Real-time PCR法检测非小细胞肺癌患者围手术期循环血中Pin1 mRNA的表达及意义
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摘要
背景:
蛋白分子中丝/苏-脯氨酸基序(ser/thr—pro)的磷酸化是一个重要的细胞内信号转导机制。Pin1是一种高度保守的、特异的多肽脯氨酰基顺/反异构酶,仅特异性地催化磷酸化的丝/苏-脯氨酸基序发生异构。这种磷酸化后的异构导致底物蛋白构象的改变,从而调节它们的功能。因此Pin1的催化反应是一条新的改变磷酸化蛋白功能的信号通道,并且在肿瘤的发生中起着重要作用。研究显示,Pin1在许多肿瘤组织中过度表达,促进细胞的异常增殖和肿瘤的发生,被称为肿瘤发生的催化分子,成为肿瘤发生发展的标志。本文定量检测了Pin1 mRNA在NSCLC患者围手术期循环中的表达情况。
目的:
1.Pin1 mRNA在非小细胞肺癌围手术期的表达及意义。
2.肺血管处理顺序的不同对Pin1 mRNA在非小细胞肺癌患者循环血中表达影响及意义。
方法:
接受根治性手术的原发性NSCLC患者26例,按预定的结扎血管顺序术前将病例随机分为先结扎肺静脉组(PV-first ligation group)和先结扎肺动脉组(PA-first ligation group)。分别采集其术前(麻醉后)外周血标本、术中结扎肺静脉后近心端和远心端血标本及术后第7日外周血标本。选择10例需手术治疗的肺部良性疾病患者作为对照。以10例健康人作为阴性对照,以Pin1作为检测标志物,运用实时荧光定量逆转录聚合酶链反应法定量检测患者循环中的Pin1 mRNA表达情况。
结果:
(1)肺癌患者循环中Pin1 mRNA表达量显著高于肺部良性病变患者和正常人,并且其表达量和患者癌症分期、淋巴结是否转移相关(p＜0.05);
(2)肺静脉远心端Pin1 mRNA的表达量高于近心端的表达量(p=0.019);PV-first Group的Pin1 mRNA在肺静脉近心端的表达量低于PA-first Group(p=0.106),而其远心端则高于PA-firstGroup.(p=0.082)
(3)手术后一周Pin1 mRNA的表达情况显著低于术前(p=0.031)。
结论:
(1)Pin1在NSCLC患者血液循环中有高表达,或许可以成为一个在肺癌早期诊断和治疗的有潜力的肿瘤标志物。
(2)肺癌根治术术中操作可导致癌细胞入血;肺癌根治术术中先结扎肺静脉,可在一定程度上阻止癌细胞入血。
BACKGROUD:
Phosphorylation of proteins on serine or threonine residues preceding proline (Ser/Thr-Pro) is a major regulatory mechanism in cell proliferation and transformation. Interestingly, the Ser/Thr-Pro motifs in proteins exist in two distinct cis and trans conformations, whose conversion rate is normally reduced on phosphorylation, but is catalyzed specifically by the prolyl isomerase Pin1(Protein interaction with NMA1). And the catalytic reaction of pin1 is a new signal pathway of changing phosphorylation protein function. Pin1 is over expressed in several different human cancers, and it is called the catalytic molecule in the tumor vegetation. This is the first report about the overexpression of pin1 mRNA in the circulation of NSCLC.
METHOD:
26 consecutive patients with NSCLC who underwent surgical resection with curative intention were randomly assigned PA-first ligation group and PV-first ligation group . The blood samples were collected just before the operation and 7 days later. During the lobectomy, blood samples of the proximal part and distal part of the pulmonary vein when it's ligated were collected.Additionally, 10 patients with benign lung disease served as control subjects undergoing surgical resection ;10 healthy-person served as negative control. All the blood samples were subjected to real-time PCR with Pin1 as marker.
RESULTS:
(1) Compared to the benign lung disease and healthy-person, the Pin1 mRNA in NSCLC is overexpressed; and correlated with lymph node positive disease and tumor stage(p < 0.05).
(2) The expression of Pin1 mRNA in the distal part of the pulmonary vein is significant higher than the proximal part(p=0.019); And the expression of proximal part in PV-first group is lower than the PA-first group (p=0.106), by contrast to diatal part. (p=0.082)
(3) The expression after 7 days of the operation was significant lower than the preoperation.
CONCLUSION:
(1) Pin1 is overexpressed in circulation of NSCLC, and may possibly be used as a tumor marker or as a target for cancer therapy.
(2) Surgical manipulation could promote the release of tumour cells into the bloodstream, but the ligation of pulmonary vein before the ligation of the pulmonary artery may partly prevent such release during surgery.
