ERCC1、P27~（kip1）、CyclinE在胃癌中的表达及其与胃癌预后相关性研究
摘要
背景与目的
胃癌是最常见的消化道恶性肿瘤,全世界每年胃癌发病率约为13.86/10万人,死亡率位居恶性肿瘤的第二位。胃癌是一种全身性疾病,单纯手术治疗尚不能取得令人满意的临床效果,必须采取以手术为主,放化疗结合的综合治疗才能进一步提高患者的生存率。传统的化疗药物主要有抗代谢类药物、烷化剂类、抗生素类、铂类和植物类等5大类药物。随着当代分子生物学和细胞生物学的发展,出现了治疗癌症的分子靶向药物(targeted medicine)。靶向药物通过作用于靶点发挥抗肿瘤作用,有相应的优势人群。近两年来研究发现,如同小分子靶向药物治疗存在优势人群一样,化疗药物也有优势人群,如何筛选优势人群,使接受化疗的患者获益最大,避免过度治疗,是我们目前面临的主要问题。核苷酸切除修复交叉互补基因1 (ERCC1)通过核苷酸切除修复通路实现对DNA的损伤修复,该通路也是铂-DNA络合物损伤修复的重要途径。如果DNA损伤不能得到及时修复,将导致细胞异常增殖,引起肿瘤的发生。同时该基因在肿瘤细胞对顺铂的耐药机制中发挥重要的作用。已有研究报道：在肺癌术后接受以顺铂为基础的化疗患者中,ERCC1过表达者预后差。细胞周期在肿瘤的发生发展中起着至关重要的作用。大多数分子的改变均涉及到基因对细胞周期的调控,其中细胞周期依赖性激酶(CDKs)、细胞周期依赖性激酶抑制因子(CDKIs)及细胞周期素(Cyclin A、D、E)是细胞周期重要的调控因子。在细胞周期G1/S调控中最重要的是细胞周期依赖性激酶2(CDK2),CyclinE与CDK2形成复合物在G1/S中起促进作用,而P27Kipl主要通过与CDK2结合,实现对其活性的抑制,在细胞周期的G1/S调控中起抑制作用。这样P27kipl与CyclinE围绕CDK2就形成了一种作用相反的关系,共同完成对细胞周期的Gl/S调控,使细胞增殖正确、有序地进行。有学者研究发现P27kipl低表达与CyclinE高表达和食管癌进展及预后有密切关系。目前关于ERCC1、P27kip1、CyclinE与胃癌关系的研究鲜见,且有关其对胃癌预后影响结果也不一致。本研究选择了ERCC1、P27kip1和CyclinE三个指标旨在探讨它们与胃癌发生、发展及其与患者生存期的关系,为临床预测疗效和评估预后提供理论基础。
材料与方法
1收集临床病理资料完整且有随访结果的45例胃癌患者作为实验组,10例正常胃组织作为对照组。
2应用免疫组化方法(EliVisionTM二步法)检测45例胃癌组织与10例正常胃组织中ERCC1、P27Kip1、CyclinE蛋白的表达情况。
345例胃癌患者术后均接受以铂类和氟尿嘧啶为基础的化疗,方案为顺铂25mg/m2,静滴,第1-3天；亚叶酸钙0.1,静滴,第1-5天；氟尿嘧啶500mg/m2,静滴,第1-5天,每3周重复,中位周期数为5个周期。手术后每2-3个月行胸腹部螺旋CT检查一次,至肿瘤复发或转移,所有复发和转移病例均经影像学、胃镜活检证实。术前均未接受放疗和化疗,所有标本经常规福尔马林固定,石蜡包埋。
4应用统计学软件SPSS11.0分析ERCC1、P27Kip1、CyclinE蛋白的表达与患者各个临床病理参数及生存期之间的关系。
结果
1实验组45例胃癌组织中ERCC1、P27Kip1、CyclinE蛋白阳性率分别为31.1%(14/45)、35.6%(16/45)、55.6%(25/45),10例正常胃组织阳性率分别为70%(7/10)、80%(8/10)、20%(2/10),两组之间表达有显著性差异(P<0.05)
2 ERCC1、P27Kip1、CyclinE蛋白表达与患者的性别、年龄、肿瘤大小、部位、分化程度均无显著性差异(P>0.05)；而与肿瘤的浸润深度、淋巴结转移、远处转移及临床分期差异有统计学意义(P<0.05)
3胃癌中P27Kipl与CyclinE蛋白表达呈负相关(P<0.05),相关系数r=-0.47。
4 ERCC1、P27Kip1阳性患者中位无疾病生存时间(DFS)分别为6.8和12个月,显著低于阴性患者的中位DFS分别为24和18个月,差异有统计学意义(P<0.05)；CyclinE表达阳性与阴性患者无疾病生存期分别为13和15个月,无统计学差异(P>0.05)
5 ERCC1、P27Kip1均阳性7例(15%),均阴性22例(48%),ERCC1(+)、P27Kipl(-)7例(15%),ERCC1(-)、P27Kip1(+)9例(20%),这四组无疾病生存期(DFS)分别为6.8、28.1、11.2、24.6个月,其中ERCC1、P27Kipl均阴性与均阳性、ERCC1(+)、P27Kip1(-)差异有统计学意义(P<0.05),与ERCC1(-)、P27Kip1(+)差异无统计学意义(P>0.05)
结论
1 ERCC1、P27Kip1的低表达和CyclinE高表达可能与胃癌的发生、发展有关。
2 ERCC1、P27Kip1、CyclinE蛋白表达均与患者的性别、年龄、肿瘤大小、部位、分化程度无相关性；与肿瘤的浸润深度、淋巴结转移、远处转移、临床分期有相关性。
3 P27Kipl与CyclinE蛋白在胃癌的发生、发展中呈负相关。
4胃癌患者术后接受以铂类和氟尿嘧啶为基础的辅助化疗,ERCC1、P27Kip1、CyclinE蛋白表达阳性的中位生存时间短于表达阴性者,提示ERCC1、P27Kip1、CyclinE蛋白高表达的胃癌患者生存期短,预后差。
5 ERCC1、P27Kip1、CyclinE三者联合检测可以预测化疗疗效和评估预后。
Background and Objectives
Gastric cancer is the most common digestive malignant tumor in the world and the second most frequent cause of cancer death, affecting about 13.8 cases per 100,000 persons every year. Satisfactory effect can not be got only by surgery because gastric cancer is a general disease. Therefore synthetic therapy of surgery combined with chemotherapy and radiotherapy should be employed to enhance the survival rate. Traditional chemotherapy medicine has five kinds, including anti-metabolism, alkylating agent, antibiotics, platinum and plants. With the development of modern molecular biology and cellular biology, targeted medicine came into being which can treat cancer. Targeted medicine plays an important part in anti-neoplasms by target point and has advantageous group itself. Recently, researches have found chemotherapy medicine also had advantageous group, just as targeted medicine. Now main question we are faced with is "how to screen the advantage group, so that the greatest benefit in patients receiving chemotherapy, to avoid over-treatment". The excision repair cross complementing group1 (ERCC1) gene carry out damage repair of the DNA via the nucleotide excision and repair pathway, which is essential for the repair of the cisplatin-DNA adducts. If DNA damage can not be repaired in time, it would lead to cell proliferation and cause cancer. Meantime, this gene in tumor cells to cisplatin resistance mechanisms plays a important role. It has been reported that the overexpression of the ERCC1 gene had a poor prognosis in lung cancer patients who received cisplatin-based adjuvant therapy after surgery. The cell cycle plays an important role in the development of cancer. Most of the molecular alterations are related to the gene in cell cycle regulation, including cyclin-dependent kinases(CDKs), cyclin-dependent kinase inhibitors (CDKIs) and Cyclin(A, D, E), which are the major regulatory factor of cell cycle. Cyclin-dependent kinases2 (CDK2) is one of the most important regulatory factor in G1/S of cell cycle, which play a positive role in G1/S when combines CyclinE, but it plays a negative role in G1/S when combines P27Kip1 (kinase inhibition protein27). Therefore, P27Kip1 and CyclinE form an adverse relationship in G1/S, which complete regulation of cell cycle and normal cell proliferation. Some scholars have found that downexpression of P27Kip1 and overexpression of CyclinE might be associated with the progress and prognosis of esophageal cancer. But the expression of ERCC1, P27Kip1 and CyclinE is unclear in gastric cancer, and the results of their impact on prognosis of gastric cancer are also inconsistent. Therefore, this study selected the ERCC1, P27Kip1 and CyclinE three indicators to explore them with the development of gastric cancer and its relationship with patient survival, clinical efficacy and prognosis prediction to provide a theoretical basis.
