CN103837679B - Sirt-1蛋白在诊断、预测骨肉瘤转移产品的应用 - Google Patents
Sirt-1蛋白在诊断、预测骨肉瘤转移产品的应用 Download PDFInfo
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Abstract
本发明公开Sirt-1蛋白在诊断、预测骨肉瘤转移产品的应用。该Sirt-1蛋白可作为骨肉瘤诊断的标记分子，提高骨肉瘤诊断和预测骨肉瘤转移的准确性。用免疫检测诊断骨肉瘤和预测骨肉瘤转移的产品包括：与Sirt-1蛋白特异性结合的抗体。诊断骨肉瘤和预测骨肉瘤转移的产品包括：用RT-PCR、实时定量PCR、免疫检测、原位杂交或基因芯片诊断骨肉瘤和预测骨肉瘤转移的产品。Sirt-1蛋白可作为诊断和预测转移的特异性标志蛋白，使骨肉瘤诊断更加准确、快速。
Description
技术领域
本发明涉及一个蛋白的应用，尤其涉及Sirt-1蛋白在诊断、预测骨肉瘤转移产品的应用。
背景技术
骨肉瘤是最常见的恶性成骨性肿瘤之一，流行病学研究发现该病好发于15-25岁的青少年，且男性发病率高于女性。骨肉瘤好发部位是长管状骨的干骺端，该肿瘤恶性程度高，预后极差，单纯截肢后患者的5年生存率低于20﹪，此外该肿瘤的另一个显著特点是肺部转移早，在临床做出骨肉瘤诊断时，其中大部分已经发生肺的微小转移。因此，有效诊断骨肉瘤，特别是研发预测骨肉瘤转移的技术是目前骨肿瘤研究中的重点和难点。
目前，越来越多的研究表明Sirt1与肿瘤的发生发展密切相关。在很多肿瘤中，Sirt1的表达水平会明显增高，且Sirt1常集中于一些异常沉默的抑癌基因（这些基因的DNA被过度甲基化）的启动子上。文献报道在乳腺癌和结肠癌中，对Sirt1的抑制增加了内源性启动子中H4-K16和H3-K7的乙酰化作用，可以满足基因重复表达的条件。Sirt1通过对组蛋白的H1-K26的脱乙酰化作用和促进H3K9me2的丢失来调节异染色质的构成。Sirt1与SUV39H1直接结合并脱去其乙酰基，促进SUV39H1的活性进而引起H3K9me3修饰水平的增加。此外，Sirt1也可以将很多非组蛋白去乙酰化，比如可以对p53进行去乙酰化，负向调节p53的功能；Sirt1还可以对DNA修复蛋白Ku70、FOXO家族蛋白、NF-kB等进行调控。尽管Sirt1的生物学功能已被逐步探明，但目前尚无文献报道Sirt1与骨肉瘤的相关性研究，更未见Sirt1表达与骨肉瘤转移的相关研究。
发明内容
本发明针对现有技术的不足，提供Sirt-1蛋白的一种新应用，该Sirt-1蛋白可作为骨肉瘤诊断的标记分子，提高骨肉瘤诊断和预测骨肉瘤转移的准确性。
所述的Sirt-1蛋白的氨基酸序列，如SEQIDNO.1所示。
为解决上述技术问题，本发明通过如下技术方案实现：
所述诊断骨肉瘤和预测骨肉瘤转移的产品包括：用RT-PCR、实时定量PCR、免疫检测、原位杂交或基因芯片诊断骨肉瘤和预测骨肉瘤转移的产品。
在本发明中，所述用免疫检测诊断骨肉瘤和预测骨肉瘤转移的产品包括：与Sirt-1蛋白特异性结合的抗体。
所述用RT-PCR诊断骨肉瘤和预测骨肉瘤转移的产品至少包括一对特异性扩增Sirt-1基因的引物：正向引物：5，-AGCTGATGAACCGCTTGCTA-3，;
反向引物：5，-CCCAAATCCAGCTCCTCCAG-3，。
所述用实时定量PCR诊断骨肉瘤和预测骨肉瘤转移的产品至少包括一对特异性扩增Sirt-1基因的引物：正向引物：5，-AACAGGTTGCGGGAATCCAA-3，;反向引物：5，-GTTCATCAGCTGGGCACCTA-3，。
所述用原位杂交诊断骨肉瘤和预测骨肉瘤转移的产品包括：与Sirt-1基因的核酸序列杂交的探针：5，-CATTTTCCATGGCGCTGAGG-3，。
所述用基因芯片诊断骨肉瘤和预测骨肉瘤转移的产品包括：与Sirt-1基因的核酸序列杂交的探针：5，-TTGCAACAGCATCTTGCCTG-3，。
在本发明中，可以使用一系列本领域已知的方法来制备针对Sirt-1蛋白特异的抗体。例如，将纯化的人Sirt-1蛋白或它的抗原片段注射入动物体内以产生多克隆抗体。同样，表达人Sirt-1蛋白或它的抗原片段的细胞也可以用来对动物致免疫而产生抗体。根据本发明制备的抗体也可以是单克隆抗体，这些单克隆抗体可用杂交瘤技术制备。本发明的抗体包括可以阻抑Sirt-1功能的抗体，也可以是不影响人Sirt-1蛋白功能的抗体。每一类抗体都可以通过对人Sirt-1蛋白的片断或功能域致免疫而产生，而人Sirt-1蛋白产物及其片段可以用重组方法产生或用多肽合成仪进行合成。与非修饰形式的Sirt-1蛋白结合的抗体，可以利用在原核细胞例如E.coli中产生的基因产物来免疫动物而得到。与翻译后修饰形式如糖基化或磷酸化Sirt-1蛋白或多肽结合的抗体，可以利用在真核细胞如酵母或昆虫细胞中产生的基因产物来免疫动物而得到。
