Impact of Overexpression of Immune Suppressor Siglec-15 on The Prognosis of Clear Renal Cell Carcinoma and Fibrosis Level

2021 ◽  
Author(s):  
Wenbo Yang ◽  
Caipeng Qin ◽  
Yiqing Du ◽  
Songchen Han ◽  
Wenjun Bai ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cell Carcinoma ◽  
Mrna Expression ◽  
Second Harmonic ◽  
Inverse Correlation ◽  
The Cancer Genome Atlas ◽  
Fuhrman Grade ◽  
Normal Tissues ◽  
Significant Difference ◽  
Immune Suppressor

Abstract Background The expression of Siglec-15, as a critical immune suppressor, in renal clear cell carcinoma (ccRCC) was few evaluated and remains unclear, especially in protein level. As previous studies reported, tumor fibrosis plays an essential role in assessing the prognosis of ccRCC, but the exact mechanism is not precise. This study evaluated the expression of Siglec-15, its role in prognosis, and the association with tumor fibrosis in ccRCC.Methods: Immunohistochemistry was used to analyze the Siglec-15 expression in one tissue microarray (cohort A, tumor: n=134, adjacent normal tissues: n=29). Subsequently, the mRNA expression of Siglec-15 and its clinical significance in ccRCC were analyzed using The Cancer Genome Atlas database (TCGA, cohort B, n = 534) and samples. Spearman correlation coefficients were calculated for correlation analysis of correlated expression genes of Siglec-15, and then functional annotation analysis was obtained with correlated expression genes. We detected the tumor fibrosis grade in cohort C (n=32) via second harmonic generation/two-photon excitation fluorescence. Results: Siglec-15 was overexpressed in tumor tissues compared with adjacent normal tissues in both cohort A (n=29, p<0.001) and cohort C (n=25, p<0.001). However, there was no significant difference in mRNA expression of Siglec-15 between tumor and adjacent normal tissues in cohort B (p>0.05). Moreover, over-expression of Siglec-15 is associated with higher Fuhrman grade in cohort A＆C (n=166, p=0.001, OR=3.132, 1.563-6.275), cohort B (n=534, p=0.008, OR=1.606, 1.138-2.267). Univariate Kaplan-Meir survival analysis showed that patients with high Siglec-15 mRNA expression had shorter survival periods without significance in cohort B (p=0.073). Multivariate analysis employing the Siglec-15 regression model revealed that AJCC and Fuhrman grade was the only significant independent prognostic indicators. Besides, an inverse correlation was found between Siglec-15 protein expression and the tumor's fibrosis level (p = 0.02).Conclusions: Siglec-15 expression increases in ccRCC compared with adjacent normal tissues. Siglec-15 was frequently expressed and positively associated with pathology grade in ccRCC. This study indicated a significant role of Siglec-15 in the prognosis and immunotherapy target of ccRCC. This study also found an inverse correlation between Siglec-15 protein expression and the fibrosis level of the tumor.

scholarly journals Transcription factors CP2 and YY1 as prognostic markers in head and neck squamous cell carcinoma: analysis of The Cancer Genome Atlas and a second independent cohort

2020 ◽  
Author(s):  
Julia Schnoell ◽  
Bernhard J. Jank ◽  
Lorenz Kadletz-Wanke ◽  
Stefan Stoiber ◽  
Clemens P. Spielvogel ◽  
...  
Keyword(s):  
Overall Survival ◽  
Squamous Cell Carcinoma ◽  
Transcription Factors ◽  
Protein Expression ◽  
Cell Carcinoma ◽  
Mrna Expression ◽  
The Cancer Genome Atlas ◽  
Cancer Genome Atlas ◽  
Simultaneous Expression ◽  
Genome Atlas

