修回日期: 2014-12-16
接受日期: 2014-12-25
在线出版日期: 2015-02-08
胰腺癌是一种侵袭能力强、生存率极低的恶性肿瘤. 最近研究显示长链非编码RNA(long noncoding RNA, lncRNA)的异常表达与胰腺癌有关. lncRNA是一类长度超过200个核苷酸的非编码RNA分子, 他不编码蛋白质, 在转录水平、转录后、表观遗传学等水平调控基因的表达, 参与肿瘤细胞的增殖、凋亡、侵袭、转移过程, 本文就lncRNA在胰腺癌中的异常表达及机制研究做一综述, 为胰腺癌的诊治提供新思路.
核心提示: 胰腺癌是一种侵袭能力强、生存率极低的恶性肿瘤, 长链非编码RNA(long noncoding RNA, lncRNA)在胰腺肿瘤的进程中扮演着重要的调节性角色, 多种lncRNA参与调控胰腺癌基因的表达, 这些lncRNA有望为胰腺癌诊治水平提高的重要的突破点.
引文著录: 潘超, 杨坤兴. 长链非编码RNA在胰腺癌中的研究进展. 世界华人消化杂志 2015; 23(4): 563-569
Revised: December 16, 2014
Accepted: December 25, 2014
Published online: February 8, 2015
Pancreatic cancer is one of the most aggressive malignances with a dismal survival rate. Recent studies have shown that dysregulated expression of long noncoding RNAs (lncRNAs) is closely associated with pancreatic cancer. lncRNAs are RNA molecules that are longer than 200 nt and lack an open reading frame. They regulate gene expression at the epigenetic, transcriptional and post-transcriptional levels and play important roles in proliferation, apoptosis, invasiveness and metastasis of tumor cells. This review focuses on the dysregulated expression and mechanism of lncRNAs in pancreatic cancer, in order to provide new clues to the diagnosis and treatment of pancreatic carcinoma.
- Citation: Pan C, Yang KX. Long noncoding RNAs in pancreatic cancer. Shijie Huaren Xiaohua Zazhi 2015; 23(4): 563-569
- URL: https://www.wjgnet.com/1009-3079/full/v23/i4/563.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v23.i4.563
胰腺癌是一种高度侵袭的恶性肿瘤, 预后极差[1]. 尽管对胰腺癌治疗研究付出了很多努力, 但胰腺癌的生存率并没有明显的提高[2,3], 目前, 外科手术切除被认为是治愈胰腺癌的唯一方式, 但术后5年生存率不到6%, 即便如此, 也仅仅只有15%-20%的患者存在手术机会[4-7]. 胰腺癌诊治的进步依赖于病理生理学机制的阐明, 研究清楚胰腺肿瘤发生、发展、侵袭、转移的机制至关重要. 最新的研究[8,9]显示长链非编码RNA(long noncoding RNA, lncRNA)在肿瘤基因表达中扮演着重要的调节性角色, 他可以在多个水平调控基因的表达, 影响细胞的生长、发育, 从而参与到肿瘤细胞的发生、发展、转移及预后中. 因此, 寻找出胰腺肿瘤组织中或血液中异常表达的、可靠的lncRNA作为早期胰腺癌诊断的标志物显得尤为重要. 此外, 将lncRNA作为胰腺癌靶向治疗的研究对象也是一个极具价值的研究方向.
人类基因组中98.5%的DNA序列是非编码的DNA序列, 而在转录序列中, 90%以上的区域也是非编码的区域[10], 依据转录本的长度, 可以将非编码RNA分为两类, 一类为小非编码RNA, 长度在20-200 nt, 另一类是长度>200 nt的长链非编码RNA[11,12], lncRNA起初被认为是RNA聚合酶Ⅱ转录的副产物, 被看为转录的"噪音", 进一步研究[13]发现lncRNA具有高度保守的空间二级结构, 复杂的亚细胞定位,有些还具有组织和时空特异性, 他们存在实际的功能, 参与到基因表达的调节. lncRNA数量众多、序列保守性差、缺乏开放的阅读框架, 但仍可以根据lncRNA与蛋白编码基因的位置关系将lncRNA分为5类: 正义lncRNA、反义lncRNA、双向lncRNA、基因间lncRNA和基因内lncRNA[14]. lncRNA的调控机制复杂多样, 在转录水平、转录后调控、基因组印记、染色质的修饰、剪接调控、细胞周期调控、表观遗传学调控中均能发挥重要作用[15-18].