Materials and Methods
1 To collect 45 cases of gastric cancer and 10 cases of normal gastric tissue with clinicopthologic data and follow-up.
2 To detect expression of ERCC1, P27Kip1 and CyclinE expression in gastric cancer and normal gastric tissue by immunohistrochemistry assay (ElivisionTM).
3 To accepte chemotherapy of platinum and fluorouracil in 45 cases gastric cancer, specific schema, cisplatin,25mg/m2, d1-3. Leucovorin,0.1, d1-5. Fluorouracil, 50mg/m2, d1-5, transfusion, which should be experimented every three weeks, the media period 5. After the operation every 2-3 months line chest or ventrum spiral computed tomography examination time to tumor recurrence or metastasis. All patients had recurrence and metastasis by imaging, endoscopy and biopsy. None received preoperative radiotherapy or chemotherapy, all specimens by routine formalin-fixed, paraffin-embedded.
4 To analyze ERCC1, P27Kip1 and CyclinE expression with various clinicopathological parameters and survival relationship in SPSS 11.0.
Results
1 The positive rate of ERCC1, P27Kip1 and CyclinE in gastric cancer was 31.1% (14/45),35.6%(16/45) and 55.6%(25/45). The positive rate of ERCC1, P27Kip1 and CyclinE in normal gastric tissue was 70%(7/10),80%(8/10) and 20%(2/10). There were the significant differences between two groups (P<0.05).
2 The expression of ERCC1, P27Kip1 and CyclinE in gastric cancer was not correlated with sex, age, size, site of tumor and degree of differentiation (P>0.05). The expression of ERCC1, P27Kip1 and CyclinE in gastric cancer was related to depth of invasion, lymph node, distant metastasis, clinical stage (P<0.05).
3 There was significantly negative correlationship between P27Kip1 and CyclinE expression in gastric cancer. The coefficient correlation was-0.47 (P<0.05).
4 The median disease-free survival of patients with ERCC1 and P27Kip1 positive in gastric cancer was 6.8 and 12 months, respectively. There was significant differences between positive and negative expression of ERCCl, P27Kip1 (P<0.05). Median disease-free survival of patients with CyclinE positive and negative in gastric cancer was 13 and 15 months, respectively. There was not significant differences between CyclinE positive and negative (P>0.05).
5 The positive of both ERCC1 and P27Kip1 was 7 cases (15%), negative of both ERCC1 and P27Kip1 was 22 cases (48%). ERCC1 positive and P27Kip1 negative were 7 cases (15%), ERCC1 negative and P27Kip1 positive were 9 cases (20%). Median disease-free survival of the four groups was 6.8,28.1,11.2 and 24.6 months, respectively. There was significant difference between median disease-free survival of patients with both ERCCl and P27Kipl positive or both ERCC1 and P27Kip1 negative or ERCC1 positive P27Kip1 negative (P<0.05). There was no significant difference between ERCC1 negative and P27Kip1 positive (P>0.05).
Conclusions
1 The low expression of ERCC1, P27Kip1 and the high expression of CyclinE were related with the occurrence and development of gastric cancer.
2 The expression of ERCC1, P27Kip1 and CyclinE in gastric cancer was not correlated with sex, age, size, site of tumor and degree of differentiation. The expression of ERCC1, P27Kip1 and CyclinE in gastric cancer was related to depth of invasion, lymph node, distant metastasis, clinical stage.
3 There was significantly negative correlationship between P27Kip1 and CyclinE expression in the development of gastric cancer.
4 The gastric cancer patients receiving platinum-based and fluorouracil chemotherapy, median disease-free survival of patients with ERCC1, P27Kip1 and CyclinE positive was shorter than those with negative expression. They showed that patients with ERCC1, P27Kip1 and CyclinE positive were associated with short survival and poor prognosis.
