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2021 ◽  
Vol 8 ◽  
Author(s):  
Zhao-wei Gao ◽  
Chong Liu ◽  
Lan Yang ◽  
Ting He ◽  
Xia-nan Wu ◽  
...  

Background: Secreted protein acidic and rich in cysteine (SPARC) plays an important role in cancer development. The roles of SPARC in the liver hepatocellular carcinoma (LIHC) are unclear.Methods: GEPIA2 and UALCAN were used to analyze the SPARC mRNA expression levels in LIHC based on the TCGA database. The GEO database was used to verify the analysis results. Immunohistochemical (IHC) analysis was used to investigate the SPARC protein levels in LIHC tissues. The Kaplan–Meier (KM) plotter was used to analyze the correlation between SPARC and prognosis. The serum SPARC levels were measured by ELISA. CCK8 and murine xenograft models were used to investigate the effect of SPARC on the liver cancer growth in vitro and in vivo. SPARC-correlated genes were screened by LinkedOmics.Results: Based on the TCGA and GEO databases, the analysis showed that the SPARC mRNA expression levels were increased in tumor tissues and peripheral blood mononuclear cell (PBMC) from LIHC compared to normal controls. The IHC analysis showed an increased level of SPARC in LIHC tissues compared to adjacent non-tumor tissues. However, we found that the serum SPARC levels were lower in LIHC than those in healthy controls. The KM plotter showed that there was no significant correlation between the SPARC mRNA levels and overall survival. However, in sorafenib-treated LIHC patients, the high SPARC expression predicts favorable prognosis. Furthermore, the endogenous SPARC overexpression promotes liver cancer cell proliferation in vitro and tumor growth in vivo, while there was no significant effect of exogenous SPARC treatment on liver cancer cell proliferation. Function enrichment analysis of SPARC-correlated genes indicated a critical role of interaction with an extracellular matrix in SPARC-promoting cancer cell proliferation.Conclusion: SPARC mRNAs were increased in LIHC tumor tissues, and SPARC overexpression may promote the liver cancer growth. Further studies are needed to clarify the potential prognostic value of SPARC, both in tissues and in circulation.


2021 ◽  
Vol 12 ◽  
Author(s):  
Zhao-wei Gao ◽  
Chong Liu ◽  
Lan Yang ◽  
Hao-chuan Chen ◽  
Long-fei Yang ◽  
...  

To investigate the expression levels and prognostic value of CD73 in lung cancer. And moreover, to identify the effect and potential mechanism of CD73 on lung cancer cells proliferation and migration. CD73 expression levels in lung cancer were analyzed base on GEPIA2 and GEO database. GEPIA2 and Kaplan-Meier Plotter (KM Plotter) was used to analyzed the correlation between CD73 expression and prognosis. GEO dataset were analyzed via GEO2R. CD73 overexpression cell model was construction via recombinant lentivirus transfection into A549 and NCI-H520 cells. CCK8 assay were used to investigate cells proliferation. Migration and invasion ability were evaluated by scratch and transwell methods. Base on GEPIA2, GSE32683, GSE116959 and GSE37745 dataset, we found that CD73 expression were significant higher in tumor tissues of lung adenocarcinoma (LUAD) compared with that in non-tumor normal tissues and in lung squamous cell carcinoma (LUSC), while there were no significant difference of CD73 expression between LUSC and normal control tissues. Interestingly, a high CD73 level predict poor overall survival (OS) of LUSC. However, GEPIA2 and KM plotter showed the opposite conclusion of prognostic value of CD73 in LUAD. By using cell experiments, we found that CD73 overexpression promoted proliferation and migration of LUAD A549 cells. However, there was no significant effect of CD73 overexpression on LUSC NCI-H520 cells. Furthermore, CD73 overexpression facilitates epithelial to mesenchymal transition (EMT) progression of A549 cells. In conclusion, our results indicated that CD73 expression were increased in LUAD and might be an poor prognostic marker for LUSC patients. CD73 play an important role in LUAD cells proliferation and migration. These data allowed to support CD73 as a therapeutic target for LUAD.


2021 ◽  
Vol 11 ◽  
Author(s):  
Limei Xiao ◽  
Jie Zhou ◽  
Hongyi Liu ◽  
Yuanyuan Zhou ◽  
Weibin Chen ◽  
...  

