and positively associated with CD4 + T cell. Furthermore, ARHGAP39 was significantly negatively correlated with immune score, stromal score, and ESTIMATE score.ConclusionsOur findings suggested that ARHGAP39 can be used as a potential therapeutic target and prognostic biomarker in breast cancer. ARHGAP39 was indeed a determinant factor of immune infiltration.
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Project description:Background: Sirtuin 7 (SIRT7), a protein-coding gene whose abnormal expression and function are associated with carcinogenesis. However, the prognosis of SIRT7 in different breast cancer subtypes and its correlation with tumor-infiltrating lymphocytes remain unclear. Methods: The expression and survival data of SIRT7 in patients with breast cancer were analyzed using Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interaction Analysis (GEPIA), The Human Protein Atlas (HPA), UALCAN, Breast Cancer Gene-Expression Miner (BC-GenExMiner), and Kaplan-Meier plotter databases. Also, the expression correlations between SIRT7 and immune infiltration gene markers were analyzed using TIMER and further verified the results using immunohistochemistry. Results: SIRT7 exhibited higher expression levels in breast cancer tissues than the adjacent normal tissues. SIRT7 expression was significantly correlated with sample type, subclass, cancer stage, menopause status, age, nodal status, estrogen receptor (ER), progesterone receptor (PR), and triple-negative status. High SIRT7 expression was associated with poor prognosis in breast cancer-luminal A [overall survival (OS): hazard ratio (HR) = 1.54, p = 1.70e-02; distant metastasis-free survival (DMFS): HR = 1.56, p = 2.60e-03]. Moreover, the expression of SIRT7 was positively correlated with the expression of IRF5 (M1 macrophages marker, r = 0.165, p = 1.13e-04) and PD1 (T cell exhaustion marker, r = 0.134, p = 1.74e-03). These results suggested that the expression of SIRT7 was related to M1 macrophages and T cell exhaustion infiltration in breast cancer-luminal. Conclusions: These findings demonstrate that the high expression of SIRT7 indicates poor prognosis in breast cancer as well as increased immune infiltration levels of M1 macrophages and T cell exhaustion in breast cancer-luminal. Thus, SIRT7 may serve as a candidate prognostic biomarker for determining prognosis associated with immune infiltration in breast cancer-luminal.
| S-EPMC7247806 | biostudies-literature
Project description:BackgroundThe kinesin-13 family member 2C (KIF2C) is a versatile protein participating in many biological processes. KIF2C is frequently up-regulated in multiple types of cancer and is associated with cancer development. However, the role of KIF2C in immune cell infiltration of tumor microenvironment and immunotherapy in breast cancer remains unclear.MethodsThe expression of KIF2C was analyzed using Tumor Immune Estimation Resource (TIMER) database and further verified by immunohistochemical staining in human breast cancer tissues. The correlation between KIF2C expression and clinical parameters, the impact of KIF2C on clinical prognosis and independent prognostic factors were analyzed by using TCGA database, the Kaplan-Meier plotter, and Univariate and multivariate Cox analyses, respectively. The nomograms were constructed according to independent prognostic factors and validated with C-index, calibration curves, ROC curves, and decision curve analysis. A gene set enrichment analysis (GSEA) was performed to explore the underlying molecular mechanisms of KIF2C. The degree of immune infiltration was assessed by the Estimation of Stromal and Immune cells in Malignant Tumor tissues using the Expression (ESTIMATE) algorithm and the single sample GSEA (ssGSEA). The Tumor mutational burden and Tumor Immune Dysfunction and Rejection (TIDE) were used to analyze immunotherapeutic efficiency. Finally, the KIF2C-related competing endogenous RNA (ceRNA) network was constructed to predict the putative regulatory mechanisms of KIF2C.ResultsKIF2C was remarkably up-regulated in 18 different types of cancers, including breast cancer. Kaplan-Meier survival analysis showed that high KIF2C expression was associated with poor overall survival (OS). KIF2C expression was associated with clinical parameters such as age, TMN stage, T status, and molecular subtypes. We identified age, stage, estrogen receptor (ER) and KIF2C expression as OS-related independent prognosis factors for breast cancer. An OS-related nomogram was developed based on these independent prognosis factors and displayed good predicting ability for OS of breast cancer patients. Finally, our results revealed that KIF2C was significantly related to immune cell infiltration, tumor mutational burden, and immunotherapy in patients with breast cancer.ConclusionKIF2C was overexpressed in breast cancer and was positively correlated with immune cell infiltration and immunotherapy response. Therefore, KIF2C can serve as a potential biomarker for prognosis and immunotherapy in breast cancer.