Abstract Purpose The transcription factors YY1 and CP2 have been associated with tumor promotion and suppression in various cancers. Recently, simultaneous expression of both markers was correlated with negative prognosis in cancer. The aim of this study was to explore the expression of YY1 and CP2 in head and neck squamous cell carcinoma (HNSCC) patients and their association with survival. Methods First, we analyzed mRNA expression and copy number variations (CNVs) of YY1 and CP2 using “The Cancer Genome Atlas” (TCGA) with 510 HNSCC patients. Secondly, protein expression was investigated via immunohistochemistry in 102 patients, who were treated in the Vienna General Hospital, utilizing a tissue microarray. Results The median follow-up was 2.9 years (1.8–4.6) for the TCGA cohort and 10.3 years (6.5–12.8) for the inhouse tissue micro-array (TMA) cohort. The median overall survival of the TCGA cohort was decreased for patients with a high YY1 mRNA expression (4.0 vs. 5.7 years, p = 0.030, corr. p = 0.180) and high YY1-CNV (3.53 vs. 5.4 years, p = 0.0355, corr. p = 0.213). Furthermore, patients with a combined high expression of YY1 and CP2 mRNA showed a worse survival (3.5 vs. 5.4 years, p = 0.003, corr. p = 0.018). The mortality rate of patients with co-expression of YY1 and CP2 mRNA was twice as high compared to patients with low expression of one or both (HR 1.99, 95% CI 1.11–3.58, p = 0.021). Protein expression of nuclear YY1 and CP2 showed no association with disease outcome in our inhouse cohort. Conclusion Our data indicate that simultaneous expression of YY1 and CP2 mRNA is associated with shorter overall survival. Thus, combined high mRNA expression might be a suitable prognostic marker for risk stratification in HNSCC patients. However, since we could not validate this finding at genomic or protein level, we hypothesize that unknown underlying mechanisms which regulate mRNA transcription of YY1 and CP2 are the actual culprits leading to a worse survival.

scholarly journals Comprehensive Analysis of ESRRA in Endometrial Cancer

2021 ◽  
Vol 20 ◽  
pp. 153303382199208
Author(s):  
Shufang Wang ◽  
Xinlong Huo
Keyword(s):  
Endometrial Cancer ◽  
Protein Expression ◽  
Immune Cell ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Expression Level ◽  
Operating Characteristics ◽  
Protein Expression Level ◽  
Normal Tissues

Background: Estrogen-related receptor alpha (ESRRA) was reported to play an important role in multiple biological processes of neoplastic diseases. The roles of ESRRA in endometrial cancer have not been fully investigated yet. Methods: Expression data and clinicopathological data of patients with uteri corpus endometrial carcinoma (UCEC) were obtained from The Cancer Genome Atlas (TCGA). Comprehensive bioinformatics analysis was performed, including receiver operating characteristics (ROC) curve analysis, Kaplan-Meier survival analysis, gene ontology (GO) enrichment analysis, and Gene Set Enrichment Analysis (GSEA). Immunohistochemistry was used to detect the protein expression level of ESRRA and CCK-8 assay was performed to evaluate the effect of ESRRA on the proliferation ability. Results: A total of 552 UCEC tissues and 35 normal tissues were obtained from the TCGA database. The mRNA and protein expression level of ESRRA was highly elevated in UCEC compared with normal tissues, and was closely associated with poor prognosis. ROC analysis indicated a very high diagnostic value of ESRRA for patients with UCEC. GO and GSEA functional analysis showed that ESRRA might be mainly involved in cellular metabolism processes, in turn, tumorigenesis and progression of UCEC. Knockdown of ESRRA inhibited the proliferation of UCEC cells in vitro. Further immune cell infiltration demonstrated that ESRRA enhanced the infiltration level of neutrophil cell and reduced that of T cell (CD4+ naïve), NK cell, and cancer associated fibroblast (CAF). The alteration of immune microenvironment will greatly help in developing immune checkpoint therapy for UCEC. Conclusions: Our study comprehensively analyzed the expression level, clinical value, and possible mechanisms of action of ESRRA in UCEC. These findings showed that ESRRA might be a potential diagnostic and therapeutic target.

