Hypoxia-induced lncRNA-NUTF2P3-001 contributes to tumorigenesis of pancreatic cancer by derepressing the miR-3923/KRAS pathway.
Hypoxia-induced lncRNA-NUTF2P3-001 contributes to tumorigenesis of pancreatic cancer by derepressing the miR-3923/KRAS pathway.
复制标题
缺氧诱导的lncRNA-NUTF2P3-001通过去抑制miR-3923/KRAS通路促进胰腺癌的肿瘤发生
DOI：
10.18632/oncotarget.6830
复制
发表时间：
2016-02-02
期刊：
影响因子：
--
通讯作者：
Zhao G
中科院分区：
文献类型：
--
作者：
Li X;Deng SJ;Zhu S;Jin Y;Cui SP;Chen JY;Xiang C;Li QY;He C;Zhao SF;Chen HY;Niu Y;Liu Y;Deng SC;Wang CY;Zhao G
最近的研究表明，长链非编码rna （lncRNAs）在许多癌症中起着至关重要的作用，但其在胰腺癌中的功能却很少被阐明。本研究鉴定了一个功能性lncRNA及其在胰腺癌肿瘤发生中的潜在作用。lncRNAs和mRNA的芯片联合检测显示，lncRNA-NUTF2P3-001在胰腺癌和慢性胰腺炎组织中显著过表达，与KRAS mRNA的表达呈正相关。下调lncRNA-NUTF2P3-001后，在体外和体内均可显著抑制胰腺癌细胞的增殖和侵袭，同时KRAS表达降低。双荧光素酶报告基因实验进一步验证了lncRNA-NUTF2P3-001和KRAS mRNA的3'UTR与miR-3923竞争性结合。此外，miR-3923过表达模拟了lncRNA-NUTF2P3-001-siRNA对被miR-3923抑制剂拯救的胰腺癌细胞的抑制作用。具体而言，本研究进一步揭示了lncrna - nutf2p53 -001在缺氧和CoCl2处理下的胰腺癌细胞中表达上调，这可能与KRAS启动子上游缺氧诱导因子-1α (HIF-1α)与缺氧反应元件（HREs）的结合有关。胰腺癌患者数据显示lncRNA-NUTF2P3-001与KRAS呈正相关，与肿瘤分期晚期、预后较差相关。因此，我们的数据为肿瘤致癌基因KRAS提供了一种新的lncrna介导的调控机制，并提示lncRNA-NUTF2P3-001和miR-3923可以作为胰腺癌的新的预测因子和治疗靶点。
Recent studies indicate that long non-coding RNAs (lncRNAs) play crucial roles in numerous cancers, while their function in pancreatic cancer is rarely elucidated. The present study identifies a functional lncRNA and its potential role in tumorigenesis of pancreatic cancer. Microarray co-assay for lncRNAs and mRNAs demonstrates that lncRNA-NUTF2P3-001 is remarkably overexpressed in pancreatic cancer and chronic pancreatitis tissues, which positively correlates with KRAS mRNA expression. After downregulating lncRNA-NUTF2P3-001, the proliferation and invasion of pancreatic cancer cell are significantly inhibited both in vitro and vivo, accompanying with decreased KRAS expression. The dual-luciferase reporter assay further validates that lncRNA-NUTF2P3-001 and 3′UTR of KRAS mRNA competitively bind with miR-3923. Furthermore, miR-3923 overexpression simulates the inhibiting effects of lncRNA-NUTF2P3-001-siRNA on pancreatic cancer cell, which is rescued by miR-3923 inhibitor. Specifically, the present study further reveals that lncRNA-NUTF2P3-001 is upregulated in pancreatic cancer cells under hypoxia and CoCl2 treatment, which is attributed to the binding of hypoxia-inducible factor-1α (HIF-1α) to hypoxia response elements (HREs) in the upstream of KRAS promoter. Data from pancreatic cancer patients show a positive correlation between lncRNA-NUTF2P3-001 and KRAS, which is associated with advanced tumor stage and worse prognosis. Hence, our data provide a new lncRNA-mediated regulatory mechanism for the tumor oncogene KRAS and implicate that lncRNA-NUTF2P3-001 and miR-3923 can be applied as novel predictors and therapeutic targets for pancreatic cancer.