CN107167604A - Flot1在作为卵巢癌生物标志物中的应用 - Google Patents
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Abstract
本发明涉及FLOT1在作为人卵巢癌生物标志物中的应用。本发明首次证实了通过检测人血清FLOT1水平可以诊断卵巢癌，FLOT1的截断值为1233pg/ml，敏感度0.722，1‑特异性0.278，AUC＝0.787，表明FLOT1可作为卵巢癌有效的生物标志物，诊断价值很高；还证实了使用FLOT1联合CA125诊断，可将卵巢癌的诊断率提高24％。提示用于检测血清FLOT1水平的试剂可用于制备诊断卵巢癌的试剂或试剂盒，同时含有检测血清FLOT1和CA125水平试剂的试剂盒能够显著提高卵巢癌的诊断率。本发明为卵巢癌的准确诊断提供了新的途径。
Description
技术领域
本发明涉及肿瘤的诊断领域，具体地说，涉及FLOT1作为卵巢癌生物标志物中的应用。
背景技术
卵巢癌是女性生殖器官常见的恶性肿瘤之一，发病率仅次于子宫颈癌和子宫体癌而列居第三位。由于卵巢的胚胎发育、组织解剖及内分泌功能较复杂，早期症状不典型。因此，探索卵巢癌的生物标志物和治疗靶点对于卵巢癌的诊断和治疗意义重大。目前临床中常用诊断卵巢癌的生物标志物为CA125，文献显示CA125仅在约70％的卵巢癌病人组织中表达(Gynecol Oncol,2007.104(3):p.508-15.)，而且也不是在所有卵巢癌病人的血液中都可以检测(J Clin Oncol,2009.27(15_suppl):p.e16579.Hum Reprod,1989.4(1):p.1-12.)。因此有必要寻找更有效的卵巢癌生物标志物。
脂筏特征蛋白(flotillin，FLOT)是细胞膜上一类高度保守的脂筏标记蛋白，广泛存在于体内不同的组织和细胞，由脂筏特征蛋白-1(FLOT1)和脂筏特征蛋白-2(FLOT2)组成。
人FLOT1是脂筏的主要组成部分，其编码基因位于染色体6p21.3区段，基因全长15kb，含13个外显子和12个内含子，编码427个氨基酸组成分子质量为48kD的蛋白质。近来研究发现，FLOT1的表达增高与多种肿瘤的发生、发展密切相关。例如Lin等[Lin C,Wu Z,Lin X,et al.Knockdown of FLOT1 impairs cell proliferation and tumorigenicityin breast cancer through upregulation of FOXO3a[J].Clin Cancer Res,2011,17(10):3089-3099]采用免疫组织化学方法检测乳腺癌组织，观察到FLOT1的高表达与患者的临床分期和生存不良呈正相关，即随FLOT1的表达水平升高，患者肿瘤的恶性表型更加明显，蛋白免疫印迹和荧光素酶报告基因分析显示，敲除FLOT1会使FOXO3a转录上调，进而抑制细胞增殖和肿瘤形成。现有研究表明FLOT1在不同恶性肿瘤的发生发展中所发挥的作用不同。
现有研究多是证明了FLOT1在肿瘤细胞或组织中表达水平的变化，也并未证明FLOT1是否能作为有效的生物标志物。目前尚未见以血清FLOT1水平作为卵巢癌生物标志物的相关报道。
发明内容
本发明的目的是针对现有技术中的不足，提供FLOT1作为卵巢癌生物标志物的用途。
本发明提供了检测血清FLOT1水平的试剂在制备诊断卵巢癌的试剂或试剂盒中的应用。
作为本发明的一个优选例，所述的检测血清FLOT1水平的试剂为ELISA试剂。
作为本发明的一个优选例，血清FLOT1水平的截断值为1233pg/ml。
本发明还提供了一种提高卵巢癌诊断率的试剂组，所述的试剂组同时含有检测血清FLOT1和CA125的试剂。
本发明还提供了所述的试剂组在制备诊断卵巢癌的试剂盒中的应用。
作为本发明的一个优选例，血清FLOT1水平的截断值为1233pg/ml，血清CA125水平的截断值为35U/L。
本发明还提供了一种提高卵巢癌诊断率的试剂盒，所述的试剂盒同时含有检测血清FLOT1和CA125的试剂。
本发明优点在于：