在本发明中，所述探针可以是DNA、RNA、DNA-RNA嵌合体、PNA或其他衍生物。所述探针的长度没有限制，只要能够完成特异性杂交、与目的核苷酸序列特异性结合，任何长度都可以。所述探针的长度可以短至25、20、15或10个碱基长度。同样，所述探针的长度可长至60、80、100、150、300个碱基对或更长，甚至整个基因。由于不同的探针长度对杂交效率、信号特异性有不同的影响，所述探针的长度通常至少是14个碱基对，最长一般不超过30个碱基对，与目的核苷酸序列互补的长度以15-25个碱基对最佳。所述探针自身互补序列最好少于4个碱基对，以免影响杂交效率。
本发明实验证明Sirt-1蛋白在骨肉瘤组织中的表达明显高于癌旁组织，且与骨肉瘤肺转移密切相关；而在原代骨肉瘤细胞中Sirt-1蛋白与其侵袭运动能力呈正相关。因此，Sirt-1蛋白可作为诊断和预测转移的特异性标志蛋白，使骨肉瘤诊断更加准确、快速。
附图说明
图1为本发明通过免疫组化法验证Sirt-1在人骨肉瘤组织和癌旁组织中的表达图；
图2为本发明通过免疫组化法检测骨肉瘤中Sirt-1蛋白水平；
图3为表达不同程度Sirt-1蛋白的原代骨肉瘤细胞在体外的侵袭运动能力。
具体实施方式
下面结合附图和实施例对本发明作进一步详细的说明。
以下实施例仅用于说明本发明而不用于限制本发明的范围。实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。
下面实施例所用的Sirt-1蛋白的氨基酸序列，如SEQIDNO.1所示。
实施例1：
选取骨肉瘤临床样本以及癌旁组织33对，用10%甲醛溶液固定7天，随后制备石蜡包埋的组织块。将样本制备厚度为8微米的石蜡切片，并采用免疫组化法检测Sirt-1蛋白的表达情况，在正置显微镜下观察Sirt-1蛋白的表达情况。如图1所示，癌组织中Sirt-1蛋白的表达显著高于癌旁组织。对这33对骨肉瘤临床样本以及癌旁组织中Sirt-1蛋白的表达情况进行统计，发现癌组织中强阳性为15例，阳性为14例，弱阳性为3例，阴性为1例；而在癌旁组织中强阳性为1例，阳性为3例，弱阳性为11例，阴性为18例（图2）。
实施例2：
对前述实施例1中的33例骨肉瘤进行3年回顾性调研，其中有22例有详细的随访记录，故在这22例样本中分析Sirt-1蛋白表达与骨肉瘤病人预后之间的关系。结果发现，Sirt-1表达越强，骨肉瘤病人的转移率越高（表1）。
表1骨肉瘤中Sirt-1蛋白水平与肺转移及3年生存率的相关性
实施例3：
选取体外培养的7株原代骨肉瘤细胞，采用免疫印迹法检测Sirt-1蛋白的表达，以Actin作为内参，如图3A所示，不同的原代骨肉瘤细胞内Sirt-1蛋白表达水平存在差异。随后采用Transwell法检测原代骨肉瘤细胞的侵袭迁移能力。如图3B所示，一般来说，原代骨肉瘤细胞中Sirt-1蛋白的高表达与其体外侵袭运动能力呈正相关。图3A中颜色越深说明，Sirt-1在该细胞表达越强，同时图3B颜色越深说明侵袭能力越强，图3A与图3B结果正相关。
SEQUENCELISTING
<110>浙江大学医学院附属第二医院
<120>Sirt-1蛋白在诊断、预测骨肉瘤转移产品的应用
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GluLysAsnGluArgThrSerValAlaGlyThrValArgLysCysTrp
420425430
ProAsnArgValAlaLysGluGlnIleSerArgArgLeuAspGlyAsn
435440445
GlnTyrLeuPheLeuProProAsnArgTyrIlePheHisGlyAlaGlu
450455460
ValTyrSerAspSerGluAspAspValLeuSerSerSerSerCysGly
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SerAsnSerAspSerGlyThrCysGlnSerProSerLeuGluGluPro
485490495
MetGluAspGluSerGluIleGluGluPheTyrAsnGlyLeuGluAsp