lncRNA是近些年的研究热点, lncRNA与人类的很多疾病有关联, 其中主要包括肿瘤疾病[19]. lncRNA的表达变化与许多临床资料的特征具有相关性[20-23], 这表明lncRNA可能在肿瘤发生、发展、侵袭、转移过程中产生重要作用. 在肿瘤治疗难点的胰腺癌中, 也有一些lncRNA的报道, 本文综述了在胰腺肿瘤中异常表达的lncRNA, 为胰腺癌的早期诊断及预后判断提供新的思考, 同时也为以后胰腺癌的治疗提供新的靶点.
肺腺癌转移相关转录子1(metastasis-associated lung adenocarcinoma transcript 1, MALAT1)是一段高度保守的长度为8700核苷酸的lncRNA, 基因定位于11q13.1. 最早是在非小细胞肺癌研究中发现[24], 现已发现在多种消化系肿瘤中高表达. 在Liu等[25]、Jiao等[26]的实验证实胰腺癌组织及胰腺癌细胞中MALAT1较正常组织及细胞高表达, 临床病理资料显示MALAT1表达水平与肿瘤的大小、分期、浸润深度有关. 在AsPC-1和CFPAC-1胰腺细胞株中, MALAT1的低表达可以引起肿瘤细胞的增殖、集落形成减缓, 细胞计数及蛋白印迹实验显示抑制MALAT1的表达可以引起G2/M细胞周期停滞并且诱导细胞的凋亡[26]. 胰腺肿瘤细胞上皮间质转化(epithelial-mesenchymal transition, EMT)变化可以增强胰腺癌的侵袭、转移的能力[27]. 而MALAT1可以通过诱导EMT变化, 让肿瘤细胞获得类似干细胞样的性能[26,28,29]. 一些基质金属蛋白酶(matrix metalloprotein, MMP)能破坏肿瘤细胞侵袭的组织学屏障, 为肿瘤生长提供空间, 促进EMT的发生[30], 研究[26]发现, 当MALAT1的表达受抑制时, MMP-2、MMP-9表达也降低. 这预示着MALAT1参与胰腺肿瘤基因的调节与金属蛋白酶、EMT密不可分.
H19是一段母源性印记基因, 位于人染色体11p15.5, 全长超过2.3 kb. 在胚胎发育阶段, 许多器官中的H19呈现高表达, 但出生之后的H19表达量则明显很少, 仅在心肌及骨骼肌中表达[31,32]. 研究发现H19基因上游4 kb处有一个差异甲基化区(differentially methylated region, DMR), 他能够参与H19的表达及调控, 与H19的功能密切相关[33]. 随着长链非编码RNA的研究增多发现H19在多种消化系肿瘤中异常表达, 同时兼具癌基因和抑癌基因的双重角色[34]. 有研究显示H19在胰腺癌组织中的表达与癌旁正常组织相比是异常增高的, 并且存在远端转移的原发胰腺癌H19表达量比没有远处转移的原发胰腺癌的表达量明显增高, 表明H19的异常表达与胰腺癌的转移能力密切相关. 而可能的机制是H19通过抑制let-7的功能来促进肿瘤侵袭[35]. MicroRNA let-7是已知的胰腺癌的一个抑制基因[36,37], let-7的靶向高迁移率族蛋白A2(high mobility group A2, HMGA2)在EMT中起重要作用, 而EMT变化在胰腺肿瘤的侵袭和转移中扮演着重要角色[38,39]. 因此, H19可以通过H19/let-7/HMGA2/EMT通路在胰腺癌的侵袭、转移中发挥作用.
