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Endothelial Nitric Oxide Synthase Traffic Inducer (NOSTRIN) is a Negative Regulator of Disease Aggressiveness in Pancreatic Cancer.

ABSTRACT: PURPOSE:Pancreatic ductal adenocarcinoma (PDAC) is refractory to available treatments. Delineating critical pathways, responsible for disease aggressiveness and therapeutic resistance, may identify effective therapeutic targets. We aimed to identify key pathways contributing to disease aggressiveness by comparing gene expression profiles of tumors from early-stage PDAC cases with extremely poor survival (?7 months) and those surviving 2 years or more following surgical resection. EXPERIMENTAL DESIGN:Gene expression profiling was performed in tumors in a test cohort of PDAC (N = 50), which included short (?7 months, N = 11) and long surviving (?2 years, N = 14) patients, using affymetrix GeneChip Human 1.0 ST array. Key genes associated with disease aggressiveness were identified, using Cox regression, Kaplan-Meier, and pathway analyses with validations in independent cohorts for mechanistic and functional analyses. RESULTS:Gene expression profiling identified 1,820 differentially expressed genes between short and long survival groups with inflammatory gene network ranking first. Lower expression of endothelial nitric oxide synthase traffic inducer (NOSTRIN) was associated with worst survival indicating its potential inhibitory role in disease progression. NOSTRIN overexpression suppressed migration and invasion of pancreatic cancer cells and enhanced sensitivity to chemotherapeutic drug gemcitabine. NOSTRIN inhibited production of nitric oxide (NO) by suppressing the activation of endothelial nitric oxide synthase (eNOS). Furthermore, miR-221, bound to the 3'UTR of NOSTRIN and suppressed its expression, and an increased miR-221 expression associated with poor survival in PDAC. CONCLUSIONS:Our findings showed that NOSTRIN is a potential negative regulator of disease aggressiveness, which may be targeted for designing improved treatment strategy in PDAC. Clin Cancer Res; 22(24); 5992-6001. ©2016 AACR.

SUBMITTER: Wang J

PROVIDER: S-EPMC5161709 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Endothelial Nitric Oxide Synthase Traffic Inducer (NOSTRIN) is a Negative Regulator of Disease Aggressiveness in Pancreatic Cancer.

Wang Jian J Yang Shouhui S He Peijun P Schetter Aaron J AJ Gaedcke Jochen J Ghadimi B Michael BM Ried Thomas T Yfantis Harris G HG Lee Dong H DH Gaida Matthias M MM Hanna Nader N Alexander H Richard HR Hussain S Perwez SP

Clinical cancer research : an official journal of the American Association for Cancer Research 20160708 24

<h4>Purpose</h4>Pancreatic ductal adenocarcinoma (PDAC) is refractory to available treatments. Delineating critical pathways, responsible for disease aggressiveness and therapeutic resistance, may identify effective therapeutic targets. We aimed to identify key pathways contributing to disease aggressiveness by comparing gene expression profiles of tumors from early-stage PDAC cases with extremely poor survival (≤7 months) and those surviving 2 years or more following surgical resection.<h4>Expe ...[more]

PMID: 27401251

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Project description:BackgroundNOSTRIN, abundantly expressed in colon, was reported to be anti-angiogenic, anti-invasive and anti-inflammatory. NOSTRIN expression was inversely related to survival of pancreatic ductal adeno-carcinoma patients. Yet its function and regulatory mechanism in CRC remains elusive.MethodsNOSTRIN's influence on EMT of CRC cells were analysed using realtime PCR array containing the functional EMT-transcriptome followed by western blotting. Regulation of oncogenic potential of CRC cells by NOSTRIN was elucidated using soft agar colony formation, trans-well invasion, wound healing and colonosphere formation assays. Biochemical assays were used to reveal mechanism of NOSTRIN function. Human CRC tissue array was used to test NOSTRIN mark in control and CRC disease stages.ResultsWe showed here that CRC cell lines with less NOSTRIN expression has more invasive and migratory potential. NOSTRIN affected EMT-associated transcriptome of CRC cells by down regulating 33 genes that were functionally annotated to transcription factors, genes important for cell growth, proliferation, migration, cell adhesion and cytoskeleton regulators in CRC cells. NOSTRIN over-expression significantly reduced soft agar colony formation, wound healing and cell invasion. In line with this, RNA interference of Nostrin enhanced metastatic potential of CRC cells. Furthermore, stable overexpression of NOSTRIN in CRC cell line not only curtailed its ability to form colonosphere but also decreased expression of stemness markers CD133, CD44 and EpCAM. NOSTRIN's role in inhibiting self-renewal was further confirmed using BrdU incorporation assay. Interestingly, NOSTRIN formed immune-complex with Cdk1 in CRC cells and aided in increase of inhibitory Y15 and T14 phosphorylation of Cdk1 that halts cytokinesis. These ex vivo findings were substantiated using human colon cancer tissue array containing cDNAs from patients' samples with various stages of disease progression. Significant decrease in NOSTRIN expression was found with initiation and progression of advanced colon cancer disease stages.ConclusionWe illustrate function of a novel molecule, NOSTRIN in curtailing EMT and maintenance of CRC cell stemness. Our data validates importance of NOSTRIN mark during onset and disease progression of CRC indicating its diagnostic potential.

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Endothelial Nitric Oxide Synthase Traffic Inducer (NOSTRIN) is a Negative Regulator of Disease Aggressiveness in Pancreatic Cancer.

Publications

Endothelial Nitric Oxide Synthase Traffic Inducer (NOSTRIN) is a Negative Regulator of Disease Aggressiveness in Pancreatic Cancer.

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