Livin、Caspase-3及ki67在壶腹部癌的表达及临床预后意义
摘要
研究背景：
在危及人类健康的所有疾病中,恶性肿瘤的病死率仍居第一位。近几十年来,关于恶性肿瘤的诊疗水平已经有很大程度的进步,但它仍是当今医学界尚未攻克的一个难题。壶腹周围癌(Periampullary Carcinoma)属于消化系统恶性肿瘤,泛指起源于Vater壶腹、胰头部、胆总管末端、十二指肠乳头及周围粘膜的恶性肿瘤,预后较差而且术前很难对肿瘤定位作出明确诊断。壶腹周围癌的发病率仅次于胃癌及结直肠癌,成为第三位威胁人类健康的消化系统恶性肿瘤。这些来源不同的恶性肿瘤,由于其特殊的解剖部位,类似的临床表现,近乎相同的治疗方法,以至于在手术时也难以将其截然分开,但它们的预后却不尽相同。壶腹部癌是指源于Vater壶腹部区域的恶性肿瘤,该处粘膜由胆总管远端粘膜、胰大导管粘膜、十二指肠乳头粘膜构成。壶腹部癌在临床上相对少见,其发病率约占胃肠道肿瘤的0.2%,约占壶腹周围癌的7-20%,在壶腹周围癌中的发病率仅次于胰头癌。
1912年德国Kausch医生对1例壶腹周围癌病人成功完成第1例胰十二指肠切除术,1935年美国外科Whipple医生系统地提出了胰十二指肠切除术,并详细描述了消化道重建的顺序为胆管、胰、胃分别与空肠吻合(Whipple术式),然而目前常用的消化道重建顺序为胰、胆管、胃分别与空肠吻合(Child术式)。壶腹周围癌组织起源均不完全相同,胰十二指肠切除术仍是壶腹周围癌治疗的主要手术方式。壶腹部解剖位置较为特殊,即使肿瘤较小也能引起以黄疸为主的首发症状,所以对壶腹部癌病人临床上大多数能够做到早期诊断。胰十二指肠切除是壶腹部癌的主要手术方式,壶腹部局部切除治疗壶腹部癌明显减少了围手术期并发症和死亡率。壶腹部癌手术切除率较高,但术后5年生存率仅为25～67%,仍有很多病人死于肿瘤局部复发和远处转移。因此,提高壶腹部癌病人长期生存率成为临床研究的重要课题,而进一步了解并研究壶腹部癌的发病机制,识别可能的预后因素和治疗相关的分子靶点成为临床亟待解决的课题。
现代医学研究证明,肿瘤细胞异常增殖、异常分化、细胞凋亡不足均恶性肿瘤的发生发展密切相关,凋亡调节失衡是恶性肿瘤形成的重要机制之一。因此,人们广泛研究细胞凋亡与肿瘤之间的关系,细胞凋亡已成为肿瘤分子细胞生物学一个新的研究热点。
Livin是近年来发现的凋亡抑制蛋白家族中一个新成员,全长约4.6kb,位于染色体20q13.3,包括7个外显子和6个内含子,含有N端一个BIR结构和C端一个RING结构,其转录产物nRNA因剪接方式不同分为Livin a与Livinβ两种亚型,结构极为相似,分别编码298和280个氨基酸。Livin在胚胎发育过程中高表达于多种组织,可能与机体生长发育有关。在正常成人的大多数终末分化组织中(除胎盘、心脏、肺、脾外),Livin呈低表达或不表达；但在多种恶性肿瘤中,Livin呈高表达,如黑色素瘤、白血病、肺癌、前列腺癌、膀胱癌、胃癌、结肠癌、肝癌、胰腺癌等。Livin的生物学功能包括抑制细胞凋亡、调控细胞周期、参与肿·瘤血管生成、抗自然细胞的杀伤作用等。大量研究表明,在许多恶性肿瘤组织中Livin异常表达与患者的预后密切相关,如肿瘤复发、较短生存率等。
Caspase家族是一类存在于细胞质中结构类似的特异性天冬氨酸-半胱氨酸蛋白酶。细胞凋亡的发生是一个复杂的、由Caspase家族成员介导的蛋白酶级联反应过程。Caspase是一类在细胞凋亡过程中起着关键作用的酶。Caspase-3又被称为(CPP32或YAMA)可能是与凋亡关系最密切的一种蛋白酶,效应因子Caspase-3的激活则被认为是该级联反应的核心。Livin主要通过其BIR区域与Caspases结合,直接抑制Caspases的活性,尤其是抑伟Caspase-3、7和9的活性,通过阻断凋亡受体及线粒体相关的凋亡途径来实现对细胞凋亡的抑制。Ki67作为标记细胞增殖状念的抗原,是表达于细胞周期S和M期中的核抗原,其表达的高低反映了细胞增殖的程度,已被广泛认为是能较可靠地全面反映细胞群体增殖活性的客观指标。
目前国内外关于Livin在壶腹部癌中的表达相关研究较少,值得进一步研究和探索。通过研究Livin在壶腹部癌中的表达情况,证实Livin与性别、年龄、肿瘤的大小、组织学类型、CA19-9、肿瘤分化、临床分期及淋巴结状态等临床病理参数的关系,并分析肿瘤组织中Livin与Caspase-3、ki67的关系,初步探讨Livin促进壶腹部癌生长的机制,进一步深入了解Livin在壶腹部癌发生发展中的作用,为壶腹部癌的治疗和判断预后提供更多的理论依据。
本文通过检测Li vin、Caspase-3及ki67在壶腹部癌的表达并评估它们与临床病理特征和预后的关系,探讨壶腹部癌组织中Livin的表达与Caspase-3表达的关系并初步讨论其意义,以确定Livin的表达水平是否可用于预测壶腹部癌患者的预后。
目的
研究Livin、Caspase-3及ki67在壶腹部癌组织中的的表达及探讨它们与临床病理参数和预后的关系。
方法
免疫组织化学(SP)法检测71例壶腹部癌组织中Livin、Caspase-3及ki67的表达情况,同时分析它们与临床病理特征及预后的关系。
结果
