哈佛醫(yī)學(xué)院貝絲·伊斯雷爾女執(zhí)事醫(yī)療中心(BIDMC)以及紐約和羅馬兩個(gè)科研團(tuán)隊(duì),，發(fā)現(xiàn)了存在新的作用巨大的基因網(wǎng)絡(luò)的證據(jù)，并且展示了這些網(wǎng)絡(luò)推動(dòng)癌癥發(fā)展或正常發(fā)育的可能方式,。這項(xiàng)研究結(jié)果對(duì)了解癌癥及人類健康的遺傳學(xué)機(jī)理具有重要意義,。
《細(xì)胞》雜志網(wǎng)絡(luò)版10月14日發(fā)表的四篇論文描述了一種可能是全新的基因活動(dòng)形式的方方面面，這種活動(dòng)涉及到大量互相影響并且在幕后擺布分子“殘局”的核糖核酸(RNA)分子,。每一篇論文都采用了各不相同的方法,，從而增加了這一有關(guān)新RNA網(wǎng)絡(luò)的基礎(chǔ)性發(fā)現(xiàn)的分量。
這些研究結(jié)果可以使研究人員拓寬思路,，以便深入探究腫瘤的形成和發(fā)展機(jī)制,，發(fā)現(xiàn)癌癥高危人群，并尋找和抑制導(dǎo)致癌癥生長和擴(kuò)散的關(guān)鍵的異常分子,。
BIDMC癌癥遺傳學(xué)計(jì)劃負(fù)責(zé)人皮爾·潘多爾菲博士和哈佛醫(yī)學(xué)院的喬治·賴斯曼教授說：“例如,，我們現(xiàn)在知道PTEN腫瘤抑制基因與一個(gè)巨大的尚未被認(rèn)識(shí)的RNA網(wǎng)絡(luò)進(jìn)行對(duì)話。
RNA通過一種新的語言交談,，如果這種語言出了差錯(cuò),，RNA網(wǎng)絡(luò)受到了破壞，那么PTEN基因就會(huì)走下坡路,，從而帶來毀滅性后果,。不過治療方面的潛力令人極其振奮。你可以改寫RNA之間的‘對(duì)話’,，以便進(jìn)行癌癥的預(yù)防和治療,。”賴斯曼是其中兩篇論文的主要作者,。
《細(xì)胞》雜志發(fā)表的另一篇相關(guān)論文指出,，新的RNA管理網(wǎng)絡(luò)似乎也延伸到了人類基因組中廣闊的非蛋白質(zhì)編碼區(qū)域,，并在正常的肌肉發(fā)育過程中發(fā)揮著重要作用,。由于人類擁有眾多與包括蠕蟲和酵母在內(nèi)的其他生物相同的蛋白質(zhì)編碼基因，被轉(zhuǎn)錄為非編碼RNA的這一廣闊區(qū)域使得人類的基因組與眾不同,。這種非編碼RNA的功能在很大程度上仍不為人所知,。
潘多爾菲說：“幾乎所有關(guān)于癌癥基因的科學(xué)分析都把重點(diǎn)放在蛋白質(zhì)編碼基因上,。”他指的是把指令從DNA傳遞至RNA、再傳遞至蛋白質(zhì)的那2%的人類基因組,。他說：“我們知道,，有將近一半被轉(zhuǎn)錄成RNA的基因組是不給蛋白質(zhì)編碼的。通過這種新的RNA‘語言’,，我們可以把這個(gè)空當(dāng)派上用場(chǎng),。”（生物谷 Bioon.com）
doi:10.1016/j.cell.2011.09.029
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Coding-Independent Regulation of the Tumor Suppressor PTEN by Competing Endogenous mRNAs
Yvonne Tay, Lev Kats, Leonardo Salmena, Dror Weiss, Shen Mynn Tan, Ugo Ala, Florian Karreth, Laura Poliseno, Paolo Provero, Ferdinando Di Cunto, Judy Lieberman, Isidore Rigoutsos, Pier Paolo Pandolfi
Here, we demonstrate that protein-coding RNA transcripts can crosstalk by competing for common microRNAs, with microRNA response elements as the foundation of this interaction. We have termed such RNA transcripts as competing endogenous RNAs (ceRNAs). We tested this hypothesis in the context of PTEN, a key tumor suppressor whose abundance determines critical outcomes in tumorigenesis. By a combined computational and experimental approach, we identified and validated endogenous protein-coding transcripts that regulate PTEN, antagonize PI3K/AKT signaling, and possess growth- and tumor-suppressive properties. Notably, we also show that these genes display concordant expression patterns with PTEN and copy number loss in cancers. Our study presents a road map for the prediction and validation of ceRNA activity and networks and thus imparts a trans-regulatory function to protein-coding mRNAs.
