环孢素蛋白CypB在胃癌中的表达和作用及其核酸适体的筛选
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摘要
胃癌是我国最常见的恶性肿瘤之一。肿瘤标志物的检测是发现早期胃癌的重要方法之一，而早期诊断和早期治疗有利于提高患者的生存率和生活质量。但是目前仍未寻找到对胃癌高特异性和高灵敏度的血清学标志物。因此，寻找新的肿瘤标志物或新的潜在治疗靶点尤为重要。属于分泌型蛋白的环孢素蛋白CyclophilinB（CypB）广泛存在于原核和真核生物。近年来研究者发现其在乳腺癌、肝癌、结肠癌和胰腺癌中都高表达，在肿瘤的恶性进展过程中发挥重要作用。目前CypB在胃癌的表达和作用都未见报道，因此有必要进行深入探讨和研究。
核酸适体（aptamer）是一类新型的医学分子工具，它是从人工合成的DNA/RNA库中经过多轮筛选得到的能与靶标进行高特异性和高亲和力结合的单链寡核苷酸。核酸适体的筛选方法被称为配体指数富集系统进化（systematic evolution of ligands byexponential enrichment，SELEX）。筛选得到的特异性核酸适体可以用于肿瘤的生物显影、诊断、靶向载药和治疗，应用前景广泛。我们希望通过筛选得到能与CypB特异性结合的核酸适体，为开发新的生物检测方法，推进其临床应用奠定工作基础。
【目的】
1.明确CypB在胃癌患者血清和组织中的表达及其与临床病理参数的相关性。
2.确定CypB对胃癌细胞生长和增殖的影响。
3.通过SELEX技术获得CypB特异性的核酸适体。
【方法】
1．收集西京消化病院胃癌患者和正常人的血清，利用酶联免疫吸附实验检测血清中CypB、CEA和CA199的表达。
2．分析CypB的血清水平与胃癌患者临床病理参数之间关系。
3．分析并比较CypB与CEA、CA19-9对胃癌的诊断价值。
4.收集西京消化病院胃癌和癌旁组织病理切片，利用免疫组化方法，检测CypB在胃癌和癌旁组织的表达和分布。
5．分析CypB在胃癌中的表达强弱与患者临床病理参数之间的关系。
6．构建CypB siRNA慢病毒载体（LV-CypB-siRNA）和相应的对照载体（LV-siRNA-con）。
7．Western blot检测CypB在胃癌细胞系中的表达，选取BGC823和SGC7901，转染LV-CypB-siRNA和对照LV-siRNA-con慢病毒载体，筛选得到稳定转染细胞株，并鉴定载体的干扰效果。
8．用MTT、平板克隆形成实验和细胞周期实验，检测下调CypB表达对BGC823和SGC7901细胞体外生长增殖能力和克隆形成能力的影响。
9．通过裸鼠体内成瘤实验观察下调CypB对胃癌细胞成瘤能力的影响。
10．运用传统的SELEX技术，富集能与CypB蛋白特异性结合的DNA核酸适体库。
11．将富集到的核酸适体进行测序、比对，选取代表性序列，重新合成，检测其与CypB蛋白的解离常数。
12．将能与CypB蛋白高亲和力结合的核酸适体标记荧光，与CypB表达阳性的胃癌细胞结合显影。
【结果】
1. CypB在胃癌患者血清表达水平显著高于正常人
经ELISA检测发现CypB在胃癌患者的血清平均值为6.13ng/ml，标准差为3.14，在正常人血清中平均值为4.34ng/ml，标准差为1.78。统计学分析发现CypB在胃癌患者表达明显高于正常人，差异具有统计学意义。通过分析发现CypB在胃癌患者的血清水平与患者的年龄、性别、肿瘤分化程度无关，与胃癌T分期和淋巴结转移相关。
利用ROC曲线下面积分析后发现，CypB同CEA和CA19-9相比，对胃癌具有更高的诊断价值。
2. CypB在胃癌组织表达显著高于癌旁组织
CypB在胃癌组织中的阳性率为82.6%（109/132），癌旁组织的阳性率为58.3%（35/60）。统计分析结果提示：胃癌组织中CypB的表达明显高于癌旁，具有统计学意义。从染色结果上发现阳性染色的CypB主要在胞浆中，很少存在于细胞核内。
通过分析发现CypB在胃癌组织的表达与患者的年龄、性别、肿瘤分化程度无关，与胃癌T分期和淋巴结转移相关。
3.下调CypB后能明显抑制胃癌细胞的生长增殖、细胞周期进展和体内成瘤能力
检测了三株胃癌细胞系和一株永生化胃上皮细胞的CypB蛋白表达，结果提示BGC823和SGC7901细胞CypB表达较高，而MKN28和GES较低。LV-CypB-siRNA慢病毒载体稳定转染BGC823和SGC7901后，细胞的生长增殖能力、单克隆形成能力和体内成瘤能力与对照组相比，都明显减弱，细胞周期也发生G1/S期的阻滞。
4.筛选得到能与CypB特异性结合的核酸适体，其解离常数Kd达nM级别
经过8轮筛选，得到了高度富集的核酸适体库，测得其与CypB的解离常数已达到nM级别。将该DNA库送测序，对测序结果进行分析比对，选择重复最多的两条核酸适体C10和C11合成，并标记荧光，检测其与CypB蛋白beads的结合力，解离常数都达到nM，且比第八轮库的结合力更强。荧光标记的C10可以在CypB阳性表达的胃癌细胞中显影。初步认为筛选得到了能与CypB特异性结合的核酸适体。
【结论】
本实验检测了CypB在胃癌患者血清中表达情况，发现与正常人相比其表达明显升高，且表达水平与胃癌的T分期和淋巴结转移密切相关。CypB在胃癌组织中表达上调，表达水平与胃癌患者T分期和淋巴结转移密切相关。CypB与CEA和CA19-9相比，对胃癌具有更高的诊断价值。功能实验发现下调CypB后能有效抑制胃癌细胞生长增殖、细胞周期进展和体内成瘤能力。提示CypB在胃癌中或许是潜在的治疗靶点。
通过筛选获得了能与CypB特异性结合的核酸适体，解离常数达到nM级别，为核酸适体的进一步应用奠定了工作基础。
【Background】