HOTAIR HOX转录反义RNA(HOX transcript antisense RNA, HOTAIR)存在于哺乳动物的基因组序列中, 长度为2158 nt, 定位于HOXC家族HOXC11与HOXC12之间的位点上, 包含6个外显子[40]. HOTAIR是目前研究的较为透彻的lncRNA, 在多种消化系肿瘤中异常表达[41,42]. HOTAIR的5'端和3'端基因序列及结构相对稳定, 能够特异性的结合多梳蛋白, 5'端与多梳蛋白抑制复合体2(polycomb repressive complex 2, PRC2)结合, 3'端结合组蛋白去甲基化酶复合体[(LSD1/CoREST)/REST]复合体, [(LSD1/CoREST)/REST]复合体由赖氨酸特异性组蛋白去甲基化酶(lysine specific demethylase 1, LSD1)、共阻遏蛋白(co-repressor of REST)、神经元基因沉默转录因子(RE1-silencing transcription factor, REST)组成. 当5'端和3'端同时结合这两种复合体时, 可以介导他们定位于HOXD位点上, 分别使染色体组蛋白H3第27位赖氨酸(histone H3 lysine K27, H3K27)三甲基化和组蛋白H3第4位赖氨酸去二甲基化(histone H3 dimethyl Lys4, H3K4me2), 从而引起下游基因的表达沉默[18]. Kim等[43]实验中指出, HOTAIR在胰腺癌肿瘤组织中高表达, 表达水平与肿瘤外的侵袭及浸润密切相关, 在胰腺癌细胞株(Pancl及L3.6pL)实验中, 抑制HOTAIR的表达, 肿瘤细胞的增殖能力减弱, 凋亡增多, 侵袭能力下降. 体外动物实验也发现敲降HOTAIR可以抑制裸鼠肿瘤的生长.
gas5(growth arrest-specific 5)位于人类染色体1q25.1, 长度为4983 bp, 含有多个内含子和外显子. 内含子编码核小RNA, 他的外显子包含开放阅读框架却不编码功能性蛋白质. 最初是作为生长停滞细胞中高表达的基因被发现. gas5是细胞周期的调节因子, 参与细胞生命活动的调节. 实验显示gas5在胰腺癌组织中的表达水平与正常组织相比是明显降低的, 而过表达gas5可以抑制胰腺细胞的增殖, 流式细胞术检测gas5对细胞周期的调控发现gas5抑制剂可以诱导G0/G1相的细胞减少及S相细胞增加. 细胞实验中发现抑制gas5表达时, 周期蛋白依赖激酶6(cyclin-dependent kinase 6, CDK6) mRNA及蛋白的表达量增加, 而CDK6是调控细胞周期进程的重要蛋白质, 他可以和Cyclin D1、D2和D3形成复合物, 可以磷酸化视网膜母细胞瘤基因蛋白(retinoblastoma protein, Rb), 促进G1/S期转换的发生, 因此gas5调控胰腺癌细胞周期活动可能是通过调节CDK6的表达实现的[44].
ENST00000480739一个新发现的lncRNA, 定位于12号染色体OS-9启动子区域上游. ENST00000480739在胰腺癌组织中表达较癌旁正常组织明显降低, 并且临床病理资料研究显示ENST00000480739的表达与胰腺癌患者的年龄、性别、肿瘤大小、组织分化程度无关, 而与TNM分期、淋巴结转移负相关. 胰腺癌术后ENST00000480739表达量高的患者的平均生存时间比低表达的患者高, 可以将ENST00000480739作为胰腺癌术后的一个新的预后因素. 在细胞及动物实验中发现ENST00000480739与肿瘤细胞的转移、侵袭密切相关, 而与增殖、凋亡及细胞周期无明显相关[45].
ENST00000480739可能通过调控OS-9基因启动子区的转录活动调节OS-9的表达, 上调OS-9基因表达可以抑制缺氧诱导因子-1α(hypoxia-inducible factor-1α, HIF-1α)的表达, 而缺氧被视为实体肿瘤不良预后的一个主要原因, HIF-1α在转移肿瘤中也可以被检测出过表达. 因此, ENST00000480739抑制肿瘤细胞的侵袭及转移可能是通过调控OS-9及HIF-1α实现的[45-47].
最新在胰腺癌中检测出异常表达的lncRNA还包括HULC(highly upregulated in liver cancer)、BC008363. HULC基因定位于6p24.3, 含有一个内含子和两个外显子, 保守存在于灵长类动物中, 最早是在肝癌组织中检测出HULC的表达量异常增高[48,49], 而HULC在胰腺癌组织中同样也检测出高表达, 结合临床病理资料分析发现HULC与肿瘤的大小、淋巴结转移及血管的侵袭有关, 预后研究显示HULC可以作总生存期的一个独立预测因素[50]. BC008363是使用基因芯片技术检测胰腺癌中异常表达的lncRNA时发现, BC008363在胰腺组织中的表达与正常组织相比是明显降低的, 并且高表达BC008363的患者比低表达的患者有更好的存活率, BC008363的继续研究有潜力成为新型胰腺癌诊断、预后的标志物[51].