1.71例壶腹部癌患者,术前彩超、CT、MRCP、ERCP的诊断符合率分别为70.4%(50/71)、85.9%(61/71)、91.3%(42/46)、91.6%(11/12)。彩超检查与CT、MRCP检查结果差异有统计学意义(P<0.05),其余各检查方法间无统计学差异(P>0.05)。
2.免疫组化结果显示71例壶腹部癌组织中,Livin、Caspase-3及ki67在壶腹部癌组织中的阳性表达分别为46.5%(33/71)、54.9%(39/71)和56.3%(40/71)。Livin、Caspase-3及ki67在癌旁组织I中的阳性表达分别为0%(0/52)、75%(39/52)和25%(13/52)。Livin及ki67在壶腹部癌中的表达明显高于癌旁组织(P<0.05)；Caspase-3在壶腹部癌中的表达明显低于癌旁组织(P<0.05)。
3.Livin的阳性表达与壶腹部癌的肿瘤分化程度和TNM分期、淋巴结转移状态有关(P<0.05),而与性别、年龄、肿瘤大小、组织学类型、CA19-9无明显相关(P>0.05)。Caspase-3与ki67在壶腹部癌中的表达均与肿瘤分化程度明显相关(P<0.05),而与其它临床病理参数无明显相关(P>0.05)。
4.Spearman等级相关分析Livin和Caspase-3表达呈负相关(r=-0.575,P<0.001), Livin和ki67表达呈正相关(r=0.308,P=0.009)。
5.Livin表达阳性患者的总生存率明显小于阴性表达患者的总生存率(P=0.001)。
6.多因素分析表明Livin阳性和淋巴结转移是壶腹部癌独立的预后因素。
结论
Livin蛋白在壶腹部癌组织中的表达明显高于癌旁组织,提示Livin表达增高与壶腹部癌的发生、发展有关。Livin与Caspase-3在壶腹部癌中的表达呈负相关,而与ki67呈正相关,提示Livin可能通过抑制Caspase-3的激活,促使细胞凋亡不能有效进行,导致肿瘤细胞过度增殖,从而为壶腹部癌的发生、发展提供了有利条件。Livin可作为壶腹部癌一个独立的预后指标。因此,我们推测Livin在壶腹部癌的发生、发展和转移中起重要作用。
Background:
With the highest fatality ratio, malignant tumor is the leading cause of death in human diseases. Although the diagnosis and treatment of malignancy has been developed to a much more advanced level during the past decades, it is still a tough problem which has not been conquered in the current medical circles. Periampullary carcinoma is a collective term used for cancers arising from or near the ampulla of Vater and include ampullary carcinoma, pancreatic head cancer, distal cholangiocarcinoma and duodenal cancer. Periampullary cancers are the third most frequent gastrointestinal tumors following gastric and colorectal cancers. These tumors exhibit similar symptoms, but different clinical outcomes, according to their anatomic origin. The exact site of origin of periampullary tumors is often difficult to ascertain preoperatively. Ampullary carcinoma, defined as a tumor grossly appearing to arise in the ampulla of Vater. Three epithelial types can be involved in this area: those arising from the bile duct, the pancreatic duct, or the duodenal mucosa. Ampullary carcinoma is a relatively uncommon neoplasm. It accounts for approximately0.2%of all tumors in the gastrointestinal tract and constitutes about7to20%of the periampullary neoplasms, being the second most frequent tumor of this region.