Gastric cancer is one of the most common malignant tumors in China. Tumorbiomarkers can help physicians to diagnose gastric cancer earlier and make more effectivetreatment decisions to improve cure rates and reduce deaths. So far, there are still no suchspecific and sensitive biomarkers for early gastric cancer. Therefore it is urgent to developnovel biomarkers for gastric caner and discover new targets for treatment of gastric caner.Cyclophilin B (CypB) is a ubiquitously expressed protein which is known to be secretedinto body fluids such as milk and blood. Recently, researchers found that CypB isover-expressed in cancer including breast caner, hepatoma, colorectal cancer andpancreatic cancer. CypB may play an important role in cancer development. Howeverthere are still no reports about the role of CypB in gastric cancer.
Aptamers are single-stranded nucleic acid ligands selected against a specific target molecule for desired functions. Aptamers are selected using an in vitro procedure termedsystematic evolution of ligands by exponential (SELEX) enrichment. Aptamers have beenstudied as a bio-material in numerous investigations concerning their use as a diagnosticand therapeutic tool, biosensing probe, and in the development of new drugs, drugdelivery systems. We hope to search for aptamers specific binding CypB, and propse theselected aptamer as potencial cancer imaging agent by targeting gastric canceroverexpressioning CypB.
【Objectives】
This study aimed:1. to investigate the expression of CypB in both serum and tissuesfrom gastric cancer patients;2. to determine the effects of CypB on growth andproliferation of gastric cancer cells;3. to isolate CypB-specific aptamer by SELEX.
【Methods】
1. Blood samples from gastric cancer patients and healthy volunteers were collected.CypB, CEA, CA19-9levels in the sera were measured by ELISA.
2. The expression of CypB in serum was correlated to the clinical and pathologicalfeatures of patients with gastric cancer.
3. The diagonosis value of CypB was compared to CEA and CA19-9.
4. The expression patterns of CypB were observed in gastric cancer and adjacentnon-tumor tissue using immunohistochemistry.
5. The correlation of CypB and clinical parameters of gastric cancer patients wasanalyzed.
6. CypB siRNA lentivirus （LV-CypB-si） and control lentivirus（LV-si-con）wasproduced.
7. CypB expression in gastric cancer cell lines was detected by Western blot.BGC823and SGC7901cells were chosen to be infected with LV-si-con andLV-CypB-si，and stable transfectants were isolated..
8. MTT and colony formation assays were used to examine the effect of CypB on thecell growth and proliferation in vitro. Cell cycle was analyzed with flowcytometry.
9. Tumorigenicity of gastric cancer cells in nude mice was applied to explore theeffect of CypB on the cell growth and cell proliferation in vivo.
