长链非编码RNA: 从科研到临床（三）
肾脏疾病与糖尿病
糖尿病经常伴随着肾病的发生[5]. 比如基因间lncRNA PVT1与二类疾病都紧密关联。研究人员在II型糖尿病人的晚期肾病进程中发现了PVT1的基因变异。高糖处理可以诱导人的肾间质细胞中PVT1和纤连蛋白1、IV型胶原蛋白、TGFβ1、PAI1等因子的高表达。相反，敲除PVT1可导致这些因子的显著下调。
LncRNA与临床应用
普遍认为lncRNA具有区分不同细胞状态或细胞内生物过程的功能，因此可以用来鉴定病理过程、提供预后评估或者为个体化疗法提供参考。其表达的时空特异性和疾病特异性使其有望成为强有效的分子标志物。已有不少研究揭示，lncRNA在多种疾病生物学标志物的应用中具备潜能（表二）。例如，研究发现LncRNA MTLIPCAR在发生左心室重塑的病人中特异性表达，并随后在788个发生心脏重塑和心脏衰竭的病人中得到验证。血液循环系统中的MTLIPCAR高表达水平可不受其他心血管疾病标志物的干扰，独立预测恶性心脏重塑。这项研究充分表明循环lncRNA具有作为分子标志物的重大潜能。
|
LncRNA |
Disease Association |
Biomarker application |
|
CDKN2B-AS1 |
Coronary artery disease[11, 12] |
Risk factor |
|
CDKN2B-AS1 |
Myocardial infarction[12] |
Risk factor |
|
KCNQ1OT1 |
Myocardial infarction[13] |
Predicts left ventricular dyfunction |
|
MIAT |
Myocardial infarction[14] |
Risk factor |
|
MT-LIPCAR |
Myocardial infarction[15] |
Predicts postinfarct remodelling |
|
SOX2OT |
Alzheimer’s disease[16] |
Risk factor |
|
H19 |
Parkinson’s Disease[17] |
Risk factor |
|
HULC |
Hepatocellular carcinoma[18] |
Diagnosis and monitoring |
|
FALEC |
Ovarian cancer[19] |
Predicts poor prognosis |
|
CCAT1 |
Colorectal cancer[20] |
Predicts therapeutic responsiveness |
表一 LncRNA在生物学标志物中的潜在应用
参考文献
[1] Fatica A, Bozzoni I. Long non-coding RNAs: new players in cell differentiation and development. Nature reviews Genetics 2014;15:7-21.
[2] Devaux Y, Zangrando J, Schroen B, Creemers EE, Pedrazzini T, Chang CP, et al. Long noncoding RNAs in cardiac development and ageing. Nature reviews Cardiology 2015;12:415-25.
[3] Satpathy AT, Chang HY. Long noncoding RNA in hematopoiesis and immunity. Immunity 2015;42:792-804.
[4] Knoll M, Lodish HF, Sun L. Long non-coding RNAs as regulators of the endocrine system. Nature reviews Endocrinology 2015;11:151-60.
[5] Lorenzen JM, Thum T. Long noncoding RNAs in kidney and cardiovascular diseases. Nature reviews Nephrology 2016;12:360-73.
[6] Schmitt AM, Chang HY. Long Noncoding RNAs in Cancer Pathways. Cancer cell 2016;29:452-63.
[7] Schmitz SU, Grote P, Herrmann BG. Mechanisms of long noncoding RNA function in development and disease. Cellular and molecular life sciences : CMLS 2016;73:2491-509.
[8] Ghosal S, Das S, Chakrabarti J. Long noncoding RNAs: new players in the molecular mechanism for maintenance and differentiation of pluripotent stem cells. Stem cells and development 2013;22:2240-53.
[9] Chen Z. Progress and prospects of long noncoding RNAs in lipid homeostasis. Molecular metabolism 2016;5:164-70.
[10] Wu P, Zuo X, Deng H, Liu X, Liu L, Ji A. Roles of long noncoding RNAs in brain development, functional diversification and neurodegenerative diseases. Brain research bulletin 2013;97:69-80.
[11] Consortium CAD, Deloukas P, Kanoni S, Willenborg C, Farrall M, Assimes TL, et al. Large-scale association analysis identifies new risk loci for coronary artery disease. Nature genetics 2013;45:25-33.
[12] Samani NJ, Erdmann J, Hall AS, Hengstenberg C, Mangino M, Mayer B, et al. Genomewide association analysis of coronary artery disease. The New England journal of medicine 2007;357:443-53.
[13] Vausort M, Wagner DR, Devaux Y. Long noncoding RNAs in patients with acute myocardial infarction. Circulation research 2014;115:668-77.
[14] Ishii N, Ozaki K, Sato H, Mizuno H, Saito S, Takahashi A, et al. Identification of a novel non-coding RNA, MIAT, that confers risk of myocardial infarction. Journal of human genetics 2006;51:1087-99.
[15] Kumarswamy R, Bauters C, Volkmann I, Maury F, Fetisch J, Holzmann A, et al. Circulating long noncoding RNA, LIPCAR, predicts survival in patients with heart failure. Circulation research 2014;114:1569-75.
[16] Arisi I, D'Onofrio M, Brandi R, Felsani A, Capsoni S, Drovandi G, et al. Gene expression biomarkers in the brain of a mouse model for Alzheimer's disease: mining of microarray data by logic classification and feature selection. Journal of Alzheimer's disease : JAD 2011;24:721-38.
[17] Kraus TF, Haider M, Spanner J, Steinmaurer M, Dietinger V, Kretzschmar HA. Altered Long Noncoding RNA Expression Precedes the Course of Parkinson's Disease-a Preliminary Report. Molecular neurobiology 2016.
[18] Xie H, Ma H, Zhou D. Plasma HULC as a promising novel biomarker for the detection of hepatocellular carcinoma. BioMed research international 2013;2013:136106.
[19] Hu X, Feng Y, Zhang D, Zhao SD, Hu Z, Greshock J, et al. A functional genomic approach identifies FAL1 as an oncogenic long noncoding RNA that associates with BMI1 and represses p21 expression in cancer. Cancer cell 2014;26:344-57.
[20] McCleland ML, Mesh K, Lorenzana E, Chopra VS, Segal E, Watanabe C, et al. CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. The Journal of clinical investigation 2016;126:639-52.
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