Inducible nitric oxide synthase enhances disease aggressiveness in pancreatic cancer.
Inducible nitric oxide synthase enhances disease aggressiveness in pancreatic cancer.
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DOI：
10.18632/oncotarget.10323
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发表时间：
2016-08-16
期刊：
影响因子：
--
通讯作者：
Hussain SP
中科院分区：
文献类型：
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作者：
Wang J;He P;Gaida M;Yang S;Schetter AJ;Gaedcke J;Ghadimi BM;Ried T;Yfantis H;Lee D;Weiss JM;Stauffer J;Hanna N;Alexander HR;Hussain SP
胰腺癌是最致命的恶性肿瘤之一，并且对现有的治疗方法很难治疗。胰腺导管腺癌（PDAC）表达高水平的诱导型一氧化氮合酶（NOS 2），其引起持续的一氧化氮（NO）产生。我们测试了一个异常增加的NO释放增强PDAC的发展和进展的假设。肿瘤中增强的NOS 2表达与PDAC患者（N = 107）的不良生存率显著相关，并在独立队列中得到验证。然后，我们在PDAC的本地小鼠模型中遗传靶向NOS 2，以检查NOS 2缺乏对疾病进展和生存的影响。在LSL-KrasG 12 D/+; LSL-Trp 53 R172 H/+; Pdx-1-Cre（KPC）小鼠中，NOS 2的基因切除显著延长了生存期并降低了肿瘤严重程度。从NOS 2缺陷型KPC（NKPC）小鼠中分离的原发性肿瘤细胞与来自KPC小鼠的肿瘤细胞相比，显示出增殖和侵袭性降低。此外，与KPC小鼠肿瘤相比，NKPC肿瘤显示pERK表达减少，Forkhead box转录因子O（FOXO 3）（肿瘤抑制因子）失活减少，oncomir-21表达减少。总之，这些发现表明，NOS 2是早期切除PDAC患者预后的预测因子，并提供了靶向NOS 2可能在这种致命恶性肿瘤中具有潜在治疗价值的原理证明。
Pancreatic cancer is one of the most lethal malignancies and is refractory to the available treatments. Pancreatic ductal adenocarcinoma (PDAC) expresses high level of inducible nitric oxide synthase (NOS2), which causes sustained production of nitric oxide (NO). We tested the hypothesis that an aberrantly increased NO-release enhances the development and progression of PDAC. Enhanced NOS2 expression in tumors significantly associated with poor survival in PDAC patients (N = 107) with validation in independent cohorts. We then genetically targeted NOS2 in an autochthonous mouse model of PDAC to examine the effect of NOS2-deficiency on disease progression and survival. Genetic ablation of NOS2 significantly prolonged survival and reduced tumor severity in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mice. Primary tumor cells isolated from NOS2-deficient KPC (NKPC) mice showed decreased proliferation and invasiveness as compared to those from KPC mice. Furthermore, NKPC tumors showed reduced expression of pERK, a diminished inactivation of Forkhead box transcription factor O (FOXO3), a tumor suppressor, and a decrease in the expression of oncomir-21, when compared with tumors in KPC mice. Taken together, these findings showed that NOS2 is a predictor of prognosis in early stage, resected PDAC patients, and provide proof-of-principle that targeting NOS2 may have potential therapeutic value in this lethal malignancy.