美國科學(xué)家的一項(xiàng)最新研究表明，一種微小的RNA分子（即microRNA）能夠促使乳腺癌細(xì)胞肆虐和擴(kuò)散,。該發(fā)現(xiàn)有望為癌癥治療提供新的標(biāo)靶,，相關(guān)論文9月26日發(fā)表于《自然》雜志,。
一般情況下，microRNA幫助調(diào)控基因活動(dòng)以及動(dòng)植物的協(xié)調(diào)發(fā)育,。已有研究表明,，這些分子也會(huì)變“邪惡”，顯著地導(dǎo)致癌癥發(fā)生,。不過,，科學(xué)家對(duì)其中的機(jī)制還知之甚少。
領(lǐng)導(dǎo)最新研究的是美國Whitehead生物醫(yī)學(xué)研究所的Robert Weinberg,，他的小組對(duì)microRNA在乳腺癌細(xì)胞擴(kuò)散和轉(zhuǎn)移過程中所起到的作用進(jìn)行了追蹤研究,。從之前29種與乳腺癌相關(guān)的microRNA中，研究人員確定出一種名為miR-10b的“兇犯”,，它不僅在非轉(zhuǎn)移癌細(xì)胞中起作用,，在一個(gè)極富侵略性的人類乳腺癌細(xì)胞系中也十分流行。當(dāng)研究人員將miR-10b滅活后,，這些細(xì)胞的侵略性減少了十分之一,。而當(dāng)科學(xué)家將miR-10b導(dǎo)入非轉(zhuǎn)移乳腺癌細(xì)胞培養(yǎng)基后，這些癌細(xì)胞變得極富侵略性,，轉(zhuǎn)移能力很強(qiáng),。
隨后，研究小組將能夠制造miR-10b的乳腺癌細(xì)胞移植入幼年雌鼠的乳腺區(qū)域,。6周后,，這些細(xì)胞開始散布到機(jī)體不同的組織中，比如肺部,。而與此相比,，非轉(zhuǎn)移癌細(xì)胞只會(huì)導(dǎo)致小鼠產(chǎn)生乳腺癌，并不會(huì)擴(kuò)散開來,。
研究人員最終確定了影響miR-10b活性的遺傳路徑,。他們發(fā)現(xiàn)，該microRNA的制造要受到一種名為Twist的基因的控制,，該基因此前被認(rèn)為是胚胎發(fā)育的“主要調(diào)控因子”,。反過來，miR-10b也會(huì)影響另外兩種與細(xì)胞遷移和癌癥形成相關(guān)基因的表達(dá),。
Weinberg和同事謹(jǐn)慎地表示,，雖然miR-10b對(duì)觸發(fā)乳腺癌細(xì)胞擴(kuò)散有重要影響，但這項(xiàng)發(fā)現(xiàn)能否帶來新的治療標(biāo)靶還不確定,。論文第一作者Li Ma說,，“盡管很有可能，但我們不能下結(jié)論說,，以miR-10b作為標(biāo)靶能夠抑制轉(zhuǎn)移,。”
不過，同行還是給了這項(xiàng)研究很高的評(píng)價(jià),。美國耶魯大學(xué)發(fā)育生物學(xué)家,、microRNA研究先驅(qū)Frank Slack表示，“這項(xiàng)工作進(jìn)行得天衣無縫,，用于治療的潛力很大,，值得繼續(xù)研究。”俄亥俄州立大學(xué)的癌癥遺傳學(xué)家Carlo Croce也認(rèn)為,，新的發(fā)現(xiàn)“非常重要,，有望為治療提供重要的標(biāo)靶。”（科學(xué)網(wǎng) 任霄鵬/編譯）
原始出處:
Nature advance online publication 26 September 2007 | doi:10.1038/nature06174; Received 29 June 2007; Accepted 16 August 2007; Published online 26 September 2007
Tumour invasion and metastasis initiated by microRNA-10b in breast cancer
Li Ma1, Julie Teruya-Feldstein2 & Robert A. Weinberg1
Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
Correspondence to: Robert A. Weinberg1 Correspondence and requests for materials should be addressed to R.A.W. (Email: [email protected]).
MicroRNAs have been implicated in regulating diverse cellular pathways. Although there is emerging evidence that some microRNAs can function as oncogenes or tumour suppressors, the role of microRNAs in mediating cancer metastasis remains unexplored. Here we show, using a combination of mouse and human cells, that microRNA-10b (miR-10b) is highly expressed in metastatic breast cancer cells and positively regulates cell migration and invasion. Overexpression of miR-10b in otherwise non-metastatic breast tumours initiates robust invasion and metastasis. Expression of miR-10b is induced by the transcription factor Twist, which binds directly to the putative promoter of mir-10b (MIRN10B). The miR-10b induced by Twist proceeds to inhibit translation of the messenger RNA encoding homeobox D10, resulting in increased expression of a well-characterized pro-metastatic gene, RHOC. Significantly, the level of miR-10b expression in primary breast carcinomas correlates with clinical progression. These findings suggest the workings of an undescribed regulatory pathway, in which a pleiotropic transcription factor induces expression of a specific microRNA, which suppresses its direct target and in turn activates another pro-metastatic gene, leading to tumour cell invasion and metastasis.
