SERPINB7 Expression Predicts Poor Pancreatic Cancer Survival Upon Gemcitabine Treatment.
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ABSTRACT:
SUBMITTER: Bianconi D
PROVIDER: S-EPMC6149193 | biostudies-literature | 2019 Jan
REPOSITORIES: biostudies-literature
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Project description:Although gemcitabine monotherapy is the standard treatment for advanced pancreatic cancer, patient outcome varies significantly, and a considerable number do not benefit adequately. We therefore searched for new biomarkers predictive of overall patient survival. Using LC-MS, we compared the base-line plasma proteome between 29 representative patients with advanced pancreatic cancer who died within 100 days and 31 patients who survived for more than 400 days after receiving at least two cycles of the same gemcitabine monotherapy. Identified biomarker candidates were then challenged in a larger cohort of 304 patients treated with the same protocol using reverse-phase protein microarray. Among a total of 45,277 peptide peaks, we identified 637 peaks whose intensities differed significantly between the two groups (p < 0.001, Welch's t test). Two MS peaks with the highest statistical significance (p = 2.6 x 10(-4) and p = 5.0 x 10(-4)) were revealed to be derived from alpha(1)-antitrypsin and alpha(1)-antichymotrypsin, respectively. The levels of alpha(1)-antitrypsin (p = 8.9 x 10(-8)) and alpha(1)-antichymotrypsin (p = 0.001) were significantly correlated with the overall survival of the 304 patients. We selected alpha(1)-antitrypsin (p = 0.0001), leukocyte count (p = 0.066), alkaline phosphatase (p = 8.3 x 10(-8)), and performance status (p = 0.003) using multivariate Cox regression analysis and constructed a scoring system (nomogram) that was able to identify a group of high risk patients having a short median survival time of 150 days (95% confidence interval, 123-187 days; p = 2.0 x 10(-15), log rank test). The accuracy of this model for prognostication was internally validated and showed good calibration and discrimination with a bootstrap-corrected concordance index of 0.672. In conclusion, an increased level of alpha(1)-antitrypsin is a biomarker that predicts short overall survival of patients with advanced pancreatic cancer receiving gemcitabine monotherapy. Although an external validation study will be necessary, the current model may be useful for identifying patients unsuitable for the standardized therapy.
| S-EPMC2860233 | biostudies-literature
Project description:Background: Recent evidence has shown that CKLF-like MARVEL transmembrane domain containing 3 (CMTM3) promoted carcinogenesis and tumor progression in a variety of cancer types. The goal of our study is to investigate the association between CMTM3 and pancreatic cancer (PC). Materials and Methods: In current study, data from public databases was used to analyze CMTM3 expression in PC. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) were used to investigate CMTM3 expression and determine its clinical significance in PC. Then CMTM3 promoting PC aggressiveness was demonstrated in vitro experiments by cell proliferation and migration assay. Functional and pathway enrichment analyses were performed to evaluate the potential role of CMTM3 in PC. Results: Results of qRT-PCR and IHC revealed that CMTM3 was significantly overexpressed in PC tissues. High CMTM3 expression was an independent risk factor for poor prognosis of PC patients. Overexpression of CMTM3 was associated with poor overall survival (P-value =0.031) and disease-free survival (P-value =0.0047) in the TCGA cohort. Functional and pathway enrichment analyses showed that CMTM3 were enriched in "Regulation of cell proliferation and regulation of cell differentiation, cell morphogenesis, regulation of cell differentiation, Hedgehog signaling pathway, Wnt signaling pathway, ECM-receptor interaction and pathways in cancer". In PC cell lines, CCK8, clone formation and transwell assays showed that CMTM3 knockdown inhibited cells proliferation and migration. Conclusion: CMTM3 was overexpressed and promotes tumor aggressiveness in PC. Our findings provided a novel therapeutic target for PC.