The first resection for a periampullary carcinoma was performed by the German surgeon Kausch in1912. It is often called the Whipple procedure, after the American surgeon Whipple who devised an improved version of the surgery in1935. Reconstruction consists of attaching the pancreas to the jejunum and attaching the hepatic duct to the jejunum to allow digestive juices and bile respectively to flow into the gastrointestinal tract and attaching the stomach to the jejunum to allow food to pass through. Whipple originally used the sequence:bile duct, pancreas and stomach, whereas presently the popular method of reconstruction is pancreas, bile duct and stomach, also known as Child's operation. Regardless of the site of origin of these tumors, most patients undergo a similar operative procedure for extirpation of their disease:radical pancreaticoduodenectomy. Because even small lesions in the ampulla can obstruct the bile duct, early jaundice and early presentation occurs, which may lead to early dignosis and high resectability rate. Pancreatoduodenectomy is the main treatment of choice for tumors of the ampulla of Vater. Local procedures such as simple ampullectomy has been proposed to obviously reduce operative complication and mortality. The overall five-year survival of25%to67%. Many patients will still experience a regional recurrence and metastasis. There is a need for a better understanding of the pathologic mechanism of ampullary carcinoma, the identification of potential prognostic factors, and clinically relevant molecular targets for therapy.
Modern medical studies have showen that the formation and development of malignant tumors are not only associated with abnormal proliferation and differentiation, but also involved in inhibition of apoptosis which was one of the important mechanisms in the forming of tumors. So, apoptosis and tumor became a hot focus in tumor molecular biological researches.
Livin is a member of the inhibitors of apoptosis (IAP) family. Livin gene spans4.6kb on chromosome20at band q13, and including six introns and seven exons. Livin protein contains a single BIR domain and a RING linger motif. Livin gene has two splice variants:Livin α and β, which are almost identical. Conceptual translation indicates that Livin a and P are almost identical proteins that share the amino-terminal BIR and carboxyterminal RING domains. The two cDNAs contain open reading frames of298and280amino acids. With the exception of the placenta, heart, lung, spleen and ovary, the messenger RNA(mRNA) for Livin is not detectable in most normal adult tissues. However, it is detectable in fetal tissues (brain, kidney,heart and spleen) and is overexpressed by some cancer cells. Livin is presented in several cancer tissures, such as melanoma, leukemia, lung cancer cells, bladder cancer, prostate cancer, gastric cancer, colon cancer, hepatocelluar carcinoma and pancreatic cancer. Livin plays critical role in apoptosis inhibition, regulating the cell cycle, participating in tumor angiogenesis and anti-nature killer cells action. The majority of the current datas suggest that Livin expression in cancer appears to be associated with unfavorable clinico-pathological parameters, such as disease relapse and shorter patient survival. It has close relation with the occurence of tumors. Livin served as a new target for apoptosis-inducing therapy of malignant tumors.
Caspase family is a class of amino acid sequence, spatial structure and substrate specificity are similar specificity of aspartic acid-cysteine protease. The occurence of apoptosis is a complex, mediated by the Caspase family members of the protease cascade process, but the district is located downstream effector. Caspases, are the key effectors of the cellular death. Among the caspases, Caspase-3(also known as CPP32, YAMA) is probably the one that so far best correlates with apoptosis. Caspase-3activation was considered to be the only way cascade. Livin mainly through its BIR district and cysteine aspartate-specific proteases(Caspases) combination of direct inhibition of cysteine protease caspases, in particular, inhibit Caspase-3,7and9activity, to resistance fault-related apoptosis receptor and mitochondrial apoptosis pathway, while the realization of the inhibition of apoptosis. Ki67is a nuclear antigen expressed mainly in the S and M phases of the cell cycle, and it has been used in many studies for estimating the growth fraction of various tumor types.
Inspite of elemantary study on Livin has been made, the specific mechanism of action in ampullary carcinoma is still unknow, which deserves further research. In this study we investigated expression of Livin, Caspase-3and ki67in ampullary carcinoma and its relation of sex, tumor size, histological type, tumor differentiation, TNM stage, CA19-9and lymph node metastasis, analysied the relation of livin with Caspase-3and ki67expression, so as to preliminarily inestigate the facilitaion mechanism of livin about tumor growth, to better understand the process of cell muliplication, proliferation, apoptotis in ampullary carcinoma, to further comprehend the role that Livin palys in the development and progression and ultimatly to provide more theoretical evidences for the treatment and prognostic judgement of ampullary carcinoma.
This experiment is to study the expression of Livin, Caspase-3and ki67in ampullary carcinoma, and explore Livin, Caspase-3and ki67expression in the relationship correlations with clinicopathologic features and prognosis by exploring the relation between Livin overexpression and Caspase-3in it, and finally discussed the potential significance to determine whether the level of Livin expression could predict poor prognosis of patients with ampullary carcinoma.
Objective
To investigate the expressions of Livin, Caspase-3and ki67and their correlations with clinicopathologic charactistics and prognosis in patients with ampullary carcinoma.
Methods
The expressions of Livin, Caspase-3and ki67were analyzed by immunohistochemistry using the streptavidin peroxidase complex method for71patients with ampullary carcinoma after surgery, and then their correlations with clinicopathologic charactistics were investigated. Meanwhile, we retrospectively analyzed the relationships between them with the survival time of the patients.
