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腾讯登录Nature：特定蛋白质分子促进结肠癌发展的分子机制
| 导读 | 近日，来自明尼苏达大学医学院和癌症研究中心的研究者和Genentech公司的研究人员共同研究发现了某些蛋白质促进结肠癌发展的分子机制。R-脊椎蛋白家族成员可以在胚胎干细胞发育期间帮助活化的细胞进行增殖。这项研究中，研究者发现了R-脊椎蛋白（R-spondins）家族成员RSPO2和RSPO3由于某种突变，其在成年个体中处于再活化的状态，可以给细胞发送信号来重新进行细胞增殖的过程，这将导致结肠癌肿瘤... |
近日，来自明尼苏达大学医学院和癌症研究中心的研究者和Genentech公司的研究人员共同研究发现了某些蛋白质促进结肠癌发展的分子机制。R-脊椎蛋白家族成员可以在胚胎干细胞发育期间帮助活化的细胞进行增殖。这项研究中，研究者发现了R-脊椎蛋白（R-spondins）家族成员RSPO2和RSPO3由于某种突变，其在成年个体中处于再活化的状态，可以给细胞发送信号来重新进行细胞增殖的过程，这将导致结肠癌肿瘤细胞的无限增殖。相关研究成果刊登在了近日的国际杂志<em>Nature</em>上。
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研究者David Largaespada说，“我们的研究成果揭示了基于肿瘤特性的个体化治疗手段，因为R-脊椎蛋白和胚胎生长直接相关，而且其在成年个体中并没有重要的功能，因此以其作为治疗靶点对个体治疗所带来的副作用或许会减小很多。
实验中，研究者分析了超过70对人类结肠癌和人工化的小鼠肿瘤模型（使Sleeping Beauty 转座子进行人工化操作），通过一系列的调查研究，研究者发现了36处可以导致基因融合的重排，这包括RSPO2和RSPO3的出现。
研究结果或许可以提供个体化的途径来治疗结肠癌，研究者表示，还需要深入研究来证实其确实可以用于治疗结肠癌病人，研究者表示，我们常常关心的是肿瘤是在哪里发生的，但是更应该关心是什么诱发产生肿瘤的。目前研究者正在进行深入研究以帮助确定是否一种阻断剂可以有效应用治疗由于产生R-脊椎蛋白所引发的结肠癌，如果试验结果成功，那么就可以开发出治疗结肠癌病人的新型疗法。
编译自：<a title="" href="http://www.sciencedaily.com/releases/2012/08/120824093515.htm" target="_blank">Newly Discovered Genetic Markers Could Signal Colon Cancer Development</a>
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<a title="" href="http://dx.doi.org/doi:10.1038/nature11282" target="_blank">doi:10.1038/nature11282</a>
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<br/><strong>Recurrent R-spondin fusions in colon cancer</strong><br/>
Somasekar Seshagiri, Eric W. Stawiski, Steffen Durinck, Zora Modrusan, Elaine E. Storm, Caitlin B. Conboy, Subhra Chaudhuri, Yinghui Guan, Vasantharajan Janakiraman, Bijay S. Jaiswal, Joseph Guillory, Connie Ha, Gerrit J. P. Dijkgraaf, Jeremy Stinson, Florian Gnad, Melanie A. Huntley, Jeremiah D. Degenhardt, Peter M. Haverty, Richard Bourgon, Weiru Wang, Hartmut Koeppen, Robert Gentleman, Timothy K. Starr, Zemin Zhang, David A. Largaespada et al.
Identifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics1. Here we analyse systematically more than 70 pairs of primary human colon tumours by applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer.
<br/>来源：生物谷
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研究者David Largaespada说，“我们的研究成果揭示了基于肿瘤特性的个体化治疗手段，因为R-脊椎蛋白和胚胎生长直接相关，而且其在成年个体中并没有重要的功能，因此以其作为治疗靶点对个体治疗所带来的副作用或许会减小很多。
实验中，研究者分析了超过70对人类结肠癌和人工化的小鼠肿瘤模型（使Sleeping Beauty 转座子进行人工化操作），通过一系列的调查研究，研究者发现了36处可以导致基因融合的重排，这包括RSPO2和RSPO3的出现。
研究结果或许可以提供个体化的途径来治疗结肠癌，研究者表示，还需要深入研究来证实其确实可以用于治疗结肠癌病人，研究者表示，我们常常关心的是肿瘤是在哪里发生的，但是更应该关心是什么诱发产生肿瘤的。目前研究者正在进行深入研究以帮助确定是否一种阻断剂可以有效应用治疗由于产生R-脊椎蛋白所引发的结肠癌，如果试验结果成功，那么就可以开发出治疗结肠癌病人的新型疗法。
编译自：<a title="" href="http://www.sciencedaily.com/releases/2012/08/120824093515.htm" target="_blank">Newly Discovered Genetic Markers Could Signal Colon Cancer Development</a>
<div id="ztload">
<div> </div>
<div>
<div>
<img src="http://www.bioon.com/biology/UploadFiles/201208/2012082722280258.jpg" alt="" width="113" height="149" border="0" />
<a title="" href="http://dx.doi.org/doi:10.1038/nature11282" target="_blank">doi:10.1038/nature11282</a>
PMC:
PMID:
</div>
<div>
<br/><strong>Recurrent R-spondin fusions in colon cancer</strong><br/>
Somasekar Seshagiri, Eric W. Stawiski, Steffen Durinck, Zora Modrusan, Elaine E. Storm, Caitlin B. Conboy, Subhra Chaudhuri, Yinghui Guan, Vasantharajan Janakiraman, Bijay S. Jaiswal, Joseph Guillory, Connie Ha, Gerrit J. P. Dijkgraaf, Jeremy Stinson, Florian Gnad, Melanie A. Huntley, Jeremiah D. Degenhardt, Peter M. Haverty, Richard Bourgon, Weiru Wang, Hartmut Koeppen, Robert Gentleman, Timothy K. Starr, Zemin Zhang, David A. Largaespada et al.
Identifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics1. Here we analyse systematically more than 70 pairs of primary human colon tumours by applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer.
<br/>来源：生物谷
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