10. DNA aptamers specific to CypB were islolated by SELEX method.
11. Binding affinity (Kd) was determined in direct binding assay by flow cytometryanalysis. The Kd of the aptamer-CypB interaction was obtained by fitting thedependence of fluorescene intensity of specific binding on the concentration of theaptamer to the equation Y=B max X/(Kd+X).(Y: fluorescene intensity; X:concentration of aptamer; B max: the number of binding site)
【Results】
1. Serum levels of CypB were increased in the gastric cancer patients.
CypB levels were greatly elevated in gastric caner patients serum comparing tothe healthy volunteer (median6.13ng/ml versus4.34ng/ml, p<0.05). The CypBlevels in gastric cancer patients were significantly correlated with tumor stage andlymph node metastasis (p<0.05), but not with patient’s age, gender and tumordifferentiation. The ROC curve analyses suggested the diagnosis value of CypBwas better than CEA and CA19-9.
2. CypB expression was significantly increased in gastric cancer tissues.
CypB was mainly located in cytoplasm and only occasionally in nuclei in gastriccancer cell. The positive rate of CypB was82.6%(109of132patients) in gastriccancer tissues, and58.3%(35of60) in adjacent non-tumor tissues. Furtheranalyses showed association of CypB expression with tumor stage and lymphnode metastasis, but not with patients’ age, gender or tumor differentiation.
3. Knock-down of CypB can inhibit gastric cancer cell growth, proliferation,cell cycle progress and tumorigenesis.
CypB expression level was obviously higher in SGC7901and BGC823thanMKN28and GES. These two cell lines were infected with LV-si-con andLV-CypB-si respectively. MTT and cloney formation assays showed asignificantly decreased rate of cell proliferation in cells transfected withLV-CypB-si. Down-regulation of CypB resulted in slightly decreased percentage of S phase and increased percentage of G1. These findings indicated that CypBcould promote the G1-S transition of gastric cancer cell.
4. Two aptmers which can bind to CypB protein with high affinity andspecificity were isolated through SELEX.
Through eight rounds of selection using CypB-his protein as target and ni-beadsas counter target, we have isolated two single-stranded DNA aptamers C10andC11that specificly bind to CypB with Kd in the nanomolar range. C10aptamerconjugated with FITC showed specific binding to CypB positive gastric cancercells BGC823and SGC7901.
【Conclusions】
Our data suggests that CypB is over-expressed in both serum and tissues of gastriccancer patients. The CypB expression level was correlated with tumor stage and lymphnode metastasis. Knock-down of CypB decreases gastric cancer cells proliferation and invivo tumorigenesis. These findings indiccate CypB could be a potential biomarker andtherapeutic target for gastric cancer.
CypB-specific aptamers were succusfully isolated, which may be used in further studyand future application of CypB.