目前, lncRNA在胰腺癌中的研究还不是很多, 但现有的研究结果显示lncRNA的异常表达与胰腺肿瘤发生、发展、侵袭、转移存在密切的联系, 虽然具体的机制尚未根本阐明, 但随着研究深入, lncRNA参与胰腺癌基因调控的机制终将被揭示. lncRNA、lncRNA调控的基因和蛋白质的异常表达为胰腺肿瘤的早期诊断及预后分析提供了新的标志物, 尤其是随着研究手段的丰富, 近来兴起的血液中lncRNA的研究将带来更好的临床应用价值. lncRNA的调控网络极其丰富, 功能也复杂多样. 同一lncRNA可以参与到不同的肿瘤的调控机制中, 甚至同一肿瘤中既有促进肿瘤发展的lncRNA, 也有抑制肿瘤的lncRNA, 为肿瘤的靶向治疗带来极大的困难, 这些困难需要研究者不断的克服, 积极寻找出胰腺肿瘤治疗的靶点, 把胰腺肿瘤的诊治水平提高到新的台阶.
肝细胞肝癌(hepatocellular carcinoma, HCC)在人类癌症中排明前十, 死亡率极高, 绝大部分患者就诊时已属晚期, 具有发病率高、预后较差、目前尚无有效治疗手段等特点. 及早研究促进肝癌发生发展的关键分子, 并进行有效干预对于改善肝癌患者的预后具有重要作用.
姚登福, 教授, 南通大学附属医院
脂肪酸结合蛋白为一族小的、高度保守的结合长链脂肪酸等疏水性配体的胞质蛋白, 其中表皮型即为表皮脂肪酸结合蛋白-5(fatty acid binding protein-5, FABP-5), 能结合和转运各种疏水性配体, 参与肿瘤生长相关的信号转导. 近年来, 越来越多的研究发现FABP-5与肿瘤的发生发展、恶性转化密切相关.
本课题组前期实验结果表明, FABP-5不仅在人肝癌组织中高表达, 在大鼠和树鼩肝癌模型中也明显上调, 并且发现FABP-5表达水平与恶性肿瘤的分化、转移有密切关系, 提示FABP-5可能成为肝癌发生发展中的关键作用分子, 有望成为一个早期诊断或预测肿瘤转移的新指标.
目前尚无FABP-5基因沉默对肝癌细胞侵袭力、生长和增殖的影响的报道, 本实验利用慢病毒为载体, 采用RNA干扰技术将重组慢病毒载体FABP-5-shRNA转入人肝癌HepG2细胞中, 研究沉默FABP-5表达对HepG2细胞增殖、凋亡和其侵袭能力的影响.
本研究结果表明, FABP-5 RNA干扰后肝癌细胞周期进程得到有效阻滞, 凋亡大幅增加, 可明显降低肝癌生长增殖功能, 肿瘤细胞的侵袭力明显受到抑制. FABP-5基因有望成为肝癌基因治疗的一个有效靶点.
RNA干扰(RNAi): 指在进化过程中高度保守的、由双链RNA(double-stranded RNA, dsRNA)诱发的、同源mRNA高效特异性降解的现象. RNAi技术可以特异性剔除或关闭特定基因的表达. 该技术已被广泛用于多方面的研究领域, 如探索基因功能、传染性疾病和恶性肿瘤的基因治疗等.
本文将最佳FABP-5-shRNA表达载体转染肝癌HepG2细胞, 沉默FABP-5基因后促进癌细胞凋亡, 细胞分裂阻滞在G2/M期, 抑制细胞增殖, 降低癌细胞侵袭力, FABP-5基因有可能成为肝癌治疗新靶点.