5 To detect ERCC1, P27Kip1 and CyclinE may predict effect of chemotherapy and evaluate prognosis.
胃癌是最常见的消化道恶性肿瘤,全世界每年胃癌发病率约为13.86/10万人,死亡率位居恶性肿瘤的第二位。胃癌是一种全身性疾病,单纯手术治疗尚不能取得令人满意的临床效果,必须采取以手术为主,放化疗结合的综合治疗才能进一步提高患者的生存率。传统的化疗药物主要有抗代谢类药物、烷化剂类、抗生素类、铂类和植物类等5大类药物。随着当代分子生物学和细胞生物学的发展,出现了治疗癌症的分子靶向药物(targeted medicine)。靶向药物通过作用于靶点发挥抗肿瘤作用,有相应的优势人群。近两年来研究发现,如同小分子靶向药物治疗存在优势人群一样,化疗药物也有优势人群,如何筛选优势人群,使接受化疗的患者获益最大,避免过度治疗,是我们目前面临的主要问题。核苷酸切除修复交叉互补基因1 (ERCC1)通过核苷酸切除修复通路实现对DNA的损伤修复,该通路也是铂-DNA络合物损伤修复的重要途径。如果DNA损伤不能得到及时修复,将导致细胞异常增殖,引起肿瘤的发生。同时该基因在肿瘤细胞对顺铂的耐药机制中发挥重要的作用。已有研究报道：在肺癌术后接受以顺铂为基础的化疗患者中,ERCC1过表达者预后差。细胞周期在肿瘤的发生发展中起着至关重要的作用。大多数分子的改变均涉及到基因对细胞周期的调控,其中细胞周期依赖性激酶(CDKs)、细胞周期依赖性激酶抑制因子(CDKIs)及细胞周期素(Cyclin A、D、E)是细胞周期重要的调控因子。在细胞周期G1/S调控中最重要的是细胞周期依赖性激酶2(CDK2),CyclinE与CDK2形成复合物在G1/S中起促进作用,而P27Kipl主要通过与CDK2结合,实现对其活性的抑制,在细胞周期的G1/S调控中起抑制作用。这样P27kipl与CyclinE围绕CDK2就形成了一种作用相反的关系,共同完成对细胞周期的Gl/S调控,使细胞增殖正确、有序地进行。有学者研究发现P27kipl低表达与CyclinE高表达和食管癌进展及预后有密切关系。目前关于ERCC1、P27kip1、CyclinE与胃癌关系的研究鲜见,且有关其对胃癌预后影响结果也不一致。本研究选择了ERCC1、P27kip1和CyclinE三个指标旨在探讨它们与胃癌发生、发展及其与患者生存期的关系,为临床预测疗效和评估预后提供理论基础。
材料与方法
1收集临床病理资料完整且有随访结果的45例胃癌患者作为实验组,10例正常胃组织作为对照组。
2应用免疫组化方法(EliVisionTM二步法)检测45例胃癌组织与10例正常胃组织中ERCC1、P27Kip1、CyclinE蛋白的表达情况。
345例胃癌患者术后均接受以铂类和氟尿嘧啶为基础的化疗,方案为顺铂25mg/m2,静滴,第1-3天；亚叶酸钙0.1,静滴,第1-5天；氟尿嘧啶500mg/m2,静滴,第1-5天,每3周重复,中位周期数为5个周期。手术后每2-3个月行胸腹部螺旋CT检查一次,至肿瘤复发或转移,所有复发和转移病例均经影像学、胃镜活检证实。术前均未接受放疗和化疗,所有标本经常规福尔马林固定,石蜡包埋。
4应用统计学软件SPSS11.0分析ERCC1、P27Kip1、CyclinE蛋白的表达与患者各个临床病理参数及生存期之间的关系。
结果
1实验组45例胃癌组织中ERCC1、P27Kip1、CyclinE蛋白阳性率分别为31.1%(14/45)、35.6%(16/45)、55.6%(25/45),10例正常胃组织阳性率分别为70%(7/10)、80%(8/10)、20%(2/10),两组之间表达有显著性差异(P<0.05)
2 ERCC1、P27Kip1、CyclinE蛋白表达与患者的性别、年龄、肿瘤大小、部位、分化程度均无显著性差异(P>0.05)；而与肿瘤的浸润深度、淋巴结转移、远处转移及临床分期差异有统计学意义(P<0.05)
3胃癌中P27Kipl与CyclinE蛋白表达呈负相关(P<0.05),相关系数r=-0.47。
4 ERCC1、P27Kip1阳性患者中位无疾病生存时间(DFS)分别为6.8和12个月,显著低于阴性患者的中位DFS分别为24和18个月,差异有统计学意义(P<0.05)；CyclinE表达阳性与阴性患者无疾病生存期分别为13和15个月,无统计学差异(P>0.05)
5 ERCC1、P27Kip1均阳性7例(15%),均阴性22例(48%),ERCC1(+)、P27Kipl(-)7例(15%),ERCC1(-)、P27Kip1(+)9例(20%),这四组无疾病生存期(DFS)分别为6.8、28.1、11.2、24.6个月,其中ERCC1、P27Kipl均阴性与均阳性、ERCC1(+)、P27Kip1(-)差异有统计学意义(P<0.05),与ERCC1(-)、P27Kip1(+)差异无统计学意义(P>0.05)
结论
1 ERCC1、P27Kip1的低表达和CyclinE高表达可能与胃癌的发生、发展有关。
2 ERCC1、P27Kip1、CyclinE蛋白表达均与患者的性别、年龄、肿瘤大小、部位、分化程度无相关性；与肿瘤的浸润深度、淋巴结转移、远处转移、临床分期有相关性。
3 P27Kipl与CyclinE蛋白在胃癌的发生、发展中呈负相关。
4胃癌患者术后接受以铂类和氟尿嘧啶为基础的辅助化疗,ERCC1、P27Kip1、CyclinE蛋白表达阳性的中位生存时间短于表达阴性者,提示ERCC1、P27Kip1、CyclinE蛋白高表达的胃癌患者生存期短,预后差。
5 ERCC1、P27Kip1、CyclinE三者联合检测可以预测化疗疗效和评估预后。
Background and Objectives
Gastric cancer is the most common digestive malignant tumor in the world and the second most frequent cause of cancer death, affecting about 13.8 cases per 100,000 persons every year. Satisfactory effect can not be got only by surgery because gastric cancer is a general disease. Therefore synthetic therapy of surgery combined with chemotherapy and radiotherapy should be employed to enhance the survival rate. Traditional chemotherapy medicine has five kinds, including anti-metabolism, alkylating agent, antibiotics, platinum and plants. With the development of modern molecular biology and cellular biology, targeted medicine came into being which can treat cancer. Targeted medicine plays an important part in anti-neoplasms by target point and has advantageous group itself. Recently, researches have found chemotherapy medicine also had advantageous group, just as targeted medicine. Now main question we are faced with is "how to screen the advantage group, so that the greatest benefit in patients receiving chemotherapy, to avoid over-treatment". The excision repair cross complementing group1 (ERCC1) gene carry out damage repair of the DNA via the nucleotide excision and repair pathway, which is essential for the repair of the cisplatin-DNA adducts. If DNA damage can not be repaired in time, it would lead to cell proliferation and cause cancer. Meantime, this gene in tumor cells to cisplatin resistance mechanisms plays a important role. It has been reported that the overexpression of the ERCC1 gene had a poor prognosis in lung cancer patients who received cisplatin-based adjuvant therapy after surgery. The cell cycle plays an important role in the development of cancer. Most of the molecular alterations are related to the gene in cell cycle regulation, including cyclin-dependent kinases(CDKs), cyclin-dependent kinase inhibitors (CDKIs) and Cyclin(A, D, E), which are the major regulatory factor of cell cycle. Cyclin-dependent kinases2 (CDK2) is one of the most important regulatory factor in G1/S of cell cycle, which play a positive role in G1/S when combines CyclinE, but it plays a negative role in G1/S when combines P27Kip1 (kinase inhibition protein27). Therefore, P27Kip1 and CyclinE form an adverse relationship in G1/S, which complete regulation of cell cycle and normal cell proliferation. Some scholars have found that downexpression of P27Kip1 and overexpression of CyclinE might be associated with the progress and prognosis of esophageal cancer. But the expression of ERCC1, P27Kip1 and CyclinE is unclear in gastric cancer, and the results of their impact on prognosis of gastric cancer are also inconsistent. Therefore, this study selected the ERCC1, P27Kip1 and CyclinE three indicators to explore them with the development of gastric cancer and its relationship with patient survival, clinical efficacy and prognosis prediction to provide a theoretical basis.