| S-EPMC8408105 | biostudies-literature
Project description:OBJECTIVES: Liver metastasis develops in 60% of patients after resection of pancreatic adenocarcinoma (PAC) and carries a dismal prognosis, but factors predictive of liver recurrence are poorly understood. Experimental evidence suggests that liver metastasis of PAC is mediated by CXCL12/CXCR4 signaling and can be inhibited by CXCR4 antagonist. We aimed to verify whether CXCR4 expression predicts early liver recurrence and poor survival after resection, and to explore the usefulness of CXCR4 status for prognosis prediction. METHODS: Ninety-seven consecutive PAC patients undergoing R0 resection were analyzed. CXCR4 expression was analyzed by immunohistochemistry, and its associations with liver recurrence-free survival and overall survival were analyzed by Kaplan-Meier estimates and multivariable Cox and accelerated failure time regression models. RESULTS: CXCR4-positive patients had a worse prognosis than CXCR4-negative patients, with a shorter liver recurrence-free survival (median: 8.7 vs. 39.7 months; P=0.004) and overall survival (median: 10.2 vs. 22.3 months; P<0.001). Overall survival for CXCR4-positive stage IIa patients was similar to that for stage IIb patients and significantly shorter than that for CXCR4-negative stage IIa patients (median: 9.7 vs. 27.4 months; P=0.002). CXCR4 positivity was significantly associated with liver recurrence (adjusted hazard ratio 2.22, 95% confidence interval (CI) 1.15-4.30; P=0.018) and predicted a 46% (95% CI 9-68%) and 35% (95% CI 7-54%) reduction in liver recurrence-free survival and overall survival, respectively. CONCLUSIONS: Tumor CXCR4 expression independently predicts early liver recurrence and poor overall survival after resection of PAC. CXCR4 status stratifies stage IIa patients into two groups with a striking difference in prognosis.
| S-EPMC3464805 | biostudies-other
Project description:Background: Nucleolar and spindle-associated protein 1 (NUSAP1) was previously reported to be associated with poor prognosis in multiple cancers. In the present study, we comprehensively investigated the clinicopathological features and potential prognostic value of NUSAP1 in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Methods: The expression profiles of the genes were extracted from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), Cancer Cell Line Encyclopedia (CCLE), Gene Expression Profiling Interactive Analysis (GEPIA), and The Human Protein Atlas databases. The association between clinicopathological characteristics and NUSAP1 was analyzed using logistic regression in TCGA patients and receiver operating characteristic (ROC) curve analysis for GSE7803, GSE9750, and GSE63514 datasets. The prognostic value of NUSAP1 in TCGA patients was evaluated using the Kaplan-Meier method and Cox regression. Gene set enrichment analysis (GSEA) was conducted using TCGA dataset. Results: A total of 68 differentially expressed genes (DEGs) were identified in CESC. ROC analysis of NUSAP1 suggested that the area under the ROC curve was 0.968. Kaplan-Meier survival analysis indicated that CESC with low expression of NUSAP1 has a worse prognosis than CESC with high NUSAP1 expression (P = 0.005). The logistic regression revealed that low NUSAP1 expression in CESC was related to advanced tumor stage in TCGA database. Moreover, Cox regression analysis showed that NUSAP1 expression correlated significantly with prognosis in the case of patients in TCGA database. GSEA demonstrated that CESC patients with high expression of NUSAP1 were enriched in the G2M checkpoint, MYC targets, and breast cancer ZNF217. Conclusion: The results suggest that identification of DEGs might enhance our understanding of the causes and molecular mechanisms underlying the development of CESC. Moreover, NUSAP1 may play an important role in CESC progression and prognosis and may serve as a valuable indicator of poor survival in CESC.