编辑:郭鹏 电编:闫晋利
| 1. | Lebedeva IV, Sarkar D, Su ZZ, Gopalkrishnan RV, Athar M, Randolph A, Valerie K, Dent P, Fisher PB. Molecular target-based therapy of pancreatic cancer. Cancer Res. 2006;66:2403-2413. [PubMed] [DOI] |
| 2. | Chen Z, Chen LY, Dai HY, Wang P, Gao S, Wang K. miR-301a promotes pancreatic cancer cell proliferation by directly inhibiting Bim expression. J Cell Biochem. 2012;113:3229-3235. [PubMed] [DOI] |
| 3. | Chen ZK, Lin LW, Weng XH, Xue ES, Lin YH. Interstitial chemotherapy with ricin-loaded thermosensitive hydrogel in pancreatic cancer xenograft. Hepatobiliary Pancreat Dis Int. 2009;8:418-423. [PubMed] |
| 4. | Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11-30. [PubMed] [DOI] |
| 5. | Butturini G, Stocken DD, Wente MN, Jeekel H, Klinkenbijl JH, Bakkevold KE, Takada T, Amano H, Dervenis C, Bassi C. Influence of resection margins and treatment on survival in patients with pancreatic cancer: meta-analysis of randomized controlled trials. Arch Surg. 2008;143:75-83; discussion 83. [PubMed] [DOI] |
| 6. | Bilimoria KY, Bentrem DJ, Ko CY, Stewart AK, Winchester DP, Talamonti MS. National failure to operate on early stage pancreatic cancer. Ann Surg. 2007;246:173-180. [PubMed] [DOI] |
| 8. | Ernst C, Morton CC. Identification and function of long non-coding RNA. Front Cell Neurosci. 2013;7:168. [PubMed] [DOI] |
| 9. | Roberts TC, Morris KV, Weinberg MS. Perspectives on the mechanism of transcriptional regulation by long non-coding RNAs. Epigenetics. 2014;9:13-20. [PubMed] [DOI] |
| 10. | ENCODE Project Consortium, Birney E, Stamatoyannopoulos JA, Dutta A, Guigó R, Gingeras TR, Margulies EH, Weng Z, Snyder M, Dermitzakis ET, Thurman RE, Kuehn MS, Taylor CM, Neph S, Koch CM, Asthana S, Malhotra A, Adzhubei I, Greenbaum JA, Andrews RM, Flicek P, Boyle PJ, Cao H, Carter NP, Clelland GK, Davis S, Day N, Dhami P, Dillon SC, Dorschner MO, Fiegler H, Giresi PG, Goldy J, Hawrylycz M, Haydock A, Humbert R, James KD, Johnson BE, Johnson EM, Frum TT, Rosenzweig ER, Karnani N, Lee K, Lefebvre GC, Navas PA, Neri F, Parker SC, Sabo PJ, Sandstrom R, Shafer A, Vetrie D, Weaver M, Wilcox S, Yu M, Collins FS, Dekker J, Lieb JD, Tullius TD, Crawford GE, Sunyaev S, Noble WS, Dunham I, Denoeud F, Reymond A, Kapranov P, Rozowsky J, Zheng D, Castelo R, Frankish A, Harrow J, Ghosh S, Sandelin A, Hofacker IL, Baertsch R, Keefe D, Dike S, Cheng J, Hirsch HA, Sekinger EA, Lagarde J, Abril JF, Shahab A, Flamm C, Fried C, Hackermüller J, Hertel J, Lindemeyer M, Missal K, Tanzer A, Washietl S, Korbel J, Emanuelsson O, Pedersen JS, Holroyd N, Taylor R, Swarbreck D, Matthews N, Dickson MC, Thomas DJ, Weirauch MT, Gilbert J, Drenkow J, Bell I, Zhao X, Srinivasan KG, Sung WK, Ooi HS, Chiu KP, Foissac S, Alioto T, Brent M, Pachter L, Tress ML, Valencia A, Choo SW, Choo CY, Ucla C, Manzano C, Wyss C, Cheung E, Clark TG, Brown JB, Ganesh M, Patel S, Tammana H, Chrast J, Henrichsen CN, Kai C, Kawai J, Nagalakshmi U, Wu J, Lian Z, Lian J, Newburger P, Zhang X, Bickel P, Mattick JS, Carninci P, Hayashizaki Y, Weissman S, Hubbard T, Myers RM, Rogers J, Stadler PF, Lowe TM, Wei CL, Ruan Y, Struhl K, Gerstein M, Antonarakis SE, Fu Y, Green ED, Kara öz U, Siepel A, Taylor J, Liefer