Dataset Information

Linc00675 is a novel marker of short survival and recurrence in patients with pancreatic ductal adenocarcinoma.

ABSTRACT:

Aim

To detect linc00675 expression in pancreatic ductal adenocarcinoma (PDAC), to analyze the relationship between the expression level of linc00675 and the clinical pathological characteristics, to explore the biological functions of linc00675, and to determine whether linc00675 has independent prognostic value in PDAC.

Methods

We studied linc00675 expression among eight histologically confirmed PDAC tissue samples and four chronic pancreatitis tissue samples through microarray screening. RT-qPCR was conducted to further investigate linc00675 expression in PDAC cell lines as well as archived tissues from a large cohort of PDAC patients. The correlations between the level of lnc00675 and clinicopathological characteristics and survival in patients with pancreatic cancer were evaluated using Correlation analysis. Univariate and multivariate analyses were conducted to predict whether lnc00675 expression is an independent prognostic and recurrence factor in patients with pancreatic cancer. After downregulating the expression of linc00675 through siRNA, MTT assay, flow cytometry, transwell assay and Western blot were used to explore the biological function of linc00675 in proliferation, invasion, and cell cycle progression of pancreatic cancer cells. The relative molecular expression levels of epithelial-mesenchymal transition were determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot.

Results

The expression of Linc00675 in PDAC tissue samples was shown to be 672 times that in chronic pancreatitis tissue samples by microarray screening (P = 3.69 × 10(-5)). This finding was confirmed in tumor tissues from 90 patients with PDAC compared with adjacent normal tissue samples by quantitative RT-PCR. We found that linc00675 overexpression positively correlated with lymph node metastasis (P = 0.005), perineural invasion (P = 0.006), and poor survival (P < 0.001). Univariate and multivariate analyses showed that linc00675 expression served as an independent predictor of overall survival (P = 0.009). Additionally, receiver operating characteristic curve analysis showed that high linc00675 might serve as a predictor of tumor progression within 6 mo to a year after surgery. In vitro functional analysis demonstrated that knockdown of linc00675 attenuated pancreatic cancer cell proliferation and invasion as well as induced S phase arrest. Suppression of linc00675 in pancreatic cancer cells resulted can reverse the progress of epithelial-mesenchymal transition.

Conclusion

Linc00675 may function as an oncogene during PDAC development, and its expression is an independent predictor of unfavorable prognosis in patients with PDAC.

SUBMITTER: Li DD

PROVIDER: S-EPMC4541386 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Publications

Linc00675 is a novel marker of short survival and recurrence in patients with pancreatic ductal adenocarcinoma.

Li Dou-Dou DD Fu Zhi-Qiang ZQ Lin Qing Q Zhou Yu Y Zhou Quan-Bo QB Li Zhi-Hua ZH Tan Lang-Ping LP Chen Ru-Fu RF Liu Yi-Min YM

World journal of gastroenterology 20150801 31

<h4>Aim</h4>To detect linc00675 expression in pancreatic ductal adenocarcinoma (PDAC), to analyze the relationship between the expression level of linc00675 and the clinical pathological characteristics, to explore the biological functions of linc00675, and to determine whether linc00675 has independent prognostic value in PDAC.<h4>Methods</h4>We studied linc00675 expression among eight histologically confirmed PDAC tissue samples and four chronic pancreatitis tissue samples through microarray s ...[more]

PMID: 26309360

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a dismal prognosis. However, while most patients die within the first year of diagnosis, very rarely, a few patients can survive for >10 years. Better understanding the molecular characteristics of the pancreatic adenocarcinomas from these very-long-term survivors (VLTS) may provide clues for personalized medicine and improve current pancreatic cancer treatment. To extend our previous investigation, we examined the proteomes of individual pancreas tumor tissues from a group of VLTS patients (survival ?10 years) and short-term survival patients (STS, survival <14 months). With a given analytical sensitivity, the protein profile of each pancreatic tumor tissue was compared to reveal the proteome alterations that may be associated with pancreatic cancer survival. Pathway analysis of the differential proteins identified suggested that MYC, IGF1R and p53 were the top three upstream regulators for the STS-associated proteins, and VEGFA, APOE and TGF?-1 were the top three upstream regulators for the VLTS-associated proteins. Immunohistochemistry analysis using an independent cohort of 145 PDAC confirmed that the higher abundance of ribosomal protein S8 (RPS8) and prolargin (PRELP) were correlated with STS and VLTS, respectively. Multivariate Cox analysis indicated that 'High-RPS8 and Low-PRELP' was significantly associated with shorter survival time (HR=2.69, 95% CI 1.46-4.92, P=0.001). In addition, galectin-1, a previously identified protein with its abundance aversely associated with pancreatic cancer survival, was further evaluated for its significance in cancer-associated fibroblasts. Knockdown of galectin-1 in pancreatic cancer-associated fibroblasts dramatically reduced cell migration and invasion. The results from our study suggested that PRELP, LGALS1 and RPS8 might be significant prognostic factors, and RPS8 and LGALS1 could be potential therapeutic targets to improve pancreatic cancer survival if further validated.

Project description:BackgroundProgrammed cell death protein 1 (PD-1) is a key immune checkpoint that regulates peripheral tolerance and protects against autoimmunity. Programmed death ligand-2 (PD-L2) is a less studied ligand to PD-1 and has yet to be fully explored, especially in pancreatic ductal adenocarcinoma (PDAC).MethodsIn this study, we performed immunohistochemistry to detect the PD-L2, CD3, CD8, transforming growth factor-β2 (TGF-β2) and FOXP3 levels in paraffin sections from 305 patients with resected PDAC as a training set. Expression levels of intratumoral and stromal immune markers were compared in relation to survival using Kaplan-Meier curves, random survival forest model and survival tree analysis. A multivariable Cox proportional-hazards model of associated markers was used to calculate the risk scores.ResultsPD-L2 was expressed in 71.5% of PDAC samples and showed strong correlations with CD3+, CD8+ T cells and FOXP3+ regulatory T cell densities. High levels of intratumoral PD-L2 and FOXP3 were related to poor survival; only stromal FOXP3 overexpression was associated with worse prognosis. Four patterns generated from survival tree analysis demonstrated that PD-L2lowstromalFOXP3low patients had the longest survival, while PD-L2highintratumoralCD3low patients had the shortest survival (P < 0.001). The area under the curve was 0.631(95% confidence interval (CI): 0.447-0.826) for the immune marker-based signature and 0.549 (95% CI: 0.323-0.829; P < 0.001) for the clinical parameter-based signature, which was consistent with the results in the validation set including 150 patients (P < 0.001). A higher risk score indicated shorter survival and could serve as an independent prognostic factor. PD-L2 was also showed associated with TGF-β2 and other immune molecules based on bioinformatics analysis.ConclusionsOur work highlighted PD-L2 as a promising immunotherapeutic target with prognostic value combined with complex tumor infiltrating cells in PDAC.

Dataset Information

Linc00675 is a novel marker of short survival and recurrence in patients with pancreatic ductal adenocarcinoma.

Aim

Methods

Results

Conclusion

Publications

Linc00675 is a novel marker of short survival and recurrence in patients with pancreatic ductal adenocarcinoma.

Similar Datasets

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