doi:10.1016/j.cell.2011.09.028
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A Long Noncoding RNA Controls Muscle Differentiation by Functioning as a Competing Endogenous RNA
Marcella Cesana, Davide Cacchiarelli, Ivano Legnini, Tiziana Santini, Olga Sthandier, Mauro Chinappi, Anna Tramontano, Irene Bozzoni
Recently, a new regulatory circuitry has been identified in which RNAs can crosstalk with each other by competing for shared microRNAs. Such competing endogenous RNAs (ceRNAs) regulate the distribution of miRNA molecules on their targets and thereby impose an additional level of post-transcriptional regulation. Here we identify a muscle-specific long noncoding RNA, linc-MD1, which governs the time of muscle differentiation by acting as a ceRNA in mouse and human myoblasts. Downregulation or overexpression of linc-MD1 correlate with retardation or anticipation of the muscle differentiation program, respectively. We show that linc-MD1 “sponges” miR-133 and miR-135 to regulate the expression of MAML1 and MEF2C, transcription factors that activate muscle-specific gene expression. Finally, we demonstrate that linc-MD1 exerts the same control over differentiation timing in human myoblasts, and that its levels are strongly reduced in Duchenne muscle cells. We conclude that the ceRNA network plays an important role in muscle differentiation.
doi:10.1016/j.cell.2011.09.041
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An Extensive MicroRNA-Mediated Network of RNA-RNA Interactions Regulates Established Oncogenic Pathways in Glioblastoma
Pavel Sumazin, Xuerui Yang, Hua-Sheng Chiu, Wei-Jen Chung, Archana Iyer, David Llobet-Navas, Presha Rajbhandari, Mukesh Bansal, Paolo Guarnieri, Jose Silva, Andrea Califano
By analyzing gene expression data in glioblastoma in combination with matched microRNA profiles, we have uncovered a posttranscriptional regulation layer of surprising magnitude, comprising more than 248,000 microRNA (miR)-mediated interactions. These include 7,000 genes whose transcripts act as miR sponges and 148 genes that act through alternative, nonsponge interactions. Biochemical analyses in cell lines confirmed that this network regulates established drivers of tumor initiation and subtype implementation, including PTEN, PDGFRA, RB1, VEGFA, STAT3, and RUNX1, suggesting that these interactions mediate crosstalk between canonical oncogenic pathways. siRNA silencing of 13 miR-mediated PTEN regulators, whose locus deletions are predictive of PTEN expression variability, was sufficient to downregulate PTEN in a 3UTR-dependent manner and to increase tumor cell growth rates. Thus, miR-mediated interactions provide a mechanistic, experimentally validated rationale for the loss of PTEN expression in a large number of glioma samples with an intact PTEN locus.
doi:10.1016/j.cell.2011.09.032
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In Vivo Identification of Tumor- Suppressive PTEN ceRNAs in an Oncogenic BRAF-Induced Mouse Model of Melanoma
Florian A. Karreth, Yvonne Tay, Daniele Perna, Ugo Ala, Shen Mynn Tan, Alistair G. Rust, Gina DeNicola, Kaitlyn A. Webster, Dror Weiss, Pedro A. Perez-Mancera, Michael Krauthammer, Ruth Halaban, Paolo Provero, David J. Adams, David A. Tuveson, Pier Paolo Pandolfi
We recently proposed that competitive endogenous RNAs (ceRNAs) sequester microRNAs to regulate mRNA transcripts containing common microRNA recognition elements (MREs). However, the functional role of ceRNAs in cancer remains unknown. Loss of PTEN, a tumor suppressor regulated by ceRNA activity, frequently occurs in melanoma. Here, we report the discovery of significant enrichment of putative PTEN ceRNAs among genes whose loss accelerates tumorigenesis following Sleeping Beauty insertional mutagenesis in a mouse model of melanoma. We validated several putative PTEN ceRNAs and further characterized one, the ZEB2 transcript. We show that ZEB2 modulates PTEN protein levels in a microRNA-dependent, protein coding-independent manner. Attenuation of ZEB2 expression activates the PI3K/AKT pathway, enhances cell transformation, and commonly occurs in human melanomas and other cancers expressing low PTEN levels. Our study genetically identifies multiple putative microRNA decoys for PTEN, validates ZEB2 mRNA as a bona fide PTEN ceRNA, and demonstrates that abrogated ZEB2 expression cooperates with BRAFV600E to promote melanomagenesis.