Results
Of the71patients with ampullary carcinoma, the accuracy rate of diagnosis with colour doppler ultrasound, CT, MRCP and ERCP was70.4%(50/71),85.9%(61/71),91.3%(42/46) and91.6%(11/12) respectively. There was a significant difference between colour doppler ultrasound and CT, MRCP (P<0.05). There was not significant difference among CT, MRCP, ERCP(P>0.05). Immunohistochemistrical results showed that the positive expressions of Livin, Caspase-3and ki67in ampullary carcinoma were46.5%(33/71),54.9%(39/71) and56.3%(40/71) respectively. The positive expressions of Livin, Caspase-3and ki67in paracancerous tissues were O(?)(0/52).75%(39/52) and25%(13/52) respectively. A very significant difference was found in the expression of Livin. Caspase-3and ki67protein between cancer tissues and paracancerous tissues (all P<0.05). The positive expression of Livin was associated with tumor differentiation, tumor-node-metastasis (TNM) stage, and lymph node metastasis (P<0.05), rather than of age, sex, tumor size, histological type, and CA19-9(P>0.05). The expression of Caspase-3and ki67were both significantly associated with tumor differentiation (P<0.05). but not with other clinicopathological features (all P>0.05). There was a significant negative correlation between Livin and Caspase-3(r=-0.575, P<0.001), and a positive correlation between Livin and ki67(r=0.308, P=0.009). Survival analysis showed that positive Livin expression group had a significantly poorer overall survival rate than negative Livin expression group did (P<0.05). Multivariate analysis demonstrated that Livin expression and lymph node metastasis were independent prognostic factor in ampullary carcinoma.
Conclusion
The positive expression rates of Livin protein were higher in ampullary carcinoma than in paracancerous tissues. It suggested that Livin protein expression was related in the development and progression of ampullary carcinoma. The expression of Livin was negatively correlated with Caspase-3, but positively correlated with ki67in ampullary carcinoma, suggesting that Livin probably inhibit Caspase-3activation directly or indirectly to protect cells apoptosis from occurring resulting in the occurring and procession of ampullary carcinoma. Livin is a valuable prognostic factor for ampullary carcinoma. Meanwhile, the current study indicates that Livin may have an important role by inhibiting apoptosis during the progress of ampullary carcinoma.
在危及人类健康的所有疾病中,恶性肿瘤的病死率仍居第一位。近几十年来,关于恶性肿瘤的诊疗水平已经有很大程度的进步,但它仍是当今医学界尚未攻克的一个难题。壶腹周围癌(Periampullary Carcinoma)属于消化系统恶性肿瘤,泛指起源于Vater壶腹、胰头部、胆总管末端、十二指肠乳头及周围粘膜的恶性肿瘤,预后较差而且术前很难对肿瘤定位作出明确诊断。壶腹周围癌的发病率仅次于胃癌及结直肠癌,成为第三位威胁人类健康的消化系统恶性肿瘤。这些来源不同的恶性肿瘤,由于其特殊的解剖部位,类似的临床表现,近乎相同的治疗方法,以至于在手术时也难以将其截然分开,但它们的预后却不尽相同。壶腹部癌是指源于Vater壶腹部区域的恶性肿瘤,该处粘膜由胆总管远端粘膜、胰大导管粘膜、十二指肠乳头粘膜构成。壶腹部癌在临床上相对少见,其发病率约占胃肠道肿瘤的0.2%,约占壶腹周围癌的7-20%,在壶腹周围癌中的发病率仅次于胰头癌。
1912年德国Kausch医生对1例壶腹周围癌病人成功完成第1例胰十二指肠切除术,1935年美国外科Whipple医生系统地提出了胰十二指肠切除术,并详细描述了消化道重建的顺序为胆管、胰、胃分别与空肠吻合(Whipple术式),然而目前常用的消化道重建顺序为胰、胆管、胃分别与空肠吻合(Child术式)。壶腹周围癌组织起源均不完全相同,胰十二指肠切除术仍是壶腹周围癌治疗的主要手术方式。壶腹部解剖位置较为特殊,即使肿瘤较小也能引起以黄疸为主的首发症状,所以对壶腹部癌病人临床上大多数能够做到早期诊断。胰十二指肠切除是壶腹部癌的主要手术方式,壶腹部局部切除治疗壶腹部癌明显减少了围手术期并发症和死亡率。壶腹部癌手术切除率较高,但术后5年生存率仅为25～67%,仍有很多病人死于肿瘤局部复发和远处转移。因此,提高壶腹部癌病人长期生存率成为临床研究的重要课题,而进一步了解并研究壶腹部癌的发病机制,识别可能的预后因素和治疗相关的分子靶点成为临床亟待解决的课题。
现代医学研究证明,肿瘤细胞异常增殖、异常分化、细胞凋亡不足均恶性肿瘤的发生发展密切相关,凋亡调节失衡是恶性肿瘤形成的重要机制之一。因此,人们广泛研究细胞凋亡与肿瘤之间的关系,细胞凋亡已成为肿瘤分子细胞生物学一个新的研究热点。
Livin是近年来发现的凋亡抑制蛋白家族中一个新成员,全长约4.6kb,位于染色体20q13.3,包括7个外显子和6个内含子,含有N端一个BIR结构和C端一个RING结构,其转录产物nRNA因剪接方式不同分为Livin a与Livinβ两种亚型,结构极为相似,分别编码298和280个氨基酸。Livin在胚胎发育过程中高表达于多种组织,可能与机体生长发育有关。在正常成人的大多数终末分化组织中(除胎盘、心脏、肺、脾外),Livin呈低表达或不表达；但在多种恶性肿瘤中,Livin呈高表达,如黑色素瘤、白血病、肺癌、前列腺癌、膀胱癌、胃癌、结肠癌、肝癌、胰腺癌等。Livin的生物学功能包括抑制细胞凋亡、调控细胞周期、参与肿·瘤血管生成、抗自然细胞的杀伤作用等。大量研究表明,在许多恶性肿瘤组织中Livin异常表达与患者的预后密切相关,如肿瘤复发、较短生存率等。