1、本发明首次证实了通过检测人血清FLOT1水平可以诊断卵巢癌，FLOT1的截断值为1233pg/ml，敏感度0.722，1-特异性0.278，AUC＝0.787，表明FLOT1可作为卵巢癌有效的生物标志物，诊断价值非常高；
2、本发明还证实了使用FLOT1联合CA125诊断，可将卵巢癌的诊断率提高24％。
综上，用于检测血清FLOT1水平的试剂可用于制备诊断卵巢癌的试剂或试剂盒；同时含有检测血清FLOT1和CA125水平试剂的试剂盒，能够显著提高卵巢癌的诊断率。目前卵巢癌的发病率高，准确诊断存在困难，本发明为解决这一临床难题提供了新的途径。
附图说明
图1：小鼠生存资料。A：OVCAR-3皮下注射组肿瘤照片；B：小鼠体重曲线。
图2：小鼠血清ELISA检测结果。A：血清CA125在Blank和OVCAR-3皮下注射组的比较；B：血清FLOT1在Blank和OVCAR-3皮下注射组的比较；C：小鼠血清CA125的ROC曲线下面积(AUC＝0.986)；D：小鼠血清FLOT1的ROC曲线下面积(AUC＝0.986)。**，P<0.01；*，P<0.05。
图3：人血清ELISA检测结果。A：血清CA125在人卵巢癌病人和正常组的比较；B：血清FLOT1在人卵巢癌病人和正常组的比较；C：人血清CA125的ROC曲线下面积(AUC＝0.685)；D：人血清FLOT1的ROC曲线下面积(AUC＝0.787)。**，P<0.01；*，P<0.05。
具体实施方式
下面结合附图对本发明提供的具体实施方式作详细说明。
实施例1 动物实验筛选出潜在卵巢癌生物标志物
1、收集OVCAR-3细胞，PBS洗2遍，用无血清的RPMI-1640培养基混悬至浓度为5*107/ml。
2、BALB-nude裸小鼠，随机分组，分为Blank和OVCAR-3皮下注射组，10只/组。SPF级房间饲养，房间温度26～28℃，相对湿度40％～60％，10小时光照，14小时无光的明暗周期。OVCAR-3细胞5*106/100μl，腋窝皮下注射。待皮下肿瘤体积至100mm3左右，10％水合氯醛处死小鼠，取血清。
结果见图1，表明成功建立卵巢癌移植瘤小鼠模型。
3、ELISA检测小鼠血清FLOT1表达水平，以CA125为对照。
ELISA试剂盒购至上海酶联生物技术有限公司。具体检测步骤如下：
1)标准品的稀释：本试剂盒提供原倍标准品一支，用户可按照下列图表在小试管中进行稀释。
1200pg/ml，5号标准品，150μl的原倍标准品加入150μl标准品稀释液；
600pg/ml，4号标准品，150μl的5号标准品加入150μl标准品稀释液；
300pg/ml，3号标准品，150μl的4号标准品加入150μl标准品稀释液；
150pg/ml，2号标准品，150μl的3号标准品加入150μl标准品稀释液；
75pg/ml，1号标准品，150μl的2号标准品加入150μl标准品稀释液。
2)加样：分别设空白孔(空白孔不加样品及酶标试剂，其余各步操作相同)、标准孔、待测样品孔。在酶标包被板上标准品准确加样50μl，待测样品孔中先加样品稀释液40μl，然后再加待测样品10μl(样品最终稀释度为5倍)。将样品加于酶标板孔底部，尽量不触及孔壁，轻轻晃动混匀。
3)温育：用封板膜封板后置37℃温育30分钟。
4)配液：将30倍(48T的20倍)浓缩洗涤液用蒸馏水30倍稀释后备用。
5)洗涤：小心揭掉封板膜，弃去液体，甩干，每孔加满洗涤液，静置30秒后弃去，如此重复5次，拍干。
6)加酶：每孔加入酶标试剂50μl，空白孔除外。
7)温育：操作同3。
8)洗涤：操作同5。
9)显色：每孔先加入显色剂A50μl，再加入显色剂B 50μl，轻轻震荡混匀，37℃避光显色10分钟。
10)终止：每孔加终止液50μl，终止反应(此时蓝色立转黄色)。
11)测定：以空白空调零，450nm波长依序测量各孔的吸光度(OD值)。测定应在加终止液后15分钟以内进行。
结果见图2，表明Blank和OVCAR-3皮下注射组小鼠血清中FLOT1和CA125的表达量均具有显著差异，提示FLOT1是潜在的卵巢癌生物标志物。
实施例2 FLOT1和CA125在人卵巢癌诊断中的比较和联合诊断