Materials and Methods
1 To collect 45 cases of gastric cancer and 10 cases of normal gastric tissue with clinicopthologic data and follow-up.
2 To detect expression of ERCC1, P27Kip1 and CyclinE expression in gastric cancer and normal gastric tissue by immunohistrochemistry assay (ElivisionTM).
3 To accepte chemotherapy of platinum and fluorouracil in 45 cases gastric cancer, specific schema, cisplatin,25mg/m2, d1-3. Leucovorin,0.1, d1-5. Fluorouracil, 50mg/m2, d1-5, transfusion, which should be experimented every three weeks, the media period 5. After the operation every 2-3 months line chest or ventrum spiral computed tomography examination time to tumor recurrence or metastasis. All patients had recurrence and metastasis by imaging, endoscopy and biopsy. None received preoperative radiotherapy or chemotherapy, all specimens by routine formalin-fixed, paraffin-embedded.
4 To analyze ERCC1, P27Kip1 and CyclinE expression with various clinicopathological parameters and survival relationship in SPSS 11.0.
Results
1 The positive rate of ERCC1, P27Kip1 and CyclinE in gastric cancer was 31.1% (14/45),35.6%(16/45) and 55.6%(25/45). The positive rate of ERCC1, P27Kip1 and CyclinE in normal gastric tissue was 70%(7/10),80%(8/10) and 20%(2/10). There were the significant differences between two groups (P<0.05).
2 The expression of ERCC1, P27Kip1 and CyclinE in gastric cancer was not correlated with sex, age, size, site of tumor and degree of differentiation (P>0.05). The expression of ERCC1, P27Kip1 and CyclinE in gastric cancer was related to depth of invasion, lymph node, distant metastasis, clinical stage (P<0.05).
3 There was significantly negative correlationship between P27Kip1 and CyclinE expression in gastric cancer. The coefficient correlation was-0.47 (P<0.05).
4 The median disease-free survival of patients with ERCC1 and P27Kip1 positive in gastric cancer was 6.8 and 12 months, respectively. There was significant differences between positive and negative expression of ERCCl, P27Kip1 (P<0.05). Median disease-free survival of patients with CyclinE positive and negative in gastric cancer was 13 and 15 months, respectively. There was not significant differences between CyclinE positive and negative (P>0.05).
5 The positive of both ERCC1 and P27Kip1 was 7 cases (15%), negative of both ERCC1 and P27Kip1 was 22 cases (48%). ERCC1 positive and P27Kip1 negative were 7 cases (15%), ERCC1 negative and P27Kip1 positive were 9 cases (20%). Median disease-free survival of the four groups was 6.8,28.1,11.2 and 24.6 months, respectively. There was significant difference between median disease-free survival of patients with both ERCCl and P27Kipl positive or both ERCC1 and P27Kip1 negative or ERCC1 positive P27Kip1 negative (P<0.05). There was no significant difference between ERCC1 negative and P27Kip1 positive (P>0.05).
Conclusions
1 The low expression of ERCC1, P27Kip1 and the high expression of CyclinE were related with the occurrence and development of gastric cancer.
2 The expression of ERCC1, P27Kip1 and CyclinE in gastric cancer was not correlated with sex, age, size, site of tumor and degree of differentiation. The expression of ERCC1, P27Kip1 and CyclinE in gastric cancer was related to depth of invasion, lymph node, distant metastasis, clinical stage.
3 There was significantly negative correlationship between P27Kip1 and CyclinE expression in the development of gastric cancer.
4 The gastric cancer patients receiving platinum-based and fluorouracil chemotherapy, median disease-free survival of patients with ERCC1, P27Kip1 and CyclinE positive was shorter than those with negative expression. They showed that patients with ERCC1, P27Kip1 and CyclinE positive were associated with short survival and poor prognosis.
5 To detect ERCC1, P27Kip1 and CyclinE may predict effect of chemotherapy and evaluate prognosis.
引文
[1]徐飚,王建明.胃癌流行病学研究[J].中华肿瘤防治杂志,2006,13(1)：127-134.
[2]Richard P, Lawrence RC, William JH, et al. Wagman gastric cancer. Cancer management. 5th [J]. NY:CMP media LLC,2004,23(3):259-272.
[3]周鑫, 揭志刚.胃癌个体化治疗[J]. Act an academiae Medicinae Jiangxi,2009,49(4): 132-134.
[4]Liu TS, Wang Y, Chen SY, et al. An updated meta-analysis of adjuvant chemotherapy after curative reaection for gastric cancer [J]. Eur J Surg Oncol,2008,34(11):1208-1216.
[5]Trip sianes K, Folkers G, Ab E, et al. The structure of the human ERCC1/XPF interaction domains reveals a comp lementary role for the two proteins in nucleotide excision repair [J]. Structure,2005,13(12):1849-1858.
[6]Chikako Kiyohara, Kouichi Yoshimasu. Geneticpolymorphisms in the nucleotide excision repair pathway and lung cancer risk:A meta-analysis [J]. Int J Med Sci,2007,4(2):59-71.
[7]周颉,傅健民.ERCC1基因变异与铂类耐药的研究进展[J].广西医学,2009,31(7)：1013-1015.
[8]Takenaka T, Yoshino I, Kouso H, et al. Combined evaluation of Rad51 and ERCC1 expressions for sensitivity to platinum agents in non-small cell lung cancer [J]. Int J Cancer, 2007,121 (4):895-900.
[9]Zhou W, Gurubhagavatula S, Liu G, et al. Excision repair cross complementation group 1 polymorphism predicts overall survival in advanced non small cell lung cancer patients treated with platinum-based chemotherapy [J]. Clin Cancer Res,2004,10(15):4939-4943.
[10]Wei Q, Frazier ML, Levin B. DNA repair:a double-edged sword [J]. J Natl Cancer Inst, 2000,92(6):440-441.
[11]De Clercq A, Inze D. Cyclin-dependent kinase inhibitors in yeast, animals and plants:a functional comparison [J]. Crit Rev Bio-chem Mol Biol,2006,41 (5):293-313.
[12]Vidal A, Koff A. Cell-cycle inhibitors:three families united by a common cause [J]. Gene, 2000,247 (122):1-15.
[13]Cobrinik D. Pocket proteins and cell cycle control [J]. Oncogene,2005,24 (17):2796-2809.
[14]张欣,张志刚.P27基因和蛋白表达的调控及其在肿瘤发生机制中的作用[J].International Journal of Pathology and Clinical Medicine,2009,29(2):170-174.
[15]邵取非,王佩飞,郑聪,等.胃癌中PTEN、cyclinE蛋白表达及临床意义[J]. Clinical Education of General Practice,2008,6(6):478-483.