| S-EPMC7086256 | biostudies-literature
Project description:BACKGROUND:The systemic immune-inflammation index based on peripheral neutrophil, lymphocyte, and platelet counts has shown a prognostic impact in several malignancies. The aim of this study was to determine the prognostic role of systemic immune-inflammation index in patients with pancreatic ductal adenocarcinoma undergoing resection. METHODS:Consecutive patients who underwent surgical resection at the department of surgery at the Medical University of Vienna between 1995 and 2014 were included into this study. The systemic immune-inflammation index was calculated by the formula platelet*neutrophil/lymphocyte. Optimal cutoffs were determined using Youden's index. Uni- and multivariate analyses were calculated by the Cox proportional hazard regression model for overall survival. RESULTS:Three hundred twenty-one patients were included in this study. Clinical data was achieved from a prospective patient database. In univariate survival analysis, elevated systemic immune-inflammation index was found to be significantly associated with shortened patients' overall survival (p?=?0.007). In multivariate survival analysis, systemic immune-inflammation index remained an independent prognostic factor for overall survival (p?=?0.004). No statistical significance could be found for platelet to lymphocyte ratio and neutrophil to lymphocyte ratio in multivariate analysis. Furthermore, area under the curve analysis showed a higher prognostic significance for systemic immune-inflammation index, compared to platelet to lymphocyte ratio and neutrophil to lymphocyte ratio. CONCLUSION:A high systemic immune-inflammation index is an independent, preoperative available prognostic factor in patients with resectable pancreatic ductal adenocarcinoma and is superior to platelet to lymphocyte ratio and neutrophil to lymphocyte ratio for predicting overall survival in pancreatic ductal adenocarcinoma patients.
| S-EPMC7064450 | biostudies-literature
Project description:Pancreatic cancer is one of the most lethal of all types of cancer, with the 5-year survival rate ranging only at 6-7%. The aberrant glucose metabolism is one of the hallmarks of cancer cells, and as a branch of glucose metabolism, hexosamine biosynthesis pathway (HBP) has been reported to play a critical role in the insulin resistance and progression of cancer. Glutamine:fructose-6-phosphate amidotransferase (GFAT1) is the rate-limiting enzyme of the HBP; nevertheless, the prognostic value of GFAT1 in pancreatic cancer remains elusive. In this study, we found that the expression of GFAT1 was increased in pancreatic cancer samples compared to peri-tumor tissues. High expression of GFAT1 was positively associated with lymph node metastasis, pTNM stage and shorter overall survival (OS) in pancreatic cancer patients. GFAT1 was identified as an independent prognosticator for OS, and combining GFAT1 expression with pTNM stage generated a predictive nomogram, which showed better prognostic efficiency for OS in patients with pancreatic cancer. In summary, high GFAT1 expression is identified as an independent predictor of adverse clinical outcome in our small number of pancreatic cancer patients, and the practical prognostic nomogram model may help clinicians in decision making and the design of clinical studies.
| S-EPMC5172351 | biostudies-literature
Project description:The highly malignant feature and difficulties for early diagnosis are the key reasons contributing to the poor prognosis of pancreatic cancer (PC) patients. NFE2L3 is a nuclear transcription factor, which has been reported an important biomarker of several tumors. But the role of NFE2L3 in PC remained undefined. Herein, through qPCR and immunohistochemistry, we found a significantly increased NFE2L3 in PC tissues as compared with adjacent non-tumor tissues. While reducing NFE2L3 expression suppressed the invasion abilities of PC cells, elevated NFE2L3 was found associated with lymph node metastasis (P = 0.001; HR = 3.95; 95% CI: 1.70 - 9.17) and advanced TNM stages (P < 0.001; HR = 4.06; 95% CI: 1.74 - 9.46). Consistently, data from both our two cohorts and the TCGA database revealed that higher NFE2L3 PC carriers had worse outcomes than those lower NFE2L3 expressers. Lastly, we confirmed the regulatory role of NFE2L3 on VEGFA, an important player involved in tumor angiogenesis. Collectively, our investigations suggested the oncogenic role of NFE2L3 in PC development and provided the rational for future adding NFE2L3 for the risk assessment of PC patients.AbbreviationsNFE2L3: NF-E2-related factor 3; UHMK1: U2AF homology motif kinase 1; VEGFA: vascular endothelial growth factor A; GEO: gene expression omnibus; TCGA: The Cancer Genome Atlas; HPDE: human pancreas duct cells; OS: overall survival; IHC: immunohistochemistry; FFPE: formalin-fixed and paraffin-embedded; SEM: standard error of mean.