核酸适体（aptamer）是一类新型的医学分子工具，它是从人工合成的DNA/RNA库中经过多轮筛选得到的能与靶标进行高特异性和高亲和力结合的单链寡核苷酸。核酸适体的筛选方法被称为配体指数富集系统进化（systematic evolution of ligands byexponential enrichment，SELEX）。筛选得到的特异性核酸适体可以用于肿瘤的生物显影、诊断、靶向载药和治疗，应用前景广泛。我们希望通过筛选得到能与CypB特异性结合的核酸适体，为开发新的生物检测方法，推进其临床应用奠定工作基础。
【目的】
1.明确CypB在胃癌患者血清和组织中的表达及其与临床病理参数的相关性。
2.确定CypB对胃癌细胞生长和增殖的影响。
3.通过SELEX技术获得CypB特异性的核酸适体。
【方法】
1．收集西京消化病院胃癌患者和正常人的血清，利用酶联免疫吸附实验检测血清中CypB、CEA和CA199的表达。
2．分析CypB的血清水平与胃癌患者临床病理参数之间关系。
3．分析并比较CypB与CEA、CA19-9对胃癌的诊断价值。
4.收集西京消化病院胃癌和癌旁组织病理切片，利用免疫组化方法，检测CypB在胃癌和癌旁组织的表达和分布。
5．分析CypB在胃癌中的表达强弱与患者临床病理参数之间的关系。
6．构建CypB siRNA慢病毒载体（LV-CypB-siRNA）和相应的对照载体（LV-siRNA-con）。
7．Western blot检测CypB在胃癌细胞系中的表达，选取BGC823和SGC7901，转染LV-CypB-siRNA和对照LV-siRNA-con慢病毒载体，筛选得到稳定转染细胞株，并鉴定载体的干扰效果。
8．用MTT、平板克隆形成实验和细胞周期实验，检测下调CypB表达对BGC823和SGC7901细胞体外生长增殖能力和克隆形成能力的影响。
9．通过裸鼠体内成瘤实验观察下调CypB对胃癌细胞成瘤能力的影响。
10．运用传统的SELEX技术，富集能与CypB蛋白特异性结合的DNA核酸适体库。
11．将富集到的核酸适体进行测序、比对，选取代表性序列，重新合成，检测其与CypB蛋白的解离常数。
12．将能与CypB蛋白高亲和力结合的核酸适体标记荧光，与CypB表达阳性的胃癌细胞结合显影。
【结果】
1. CypB在胃癌患者血清表达水平显著高于正常人
经ELISA检测发现CypB在胃癌患者的血清平均值为6.13ng/ml，标准差为3.14，在正常人血清中平均值为4.34ng/ml，标准差为1.78。统计学分析发现CypB在胃癌患者表达明显高于正常人，差异具有统计学意义。通过分析发现CypB在胃癌患者的血清水平与患者的年龄、性别、肿瘤分化程度无关，与胃癌T分期和淋巴结转移相关。
利用ROC曲线下面积分析后发现，CypB同CEA和CA19-9相比，对胃癌具有更高的诊断价值。
2. CypB在胃癌组织表达显著高于癌旁组织
CypB在胃癌组织中的阳性率为82.6%（109/132），癌旁组织的阳性率为58.3%（35/60）。统计分析结果提示：胃癌组织中CypB的表达明显高于癌旁，具有统计学意义。从染色结果上发现阳性染色的CypB主要在胞浆中，很少存在于细胞核内。
通过分析发现CypB在胃癌组织的表达与患者的年龄、性别、肿瘤分化程度无关，与胃癌T分期和淋巴结转移相关。
3.下调CypB后能明显抑制胃癌细胞的生长增殖、细胞周期进展和体内成瘤能力
检测了三株胃癌细胞系和一株永生化胃上皮细胞的CypB蛋白表达，结果提示BGC823和SGC7901细胞CypB表达较高，而MKN28和GES较低。LV-CypB-siRNA慢病毒载体稳定转染BGC823和SGC7901后，细胞的生长增殖能力、单克隆形成能力和体内成瘤能力与对照组相比，都明显减弱，细胞周期也发生G1/S期的阻滞。
4.筛选得到能与CypB特异性结合的核酸适体，其解离常数Kd达nM级别
经过8轮筛选，得到了高度富集的核酸适体库，测得其与CypB的解离常数已达到nM级别。将该DNA库送测序，对测序结果进行分析比对，选择重复最多的两条核酸适体C10和C11合成，并标记荧光，检测其与CypB蛋白beads的结合力，解离常数都达到nM，且比第八轮库的结合力更强。荧光标记的C10可以在CypB阳性表达的胃癌细胞中显影。初步认为筛选得到了能与CypB特异性结合的核酸适体。
【结论】
本实验检测了CypB在胃癌患者血清中表达情况，发现与正常人相比其表达明显升高，且表达水平与胃癌的T分期和淋巴结转移密切相关。CypB在胃癌组织中表达上调，表达水平与胃癌患者T分期和淋巴结转移密切相关。CypB与CEA和CA19-9相比，对胃癌具有更高的诊断价值。功能实验发现下调CypB后能有效抑制胃癌细胞生长增殖、细胞周期进展和体内成瘤能力。提示CypB在胃癌中或许是潜在的治疗靶点。
通过筛选获得了能与CypB特异性结合的核酸适体，解离常数达到nM级别，为核酸适体的进一步应用奠定了工作基础。
【Background】
Gastric cancer is one of the most common malignant tumors in China. Tumorbiomarkers can help physicians to diagnose gastric cancer earlier and make more effectivetreatment decisions to improve cure rates and reduce deaths. So far, there are still no suchspecific and sensitive biomarkers for early gastric cancer. Therefore it is urgent to developnovel biomarkers for gastric caner and discover new targets for treatment of gastric caner.Cyclophilin B (CypB) is a ubiquitously expressed protein which is known to be secretedinto body fluids such as milk and blood. Recently, researchers found that CypB isover-expressed in cancer including breast caner, hepatoma, colorectal cancer andpancreatic cancer. CypB may play an important role in cancer development. Howeverthere are still no reports about the role of CypB in gastric cancer.