LA, Wetterstrand KA, Good PJ, Feingold EA, Guyer MS, Cooper GM, Asimenos G, Dewey CN, Hou M, Nikolaev S, Montoya-Burgos JI, L öytynoja A, Whelan S, Pardi F, Massingham T, Huang H, Zhang NR, Holmes I, Mullikin JC, Ureta-Vidal A, Paten B, Seringhaus M, Church D, Rosenbloom K, Kent WJ, Stone EA; NISC Comparative Sequencing Program; Baylor College of Medicine Human Genome Sequencing Center; Washington University Genome Sequencing Center; Broad Institute; Children's Hospital Oakland Research Institute, Batzoglou S, Goldman N, Hardison RC, Haussler D, Miller W, Sidow A, Trinklein ND, Zhang ZD, Barrera L, Stuart R, King DC, Ameur A, Enroth S, Bieda MC, Kim J, Bhinge AA, Jiang N, Liu J, Yao F, Vega VB, Lee CW, Ng P, Shahab A, Yang A, Moqtaderi Z, Zhu Z, Xu X, Squazzo S, Oberley MJ, Inman D, Singer MA, Richmond TA, Munn KJ, Rada-Iglesias A, Wallerman O, Komorowski J, Fowler JC, Couttet P, Bruce AW, Dovey OM, Ellis PD, Langford CF, Nix DA, Euskirchen G, Hartman S, Urban AE, Kraus P, Van Calcar S, Heintzman N, Kim TH, Wang K, Qu C, Hon G, Luna R, Glass CK, Rosenfeld MG, Aldred SF, Cooper SJ, Halees A, Lin JM, Shulha HP, Zhang X, Xu M, Haidar JN, Yu Y, Ruan Y, Iyer VR, Green RD, Wadelius C, Farnham PJ, Ren B, Harte RA, Hinrichs AS, Trumbower H, Clawson H, Hillman-Jackson J, Zweig AS, Smith K, Thakkapallayil A, Barber G, Kuhn RM, Karolchik D, Armengol L, Bird CP, de Bakker PI, Kern AD, Lopez-Bigas N, Martin JD, Stranger BE, Woodroffe A, Davydov E, Dimas A, Eyras E, Hallgrímsdóttir IB, Huppert J, Zody MC, Abecasis GR, Estivill X, Bouffard GG, Guan X, Hansen NF, Idol JR, Maduro VV, Maskeri B, McDowell JC, Park M, Thomas PJ, Young AC, Blakesley RW, Muzny DM, Sodergren E, Wheeler DA, Worley KC, Jiang H, Weinstock GM, Gibbs RA, Graves T, Fulton R, Mardis ER, Wilson RK, Clamp M, Cuff J, Gnerre S, Jaffe DB, Chang JL, Lindblad-Toh K, Lander ES, Koriabine M, Nefedov M, Osoegawa K, Yoshinaga Y, Zhu B, de Jong PJ. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature. 2007;447:799-816. [PubMed] |
| 11. | Tano K, Akimitsu N. Long non-coding RNAs in cancer progression. Front Genet. 2012;3:219. [PubMed] [DOI] |
| 12. | Liu MX, Chen X, Chen G, Cui QH, Yan GY. A computational framework to infer human disease-associated long noncoding RNAs. PLoS One. 2014;9:e84408. [PubMed] [DOI] |
| 13. | Louro R, Smirnova AS, Verjovski-Almeida S. Long intronic noncoding RNA transcription: expression noise or expression choice? Genomics. 2009;93:291-298. [PubMed] [DOI] |
| 14. | Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs. Cell. 2009;136:629-641. [PubMed] [DOI] |
| 15. | Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009;10:155-159. [PubMed] [DOI] |
| 16. | Pandey RR, Kanduri C. Transcriptional and Posttranscriptional Programming by Long Noncoding RNAs. Prog Mol Subcell Biol. 2011;51:1-27. [PubMed] [DOI] |
| 17. | Gong C, Maquat LE. lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3' UTRs via Alu elements. Nature. 2011;470:284-288. [PubMed] [DOI] |
| 18. | Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, Shi Y, Segal E, Chang HY. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010;329:689-693. [PubMed] [DOI] |