scholarly journals Identification of novel DNA hypermethylation of the adenylate kinase 5 promoter in colorectal adenocarcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bokyung Ahn ◽  
Yang Seok Chae ◽  
Soo Kyung Lee ◽  
Moa Kim ◽  
Hyeon Soo Kim ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cell Lines ◽  
Adenylate Kinase ◽  
Dna Methyltransferase ◽  
Colorectal Adenocarcinoma ◽  
Adenine Nucleotides ◽  
Inverse Correlation ◽  
Dna Hypermethylation ◽  
Normal Tissues ◽  
The Difference

AbstractAdenylate kinase 5 (AK5) belongs to the adenylate kinase family that catalyses reversible phosphate transfer between adenine nucleotides, and it is related to various energetic signalling mechanisms. However, the role of AK5 in colorectal cancer (CRC) has not been reported. In this study, AK5 was significantly hypermethylated in CRC compared to adjacent normal tissues (P < 0.0001) and normal tissues (P = 0.0015). Although the difference in mRNA expression was not statistically significant in all of them, the selected 49 cases of CRC tissues with AK5 hypermethylation with the cut off value of 40% showed a significant inverse correlation with mRNA expression (P = 0.0003). DNA methylation of AK5 promoter significantly decreased and AK5 expression recovered by 5-aza-2′-deoxycytidine, DNA methyltransferase inhibitor in CRC cell lines. In addition, AK5 promoter activity significantly decreased due to DNA methyltransferase, and it increased due to 5-aza. Moreover, AK5 regulated the phosphorylated AMPK and mTOR phosphorylation and inhibited the cell migration and cell invasion in CRC cell lines. Furthermore, low AK5 expression is associated with poor differentiation (P = 0.014). These results demonstrate that the AK5 promoter is frequently hypermethylated and induced methylation-mediated gene down-regulation. AK5 expression regulates AMPK/mTOR signalling and may be closely related to metastasis in colorectal adenocarcinoma.

Screening of cervical cancer-related hub genes based on comprehensive bioinformatics analysis

2021 ◽  
pp. 1-13
Author(s):  
Simei Tu ◽  
Hao Zhang ◽  
Xiaocheng Yang ◽  
Wen Wen ◽  
Kangjing Song ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cervical Cancer ◽  
Molecular Mechanisms ◽  
Disease Free Survival ◽  
The Cancer Genome Atlas ◽  
Mrna Levels ◽  
Hub Genes ◽  
Normal Tissues ◽  
Significant Difference ◽  
Core Genes

BACKGROUND: Since the molecular mechanisms of cervical cancer (CC) have not been completely discovered, it is of great significance to identify the hub genes and pathways of this disease to reveal the molecular mechanisms of cervical cancer. OBJECTIVE: The study aimed to identify the biological functions and prognostic value of hub genes in cervical cancer. METHODS: The gene expression data of CC patients were downloaded from the Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database. The core genes were screened out by differential gene expression analysis and weighted gene co-expression network analysis (WGCNA). R software, the STRING online tool and Cytoscape software were used to screen out the hub genes. The GEPIA public database was used to further verify the expression levels of the hub genes in normal tissues and tumour tissues and determine the disease-free survival (DFS) rates of the hub genes. The protein expression of the survival-related hub genes was identified with the Human Protein Atlas (HPA) database. RESULTS: A total of 64 core genes were screened, and 10 genes, including RFC5, POLE3, RAD51, RMI1, PALB2, HDAC1, MCM4, ESR1, FOS and E2F1, were identified as hub genes. Compared with that in normal tissues, RFC5, POLE3, RAD51,RMI1, PALB2, MCM4 and E2F1 were all significantly upregulated in cervical cancer, ESR1 was significantly downregulated in cervical cancer, and high RFC5 expression in CC patients was significantly related to OS. In the DFS analysis, no significant difference was observed in the expression level of RFC5 in cervical cancer patients. Finally, RFC5 protein levels verified by the HPA database were consistently upregulated with mRNA levels in CC samples. CONCLUSIONS: RFC5 may play important roles in the occurrence and prognosis of CC. It could be further explored and validated as a potential predictor and therapeutic target for CC.