[16]王梅,刘丽娜,等.P27kip1、cyclinE在胃癌中的表达及其意义[J]. Chinese Clinical Oncology,2006,11(4):294-294.
[17]Ma XM, Liu JH, Guo JW, et al. Correlation of Skp2 expression in gastric carcinoma to expression of P27 and PTEN[J]. Ai Zheng,2006,25(1):56-61.
[18]Sonoda H, Inoue H, Ogawa K, et al. Significance of skp2 expression in primary breast cancer [J]. Clin Cancer Res,2006,12(4):1215-1220.
[19]Shapira M, Ben-Izhak O, Linn S, et al. The prognostic impact of the ubiquitin ligase subunits Skp2 and Cksl in colorectal carcinoma [J]. Cancer,2005,103(7):1336-1346.
[20]Li H, Jiang X, Zhou X. Expression of Skp2 and P27 proteins in laryngeal suqmaous cell careinoma and their significances [J]. Lin Chuang Er Bi Yan Hou Ke Za Zhi,2005,19(9): 409-411.
[21]Schraml P, Bucher C, Bissig H, et al. Cyclin E overexpression and amplification in human tumours[J]. J Pathol,2003,200(3):375-382.
[22]Hunt KK, Keyomarsi K. Cyclin E as a prognostic and predictive marker in breast cancer [J]. Semin Cancer Biol,2005,15(4):319-326.
[23]Moragoda L, Jaszewski R, Majumdar AP. Curcumin induced modulation of cell cycle and apoptosis in gastric and colon cancer cells [J]. Anticancer Res,2001,21(2):873-878.
[24]Wachters FM, Wong LS, Timens W, et al. ERCC1, hRad51 and BRCA1 protein expression in relation to tumor response and survival of stage Ⅲ/ⅣNSCLC patients treated with chemotherapy [J]. Lung Cancer,2005,50 (2):211-219.
[25]Xiangming C, Natsugoe S. The cooperative role of p27 with cyclinE in the prognosis of advanced gastric carcinoma [J]. Cancer,2000,89 (6):1214-1219.
[26]Mari E, Floriani I, Tinazzi A. Efficacy of adjuvant chemotherapy after curative resection for gastric cancer:a meta-analysis of published randomised trials. A study of the GISCAD (Gruppo Italiano per Studio dei Carcinomi dell'Apparato Digerente) [J]. Ann Onto1,2000, 11(7):837-843.
[27]Panzini L, Gianni L, Fattori PP, et al. Adjuvant chemotherapy in gastric cancer:a meta-analysis of randomized trials and a comparison witll previous meta-analyses [J]. Tumori,2002,88(1):21-27.
[28]Dank M, Zaluski J, Barone C, et al. Randomized phase 3 trial of irinotecan (CPT-11)+ 5FU/folinc acid(FA) vs CDDP+5FU in 1st-line advanced gastric cancer patients[J]. Proc Am Soc CLIN Oncol,2005,23(16):4003.
[29]Reed E, Dabholkar M, Thornton K, et al. Evidence for order in the appearance of mRNAs of nucleotide excision repair genes, in human ovarian cancer tissues [J]. Oncol Rep,2000,7(11): 1123-1128.
[30]Bernstein C, Bernstein H, Payne CM, et al. DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways:fail-safe protection against carcinogenesis [J]. Mutat Res, 2002,511(2):145-178.
[31]周彩存,徐妍,苏春霞,等.ERCC1在非小细胞肺癌中表达及其临床意义[J].中国癌症杂志,2006,16(8)：622-625.
[32]张萌,刘巍,等.ERCC1基因在食管癌中的研究进展[J].中国肿瘤杂志,2009,18(3)：218-221.
[33]Konstantinos Tripsianes, Gert E, Folkers, et al. Analysis of the XPA and ssDNA-binding surfaces on the central domain of human ERCC1 reveals evidence for sub functionalization [J]. Nucleic Acids Research,2007,35(17):5789-5798.
[34]Zhou W, Liu G, Park S, et al. Gene-smoking interaction associations for the ERCC1 polymorphisms in the risk of lung cancer [J]. Cancer Epidermal Biomarkers Prev,2005,1(2): 491-496.
[35]林莉,刘晓晴.DNA损伤修复与铂类耐药研究进展[J].中国肿瘤,2006,15(2)：29-31.
[36]Siddik ZH. Cisplatin:mode of cytotoxic action and molecular basis of resistance [J]. Oncogene,2003,22(47):7265-7279.
[37]Arriagada R, Bergman B, Dunant A, et al. Vansteenkiste J. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer [J]. New Engl J Med,2004,350(4):351-360.
[38]Olanssen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy [J]. New Engl J Med,2006,355(10): 983-991.
[39]Kwon HC, Roh M, Oh S, et al. Prognostic value of expression of ERCC1, thymidylate synthase, and glutathione S-transferase P1 for 5-fluorouracil/oxaliptin chemotherapy in advanced gastric cancer [J]. Ann Oncol,2007,18(3):504-509.
[40]Lord RV, Brabender J, Gandara D, et al. Low ERCC1 expression correlates with rolonged survival aftere cisplatin plus gemeitabine chemotherapy in non small cell lung cancer [J]. Clin Cancer Res,2002,8(7):2286-2291.
[41]逯晓波,王雪莲,李晓霞,等.实时定量PCR测定大肠癌细胞系中ERCC1mRNA水平及草酸铂药物抵抗的关联性分析[J].沈阳药科大学学报,2008,25(5)：404-405.
[42]Liu GY, Qu QX, Mi RR, et al. Relationship between nucleotide excision repair gene ERCC1 and resistance to cisplatin in ovarian cancer [J]. Zhonghua Zhong Liu Za Zhi,2008,30(3): 184-187.
[43]Bellmunt J, Paz-ares L, Cuello M, et al. Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy [J]. Ann Oncol,2007,18 (3):522-528.
[44]Sun Kyung Baek, Si-Young Kim, Jae Jin Lee, et al. Inereased ERCC1 expression correlates with improved outcome of patients with cisplatin as an adjuvant therapy for curatively resected gastric cancer [J]. Cancer Res Treat,2006,38(1):19-24.
[45]Polyak K, Kato JY, Solomon MJ, et al. P27kip1, a cyclin-Cdk inhibitor, inks transforming growth factor-bata and contact inhibition to cell cycle arrest[J]. Genes Dev,1994,8(1):9-22.
[46]Caldon CE, Daly RJ, Sutherland RL, et al. Cell cycle control in breast cancer cells [J]. Cell Biochem,2006,97 (2):261-274.
[47]Assoian RK. Stopping and going with p27kipl [J]. Dev Cell,2004,6(4):458-459.
[48]Vemon AE, Devine C, Philpott A, et al. The cdk inhibitor p27kip1 is required for differentiation of primary neurones in Xenopus [J]. Development,2003,130(1):85-92.
[49]Ohtani M, Isoiak i H, Fujii K, et al. Impact of the apoptosis in tumor cell the overall survival of patients with non-early stage gastric carcinoma [J]. Cancer,1999,85(8):1711-1718.