There is an urgent need to improve our understanding of breast cancer brain metastases (BCBMs). Thus, we obtained transcriptome data of BCBMs, primary breast cancers (BCs), and extracranial metastases (BCEMs) from the Gene Expression Omnibus (GEO) database, including GSE43837, GSE14017, and GSE14018, for immune and metabolic analysis. Firstly, we performed immune and metabolic analysis on BCBMs and primary breast cancers of GSE43837 using RNA sequence. We identified significant immunosuppression and gene signatures associated with immune infiltration in BCBMs; the lower the expression of the signatures, the worse the prognosis of breast cancer patients in the Kaplan–Meier (KM) plotter [Breast cancer] database. We also identified increased oxidative phosphorylation (OXPHOS) utilization in BCBMs compared with BCs and gene signatures associated with increased OXPHOS utilization in BCBMs; the higher the expression of the signatures, the worse the prognosis of breast cancer patients in the KM plotter [Breast cancer] database, which can predict the prognosis of breast cancer patients better, as it can also predict the prognosis of patients with different breast cancer subtypes. In addition, we performed immune and metabolic analysis on BCBMs and extracranial metastases of GSE14017 and GSE14018 using RNA sequence. Compared with extracranial metastases, we identified more significant immunosuppression but no difference in OXPHOS utilization in BCBMs, which may be because OXPHOS was also involved in extracranial metastases. We have proven that OXPHOS was functionally significant in metastasis in vitro assays. Oligomycin, an OXPHOS inhibitor, substantially attenuated the migration and invasion potential of breast cancer cells. Our study provides new insights into the pathogenesis of BCBMs.SignificanceOur study reports the most comprehensive gene expression analysis of BCBMs, BCs and extracranial metastases to date. We identified immunosuppression and OXPHOS enrichment in BCBMs compared with BCs, which provide new insights into the pathogenesis of BCBMs and will facilitate the development of new therapeutic strategies for patients with BCBMs.


2021 ◽  
Author(s):  
Furkan Celebi Ileri ◽  
Tolga Acun

Aim: DNAJA1 is associated with several cancers, but its biomarker potential in breast cancer is not adequately known. Materials & methods: Q-RT-PCR, immunohistochemistry, COBRA methods and in silico tools (KM-Plotter, UALCAN) were used to analyze the expression level, methylation status and prognostic value of DNAJA1 in breast cancer. Results: DNAJA1 expression was significantly higher in clinical tumor samples compared with normal samples. High DNAJA1 mRNA expression is associated with poor survival values in breast cancer. DNAJA1 promoter region is hypomethylated in cell lines and clinical samples. Conclusion: High DNAJA1 expression predicts poor clinical survival outcomes for breast cancer. Other than promoter methylation, epigenetic factors also warrant investigation in future studies as a regulatory mechanism of DNAJA1 expression in breast cancer.


2021 ◽  
Author(s):  
Zhenzhen Li ◽  
Xiong Chaoliang ◽  
Jin Wei ◽  
Ping Chen ◽  
Yanping Zhang ◽  
...  

Abstract Background Anaplastic thyroid cancer (ATC) has a high degree of malignancy and a poor prognosis. Its incidence accounts for approximately 10–15% of all thyroid cancers. The purpose of this study was to determine the differentially expressed genes (DEGs) of ATC through biometric analysis technology, clarify the potential interactions between them, and screen genes related to the prognosis of ATC. Methods The GSE29265, GSE65144, GSE33630, and GSE85457 expression profiles downloaded from the Gene Expression Omnibus database (GEO) contained a total of 117 tissue samples (81 normal thyroid tissue samples and 36 ATC samples). The four datasets were integrated and analyzed by the limma packages to obtain DEGs. With these DEGs, we performed gene ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway analyses using the Database for Annotation, Visualization and Integrated Discovery, protein-protein interaction (PPI) analysis using Cytoscape, and survival analysis using the Kaplan-Meier (KM) plotter. Results. After R integration analysis of the four datasets, 764 DEGs were obtained, i.e., 314 upregulated and 450 downregulated genes. Among the hub DEGs obtained in the PPI network, the expression levels of thymidylate synthase (TYMS), fibronectin 1, chordin-like 1, syndecan 2, integrin alpha 2, collagen type I alpha 1 chain, collagen type IX alpha 3 chain (COL9A3), and collagen type XXIII alpha 1 chain (COL23A1) were associated with ATC prognosis. These results showed that the overall survival and recurrence-free survival of TYMS, COL9A3, and COL23A1 were statistically significant in our KM plotter survival analysis; thus, these DEGs may be used as potential biomarkers of ATC. Conclusion This study identified several potential target genes and pathways that may affect the development of ATC. These findings provide new insights for the detection of novel diagnostic and therapeutic biomarkers for ATC.