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Project description:Gastric cancer (GC) is a complex and heterogeneous disease, making it difficult to ascertain the optimal therapeutic approach for individual GC patients. Stromal and immune cell infiltration in GC has a strong correlation with clinical outcomes; however, the underlying mechanisms that drive immunosuppression remain vastly undiscovered. Recent studies validated that anthrax toxin receptor 1 (ANTXR1) is aberrantly expressed in several cancers and holds promise as a new therapeutic target for cancer. However, its immunological roles in GC are still unclear. Here, we show that we identify the distinct stromal and immune cell infiltration in GC between the high and low ANTXR1 expression group by analyzing genomic data. Clinically, ANTXR1 is highly expressed in GC and correlates with adverse clinicopathological characteristics. Additionally, high ANTXR1 expression is linked to markedly poor clinical outcomes and resistance to chemotherapy, whereas the low ANTXR1 expression group is correlated with better outcomes and response to chemotherapy in GC patients. We further revealed the differential landscape of somatic tumor mutation burden (TMB) between the two groups and observed that patients with high ANTXR1 expression suffered from a lower TMB, potentially leading to less sensitivity to checkpoint therapy. Molecularly, results displayed that ANTXR1 is an immunosuppressive element, which may perform its function via promoting the secretion of immunosuppressive factors that play a significant role in modulating tumor-associated fibroblast transformation, M2 macrophage polarization, and T cell exhaustion. Gene set enrichment analysis revealed that cancer-related pathways including epithelial-to-mesenchymal transition, focal adhesion, and transforming growth factor-β (TGF-β) signaling pathways were enriched in high ANTXR1 expression tumors. Our work suggests that ANTXR1 could not only serve as a valuable prognostic biomarker in GC but also be deemed as a potential immunotherapeutic target and useful biomarker of sensitivity to chemotherapy.
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Project description:To characterize the implications of lipid metabolism-related gene thioesterase superfamily member 6 (THEM6) in breast cancer. Several databases including The Cancer Genome Atlas (TCGA) were utilized for our meticulous bioinformatics analysis. We further performed qRT-PCR, immunoblotting and IHC assays to validate the expression of THEM6 in various breast cancer cells and tissues. In addition, we have carried out relevant functional experiments to explore the regulatory role of THEM6 in vitro. Lipid metabolism-related genes are independent factors for overall survival. According to several databases, THEM6 was significantly more expressed in cancerous tissues of breast invasive carcinoma (BRCA) compared to its paracancerous tissues. Furthermore, THEM6 overexpression was correlated with poorer overall survival of BRCA patients, serving as a separate prognostic factor for BRCA. Biological functional analyses revealed that THEM6 was associated with tumor progression and pathogenesis. Finally, we discovered that in BRCA, THEM6 expression was linked to multiple immune cell types. qRT-PCR and Western blotting experiments demonstrated a general upregulation of THEM6 expression in breast carcinoma cells. IHC showed that THEM6 was expressed in both breast cancer tissues and para-cancer tissues, but its expression level was significantly higher in carcinoma tissues. In vitro studies indicated that THEM6 increased proliferation, invasion, and inhibited apoptosis of breast carcinoma cells, while also affecting the cell cycle and promoting cancer progression. Furthermore, THEM6 may influence macrophage recruitment and polarization in the tumor microenvironment by regulating CCL2 secretion, which in turn affects macrophage recruitment in the tumor microenvironment. Our findings indicate that the overexpression of THEM6, which is linked to the development of breast cancer, is a predictor of a poor prognosis and has an impact on the degree of immune cell infiltration. Therefore, THEM6 has the potential to be a valuable target for BRCA.