[50]Mcallister SS, Becker-hapak M, Pintucci G, et al. Novel P27kipl terminal scatter domain mediates Rac-dependent cell migration independent of cell cyclin arrest functions [J]. Mol cell Biol,2003,23(1):216-221.
[51]Nitti D, Belluco C, Mammano E, et al. Low level of p27 (kip1) protein expression in gastric adenocarcinoma is associated with disease progression and poor outcome [J]. J Surg Oncol, 2002,81(4):175-176.
[52]Li JQ, Miki H, Wu F, et al. CyclinA correlates with carcinogenesis and metastasis, and p27 (kipl) correlates with lymphatic invasion, in colorectal neoplasms [J]. Hum Pathol,2002, 33(10):1006-1015.
[53]Auld CA, Fenandes KM, Morrison RF, et al. Skp2-mediated p27 (Kip1) degradation during S/G2 phase p rogression of a dipocyte hyperp lasia [J]. J Cell Physiol,2007,211 (1): 101-111.
[54]Wu FY, Wang SE, SandersME, et al. Reduction of cytosolic p27 (Kipl) inhibits cancer cell motility, survival, and tumorigenicity [J]. Cancer Res,2006,66 (4):2162-2172.
[55]Porter PL, Barlow WE, Yeh IT, et al. p27 Kipl and cyclin E expression and breast cancer survival after treatment with adjuvant chemotherapy[J]. J Nat Cancer Inst,2006,98 (23): 1723-1731.
[56]Doganavsargil B, Simsir A, Boyacioglu H, et al. a comparison of p21 and p27 immunoexpression in benign glands, prostatic intraepithelial neop lasia and prostate adenocarcinoma[J]. BJU Intern,2006,97 (3):644-648.
[57]Kim JY, Lim SJ, Kim HJ, et al. Clinical Significance of p27 and Skp2 Protein Expression in Uterine CervicalNeop lasm[J]. Intern J Gynecol Pathol,2007,26 (3):242-247.
[58]Nowee ME, Dorsman JC, Piek JMJ, et al. HER-2/neu and p27Kip1 in progression of Fallopian tube carcinoma:an immunohis-tochemical and array comparativegenomic hybridization study [J]. Histopathology,2007,51 (5):666-673.
[59]Galizia G, Lieto E, Ferraraccio F, et al. Determination of molecular marker expression can predict clinical outcome in colon carcinomas [J]. Clin Cancer Res,2004,10(10):3490-3499.
[60]Tchernev G, Orfanos CE. Downregulation of cell cycle modulators p21, p27, p53, Rb and proapoptotic Bcl2-related proteins Bax and Bak in cutaneous melanoma is associated with worse patient prognosis:preliminary findings [J]. J Cutan Pathol,2007,34 (3):247-256.
[61]Rabbani F, Kopp ie TM, Charytonowicz E, et al. Prognostic significance of p27Kip1 expression in bladder cancer [J]. BJU Intern,2007,100 (2):259-263.
[62]Galizia G, Ferraraccio F, Lieto E, et al. p27 Downregulation and metallothionein overexpression in gastric cancer patients are associated with a poor survival rate [J]. J Surg Oncol,2006,93 (3):241-252.
[63]Shin JY, Kim HS, Park J, et al. Mechanism for inactivation of the KIP family cyclin-dependent kinase inbitior genes in gastric cancer cell[J] C. ancer Res,2000,60(2): 262-265.
[64]Jan-Patrik, Wiksten, Johan Lundi, et al. The prognostic value of p27 in gastric cancer [J]. Oncology,2002,63(2):180-184.
[65]李志琴,章静波.细胞周期调控与肿瘤[J].癌症进展杂志,2004,2(1)：70-75.
[66]Murray AW, Mark D. Can sequencing shed light on cell cycling [J]. Nature,2001,294 (5540):173-177.
[67]石玉宝,李勇,范立侨,等.CyclinE和P27kipl蛋白表达与胃癌临床生物学行为关系的研究[J].中国现代医学杂志,2009,19(20)：3087-3090.
[68]Mussman JG, Horn HF, Carroll DE, et al. Synergistic induction of centrosome hyperamplification by loss of p53 and cyclinE overexpression [J]. Oncogene,2000,19(13): 1635-1646.
[69]丁俊,李可为,王坚,等.P27、CyclinD、CyclinE在原发性胆囊癌中的表达及临床意义[J].肝胆胰外科杂志,2009,21(3)：191-195.
[70]郭静,唐仁泉.CyclinE和p27在乳腺癌中的表达及临床意义[J].当代医学,2009,15(7)：130-131.
[1]Jemal A, Siegel R, Ward E, et al. Cancer statistics, CA Cancer [J]. Clin 2008,58(2):71-96.
[2]D'Angelica M, Gonen M, Brennan MF, et al. Patterns of initial recurrence in completely resected gastric adenocarcinoma. Ann Surg 2004,240(5):808-816.
[3]Janunger KG, Hafstrom L, Glimelius B. Chemotherapy in gastric cancer. a review and updated meta-analysis. Eur J Surg 2002,168(11):597-608.
[4]Wilson MD, Ruttan CC, Koop BF, et al. ERCC1:a comparative genomic perspective. Environ Mol Mutagen,2001,38(2-3):209-215.
[5]Konstantinos Tripsianes, Gert E, Folkers, et al. Analysis of the XPA and cDNA-binding surfaces on the central domain of human ERCC1 reveals evidence for subfunctionalization [J]. Nucleic Acids Research,2007,35(17):5789-5798.
[6]Jaspers NG, Raams A, Silengo MC, et al. First reported patient with human ERCC1 deficiency has cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure [J]. Am. J. Hum. Genet,2007,80(2): 457-466.
[7]Chikako Kiyohara, Kouichi Yoshimasu. Genetic polymorphisms in the nucleotide excision repair pathway and lung cancer risk:A meta-analysis [J]. Int J Med Sci,2007,4(2):59-71.
[8]Zhou W, Liu G, Park S, et al. Gene-smoking interaction associations for the ERCC1 polymorphisms in the risk of lung cancer [J]. Cancer Epidermal Biomarkers Prev,2005,1(2): 491-496.
[9]Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer [J]. N Engl J Med,2004,350(4): 351-360.
[10]龚玮华,丁红华,王理伟等.切除修复交叉互补基因1的研究进展[J]. World Health Digest,2008,5(5):305-308.
[11]Ahaha R, Liang X, YU J J, et al. Excision repair cross comp lamenting-group 1:gene expression and platinum resistance [J]. Int J MolMed,2004,14 (6):959-970.
[12]林莉,刘晓晴.DNA损伤修复与铂类耐药研究进展[J].中国肿瘤,2006,15(1)：29-31.
[13]Siddik ZH. Cisplatin:mode of cytotoxic action and molecular basis of resistance [J]. Oncogene,2003,22(47):7265-7279.