500505510
GluProAspValProGluArgAlaGlyGlyAlaGlyPheGlyThrAsp
515520525
GlyAspAspGlnGluAlaIleAsnGluAlaIleSerValLysGlnGlu
530535540
ValThrAspMetAsnTyrProSerAsnLysSer
545550555
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Claims (3)
1.检测Sirt-1蛋白的试剂在制备诊断骨肉瘤产品或制备预测骨肉瘤转移产品中的应用。
2.如权利要求1所述的检测Sirt-1蛋白的试剂在制备诊断骨肉瘤产品或制备预测骨肉瘤转移产品中的应用，其特征在于Sirt-1蛋白的氨基酸序列如SEQIDNO.1所示。
3.如权利要求1所述的检测Sirt-1蛋白的试剂在制备诊断骨肉瘤产品或制备预测骨肉瘤转移产品中的应用，其特征在于诊断骨肉瘤或预测骨肉瘤转移的产品用于免疫检测，并包括：与Sirt-1蛋白特异性结合的抗体。
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| CN201410057837.XA CN103837679B (zh) | 2014-02-20 | 2014-02-20 | Sirt-1蛋白在诊断、预测骨肉瘤转移产品的应用 |
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| CN103837679B true CN103837679B (zh) | 2016-06-08 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101257897A (zh) * | 2005-07-07 | 2008-09-03 | 西特里斯药业公司 | 用于治疗或预防肥胖、胰岛素抵抗障碍和线粒体相关障碍的方法和相关组合物 |
| CN102307997A (zh) * | 2008-12-04 | 2012-01-04 | 欧科库尔纳有限责任公司 | 通过抑制针对沉默调节蛋白1的天然反义转录物来治疗沉默调节蛋白1(sirt1)相关的疾病 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8043804B2 (en) * | 2007-05-23 | 2011-10-25 | The Trustees Of Columbia University In The City Of New York | DBC1, a novel native inhibitor of anti-aging protein SIRT1 |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101257897A (zh) * | 2005-07-07 | 2008-09-03 | 西特里斯药业公司 | 用于治疗或预防肥胖、胰岛素抵抗障碍和线粒体相关障碍的方法和相关组合物 |
| CN102307997A (zh) * | 2008-12-04 | 2012-01-04 | 欧科库尔纳有限责任公司 | 通过抑制针对沉默调节蛋白1的天然反义转录物来治疗沉默调节蛋白1(sirt1)相关的疾病 |
Non-Patent Citations (3)
| Title |
|---|
| AAH12499.1;Strausberg,R.;《GenBank》;20031007;第1-2页 * |
| Resveratrol inhibits proliferation and promotes apoptosis of osteosarcoma cells;Yan Li et al.;《European Journal of Pharmacology》;20090311;第609卷;第13-18页 * |
| SIRT1 inhibition by melatonin exerts antitumor activity in human osteosarcoma cells;Yedong Cheng et al.;《European Journal of Pharmacology》;20130529;第715卷;第219-229页 * |
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