Let-7

let-7 microRNA precursor
	預測的let-7二級結構和保守序列
識別符
代號	let-7
Rfam	RF00027
miRBase	MI0000001
miRBase	MIPF0000002
	其他數據
RNA類型	Gene; miRNA
域	Eukaryota

let-7是最早發現的兩種microRNA之一（第一種是lin-4），2000年由加里·魯夫昆等人發現於模式生物秀麗隱桿線蟲的基因組中^[1]，之後通過BLAST在果蠅和人類基因組中發現了同源物^[2]，形成了let-7非編碼RNA家族。人類miR-98 microRNA前體是let-7家族成員。目前已在多種物種中預測或通過實驗證實Let-7 miRNA（MIPF0000002^[3]）。miRNA最初轉錄為長轉錄本（長達數百個核苷酸），稱為初級miRNA（pri-miRNA），在細胞核中由Drosha和Pasha加工成約70個核苷酸的髮夾結構。這些前體（前miRNA, pre-miRNA）通過exportin5（英語：XPO5）輸出到細胞質中，隨後在Dicer酶的作用下加工成約22個核苷酸的成熟miRNA。Dicer參與miRNA加工表明其與RNA干擾現象存在關聯。

基因組位置

在人類基因組中，簇let-7a-1/let-7f-1/let-7d位於9q22.3的B區域內，具有定義標記D9S280-D9S1809。 D11S1345-D11S1316位點之間的一個最小LOH（雜合性丟失）區域包含miR-125b1/let-7a-2/miR-100簇。 miR-99a/let-7c/miR-125b-2 簇位於HD的21p11.1 區（純合缺失）。簇let-7g/miR-135-1位於區域3的3p21.1-p21.2處。^[4]

let-7家族

let-7基因最早在線蟲中被發現，是一種關鍵的發育調節因子，並成為已知的第兩種 microRNA 之一（另一種是lin-4）。^[1] 很快，"let-7"在果蠅中也被發現，並通過BLAST（基本局部比對搜索工具）研究被確認為第一個已知的人類 miRNA。^[2] let-7 家族成員的成熟形式在物種間高度保守。

表達調控

儘管在未分化細胞中檢測不到成熟的let-7成員的水平，但是let-7的初級轉錄本和髮夾結構前體存在於這些細胞中。^[5] 這表明成熟的let-7 miRNA可能以轉錄後（英語：Post-transcriptional regulation）方式受到調控。

Let-7的目標

可能用於癌症的臨床治療

鑒於在線蟲中，let-7 功能喪失會導致細胞過度擴散和未分化的突出表型，以及其靶點在細胞命運決定上的作用，let-7 與人類癌症密切相關，並作為一種腫瘤抑制因子。

預後生物標記

許多報告顯示，在許多癌症中，let-7的表達水準經常偏低，而且let-7的染色體簇經常被刪除。^[4]在分化程度較高的腫瘤中，let-7的表達水平較高，而這些腫瘤中活化的癌基因（如RAS和HMGA2）的水平也較低。因此，let-7的表達水準可能是與分化階段相關的幾種癌症的預後標誌。^[6] 例如，在肺癌中，let-7的表達減少與術後存活率降低有顯著相關性。^[7]在1262位乳癌患者中，let-7b和 let-7g microRNA的表達與整體存活率顯著相關。^[8]

治療

人類同源物

參考文獻

^ ^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.

外部連結

[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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