Aptamers are single-stranded nucleic acid ligands selected against a specific target molecule for desired functions. Aptamers are selected using an in vitro procedure termedsystematic evolution of ligands by exponential (SELEX) enrichment. Aptamers have beenstudied as a bio-material in numerous investigations concerning their use as a diagnosticand therapeutic tool, biosensing probe, and in the development of new drugs, drugdelivery systems. We hope to search for aptamers specific binding CypB, and propse theselected aptamer as potencial cancer imaging agent by targeting gastric canceroverexpressioning CypB.
【Objectives】
This study aimed:1. to investigate the expression of CypB in both serum and tissuesfrom gastric cancer patients;2. to determine the effects of CypB on growth andproliferation of gastric cancer cells;3. to isolate CypB-specific aptamer by SELEX.
【Methods】
1. Blood samples from gastric cancer patients and healthy volunteers were collected.CypB, CEA, CA19-9levels in the sera were measured by ELISA.
2. The expression of CypB in serum was correlated to the clinical and pathologicalfeatures of patients with gastric cancer.
3. The diagonosis value of CypB was compared to CEA and CA19-9.
4. The expression patterns of CypB were observed in gastric cancer and adjacentnon-tumor tissue using immunohistochemistry.
5. The correlation of CypB and clinical parameters of gastric cancer patients wasanalyzed.
6. CypB siRNA lentivirus （LV-CypB-si） and control lentivirus（LV-si-con）wasproduced.
7. CypB expression in gastric cancer cell lines was detected by Western blot.BGC823and SGC7901cells were chosen to be infected with LV-si-con andLV-CypB-si，and stable transfectants were isolated..
8. MTT and colony formation assays were used to examine the effect of CypB on thecell growth and proliferation in vitro. Cell cycle was analyzed with flowcytometry.
9. Tumorigenicity of gastric cancer cells in nude mice was applied to explore theeffect of CypB on the cell growth and cell proliferation in vivo.
10. DNA aptamers specific to CypB were islolated by SELEX method.
11. Binding affinity (Kd) was determined in direct binding assay by flow cytometryanalysis. The Kd of the aptamer-CypB interaction was obtained by fitting thedependence of fluorescene intensity of specific binding on the concentration of theaptamer to the equation Y=B max X/(Kd+X).(Y: fluorescene intensity; X:concentration of aptamer; B max: the number of binding site)
【Results】
1. Serum levels of CypB were increased in the gastric cancer patients.
CypB levels were greatly elevated in gastric caner patients serum comparing tothe healthy volunteer (median6.13ng/ml versus4.34ng/ml, p<0.05). The CypBlevels in gastric cancer patients were significantly correlated with tumor stage andlymph node metastasis (p<0.05), but not with patient’s age, gender and tumordifferentiation. The ROC curve analyses suggested the diagnosis value of CypBwas better than CEA and CA19-9.
2. CypB expression was significantly increased in gastric cancer tissues.
CypB was mainly located in cytoplasm and only occasionally in nuclei in gastriccancer cell. The positive rate of CypB was82.6%(109of132patients) in gastriccancer tissues, and58.3%(35of60) in adjacent non-tumor tissues. Furtheranalyses showed association of CypB expression with tumor stage and lymphnode metastasis, but not with patients’ age, gender or tumor differentiation.
3. Knock-down of CypB can inhibit gastric cancer cell growth, proliferation,cell cycle progress and tumorigenesis.
CypB expression level was obviously higher in SGC7901and BGC823thanMKN28and GES. These two cell lines were infected with LV-si-con andLV-CypB-si respectively. MTT and cloney formation assays showed asignificantly decreased rate of cell proliferation in cells transfected withLV-CypB-si. Down-regulation of CypB resulted in slightly decreased percentage of S phase and increased percentage of G1. These findings indicated that CypBcould promote the G1-S transition of gastric cancer cell.
4. Two aptmers which can bind to CypB protein with high affinity andspecificity were isolated through SELEX.
Through eight rounds of selection using CypB-his protein as target and ni-beadsas counter target, we have isolated two single-stranded DNA aptamers C10andC11that specificly bind to CypB with Kd in the nanomolar range. C10aptamerconjugated with FITC showed specific binding to CypB positive gastric cancercells BGC823and SGC7901.
【Conclusions】
Our data suggests that CypB is over-expressed in both serum and tissues of gastriccancer patients. The CypB expression level was correlated with tumor stage and lymphnode metastasis. Knock-down of CypB decreases gastric cancer cells proliferation and invivo tumorigenesis. These findings indiccate CypB could be a potential biomarker andtherapeutic target for gastric cancer.
CypB-specific aptamers were succusfully isolated, which may be used in further studyand future application of CypB.
引文
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