1、FLOT1和CA125在人卵巢癌血清中高表达。卵巢癌病人血清18例，正常对照血清18例。卵巢癌病人血清为术前且未经放化疗的血清，正常对照血清为健康人群的血清，且年龄与卵巢患者的中位年龄相近，两组年龄无统计学意义。ELISA检测人血清FLOT1表达水平，CA125为对照(**，P<0.01)。
结果见图3，表明卵巢癌病人相比于健康人群，血清中的FLOT1和CA125均显著升高，FLOT1作为卵巢癌的诊断标志物具备很高的准确性。
2、利用IBM SPSS Statistics 21软件作ROC曲线。计算约登指数＝真阳性率-假阳性率＝敏感度-(1-特异性)。取约登指数最高的值为截断值(cut-off值)。得出CA125的截断值为35U/L，敏感度0.778，1-特异性0.222；FLOT1的截断值为1233pg/ml，敏感度0.722，1-特异性0.278。
FLOT1联合CA125可提高卵巢癌的诊断率，FLOT1联合CA125卵巢癌的诊断率比CA125诊断率提高24％(表1)。
表1 不同生物标志物诊断的准确率比较
| 卵巢癌 | 阳性 | 总例数 | 阳性率 |
| CA125 | 13 | 18 | 0.72 |
| FLOT1 | 14 | 18 | 0.78 |
| CA125联合FLOT1 | 16 | 18 | 0.89 |
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员，在不脱离本发明方法的前提下，还可以做出若干改进和补充，这些改进和补充也应视为本发明的保护范围。
Claims (7)
1.检测血清FLOT1水平的试剂在制备诊断卵巢癌的试剂或试剂盒中的应用。
2.根据权利要求1所述的应用，其特征在于，所述的检测血清FLOT1水平的试剂为ELISA试剂。
3.根据权利要求1所述的应用，其特征在于，血清FLOT1水平的截断值为1233pg/ml。
4.一种提高卵巢癌诊断率的试剂组，其特征在于，所述的试剂组同时含有检测血清FLOT1和CA125的试剂。
5.权利要求4所述的试剂组在制备诊断卵巢癌的试剂盒中的应用。
6.根据权利要求5所述的应用，其特征在于，血清FLOT1水平的截断值为1233pg/ml，血清CA125水平的截断值为35U/L。
7.一种提高卵巢癌诊断率的试剂盒，其特征在于，所述的试剂盒同时含有检测血清FLOT1和CA125的试剂。
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| CN109825571A (zh) * | 2019-03-04 | 2019-05-31 | 中国科学院昆明动物研究所 | 抑郁症检测生物标记物及其试剂盒 |
| CN112680523A (zh) * | 2021-01-25 | 2021-04-20 | 复旦大学附属中山医院 | 用于判断卵巢癌患者预后的分子模型及应用 |
| CN113341156A (zh) * | 2021-06-01 | 2021-09-03 | 中国医学科学院北京协和医院 | 鉴别卵巢子宫内膜异位症/卵巢癌的试剂及其应用 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109825571A (zh) * | 2019-03-04 | 2019-05-31 | 中国科学院昆明动物研究所 | 抑郁症检测生物标记物及其试剂盒 |
| CN112680523A (zh) * | 2021-01-25 | 2021-04-20 | 复旦大学附属中山医院 | 用于判断卵巢癌患者预后的分子模型及应用 |
| CN112680523B (zh) * | 2021-01-25 | 2022-07-29 | 复旦大学附属中山医院 | 用于判断卵巢癌患者预后的分子模型及应用 |
| CN113341156A (zh) * | 2021-06-01 | 2021-09-03 | 中国医学科学院北京协和医院 | 鉴别卵巢子宫内膜异位症/卵巢癌的试剂及其应用 |
| CN113341156B (zh) * | 2021-06-01 | 2022-02-22 | 中国医学科学院北京协和医院 | 鉴别卵巢子宫内膜异位症/卵巢癌的试剂及其应用 |
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