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Project description:DDX56, a member of the RNA helicase family, is upregulated in colon adenocarcinoma, lung squamous cell carcinoma, and osteosarcoma. However, the relationships between DDX56 and other tumors are not clear, and the molecular mechanism of its action is not fully understood. Here, we explore the biological functions of DDX56 in 31 solid tumors and clarify that DDX56 can promote oncogenesis and progression in multiple tumor types based on multi-omics data. Bioinformatics analysis revealed that the cancer-promoting effects of DDX56 were achieved by facilitating tumor cell proliferation, inhibiting apoptosis, inducing drug resistance, and influencing immune cell infiltration. Furthermore, we found that copy number alterations and low DNA methylation of DDX56 were likely to be related to aberrantly high DDX56 expression. Our results suggest that DDX56 is a potential pan-cancer biomarker that could be used to predict survival and response to therapy, as well as a potential novel therapeutic target. We validated some of our results and illustrated their reliability using CRISPR Screens data. In conclusion, our results clarify the role of DDX56 in the occurrence and development of multiple cancers and provide insight into the molecular mechanisms involved in the process of pathogenesis, indicating a direction for future research on DDX56 in cancers.
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Project description:Background: Colorectal cancer (CRC) is one of the most common gastrointestinal tumors, ranking in the top 5 of all common tumors in terms of incidence and mortality. However, the mechanisms driving the evolution of colorectal cancer remain unclear. Therefore, we investigated the association between Mapk14 expression and clinicopathological and tumor-infiltrating immune cells. Methods: In this study, we collected CRC patient data from The Cancer Genome Atlas (TCGA), compared the expression level in CRC and normal colorectal tissue using the Wilcoxon rank sum test and assessed the relationship between Mapk14 and clinicopathological features using the Welch one-way ANOVA test. Kaplan-Meier and timeROC GSE17537 datasets were obtained from the Gene Expression Omnibus (GEO) dataset to assess the prognostic impact of the Mapk14 gene on colorectal cancer. Second, we further explored the methylation level of Mapk14 and its influencing factors. Single-cell sequencing of Mapk14 in the tumor immune microenvironment (TIME) was analyzed using the GSE108989 dataset. Further analyses based on the TIMER method were performed to assess the correlation between Mapk14 and tumor immune infiltration, immune checkpoints, tumor mutational load and microsatellite instability. Finally, the results of the bioinformatics analysis were verified by an immunohistochemical analysis. Results: The results showed that the expression of Mapk14 was upregulated in CRC tumor tissues compared with normal colorectal tissues and the high expression of Mapk14 was associated with poor clinicopathological features and poor prognoses in the CRC array. In addition, cg05798012 and cg25375420 of Mapk14 are the main DNA methylation sites affecting OS. Single-cell sequencing of the tumor immune microenvironment showed that the abundance and cell state of dysfunctional T cells changed greatly. Importantly, the abnormal overexpression of Mapk14 in colorectal cancer is related to the level of immune infiltration of immune cells (including CD8+ T cells, neutrophils, dendritic cells, B cells, CD4+ T cells, and macrophages). The high expression of Mapk14 was significantly correlated with immune checkpoints (including SIGLEC15, TIGIT, LAG3, CTLA4 and PDCDILG2), while the high expression of Mapk14 was negatively correlated with TMB and MSI but mostly positively correlated with drug sensitivity. Finally, the immunohistochemical results confirmed that the clinical stage (Ⅰ, Ⅱ, Ⅲ and Ⅳ) and M stage (M0 and M1) affected the abnormally high expression of Mapk14. Conclusion: A comprehensive bioinformatics study and experimental validation revealed that Mapk14 could serve as a novel prognostic biomarker associated with immune infiltration and pharmacotherapy and may represent a potential therapeutic target for the treatment of CRC.
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