| S-EPMC6226237 | biostudies-literature
Project description:Background and aim:Periostin is a protein from the Fascilin family. It is commonly present in normal tissues and is responsible for cell adhesion. Evidence has emerged showing that changes in periostin expression play an important role in tumor initiation, development, and progression. This study aims to investigate the effect of periostin in gastric cancer (GC) patients who underwent gastrectomy. Seven hundred and forty-seven GC patients who underwent gastrectomy between December 2006 and July 2011 were included in this study. Methods:Seven hundred and forty-seven cancer tissues and 70 paired adjacent normal tissues were collected. Periostin expression was evaluated by immunohistochemistry. The Gene Expression Omnibus database was used to study the association between the mRNA level and patient's overall survival. The tumor microenvironment was also studied. Results:Periostin expression in stroma was downregulated in tumor tissues but it was upregulated in the epithelial cells. After dividing the tissues according to the Lauren Classification, we found that periostin expression in stroma and epithelial cells was higher in intestinal type than in diffuse type (P<0.001 and P=0.010, respectively). Periostin was an independent predictor of lymph node (LN) metastasis in GC patients. The study of CD163(+) tumor-associated macrophages (TAMs) revealed that in diffuse type GC, periostin expression was associated with CD163(+) TAMs. Conclusion:We found that the periostin expression can predict LN metastasis in patients undergoing curative gastrectomy. Intestinal type GC patients with high periostin level had both a favorable survival and lesser LN metastasis.
| S-EPMC6302807 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor outcomes with current therapies. Gemcitabine is the primary adjuvant drug used clinically, but its effectiveness is limited. In this study, our objective was to use a rationale-driven approach to identify novel biomarkers for outcome in patients with early-stage resected PDAC treated with adjuvant gemcitabine. Using a synthetic lethal screen in human PDAC cells, we identified 93 genes, including 55 genes linked to DNA damage responses (DDR), that demonstrated gemcitabine sensitization when silenced, including CHD7, which functions in chromatin remodeling. CHD7 depletion sensitized PDAC cells to gemcitabine and delayed their growth in tumor xenografts. Moreover, CHD7 silencing impaired ATR-dependent phosphorylation of CHK1 and increased DNA damage induced by gemcitabine. CHD7 was dysregulated, ranking above the 90th percentile in differential expression in a panel of PDAC clinical specimens, highlighting its potential as a biomarker. Immunohistochemical analysis of specimens from 59 patients with resected PDAC receiving adjuvant gemcitabine revealed that low CHD7 expression was associated with increased recurrence-free survival (RFS) and overall survival (OS), in univariate and multivariate analyses. Notably, CHD7 expression was not associated with RFS or OS for patients not receiving gemcitabine. Thus, low CHD7 expression was correlated selectively with gemcitabine sensitivity in this patient population. These results supported our rationale-driven strategy to exploit dysregulated DDR pathways in PDAC to identify genetic determinants of gemcitabine sensitivity, identifying CHD7 as a novel biomarker candidate to evaluate further for individualizing PDAC treatment.
| S-EPMC4025946 | biostudies-literature
Project description:BackgroundNeuroligin1 (NLGN1) is a main component of excitatory glutamatergic synapses complex and is important for synapse assembly and function. The clinical value of NLGN1 in colorectal cancer (CRC) is not clear.MethodsWe obtained the expression data of 1143 CRC patients from 3 independent Gene Expression Omnibus (GEO) datasets (GSE32323, GSE24551, GSE39582) and The Cancer Genome Atlas (TCGA) to make the comparison of the NLGN1 expression level between CRC tissues and matched noncancerous tissues, and to evaluate its value in predicting survival of CRC patients. At the protein level, these results were further confirmed by immunohistochemical staining of 52 CRC samples in our own centre. Finally, the function of NLGN1 was explored by gene set enrichment analysis (GSEA).ResultsIncreased mRNA and protein levels of NLGN1 expression were associated with worse overall survival or recurrence-free survival in CRC patients from 2 GEO datasets, the TCGA database, and our cohort. In addition, multivariate regression analysis showed that NLGN1 was an independent poor prognostic factor of survival in patients with CRC in TCGA database (OR = 2.524, P = 0.010). Functional analysis revealed that NLGN1 was correlated with function involving the Hedgehog signaling pathway, mismatch repair process, and some material metabolism processes.ConclusionsThis study is the first to implicate and verify NLGN1 as a new poor prognostic marker for CRC.
| S-EPMC8327451 | biostudies-literature