Endothelial Nitric Oxide Synthase Traffic Inducer (NOSTRIN) is a Negative Regulator of Disease Aggressiveness in Pancreatic Cancer.
Endothelial Nitric Oxide Synthase Traffic Inducer (NOSTRIN) is a Negative Regulator of Disease Aggressiveness in Pancreatic Cancer.
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DOI：
10.1158/1078-0432.ccr-16-0511
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发表时间：
2016-12-15
期刊：
影响因子：
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通讯作者：
Hussain SP
中科院分区：
文献类型：
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作者：
Wang J;Yang S;He P;Schetter AJ;Gaedcke J;Ghadimi BM;Ried T;Yfantis HG;Lee DH;Gaida MM;Hanna N;Alexander HR;Hussain SP
胰腺导管腺癌（PDAC）是一种难以治疗的疾病。描述疾病侵袭性和治疗耐药性的关键途径，可以确定有效的治疗靶点。我们的目的是通过比较生存期极差（≤7个月）的早期PDAC患者和手术切除后存活2年或更长时间的患者肿瘤的基因表达谱，确定促进疾病侵袭性的关键途径。采用affymetrix GeneChip Human 1.0 ST阵列，在PDAC测试队列（N=50）中进行肿瘤基因表达谱分析，其中包括短期（≤7个月，N=11）和长期（≥2年，N=14）患者。利用Cox回归、Kaplan Meier分析和通路分析确定与疾病侵袭性相关的关键基因，并在独立队列中进行机制和功能分析验证。基因表达谱鉴定出短生存组和长生存组差异表达基因1820个，其中炎症基因网络居首位。内皮型一氧化氮合酶交通诱导因子（Endothelial Nitric Oxide Synthase Traffic Inducer， NOSTRIN）的低表达与最差生存率相关，表明其在疾病进展中的潜在抑制作用。NOSTRIN过表达抑制胰腺癌细胞的迁移和侵袭，增强对化疗药物吉西他滨的敏感性。NOSTRIN通过抑制内皮一氧化氮合酶（eNOS）的激活来抑制一氧化氮（NO）的产生。此外，miR-221与NOSTRIN的3'UTR结合并抑制其表达，miR-221表达的增加与PDAC的生存率低相关。我们的研究结果表明，NOSTRIN是一种潜在的疾病侵袭性负调节因子，这可能是设计改进PDAC治疗策略的目标。
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. 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. Gene-expression profiling identified 1,820 differentially expressed genes between short and long survival groups with inflammatory gene network ranking 1st. 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. Our findings showed that NOSTRIN is a potential negative regulator of disease aggressiveness, which may be targeted for designing improved treatment strategy in PDAC.