[14]Olaussen KA, Mountzios G, Soria JC, et al. ERCC1 as a risk stratifier in platinum-based chemotherapy for non-small-cell lung cancer [J]. CurrOp in Pulm Med,2007,13 (4): 284-289.
[15]Kwon HC, Roh M, Oh S, et al. Prognostic value of expression of ERCC1, thymidylate synthase, and glutathione S-transferase P1 for 5-Fu/Oxaliplatin chemotherapy in advanced gastric cancer [J]. Ann oncol,2007,18(3):504-509.
[16]Olaussen KA, Dunant A. DNA repair by ERCC1 in NSCLC and cisplatin-based adjuvant chemotherapy [J]. N Eng J MED,2006,335(10):983-991.
[17]Park DJ, Lenz HJ. Determination of chemosensitivity in gastric cancer [J]. Curr Opin Pharmacol,2006,6(4):337-344.
[18]刘晓芳.顺铂对ERCCI在293细胞中表达的影响[J].中国公共卫生,2003,19(4)：441-442.
[19]Fujii.t. ERCC1 protein expression predicts the response of cisplatin-based neoadjuvant chemotherapy in non-small-cell lung cancer [J]. Lung cancer,2008,59(3):377-384.
[20]International adjuvant lung cancer trial collaborative group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer [J]. N Eng I J Med,2004,350(4):351-360.
[21]Pare L, Marcuello E, Altes A, et al. Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving oxaliplatin/5-fluorouracil as first-line chemotherapy [J]. Br J Cancer,2008,99(7):1050.
[22]Bellmunt J, Paz-ares L, Cuello M, et al. Gene expression of ERCC1 as a novel p rognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy [J]. Ann Oncol,2007,18 (3):522-528.
[23]唐琳,梁军,李玉军.上皮性卵巢癌ERCC1表达与顺铂化疗耐药的关系[J].齐鲁医学杂志,2009,24(5)：388-390.
[24]刘静,瞿全新.RNA干扰ERCC1基因表达对卵巢癌细胞耐药的影响[J].河北医学,2006,12(9)：893-895.
[25]Polyak K, KatoJY, Solomon MJ, et al. P27, a cyclin-CDK Inhibitor links transforming growth factor beta Ond contact Inhibitor to cell cycle arrest [J]. GenesDev,1994,8(1):9-10.
[26]Vemon AE, Devine C, Philpott A. The cdk inhibitor p27Xicl is required for differentiation of primary neurones in Xenopus [J]. Development,2003,130(1):85-92.
[27]KatnerAL, Gootam P, Hoang QB, et al. A recombinant adenovirus expressing p27kip1 induces cell cycle arrest and apoptosis in human renal carcinoma cell [J]. JUrol,2002,168(2): 766-769.
[28]殷敏智,张忠德.肾盂输尿管癌中p27及Ki-67表达的临床意义[J].重庆医学,2003,32(1)：1726-1728.
[29]Fujieda S, Inuzuka M, Tanaka N, et al. Expression of p27 is associated with Bax expression and spontaneous apoptosis in oral an doropharyngeal carcinoma [J]. IntJ Cancer,1999,84(3): 315-318.
[30]张欣,张志刚.p27基因和蛋白表达的调控及其在肿瘤发生机制中的作用[J]. International Journal of Pathology and Clinical Medicine,2009,29(2):170-174.
[31]Nitti D, Belluco C, Mammano E, et al. Low level of p27 porotein expression in gastric adenlocarcinomais associated with disease progression and poor outcome [J]. Sting Oncol, 2002,81(4):167-175.
[32]Gelen MT, Elpek GO, Aksoy NH, et al. P27 expression and pro liferation in gastrointestinal tromaltumors[J]. Turk-J-Gastro-entero,2003,14(2):132-137.
[33]Langner C, Von WR, Ratschek M, et al. Biological significance of P27kip1 and Skp2 expression in renal cell carcinpma.A systrmatic analysis of primary and metastatic tumor tissues using a tissue microarray technique[J]. Virchows Arch,2004, 445(6):631-636.
[34]Lebe B, Saroglu S, Soken S, et al. The clinical significance of p53, p21 and p27 expressions in rectal carcinoma [J]. Appl Immunohistochem MolMorphol,2005,13 (1):38-44.
[35]阎庆辉,任鹏涛,王凤安,等.大肠癌中p21,p27及c-Met的表达[J].中华实验外科杂志,2005,22(9)：1030.
[36]Koff Cross F, Fisher A, Schumacher J, et al. Roberts JM. Human cyclinE, a new cyclin that interacts with two members of the CDC2 gene family [J]. cpff,1991,66(6):1217-1228.
[37]Nakayama K, Nagahama H, Minamishima YA, et al. arrgeted disrup-tion of SKP2 results in accumulation of cyclin E and p27(kipl), polyploidy and centrosome overduplication[J]. EMBO J,2000,19(9):2069-2081.
[38]Hinchcliffe EH, Lj C, Thompson EA, et al. Requirement of CDK2/cyclinE activity for repeated centrosome reproduction in xenoPus egg extracts [J]. Science,1999,283(5043): 851-854.
[39]MussmanJ G, Horn HF, Carroll DE, et al. Synergistic indoction of centrosome hyPeramPlification by loss of p53 and cyclinE overexpression[J]. Oncogene,2000,19 (13): 1635-1646.
[40]周彦明,李玉民,朱有全,等.Cyclin E和P27蛋白在胆囊癌组织中的表达及其意义[J].中国普外基础与临床杂志,2004,11(2)：148-150.
[41]Oya M, Yao T, TsuneyoshiM. Expressions of cell-cycl regul atory gene products in conventional gastric adenomas:possible immunohistochemical markers of malignant transformation [J]. Hum Pathol,2000,31 (3):279-287.
[42]丁俊,李可为,王坚,等.P27、CyclinD、CyclinE在原发性胆囊癌中的表达及临床意义[J].肝胆胰外科杂志,2009,21(3)：191-195.
[43]Lindahl T. Over expression of cyclinE protein is associated with specific mutation types in p53 gene and poor survival in human breast cancer [J]. Car-cinogenesis,2004,25 (3):375.
[44]Takano Y, Kato Y, van Diest P J, et al. CyclinD2 overexpression and lack of p27 correlate positively and cyclinE inverse1y with a poor prognosis in gastric cancer cases [J]. AmJ Pathol,2000,156 (2):585-594.
[45]Yasui W, Kudo Y. Reduced expression of cyclin-dependent kinase inhibitor p27kipl is associated with advanced stage and invasiveness of gastric carcinomas [J]. Jpnj Cancer Res, 1997,88(6):625-629.
[46]刘勇,路名芝.细胞周期调控因子p27, cyclinE和Ki-67在早期胃癌中的表达[J].九江医学,2002,17(2)：233-235.
[47]陈清波,常青,夏和顺.CyclinE、p27蛋白表达及Hp感染与胃癌发生关系的研究[J].中华实用医学,2005,4(5)：222-225.
