Long non-coding RNAs in pancreatic cancer

描述（由申请人提供）：胰腺癌是西方国家癌症相关死亡的第四大原因，也是最具破坏性的原因之一，其发病率和死亡率几乎相同。到确诊时，中位生存期小于 只有5%的病人能在五年后存活。胰腺导管腺癌（PDAC）占所有胰腺癌的90%以上;它通常在生命后期被发现，尽管称为胰腺上皮内瘤变（PanIN）的前体病变在年轻个体中普遍存在。早期发现病变，当肿瘤仍然局限于 胰腺癌允许手术切除结合化疗，这是目前唯一显示出预期寿命显著增加的治疗方法。不幸的是，早期病变大多无症状，并且在诊断时，PDAC通常已经浸润周围组织或已经转移。因此，更好地了解PDAC的启动、胰腺肿瘤生物学和整个PDAC进展过程中受影响的信号通路将为我们提供更好的工具来鉴定早期生物标志物，并开发具有治疗潜力的新的、更特异的靶点。在这项研究中，我们建议确定长的非编码RNA（lncRNA），可能参与胰腺癌的进展。lncRNA是一组不同的转录本，类似于mRNA，但不编码蛋白质。虽然目前还不清楚目前注释的lncRNA中哪一部分是真正功能性的，但有相当多的证据表明lncRNA参与癌症。此外，几种lncRNA已显示在已知在PDAC中改变的调节途径中起作用。LincRNA也被证明比编码基因更具组织特异性，这使它们成为药物靶向的最佳选择，以及良好的生物标志物候选者。先前，微阵列分析鉴定了在PDAC中差异调节的lncRNA。然而，该研究仅查询了76个注释良好的lncRNA，而预测哺乳动物基因组中存在约10，000个lncRNA。在这项研究中，我们提出了一种系统的方法来识别和表征lncRNA，这可能是重要的进展和/或维持胰腺癌。该补助金的目的是：1。使用高通量测序数据和计算生物学鉴定胰腺癌肿瘤和循环液的不同阶段中的lncRNA; 2.选择并验证在PDAC和健康胰腺中差异表达的lncRNA的子集;以及3.确定候选lncRNA调控的功能和分子途径。这是一个令人兴奋的发现为基础的方法来表征新的因素参与PDAC生物学。

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer-related deaths in western countries and also one of the most devastating, with nearly identical incidence and mortality rates. By the time of diagnosis, the median survival is less than six months and only 5% of patients will survive after five years. Pancreatic ductal adenocarcinoma (PDAC) accounts for over 90% of all pancreatic cancer; it is usually detected late in life, although precursor lesions called Pancreatic Intraepithelial Neoplasias (PanINs) are prevalent in young individuals. Early detection of lesions, when the tumor is still confined to the pancreas, allows for surgical resection combined with chemotherapy, which is currently the only treatment that shows substantial increase in life expectancy Unfortunately, early lesions are mostly asymptomatic and by the time of diagnosis PDAC has usually infiltrated surrounding tissues or has already metastasized. Thus, a better understanding of the initiation of PDAC, pancreatic tumor biology and the signaling pathways affected throughout PDAC progression will provide us with better tools to identify early stage biomarkers and to develop novel and more specific targets with therapeutic potential. In this study we propose to identify long non-coding RNAs (lncRNAs) that may be involved in the progression of pancreatic cancer. LncRNAs are a diverse group of transcripts that resemble mRNAs but do not encode proteins. Although it is not clear what fraction of the currently annotated lncRNAs are truly functional there is considerable evidence that lncRNAs are involved in cancer. Furthermore, several lncRNAs have been shown to function in regulatory pathways that are known to be altered in PDAC. LincRNAs have also been shown to be more tissue-specific than coding genes, which make them optimal for drug targeting, as well as good biomarker candidates. Previously, a microarray analysis identified lncRNAs that are differentially regulated in PDAC. However, the study queried only 76 well-annotated lncRNAs, whereas it is predicted that approximately 10,000 lncRNAs exist in the mammalian genome. In this study, we propose to perform a systematic approach to identify and characterize lncRNAs that could be important for the progression and/or maintenance of pancreatic cancer. The aims of this grant are to: 1. Identify lncRNAs in different stages of pancreatic adenocarcinoma tumors and circulating fluids using high throughput sequencing data and computational biology; 2. Select and validate a subset of lncRNAs differentially expressed in PDAC and healthy pancreas; and 3. Identify the functions and molecular pathways regulated by candidate lncRNAs. This is an exciting discovery based approach to characterize novel factors involved in PDAC biology.