蛋白分子中丝/苏-脯氨酸基序(ser/thr—pro)的磷酸化是一个重要的细胞内信号转导机制。Pin1是一种高度保守的、特异的多肽脯氨酰基顺/反异构酶,仅特异性地催化磷酸化的丝/苏-脯氨酸基序发生异构。这种磷酸化后的异构导致底物蛋白构象的改变,从而调节它们的功能。因此Pin1的催化反应是一条新的改变磷酸化蛋白功能的信号通道,并且在肿瘤的发生中起着重要作用。研究显示,Pin1在许多肿瘤组织中过度表达,促进细胞的异常增殖和肿瘤的发生,被称为肿瘤发生的催化分子,成为肿瘤发生发展的标志。本文定量检测了Pin1 mRNA在NSCLC患者围手术期循环中的表达情况。
目的:
1.Pin1 mRNA在非小细胞肺癌围手术期的表达及意义。
2.肺血管处理顺序的不同对Pin1 mRNA在非小细胞肺癌患者循环血中表达影响及意义。
方法:
接受根治性手术的原发性NSCLC患者26例,按预定的结扎血管顺序术前将病例随机分为先结扎肺静脉组(PV-first ligation group)和先结扎肺动脉组(PA-first ligation group)。分别采集其术前(麻醉后)外周血标本、术中结扎肺静脉后近心端和远心端血标本及术后第7日外周血标本。选择10例需手术治疗的肺部良性疾病患者作为对照。以10例健康人作为阴性对照,以Pin1作为检测标志物,运用实时荧光定量逆转录聚合酶链反应法定量检测患者循环中的Pin1 mRNA表达情况。
结果:
(1)肺癌患者循环中Pin1 mRNA表达量显著高于肺部良性病变患者和正常人,并且其表达量和患者癌症分期、淋巴结是否转移相关(p＜0.05);
(2)肺静脉远心端Pin1 mRNA的表达量高于近心端的表达量(p=0.019);PV-first Group的Pin1 mRNA在肺静脉近心端的表达量低于PA-first Group(p=0.106),而其远心端则高于PA-firstGroup.(p=0.082)
(3)手术后一周Pin1 mRNA的表达情况显著低于术前(p=0.031)。
结论:
(1)Pin1在NSCLC患者血液循环中有高表达,或许可以成为一个在肺癌早期诊断和治疗的有潜力的肿瘤标志物。
(2)肺癌根治术术中操作可导致癌细胞入血;肺癌根治术术中先结扎肺静脉,可在一定程度上阻止癌细胞入血。
BACKGROUD:
Phosphorylation of proteins on serine or threonine residues preceding proline (Ser/Thr-Pro) is a major regulatory mechanism in cell proliferation and transformation. Interestingly, the Ser/Thr-Pro motifs in proteins exist in two distinct cis and trans conformations, whose conversion rate is normally reduced on phosphorylation, but is catalyzed specifically by the prolyl isomerase Pin1(Protein interaction with NMA1). And the catalytic reaction of pin1 is a new signal pathway of changing phosphorylation protein function. Pin1 is over expressed in several different human cancers, and it is called the catalytic molecule in the tumor vegetation. This is the first report about the overexpression of pin1 mRNA in the circulation of NSCLC.
METHOD:
26 consecutive patients with NSCLC who underwent surgical resection with curative intention were randomly assigned PA-first ligation group and PV-first ligation group . The blood samples were collected just before the operation and 7 days later. During the lobectomy, blood samples of the proximal part and distal part of the pulmonary vein when it's ligated were collected.Additionally, 10 patients with benign lung disease served as control subjects undergoing surgical resection ;10 healthy-person served as negative control. All the blood samples were subjected to real-time PCR with Pin1 as marker.
RESULTS:
(1) Compared to the benign lung disease and healthy-person, the Pin1 mRNA in NSCLC is overexpressed; and correlated with lymph node positive disease and tumor stage(p < 0.05).
(2) The expression of Pin1 mRNA in the distal part of the pulmonary vein is significant higher than the proximal part(p=0.019); And the expression of proximal part in PV-first group is lower than the PA-first group (p=0.106), by contrast to diatal part. (p=0.082)
(3) The expression after 7 days of the operation was significant lower than the preoperation.
CONCLUSION:
(1) Pin1 is overexpressed in circulation of NSCLC, and may possibly be used as a tumor marker or as a target for cancer therapy.
(2) Surgical manipulation could promote the release of tumour cells into the bloodstream, but the ligation of pulmonary vein before the ligation of the pulmonary artery may partly prevent such release during surgery.
引文
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[2] Lu KP, Hanes SD, Hunter T. A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature, 1996;380:544-547.
[3] Bayer E, Goettsch S, Mueller JW, Griewel B, Guiberman E, Mayr LM, et al. Structural analysis of the mitotic regulator hPin1 in solution: insights into domain architecture and substrate binding. J Biol Chem , 2003;278:26183-26193.
[4] Lu KP. Pinning down cell signaling, cancer and Alzheimer's disease. Trends Biochem Sci ,2004;29:200-209.
[5] Blume-Jensen, P., and Hunter, T. (2001). Oncogenic kinase signalling. Nature 411:355-365.
[6] Yaffe MB, Schutkowski M, Shen M, et al. Sequence-specific and phosphorylation-dependent proline isomerization: a potential mitotic regulatory mechanism. Science., 1997;278:1957-1960.
[7] Ranganathan R, Lu KP, Hunter T, Noel JP. Structural and functional analysis of the mitotic peptidyl-prolyl isomerase Pin1 suggests that substrate recognition is phosphorylation dependent. Cell. 1997;89:875-886.
[8] Lu KP, Liou YC, Zhou XZ. Pinning down the proline-directed phosphorylation signaling. Trends Cell Biol. 2002;12:164-172.
[9] Wulf GM , Ryo A , Wulf GG, e t a l.Pinl is overexp ressed in breast cancer and cooperates with Ras signaling in in creasing the transcrip tional activity of cJun towards cyclinDl . EMBO J ,2001, 20 ( 13 ): 3459 - 3472.
[10] Ryo A, Liou YC, Lu KP , etal. Prolyl isomerase Pinl: a catalyst foroncogenesis and a potential therapeutic target in cancer. J Cell Sci, 2003 ,116 ( 5 ) : 773 -783.
[11] Ayala G, Wang D , Wulf G, et al.The p rolyl isomerase Pinl is a novel prognostic marker in human p rostatecancer . Cancer Res, 2003 , 63( 19 ) : 6244-6251.
[12] Pang R , Yuen J , Yuen MF, et al.P IN1 overexp ression and beta- catenin gene mutations are distinct oncogenic events in human hepatocellular carcinom . Oncogene , 2004 , 23 ( 23 )4182 - 4186.
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