scholarly journals Prognostic value of CLIC3 mRNA overexpression in bladder cancer

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e8348
Author(s):  
Mei Chen ◽  
Shufang Zhang ◽  
Xiaohong Wen ◽  
Hui Cao ◽  
Yuanhui Gao
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Mrna Expression ◽  
Prognostic Value ◽  
Multivariate Analyses ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Functional Enrichment ◽  
Receptor Interaction ◽  
Normal Tissues

Background Human intracellular chloride channel 3 (CLIC3) is involved in the development of various cancers, but the expression and prognostic value of CLIC3 mRNA in bladder cancer (BC) remain unclear. Methods The gene expression data and clinical information of CLIC3 were obtained from the Gene Expression Omnibus (GEO) database and verified in the Oncomine and The Cancer Genome Atlas (TCGA) database. The expression of CLIC3 mRNA in BC tissues and adjacent normal tissues was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The Kaplan-Meier method was used to analyze the relationship between the expression of CLIC3 mRNA and the prognosis of BC. Cox univariate and multivariate analyses were performed on the overall survival and tumor-specific survival of BC patients. The genes coexpressed with CLIC3 were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). CLIC3-related signal transduction pathways in BC were explored with gene set enrichment analysis (GSEA). Results The expression of CLIC3 mRNA in BC tissues was higher than that in normal tissues (P < 0.01). High CLIC3 mRNA expression was associated with age (P = 0.021) and grade (P = 0.045) in BC patients. High CLIC3 mRNA expression predicted a poor prognosis in BC patients (P < 0.05). Cox univariate and multivariate analyses showed that high CLIC3 mRNA expression was associated with tumor-specific survival in BC patients (P < 0.05). Functional enrichment analyses indicated that CLIC3 may be significantly associated with the cell cycle, focal adhesion, the extracellular matrix (ECM) receptor interaction and the P53 signaling pathway. Conclusions CLIC3 mRNA is highly expressed in BC, and its high expression is related to the adverse clinicopathological factors and prognosis of BC patients. CLIC3 can be used as a biomarker for the prognosis of BC patients.

scholarly journals Expression and clinical significance of PTPN12 in clear cell renal cell carcinoma

2020 ◽  
Vol 48 (12) ◽  
pp. 030006052093604
Author(s):  
Yi Jin ◽  
Tian-xi Wang ◽  
Hao Li ◽  
Peng Guo ◽  
Qing-qing Wang
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Mrna Expression ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Expression Levels ◽  
Relative Expression ◽  
Normal Tissues ◽  
Mrna Expression Levels

Background Clear cell renal cell carcinoma (ccRCC) is a common urological disease. Expression of the protein tyrosine phosphatase 12 gene ( PTPN12) is decreased in many cancers; however, the relationship between PTPN12 gene function and renal cancer remains unclear. Methods We detected PTPN12 protein expression in ccRCC and corresponding normal tissues from 64 patients with ccRCC by immunohistochemistry, and relative PTPN12 mRNA levels by real-time quantitative polymerase chain reaction. The relationships between the relative expression levels of PTPN12 mRNA and the patients’ clinical data were analyzed. Results PTPN12 protein and mRNA expression levels were significantly lower in ccRCC compared with the corresponding normal tissues. The mRNA expression levels in the ccRCC and corresponding normal tissues from the 64 patients with ccRCC were 0.459±0.445 and 1.001±0.128, respectively, compared with the control (glyceraldehyde 3-phosphate dehydrogenase). There was a significant correlation between relative expression of PTPN12 mRNA in ccRCC tissues and tumor diameter and clinical stage. Conclusion The expression levels of PTPN12 protein and mRNA were significantly lower in ccRCC tissues compared with normal tissues. The role of PTPN12 may provide new insights and evidence to aid the diagnosis and targeted therapy of ccRCC.