| 20. | Nie Y, Liu X, Qu S, Song E, Zou H, Gong C. Long non-coding RNA HOTAIR is an independent prognostic marker for nasopharyngeal carcinoma progression and survival. Cancer Sci. 2013;104:458-464. [PubMed] [DOI] |
| 21. | Taft RJ, Pang KC, Mercer TR, Dinger M, Mattick JS. Non-coding RNAs: regulators of disease. J Pathol. 2010;220:126-139. [PubMed] [DOI] |
| 22. | Yang Z, Zhou L, Wu LM, Lai MC, Xie HY, Zhang F, Zheng SS. Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation. Ann Surg Oncol. 2011;18:1243-1250. [PubMed] [DOI] |
| 23. | Crea F, Watahiki A, Quagliata L, Xue H, Pikor L, Parolia A, Wang Y, Lin D, Lam WL, Farrar WL. Identification of a long non-coding RNA as a novel biomarker and potential therapeutic target for metastatic prostate cancer. Oncotarget. 2014;5:764-774. [PubMed] |
| 24. | Ji P, Diederichs S, Wang W, B öing S, Metzger R, Schneider PM, Tidow N, Brandt B, Buerger H, Bulk E. MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene. 2003;22:8031-8041. [PubMed] [DOI] |
| 25. | Liu JH, Chen G, Dang YW, Li CJ, Luo DZ. Expression and prognostic significance of lncRNA MALAT1 in pancreatic cancer tissues. Asian Pac J Cancer Prev. 2014;15:2971-2977. [PubMed] |
| 26. | Jiao F, Hu H, Yuan C, Wang L, Jiang W, Jin Z, Guo Z, Wang L. Elevated expression level of long noncoding RNA MALAT-1 facilitates cell growth, migration and invasion in pancreatic cancer. Oncol Rep. 2014;32:2485-2492. [PubMed] [DOI] |
| 27. | Pan JJ, Yang MH. The role of epithelial-mesenchymal transition in pancreatic cancer. J Gastrointest Oncol. 2011;2:151-156. [PubMed] [DOI] |
| 28. | Sarkar FH, Li Y, Wang Z, Kong D. Pancreatic cancer stem cells and EMT in drug resistance and metastasis. Minerva Chir. 2009;64:489-500. [PubMed] |
| 29. | Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871-890. [PubMed] [DOI] |
| 30. | Łukaszewicz M, Mroczko B, Szmitkowski M. [The role of metalloproteinases and their inhibitors in pancreatic cancer]. Postepy Hig Med Dosw (Online). 2008;62:141-147. [PubMed] |
| 31. | Cai X, Cullen BR. The imprinted H19 noncoding RNA is a primary microRNA precursor. RNA. 2007;13:313-316. [PubMed] [DOI] |
| 32. | Gabory A, Jammes H, Dandolo L. The H19 locus: role of an imprinted non-coding RNA in growth and development. Bioessays. 2010;32:473-480. [PubMed] [DOI] |
| 33. | Yang F, Bi J, Xue X, Zheng L, Zhi K, Hua J, Fang G. Up-regulated long non-coding RNA H19 contributes to proliferation of gastric cancer cells. FEBS J. 2012;279:3159-3165. [PubMed] [DOI] |
| 34. | Zhang L, Yang F, Yuan JH, Yuan SX, Zhou WP, Huo XS, Xu D, Bi HS, Wang F, Sun SH. Epigenetic activation of the MiR-200 family contributes to H19-mediated metastasis suppression in hepatocellular carcinoma. Carcinogenesis. 2013;34:577-586. [PubMed] [DOI] |
| 35. | Ma C, Nong K, Zhu H, Wang W, Huang X, Yuan Z, Ai K. H19 promotes pancreatic cancer metastasis by derepressing let-7's suppression on its target HMGA2-mediated EMT. Tumour Biol. 2014;35:9163-9169. [PubMed] [DOI] |
| 36. | Saito Y, Suzuki H, Matsuura M, Sato A, Kasai Y, Yamada K, Saito H, Hibi T. MicroRNAs in Hepatobiliary and Pancreatic Cancers. Front Genet. 2011;2:66. [PubMed] [DOI] |
| 37. | Jiang J, Lee EJ, Gusev Y, Schmittgen TD. Real-time expression profiling of microRNA precursors in human cancer cell lines. Nucleic Acids Res. 2005;33:5394-5403. [PubMed] [DOI] |