Caspase家族是一类存在于细胞质中结构类似的特异性天冬氨酸-半胱氨酸蛋白酶。细胞凋亡的发生是一个复杂的、由Caspase家族成员介导的蛋白酶级联反应过程。Caspase是一类在细胞凋亡过程中起着关键作用的酶。Caspase-3又被称为(CPP32或YAMA)可能是与凋亡关系最密切的一种蛋白酶,效应因子Caspase-3的激活则被认为是该级联反应的核心。Livin主要通过其BIR区域与Caspases结合,直接抑制Caspases的活性,尤其是抑伟Caspase-3、7和9的活性,通过阻断凋亡受体及线粒体相关的凋亡途径来实现对细胞凋亡的抑制。Ki67作为标记细胞增殖状念的抗原,是表达于细胞周期S和M期中的核抗原,其表达的高低反映了细胞增殖的程度,已被广泛认为是能较可靠地全面反映细胞群体增殖活性的客观指标。
目前国内外关于Livin在壶腹部癌中的表达相关研究较少,值得进一步研究和探索。通过研究Livin在壶腹部癌中的表达情况,证实Livin与性别、年龄、肿瘤的大小、组织学类型、CA19-9、肿瘤分化、临床分期及淋巴结状态等临床病理参数的关系,并分析肿瘤组织中Livin与Caspase-3、ki67的关系,初步探讨Livin促进壶腹部癌生长的机制,进一步深入了解Livin在壶腹部癌发生发展中的作用,为壶腹部癌的治疗和判断预后提供更多的理论依据。
本文通过检测Li vin、Caspase-3及ki67在壶腹部癌的表达并评估它们与临床病理特征和预后的关系,探讨壶腹部癌组织中Livin的表达与Caspase-3表达的关系并初步讨论其意义,以确定Livin的表达水平是否可用于预测壶腹部癌患者的预后。
目的
研究Livin、Caspase-3及ki67在壶腹部癌组织中的的表达及探讨它们与临床病理参数和预后的关系。
方法
免疫组织化学(SP)法检测71例壶腹部癌组织中Livin、Caspase-3及ki67的表达情况,同时分析它们与临床病理特征及预后的关系。
结果
1.71例壶腹部癌患者,术前彩超、CT、MRCP、ERCP的诊断符合率分别为70.4%(50/71)、85.9%(61/71)、91.3%(42/46)、91.6%(11/12)。彩超检查与CT、MRCP检查结果差异有统计学意义(P<0.05),其余各检查方法间无统计学差异(P>0.05)。
2.免疫组化结果显示71例壶腹部癌组织中,Livin、Caspase-3及ki67在壶腹部癌组织中的阳性表达分别为46.5%(33/71)、54.9%(39/71)和56.3%(40/71)。Livin、Caspase-3及ki67在癌旁组织I中的阳性表达分别为0%(0/52)、75%(39/52)和25%(13/52)。Livin及ki67在壶腹部癌中的表达明显高于癌旁组织(P<0.05)；Caspase-3在壶腹部癌中的表达明显低于癌旁组织(P<0.05)。
3.Livin的阳性表达与壶腹部癌的肿瘤分化程度和TNM分期、淋巴结转移状态有关(P<0.05),而与性别、年龄、肿瘤大小、组织学类型、CA19-9无明显相关(P>0.05)。Caspase-3与ki67在壶腹部癌中的表达均与肿瘤分化程度明显相关(P<0.05),而与其它临床病理参数无明显相关(P>0.05)。
4.Spearman等级相关分析Livin和Caspase-3表达呈负相关(r=-0.575,P<0.001), Livin和ki67表达呈正相关(r=0.308,P=0.009)。
5.Livin表达阳性患者的总生存率明显小于阴性表达患者的总生存率(P=0.001)。
6.多因素分析表明Livin阳性和淋巴结转移是壶腹部癌独立的预后因素。
结论
Livin蛋白在壶腹部癌组织中的表达明显高于癌旁组织,提示Livin表达增高与壶腹部癌的发生、发展有关。Livin与Caspase-3在壶腹部癌中的表达呈负相关,而与ki67呈正相关,提示Livin可能通过抑制Caspase-3的激活,促使细胞凋亡不能有效进行,导致肿瘤细胞过度增殖,从而为壶腹部癌的发生、发展提供了有利条件。Livin可作为壶腹部癌一个独立的预后指标。因此,我们推测Livin在壶腹部癌的发生、发展和转移中起重要作用。
Background:
With the highest fatality ratio, malignant tumor is the leading cause of death in human diseases. Although the diagnosis and treatment of malignancy has been developed to a much more advanced level during the past decades, it is still a tough problem which has not been conquered in the current medical circles. Periampullary carcinoma is a collective term used for cancers arising from or near the ampulla of Vater and include ampullary carcinoma, pancreatic head cancer, distal cholangiocarcinoma and duodenal cancer. Periampullary cancers are the third most frequent gastrointestinal tumors following gastric and colorectal cancers. These tumors exhibit similar symptoms, but different clinical outcomes, according to their anatomic origin. The exact site of origin of periampullary tumors is often difficult to ascertain preoperatively. Ampullary carcinoma, defined as a tumor grossly appearing to arise in the ampulla of Vater. Three epithelial types can be involved in this area: those arising from the bile duct, the pancreatic duct, or the duodenal mucosa. Ampullary carcinoma is a relatively uncommon neoplasm. It accounts for approximately0.2%of all tumors in the gastrointestinal tract and constitutes about7to20%of the periampullary neoplasms, being the second most frequent tumor of this region.
The first resection for a periampullary carcinoma was performed by the German surgeon Kausch in1912. It is often called the Whipple procedure, after the American surgeon Whipple who devised an improved version of the surgery in1935. Reconstruction consists of attaching the pancreas to the jejunum and attaching the hepatic duct to the jejunum to allow digestive juices and bile respectively to flow into the gastrointestinal tract and attaching the stomach to the jejunum to allow food to pass through. Whipple originally used the sequence:bile duct, pancreas and stomach, whereas presently the popular method of reconstruction is pancreas, bile duct and stomach, also known as Child's operation. Regardless