2021 ◽  
Author(s):  
Renan Gomes Nascimento

Introdução: A expressão alterada dos membros da família PHLDB (Pleckstrin homology‐like domain family b) vem sendo frequentemente relatada em diferentes neoplasias malignas, embora as funções bioquímicas exatas não estejam totalmente elucidadas. Objetivo: Neste estudo, buscamos avaliar a expressão gênica da família PHLDB em amostras normais e tumorais da mama e estimar o valor prognóstico desses potenciais biomarcadores. Material e métodos: A expressão da família PHLDB foi avaliada usando o banco de dados UALCAN e GEPIA2. A relevância entre o nível de expressão dos integrantes da família PHLDB e os parâmetros clínico-patológicos, bem como os dados de sobrevida de pacientes com câncer de mama, foram analisados usando as plataformas de web KM Plotter, PrognoScan, bc-GenExMiner. Resultados: Identificamos que a expressão de PHLDB1 e PHLDB2 é reduzida em amostrais tumorais quando comparado às amostras normais da mama. Contrariamente, PHLDB3 apresentouse mais expresso nos tumores vs tecido normal adjacente. As evidencias amostrais permitiram inferir que existe associação estatisticamente significante entre o status da expressão da família PHLDB com diversas variáveis testadas, incluindo status linfonodal, classificação SBR, status mutacional de TP53 e subtipo molecular. Por fim, notamos que níveis reduzidos da expressão dos integrantes da família PHLDB foram significativamente associados com redução nas taxas cumulativas de sobrevida global e sobrevida livre de doença. Conclusão: A expressão alterada dos membros da família PHLDB foi observada como um evento frequente nos tumores de mama. Além disso, nossas descobertas fornecem novas compreensões sobre o papel potencial da família PHLDB como potenciais biomarcadores prognósticos em câncer de mama.


2021 ◽  
Author(s):  
Zhenzhen Li ◽  
Chaoliang Xiong ◽  
Jin Wei ◽  
Ping Chen ◽  
Yanping Zhang ◽  
...  

Abstract BackgroundAnaplastic thyroid cancer (ATC) has a high degree of malignancy and a poor prognosis. Its incidence accounts for approximately 10-15% of all thyroid cancers. The purpose of this study was to determine the differentially expressed genes (DEGs) of ATC through biometric analysis technology, clarify the potential interactions between them, and screen genes related to the prognosis of ATC.MethodsThe GSE29265, GSE65144, GSE33630, and GSE85457 expression profiles downloaded from the Gene Expression Omnibus database (GEO) contained a total of 117 tissue samples (81 normal thyroid tissue samples and 36 ATC samples). The four datasets were integrated and analyzed by the limma packages to obtain DEGs. With these DEGs, we performed gene ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway analyses using the Database for Annotation, Visualization and Integrated Discovery, protein-protein interaction (PPI) analysis using Cytoscape, and survival analysis using the Kaplan-Meier (KM) plotter.Results.After R integration analysis of the four datasets, 764 DEGs were obtained, i.e., 314 upregulated and 450 downregulated genes. Among the hub DEGs obtained in the PPI network, the expression levels of thymidylate synthase (TYMS), fibronectin 1, chordin-like 1, syndecan 2, integrin alpha 2, collagen type I alpha 1 chain, collagen type IX alpha 3 chain (COL9A3), and collagen type XXIII alpha 1 chain (COL23A1) were associated with ATC prognosis. These results showed that the overall survival and recurrence-free survival of TYMS, COL9A3, and COL23A1 were statistically significant in our KM plotter survival analysis; thus, these DEGs may be used as potential biomarkers of ATC.ConclusionThis study identified several potential target genes and pathways that may affect the development of ATC. These findings provide new insights for the detection of novel diagnostic and therapeutic biomarkers for ATC.


2021 ◽  
Vol 10 ◽  
Author(s):  
Yuehong Cui ◽  
Qian Li ◽  
Wei Li ◽  
Yan Wang ◽  
Fang Lv ◽  
...  

IntroductionAlthough traditional treatments confer survival benefits to patients with gastric cancer (GC), many patients experience relapse soon after postoperative adjuvant therapy. Immune-related mechanisms play an important role in GC, and immunotherapeutic strategies are considered to be a promising direction for the treatment of GC. Thus, our study aimed to investigate the expression and prognostic significance of immune-related genes in GC.MethodsFormalin-fixed, paraffin-embedded samples were collected from 48 resectable GC patients. The transcriptome data of the tumor immune microenvironment were assessed using an immuno-oncology 395-gene panel RNA sequencing platform. The prognostic value of the 395 genes was analyzed and validated in the KM plotter and GEPIA databases. The data from The Cancer Genome Atlas (TCGA, downloaded from UCSC Xena repository) and Tumor IMmune Estimation Resource (TIMER) were used to evaluate the correlations between prognostic factors and immune signatures.ResultsAmong the 395 genes, NOTCH3 was identified as a good prognostic factor for GC patients. Its prognostic value was also suggested in both our GC cohort from Zhongshan Hospital and the public databases (KM plotter and GEPIA database). Mechanistically, high NOTCH3 expression correlated with a lower infiltration of activated CD8+ T cells and a higher infiltration of immunosuppressive cells including Tregs and M2 macrophages in the tumor microenvironment. Moreover, high NOTCH3 expression was accompanied by the increased expression of a series of immune checkpoint inhibitors, resulting in a dampened immune response. Interestingly, NOTCH3 expression had a negative association with well-documented predictive biomarkers of immune checkpoint blockade (ICB) immunotherapy, including tumor mutation burden (TMB), gene expression profiling (GEP) score and innate anti-PD-1 resistance (IPRES) signature.ConclusionThese findings uncovered a new mechanism by which NOTCH3 participates in the immune tolerance of GC, implying the potential of NOTCH3 as a therapeutic target or predictive marker for GC patients.


