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RNA激活

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RNA激活（RNA activation, RNAa) 是一種由小分子RNA介導的特異性基因表達上調機制，是李龍承等[1]於2006年首先在人細胞中發現並命名的。隨後，其他研究小組也報道了相似的現象，證明了RNA激活是從人及大小鼠等哺乳類動物到植物及線蟲中的保守現象[2][3][4][5][6][7][8][9][10]。RNA激活是由靶向基因啟動子區域的雙鏈小RNA（dsRNA）分子介導並需要Argonaute（AGO）蛋白的參與[1][11]。這類能夠誘導RNA激活現象（即激活基因表達）的dsRNA被稱為小激活RNA（small activating RNA，saRNA）[12]。saRNA可通過人工設計及化學合成而獲得，也可為天然存在的內源性RNA如miRNA；前者介導的RNA激活被稱為外源性RNA激活，後者為內源性RNA激活。

與RNA干擾（RNAi）的異同

介導外源性RNA激活的saRNA與介導RNAi的siRNA結構相似， 是含21個核苷酸的雙鏈RNA（dsRNA），其兩條鏈在各自的3』端含2個核苷酸的突出。和RNAi一樣，RNAa也需要AGO蛋白特別是AGO2的參與，其作用可能是處理和活化saRNA分子，並介導saRNA與其啟動子上的靶位點結合。與RNAi（主要發生在胞漿）不同的是，RNA激活機製發生在細胞核，介導RNA激活的saRNA靶向啟動子而不是mRNA序列，此外，RNA激活具有特殊的時效性，表現為其效果（基因表達上調）的出現呈現48小時左右的滯後，及效果的長久性（10-14天）[1][13][14]。其機制被認為是因為RNA激活導致了表觀遺傳的改變[15]。

內源性RNA激活

2008年Place等[16]報道了天然存在的miRNA也能夠靶向啟動子序列而誘導RNA激活。他們發現人CDH1及CSDC2基因啟動子存在miR-373的靶位點，在人腫瘤細胞中引入miR-373的模擬物（mimics）能激活其靶基因的表達。後來，Huang等進一步證實了內源性miRNA介導的RNAa，並且發現該機制在正常及腫瘤細胞的增殖中起重要作用[17]。Xiao等還報道了靶向增強子區域的miRNA也能夠誘導RNA激活[18]。Chaluvally-Raghavan等發現miR-551b-3p通過靶向激活STAT3而促進卵巢癌細胞增殖、生存和腫瘤生長[19]。目前對於有多少基因受到內源性RNA激活機制的調控還不清楚，但有研究發現miRNA[20]及AGO蛋白[21]在人基因組的啟動子區存在廣泛的結合位點，提示miRNA可能在轉錄或者表觀遺傳水平調控大量的基因。

RNA激活的應用

RNA激活是一種簡單易行的上調基因表達的方法，在生物醫學領域具有廣泛的潛在用途，包括作為工具用於研究基因的功能[22]和對細胞進行重新編程[23][24][25][26]，以及作為治療疾病的手段，包括腫瘤、心血管疾病、勃起功能障礙等[27][28][29][30][31][32]。目前，治療肝癌的saRNA藥已經進入臨床試驗[28]。

參考來源

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