of the site of origin of these tumors, most patients undergo a similar operative procedure for extirpation of their disease:radical pancreaticoduodenectomy. Because even small lesions in the ampulla can obstruct the bile duct, early jaundice and early presentation occurs, which may lead to early dignosis and high resectability rate. Pancreatoduodenectomy is the main treatment of choice for tumors of the ampulla of Vater. Local procedures such as simple ampullectomy has been proposed to obviously reduce operative complication and mortality. The overall five-year survival of25%to67%. Many patients will still experience a regional recurrence and metastasis. There is a need for a better understanding of the pathologic mechanism of ampullary carcinoma, the identification of potential prognostic factors, and clinically relevant molecular targets for therapy.
Modern medical studies have showen that the formation and development of malignant tumors are not only associated with abnormal proliferation and differentiation, but also involved in inhibition of apoptosis which was one of the important mechanisms in the forming of tumors. So, apoptosis and tumor became a hot focus in tumor molecular biological researches.
Livin is a member of the inhibitors of apoptosis (IAP) family. Livin gene spans4.6kb on chromosome20at band q13, and including six introns and seven exons. Livin protein contains a single BIR domain and a RING linger motif. Livin gene has two splice variants:Livin α and β, which are almost identical. Conceptual translation indicates that Livin a and P are almost identical proteins that share the amino-terminal BIR and carboxyterminal RING domains. The two cDNAs contain open reading frames of298and280amino acids. With the exception of the placenta, heart, lung, spleen and ovary, the messenger RNA(mRNA) for Livin is not detectable in most normal adult tissues. However, it is detectable in fetal tissues (brain, kidney,heart and spleen) and is overexpressed by some cancer cells. Livin is presented in several cancer tissures, such as melanoma, leukemia, lung cancer cells, bladder cancer, prostate cancer, gastric cancer, colon cancer, hepatocelluar carcinoma and pancreatic cancer. Livin plays critical role in apoptosis inhibition, regulating the cell cycle, participating in tumor angiogenesis and anti-nature killer cells action. The majority of the current datas suggest that Livin expression in cancer appears to be associated with unfavorable clinico-pathological parameters, such as disease relapse and shorter patient survival. It has close relation with the occurence of tumors. Livin served as a new target for apoptosis-inducing therapy of malignant tumors.
Caspase family is a class of amino acid sequence, spatial structure and substrate specificity are similar specificity of aspartic acid-cysteine protease. The occurence of apoptosis is a complex, mediated by the Caspase family members of the protease cascade process, but the district is located downstream effector. Caspases, are the key effectors of the cellular death. Among the caspases, Caspase-3(also known as CPP32, YAMA) is probably the one that so far best correlates with apoptosis. Caspase-3activation was considered to be the only way cascade. Livin mainly through its BIR district and cysteine aspartate-specific proteases(Caspases) combination of direct inhibition of cysteine protease caspases, in particular, inhibit Caspase-3,7and9activity, to resistance fault-related apoptosis receptor and mitochondrial apoptosis pathway, while the realization of the inhibition of apoptosis. Ki67is a nuclear antigen expressed mainly in the S and M phases of the cell cycle, and it has been used in many studies for estimating the growth fraction of various tumor types.