2020 ◽  
Author(s):  
Katie K. Crean-Tate ◽  
Chad Braley ◽  
Goutam Dey ◽  
Emily Esakov ◽  
Caner Saygin ◽  
...  

AbstractObjectiveTo evaluate LCK inhibitors (LCKi) as chemosensitizing agents for platinum-resistant endometrioid ovarian carcinoma.MethodsKM Plotter survival data was obtained for endometrioid ovarian cancer based on LCK mRNA expression. Cisplatin resistant endometrioid ovarian carcinoma cell lines were cultured and treated first with LCKi or vehicle, then combination LCKi-cisplatin. Cell viability was assessed via CellTiter-Glo, and apoptosis with Caspase 3/7 Assay. Protein lysates were isolated from treated cells, with γ-H2Ax, a DNA adduct marker, assessed. In vivo study compared mice treated with vehicle or LCK inhibitor followed by LCK inhibitor, cisplatin, or combination therapy. One-way ANOVA and two sample t-test were used to assess statistical significance with GraphPad Prism.ResultsKM plotter data indicated LCK expression is associated with significantly worse median progression-free survival (HR 3.19, p=0.02), and a trend toward decreased overall survival in endometrioid ovarian tumors with elevated LCK expression (HR 2.45, p=0.41). In vitro, cisplatin resistant ovarian endometrioid cells treated first with LCKi followed by combination LCKi-cisplatin treatment showed decreased cell viability and increased apoptosis. Immunoblot studies revealed inhibition of LCK led to increased expression of γ-H2AX. In vivo results demonstrate treatment with LCKi followed by LCKi-cisplatin leads to significantly slowed tumor growth.ConclusionsWe identified a targetable pathway for chemosensitization of platinum resistant endometrioid ovarian cancer with initial treatment of LCKi followed by co-treatment with LCKi-cisplatin.


2020 ◽  
Author(s):  
Haixing Jiang ◽  
Ziyu Liang ◽  
Shanyu Qin ◽  
Kang Liu

Abstract BACKGROUND: Despite multiple functions in the disease, the prognosis of the heat shock protein (HSP) 70 family in Hepatocellular Carcinoma (HCC) remains unclear. METHODS: The UALCAN database has provided information about the expression level of HSP70 family members in both HCC and in normal tissues. Overall survival (OS) was conducted by Kaplan-Meier plotter (KM plotter). Gene ontology (GO) and KEGG pathway enrichment analyses were accomplished by DAVID database. GeneMANIA and STRING were applied to construct gene-gene and protein-protein interaction (PPI) networks. RESULTS: From the UALCAN database, we found that the expression levels of eight members of the HSP70 family in HCC patients were higher than in normal liver tissues. These eight members were, namely, HSPA1A, HSPA1B, HSPA1L, HSPA2, HSPA5, HSPA6, HSPA8 and HSPA9. From KM plotter database, high expression of HSPA1A, HSPA1B, HSPA6 and HSPA8 has been observed to be associated with worse OS in patients with HCC (hazard ratio [HR] =1.49, 95% confidence interval [CI]: 1.03-2.15, P=0.031; HR=1.49, 95%CI: 1.05-2.12, P=0.026; HR=1.53, 95%CI: 1.06-2.2, P=0.021 and HR=1.81, 95%CI: 1.21-2.71, P=0.0036, respectively). We also found that the high expressions of HSPA1A, HSPA1B, HSPA6 and HSPA8 were related to unfavorable OS of HCC patients with other factors such as clinical stage, gender, race and hepatitis virus. From GO and KEEG analysis, we detected a close relationship between these eight genes and Biological process, Cellular component, Molecular function and cancer related signaling pathways. The PPI network and GeneMANIA results showed that there was a strong co-expression relationship between the protein homology and the genes. CONCLUSIONS: According to previous studies and analysis, when HSPA1A, HSPA1B, HSPA6 and HSPA8 were highly expressed in HCC patients, they generally demonstrated lower OS. Therefore, the members of HSP70 family are likely to be used as drug targets and prognostic biomarkers when treating HCC patients.


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