| 38. | Thuault S, Tan EJ, Peinado H, Cano A, Heldin CH, Moustakas A. HMGA2 and Smads co-regulate SNAIL1 expression during induction of epithelial-to-mesenchymal transition. J Biol Chem. 2008;283:33437-33446. [PubMed] [DOI] |
| 39. | Luo Y, Li W, Liao H. HMGA2 induces epithelial-to-mesenchymal transition in human hepatocellular carcinoma cells. Oncol Lett. 2013;5:1353-1356. [PubMed] [DOI] |
| 40. | He S, Liu S, Zhu H. The sequence, structure and evolutionary features of HOTAIR in mammals. BMC Evol Biol. 2011;11:102. [PubMed] [DOI] |
| 41. | Guo W, Dong Z, Bai Y, Guo Y, Shen S, Kuang G, Xu J. Associations between polymorphisms of HOTAIR and risk of gastric cardia adenocarcinoma in a population of north China. Tumour Biol. 2014; Dec 5. [Epub ahead of print]. [PubMed] |
| 42. | Xue Y, Ma G, Gu D, Zhu L, Hua Q, Du M, Chu H, Tong N, Chen J, Zhang Z. Genome-wide analysis of long noncoding RNA signature in human colorectal cancer. Gene. 2015;556:227-234. [PubMed] [DOI] |
| 43. | Kim K, Jutooru I, Chadalapaka G, Johnson G, Frank J, Burghardt R, Kim S, Safe S. HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene. 2013;32:1616-1625. [PubMed] [DOI] |
| 44. | Lu X, Fang Y, Wang Z, Xie J, Zhan Q, Deng X, Chen H, Jin J, Peng C, Li H. Downregulation of gas5 increases pancreatic cancer cell proliferation by regulating CDK6. Cell Tissue Res. 2013;354:891-896. [PubMed] [DOI] |
| 45. | Sun YW, Chen YF, Li J, Huo YM, Liu DJ, Hua R, Zhang JF, Liu W, Yang JY, Fu XL. A novel long non-coding RNA ENST00000480739 suppresses tumour cell invasion by regulating OS-9 and HIF-1α in pancreatic ductal adenocarcinoma. Br J Cancer. 2014;111:2131-2141. [PubMed] [DOI] |
| 46. | Hashimoto O, Shimizu K, Semba S, Chiba S, Ku Y, Yokozaki H, Hori Y. Hypoxia induces tumor aggressiveness and the expansion of CD133-positive cells in a hypoxia-inducible factor-1α-dependent manner in pancreatic cancer cells. Pathobiology. 2011;78:181-192. [PubMed] [DOI] |
| 47. | Fujiwara S, Nakagawa K, Harada H, Nagato S, Furukawa K, Teraoka M, Seno T, Oka K, Iwata S, Ohnishi T. Silencing hypoxia-inducible factor-1alpha inhibits cell migration and invasion under hypoxic environment in malignant gliomas. Int J Oncol. 2007;30:793-802. [PubMed] |
| 48. | Zhao Y, Guo Q, Chen J, Hu J, Wang S, Sun Y. Role of long non-coding RNA HULC in cell proliferation, apoptosis and tumor metastasis of gastric cancer: a clinical and in vitro investigation. Oncol Rep. 2014;31:358-364. [PubMed] [DOI] |
| 49. | Liu Y, Pan S, Liu L, Zhai X, Liu J, Wen J, Zhang Y, Chen J, Shen H, Hu Z. A genetic variant in long non-coding RNA HULC contributes to risk of HBV-related hepatocellular carcinoma in a Chinese population. PLoS One. 2012;7:e35145. [PubMed] [DOI] |
| 50. | Peng W, Gao W, Feng J. Long noncoding RNA HULC is a novel biomarker of poor prognosis in patients with pancreatic cancer. Med Oncol. 2014;31:346. [PubMed] [DOI] |
| 51. | Li J, Liu D, Hua R, Zhang J, Liu W, Huo Y, Cheng Y, Hong J, Sun Y. Long non-coding RNAs expressed in pancreatic ductal adenocarcinoma and lncRNA BC008363 an independent prognostic factor in PDAC. Pancreatology. 2014;14:385-390. [PubMed] [DOI] |