Inspite of elemantary study on Livin has been made, the specific mechanism of action in ampullary carcinoma is still unknow, which deserves further research. In this study we investigated expression of Livin, Caspase-3and ki67in ampullary carcinoma and its relation of sex, tumor size, histological type, tumor differentiation, TNM stage, CA19-9and lymph node metastasis, analysied the relation of livin with Caspase-3and ki67expression, so as to preliminarily inestigate the facilitaion mechanism of livin about tumor growth, to better understand the process of cell muliplication, proliferation, apoptotis in ampullary carcinoma, to further comprehend the role that Livin palys in the development and progression and ultimatly to provide more theoretical evidences for the treatment and prognostic judgement of ampullary carcinoma.
This experiment is to study the expression of Livin, Caspase-3and ki67in ampullary carcinoma, and explore Livin, Caspase-3and ki67expression in the relationship correlations with clinicopathologic features and prognosis by exploring the relation between Livin overexpression and Caspase-3in it, and finally discussed the potential significance to determine whether the level of Livin expression could predict poor prognosis of patients with ampullary carcinoma.
Objective
To investigate the expressions of Livin, Caspase-3and ki67and their correlations with clinicopathologic charactistics and prognosis in patients with ampullary carcinoma.
Methods
The expressions of Livin, Caspase-3and ki67were analyzed by immunohistochemistry using the streptavidin peroxidase complex method for71patients with ampullary carcinoma after surgery, and then their correlations with clinicopathologic charactistics were investigated. Meanwhile, we retrospectively analyzed the relationships between them with the survival time of the patients.
Results
Of the71patients with ampullary carcinoma, the accuracy rate of diagnosis with colour doppler ultrasound, CT, MRCP and ERCP was70.4%(50/71),85.9%(61/71),91.3%(42/46) and91.6%(11/12) respectively. There was a significant difference between colour doppler ultrasound and CT, MRCP (P<0.05). There was not significant difference among CT, MRCP, ERCP(P>0.05). Immunohistochemistrical results showed that the positive expressions of Livin, Caspase-3and ki67in ampullary carcinoma were46.5%(33/71),54.9%(39/71) and56.3%(40/71) respectively. The positive expressions of Livin, Caspase-3and ki67in paracancerous tissues were O(?)(0/52).75%(39/52) and25%(13/52) respectively. A very significant difference was found in the expression of Livin. Caspase-3and ki67protein between cancer tissues and paracancerous tissues (all P<0.05). The positive expression of Livin was associated with tumor differentiation, tumor-node-metastasis (TNM) stage, and lymph node metastasis (P<0.05), rather than of age, sex, tumor size, histological type, and CA19-9(P>0.05). The expression of Caspase-3and ki67were both significantly associated with tumor differentiation (P<0.05). but not with other clinicopathological features (all P>0.05). There was a significant negative correlation between Livin and Caspase-3(r=-0.575, P<0.001), and a positive correlation between Livin and ki67(r=0.308, P=0.009). Survival analysis showed that positive Livin expression group had a significantly poorer overall survival rate than negative Livin expression group did (P<0.05). Multivariate analysis demonstrated that Livin expression and lymph node metastasis were independent prognostic factor in ampullary carcinoma.
Conclusion
The positive expression rates of Livin protein were higher in ampullary carcinoma than in paracancerous tissues. It suggested that Livin protein expression was related in the development and progression of ampullary carcinoma. The expression of Livin was negatively correlated with Caspase-3, but positively correlated with ki67in ampullary carcinoma, suggesting that Livin probably inhibit Caspase-3activation directly or indirectly to protect cells apoptosis from occurring resulting in the occurring and procession of ampullary carcinoma. Livin is a valuable prognostic factor for ampullary carcinoma. Meanwhile, the current study indicates that Livin may have an important role by inhibiting apoptosis during the progress of ampullary carcinoma.
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62. Sun JG, Liao RX, Zhang SX, et al. Role of inhibitor of apoptosis protein Livin in radiation resistance in nonsmall cell lung cancer. Cancer Biother Radiopharm, 2011,26(5):585-592.
63. Ding ZY, Liu GH, Olsson B, et al. Upregulation of the antiapoptotic factor Livin contributes to cisplatin resistance in colon cancer cells. Tumour Biol, 2013,34(2):683-693.
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3. Vucic D, Stennicke HR, Pisabarro MT, et al. ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Curr Biol,2000, 10(21):1359-1366.
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5. Hinds MG, Norton RS, Vaux DL, et al. Solution structure of a baculoviral inhibitor of apoptosis (IAP) repeat. Nat Struct Biol,1999,6(7):648-651.