Src pathway activation in RCC and the correlation with grade and survival and the development of a rational new target in RCC.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 453-453
Author(s):  
Chung-Han Lee ◽  
Martin Henner Voss ◽  
Roy Mano ◽  
Robert John Motzer ◽  
James Hsieh
Keyword(s):  
Overall Survival ◽  
Mrna Expression ◽  
Cell Lines ◽  
Survival Data ◽  
Therapeutic Potential ◽  
The Cancer Genome Atlas ◽  
Primary Tumors ◽  
Fuhrman Grade ◽  
Inhibitory Site ◽  
Src Pathway

453 Background: Loss of the VHL tumor suppressor in clear cell renal cell carcinoma (ccRCC) leads to the accumulation of Hypoxia Inducible Factor (HIF) and aberrant transcription of downstream targets such as VEGF. Inhibition of VEGF is the underlying therapeutic principle of several approved targeted agents; however, other HIF transcriptional targets remain to be explored. Increased expression of the HIF transcriptional target CUB domain-containing protein 1 (CDCP1) is associated with poor survival in ccRCC. CDCP1 is a substrate and binding partner for Src-family tyrosine kinases (SFKs) and dictates substrate specificity. Crosstalk between the SFK signaling cascade and the HIF pathway may result in feed forward signal amplification. Upregulation of Src signaling increases HIF-dependent transcription by both VHL-dependent and -independent mechanisms. Reciprocally, HIF accumulation can activate Src through PDGFRα, focal adhesion kinase, and CDCP1. Methods: Data from The Cancer Genome Atlas (TCGA) was used to assess mRNA expression and protein phosphorylation as well as clinical parameters and outcome in patients with ccRCC. Correlations were analyzed via Mann-Whitney U-test. Survival data was obtained using the TCGA portal, and analyzed by logrank test. To investigate the therapeutic potential of Src inhibition, the IC50 of Dasatinib in primary tumors derived cell lines were determined by an AlamarBlue Assay. Results: Increased Src and CDCP1 mRNA expression and decreased phosphorylation on the Src inhibitory site Y527 correlated with increased Fuhrman grade. Decreased phosphorylation on the inhibitory site Y527 correlated with worse median overall survival (78.4 vs. 19.7 months, p< 0.00001). Similarly, increased Src and CDCP1 mRNA expression correlated with worse overall survival (78.4 vs. 26.9 months, p < 0.00001, 78.4 vs. 37.2 months, p = 0.005). In vitro inhibition of Src with Dasatinib induces growth inhibition of primary cell lines with sarcomatoid or rhabdoid features, histomorphologic criteria associated with higher grade disease and worse prognosis. Conclusions: The Src pathway might be biologically relevant for ccRCC, and Src inhibition may have therapeutic potential.

scholarly journals The tissue differentiation and cancer manifolds in gene and protein expression spaces

2021 ◽  
Author(s):  
J Nieves ◽  
A Gonzalez
Keyword(s):  
Protein Expression ◽  
Cancer Progression ◽  
Tissue Differentiation ◽  
The Cancer Genome Atlas ◽  
Normal Tissues ◽  
Gene And Protein Expression ◽  
Human Protein Atlas ◽  
Cancer Genome Atlas ◽  
Tissue Of Origin ◽  
Using Data

AbstractIt is well known that, for a particular tissue, the homeostatic and cancer attractors are well apart both in gene expression and in protein expression spaces. By using data for 15 tissues and the corresponding tumors from The Cancer Genome Atlas, and for 49 normal tissues and 20 tumors from The Human Protein Atlas, we show that the set of normal attractors are also well separated from the set of tumors. Roughly speaking, one may say that there is a cancer progression axis orthogonal to the normal tissue differentiation and cancer manifolds. This separation suggests that therapies targeting common genes, which define the cancer axis, may be effective, irrespective of the tissue of origin.

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