Let-7

let-7 microRNA precursor
	预测的let-7二级结构和保守序列
识别符
代号	let-7
Rfam	RF00027
miRBase	MI0000001
miRBase	MIPF0000002
	其他数据
RNA类型	Gene; miRNA
域	Eukaryota

let-7是最早发现的两种microRNA之一（第一种是lin-4），2000年由加里·鲁夫昆等人发现于模式生物秀丽隐杆线虫的基因组中^[1]，之后通过BLAST在果蝇和人类基因组中发现了同源物^[2]，形成了let-7非编码RNA家族。人类miR-98 microRNA前体是let-7家族成员。目前已在多种物种中预测或通过实验证实Let-7 miRNA（MIPF0000002^[3]）。miRNA最初转录为长转录本（长达数百个核苷酸），称为初级miRNA（pri-miRNA），在细胞核中由Drosha和Pasha加工成约70个核苷酸的发夹结构。这些前体（前miRNA, pre-miRNA）通过exportin5（英语：XPO5）输出到细胞质中，随后在Dicer酶的作用下加工成约22个核苷酸的成熟miRNA。Dicer参与miRNA加工表明其与RNA干扰现象存在关联。

基因组位置

在人类基因组中，簇let-7a-1/let-7f-1/let-7d位于9q22.3的B区域内，具有定义标记D9S280-D9S1809。 D11S1345-D11S1316位点之间的一个最小LOH（杂合性丢失）区域包含miR-125b1/let-7a-2/miR-100簇。 miR-99a/let-7c/miR-125b-2 簇位于HD的21p11.1 区（纯合缺失）。簇let-7g/miR-135-1位于区域3的3p21.1-p21.2处。^[4]

let-7家族

let-7基因最早在线虫中被发现，是一种关键的发育调节因子，并成为已知的第两种 microRNA 之一（另一种是lin-4）。^[1] 很快，"let-7"在果蝇中也被发现，并通过BLAST（基本局部比对搜索工具）研究被确认为第一个已知的人类 miRNA。^[2] let-7 家族成员的成熟形式在物种间高度保守。

表达调控

尽管在未分化细胞中检测不到成熟的let-7成员的水平，但是let-7的初级转录本和发夹结构前体存在于这些细胞中。^[5] 这表明成熟的let-7 miRNA可能以转录后（英语：Post-transcriptional regulation）方式受到调控。

Let-7的目标

可能用于癌症的临床治疗

鉴于在线虫中，let-7 功能丧失会导致细胞过度扩散和未分化的突出表型，以及其靶点在细胞命运决定上的作用，let-7 与人类癌症密切相关，并作为一种肿瘤抑制因子。

预后生物标记

许多报告显示，在许多癌症中，let-7的表达水准经常偏低，而且let-7的染色体簇经常被删除。^[4]在分化程度较高的肿瘤中，let-7的表达水平较高，而这些肿瘤中活化的癌基因（如RAS和HMGA2）的水平也较低。因此，let-7的表达水准可能是与分化阶段相关的几种癌症的预后标志。^[6] 例如，在肺癌中，let-7的表达减少与术后存活率降低有显著相关性。^[7]在1262位乳癌患者中，let-7b和 let-7g microRNA的表达与整体存活率显著相关。^[8]

治疗

人类同源物

参考文献

^ ^1.0 ^1.1 Reinhart B.J.; et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature. 2000, 403 (6772): 901–906. Bibcode:2000Natur.403..901R. PMID 10706289. S2CID 4384503. doi:10.1038/35002607.
^ ^2.0 ^2.1 Pasquinelli A.E.; et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature. 2000, 408 (6808): 86–89. Bibcode:2000Natur.408...86P. PMID 11081512. S2CID 4401732. doi:10.1038/35040556.
^ MIPF0000002
^ ^4.0 ^4.1 Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proceedings of the National Academy of Sciences of the United States of America. March 2004, 101 (9): 2999–3004. Bibcode:2004PNAS..101.2999C. PMC 365734 . PMID 14973191. doi:10.1073/pnas.0307323101 .
^ Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM. Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes & Development. August 2006, 20 (16): 2202–2207. PMC 1553203 . PMID 16882971. doi:10.1101/gad.1444406.
^ Shell S, Park SM, Radjabi AR, Schickel R, Kistner EO, Jewell DA, et al. Let-7 expression defines two differentiation stages of cancer. Proceedings of the National Academy of Sciences of the United States of America. July 2007, 104 (27): 11400–11405. Bibcode:2007PNAS..10411400S. PMC 2040910 . PMID 17600087. doi:10.1073/pnas.0704372104 .
^ Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Research. June 2004, 64 (11): 3753–3756. PMID 15172979. doi:10.1158/0008-5472.CAN-04-0637 .
^ Lánczky A, Nagy Á, Bottai G, Munkácsy G, Szabó A, Santarpia L, Győrffy B. miRpower: a web-tool to validate survival-associated miRNAs utilizing expression data from 2178 breast cancer patients. Breast Cancer Research and Treatment. December 2016, 160 (3): 439–446. PMID 27744485. S2CID 11165696. doi:10.1007/s10549-016-4013-7.

外部链接

[Reinhart-1] 1.0 ^1.1 Reinhart B.J.; et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature. 2000, 403 (6772): 901–906. Bibcode:2000Natur.403..901R. PMID 10706289. S2CID 4384503. doi:10.1038/35002607.

[Pasquinelli-2] 2.0 ^2.1 Pasquinelli A.E.; et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature. 2000, 408 (6808): 86–89. Bibcode:2000Natur.408...86P. PMID 11081512. S2CID 4401732. doi:10.1038/35040556.

[3] MIPF0000002

[Calin-4] 4.0 ^4.1 Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proceedings of the National Academy of Sciences of the United States of America. March 2004, 101 (9): 2999–3004. Bibcode:2004PNAS..101.2999C. PMC 365734 . PMID 14973191. doi:10.1073/pnas.0307323101 .

[fifteen-5] Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM. Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes & Development. August 2006, 20 (16): 2202–2207. PMC 1553203 . PMID 16882971. doi:10.1101/gad.1444406.

[gys30-6] Shell S, Park SM, Radjabi AR, Schickel R, Kistner EO, Jewell DA, et al. Let-7 expression defines two differentiation stages of cancer. Proceedings of the National Academy of Sciences of the United States of America. July 2007, 104 (27): 11400–11405. Bibcode:2007PNAS..10411400S. PMC 2040910 . PMID 17600087. doi:10.1073/pnas.0704372104 .

[gys31-7] Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Research. June 2004, 64 (11): 3753–3756. PMID 15172979. doi:10.1158/0008-5472.CAN-04-0637 .

[8] Lánczky A, Nagy Á, Bottai G, Munkácsy G, Szabó A, Santarpia L, Győrffy B. miRpower: a web-tool to validate survival-associated miRNAs utilizing expression data from 2178 breast cancer patients. Breast Cancer Research and Treatment. December 2016, 160 (3): 439–446. PMID 27744485. S2CID 11165696. doi:10.1007/s10549-016-4013-7.

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