6.王璐,朱莹,陈旻静,等Livin与Caspase-9在皮肤鳞状细胞癌组织中的表达及其临床意义.中华实验外科杂志,2012,29(5)：943-945.
7.苏晓燕,王修珍,顾振纶,等Livin及半胱氨酸天冬氨酸蛋白酶3蛋白在子宫颈鳞癌组织中的表达及意义.中华妇产科杂志,2010,45(6)：465-467.
8.焦伊胜,王永来,张淑兰,等Livin、Smac在上皮性卵巢癌中的表达及意义.现代肿瘤医学,2009,17(2)：296-299.
9. Tanabe H, Yagihashi A, Tsuji N, et al. Expression of survivin mRNA and livin mRNA in non-small-cell lung cancer. Lung Cancer,2004,46(3):299-304.
10. Cheng T, Zhang JG, Cheng YH, et al. Relationship between PTEN and Livin expression and malignancy of renal cell carcinomas. Asian Pac J Cancer Prev, 2012,13(6):2681-2685.
11. Gazzaniga P, Gradilone A, Giuliani L, et al. Expression and prognostic significance of LIVIN, SURVIVIN and other apoptosis-related genes in the progression of superficial bladder cancer. Ann Oncol,2003,14(1):85-90.
12. Liang YZ, Fang TY, Xu HG, et al. Expression of CD44v6 and Livin in gastric cancer tissue. Chin Med J (Engl),2012,125(17):3161-3165.
13. Wang X, Xu J, Ju S, et al. Livin gene plays a role in drug resistance of colon cancer cells. Clin Biochem,2010,43(7-8):655-660.
14.赵永福,吕以东,刘洪峰,等Livin和Smac蛋白在胰腺癌中的表达及其意义.中华胰腺病杂志,2011,11(4)：275-277.
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1. Kerr JF, Wyllie AH, Currie AR. Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer,1972,26(4):239-257.
2. Salvesen GS, Duckett CS. IAP proteins:blocking the road to death's door. Nat Rev Mol Cell Biol,2002,3(6):401-410.
3. Vucic D, Stennicke HR, Pisabarro MT, et al. ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Curr Biol,2000, 10(21):1359-1366.
4. Ashhab Y, Alian A, Polliack A, et al. Two splicing variants of a new inhibitor of apoptosis gene with different biological properties and tissue distribution pattern. FEBS Lett,2001,495(1-2):56-60.
5. Hinds MG, Norton RS, Vaux DL, et al. Solution structure of a baculoviral inhibitor of apoptosis (IAP) repeat. Nat Struct Biol,1999,6(7):648-651.
6.王璐,朱莹,陈旻静,等Livin与Caspase-9在皮肤鳞状细胞癌组织中的表达及其临床意义.中华实验外科杂志,2012,29(5)：943-945.
7.苏晓燕,王修珍,顾振纶,等Livin及半胱氨酸天冬氨酸蛋白酶3蛋白在子宫颈鳞癌组织中的表达及意义.中华妇产科杂志,2010,45(6)：465-467.
8.焦伊胜,王永来,张淑兰,等Livin、Smac在上皮性卵巢癌中的表达及意义.现代肿瘤医学,2009,17(2)：296-299.
9. Tanabe H, Yagihashi A, Tsuji N, et al. Expression of survivin mRNA and livin mRNA in non-small-cell lung cancer. Lung Cancer,2004,46(3):299-304.
10. Cheng T, Zhang JG, Cheng YH, et al. Relationship between PTEN and Livin expression and malignancy of renal cell carcinomas. Asian Pac J Cancer Prev, 2012,13(6):2681-2685.
11. Gazzaniga P, Gradilone A, Giuliani L, et al. Expression and prognostic significance of LIVIN, SURVIVIN and other apoptosis-related genes in the progression of superficial bladder cancer. Ann Oncol,2003,14(1):85-90.
12. Liang YZ, Fang TY, Xu HG, et al. Expression of CD44v6 and Livin in gastric cancer tissue. Chin Med J (Engl),2012,125(17):3161-3165.
13. Wang X, Xu J, Ju S, et al. Livin gene plays a role in drug resistance of colon cancer cells. Clin Biochem,2010,43(7-8):655-660.
14.赵永福,吕以东,刘洪峰,等Livin和Smac蛋白在胰腺癌中的表达及其意义.中华胰腺病杂志,2011,11(4)：275-277.
15. Yagihashi A, Asanuma K Tsuji N, et al. Detection of anti—livin antibody in gastrointestinal cancer patients. Clin Chem,2003,49(7):1206-1208.
16.余杰雄,汤志华,陈积圣,等Livin基因在胆管癌组织中的表达及其临床意义.中华普通外科杂志,2009,24(7)：596-597.
17. Nedelcu T, Kubista B, Koller A, et al. Livin and Bcl-2 expression in high-grade osteosarcoma. J Cancer Res Clin Oncol,2008,134(2):237-244.
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