[2]Richard P, Lawrence RC, William JH, et al. Wagman gastric cancer. Cancer management. 5th [J]. NY:CMP media LLC,2004,23(3):259-272.
[3]周鑫, 揭志刚.胃癌个体化治疗[J]. Act an academiae Medicinae Jiangxi,2009,49(4): 132-134.
[4]Liu TS, Wang Y, Chen SY, et al. An updated meta-analysis of adjuvant chemotherapy after curative reaection for gastric cancer [J]. Eur J Surg Oncol,2008,34(11):1208-1216.
[5]Trip sianes K, Folkers G, Ab E, et al. The structure of the human ERCC1/XPF interaction domains reveals a comp lementary role for the two proteins in nucleotide excision repair [J]. Structure,2005,13(12):1849-1858.
[6]Chikako Kiyohara, Kouichi Yoshimasu. Geneticpolymorphisms in the nucleotide excision repair pathway and lung cancer risk:A meta-analysis [J]. Int J Med Sci,2007,4(2):59-71.
[7]周颉,傅健民.ERCC1基因变异与铂类耐药的研究进展[J].广西医学,2009,31(7)：1013-1015.
[8]Takenaka T, Yoshino I, Kouso H, et al. Combined evaluation of Rad51 and ERCC1 expressions for sensitivity to platinum agents in non-small cell lung cancer [J]. Int J Cancer, 2007,121 (4):895-900.
[9]Zhou W, Gurubhagavatula S, Liu G, et al. Excision repair cross complementation group 1 polymorphism predicts overall survival in advanced non small cell lung cancer patients treated with platinum-based chemotherapy [J]. Clin Cancer Res,2004,10(15):4939-4943.
[10]Wei Q, Frazier ML, Levin B. DNA repair:a double-edged sword [J]. J Natl Cancer Inst, 2000,92(6):440-441.
[11]De Clercq A, Inze D. Cyclin-dependent kinase inhibitors in yeast, animals and plants:a functional comparison [J]. Crit Rev Bio-chem Mol Biol,2006,41 (5):293-313.
[12]Vidal A, Koff A. Cell-cycle inhibitors:three families united by a common cause [J]. Gene, 2000,247 (122):1-15.
[13]Cobrinik D. Pocket proteins and cell cycle control [J]. Oncogene,2005,24 (17):2796-2809.
[14]张欣,张志刚.P27基因和蛋白表达的调控及其在肿瘤发生机制中的作用[J].International Journal of Pathology and Clinical Medicine,2009,29(2):170-174.
[15]邵取非,王佩飞,郑聪,等.胃癌中PTEN、cyclinE蛋白表达及临床意义[J]. Clinical Education of General Practice,2008,6(6):478-483.
[16]王梅,刘丽娜,等.P27kip1、cyclinE在胃癌中的表达及其意义[J]. Chinese Clinical Oncology,2006,11(4):294-294.
[17]Ma XM, Liu JH, Guo JW, et al. Correlation of Skp2 expression in gastric carcinoma to expression of P27 and PTEN[J]. Ai Zheng,2006,25(1):56-61.
[18]Sonoda H, Inoue H, Ogawa K, et al. Significance of skp2 expression in primary breast cancer [J]. Clin Cancer Res,2006,12(4):1215-1220.
[19]Shapira M, Ben-Izhak O, Linn S, et al. The prognostic impact of the ubiquitin ligase subunits Skp2 and Cksl in colorectal carcinoma [J]. Cancer,2005,103(7):1336-1346.
[20]Li H, Jiang X, Zhou X. Expression of Skp2 and P27 proteins in laryngeal suqmaous cell careinoma and their significances [J]. Lin Chuang Er Bi Yan Hou Ke Za Zhi,2005,19(9): 409-411.
[21]Schraml P, Bucher C, Bissig H, et al. Cyclin E overexpression and amplification in human tumours[J]. J Pathol,2003,200(3):375-382.
[22]Hunt KK, Keyomarsi K. Cyclin E as a prognostic and predictive marker in breast cancer [J]. Semin Cancer Biol,2005,15(4):319-326.
[23]Moragoda L, Jaszewski R, Majumdar AP. Curcumin induced modulation of cell cycle and apoptosis in gastric and colon cancer cells [J]. Anticancer Res,2001,21(2):873-878.
[24]Wachters FM, Wong LS, Timens W, et al. ERCC1, hRad51 and BRCA1 protein expression in relation to tumor response and survival of stage Ⅲ/ⅣNSCLC patients treated with chemotherapy [J]. Lung Cancer,2005,50 (2):211-219.
[25]Xiangming C, Natsugoe S. The cooperative role of p27 with cyclinE in the prognosis of advanced gastric carcinoma [J]. Cancer,2000,89 (6):1214-1219.
[26]Mari E, Floriani I, Tinazzi A. Efficacy of adjuvant chemotherapy after curative resection for gastric cancer:a meta-analysis of published randomised trials. A study of the GISCAD (Gruppo Italiano per Studio dei Carcinomi dell'Apparato Digerente) [J]. Ann Onto1,2000, 11(7):837-843.
[27]Panzini L, Gianni L, Fattori PP, et al. Adjuvant chemotherapy in gastric cancer:a meta-analysis of randomized trials and a comparison witll previous meta-analyses [J]. Tumori,2002,88(1):21-27.
[28]Dank M, Zaluski J, Barone C, et al. Randomized phase 3 trial of irinotecan (CPT-11)+ 5FU/folinc acid(FA) vs CDDP+5FU in 1st-line advanced gastric cancer patients[J]. Proc Am Soc CLIN Oncol,2005,23(16):4003.
[29]Reed E, Dabholkar M, Thornton K, et al. Evidence for order in the appearance of mRNAs of nucleotide excision repair genes, in human ovarian cancer tissues [J]. Oncol Rep,2000,7(11): 1123-1128.
[30]Bernstein C, Bernstein H, Payne CM, et al. DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways:fail-safe protection against carcinogenesis [J]. Mutat Res, 2002,511(2):145-178.
[31]周彩存,徐妍,苏春霞,等.ERCC1在非小细胞肺癌中表达及其临床意义[J].中国癌症杂志,2006,16(8)：622-625.
[32]张萌,刘巍,等.ERCC1基因在食管癌中的研究进展[J].中国肿瘤杂志,2009,18(3)：218-221.
[33]Konstantinos Tripsianes, Gert E, Folkers, et al. Analysis of the XPA and ssDNA-binding surfaces on the central domain of human ERCC1 reveals evidence for sub functionalization [J]. Nucleic Acids Research,2007,35(17):5789-5798.
[34]Zhou W, Liu G, Park S, et al. Gene-smoking interaction associations for the ERCC1 polymorphisms in the risk of lung cancer [J]. Cancer Epidermal Biomarkers Prev,2005,1(2): 491-496.
[35]林莉,刘晓晴.DNA损伤修复与铂类耐药研究进展[J].中国肿瘤,2006,15(2)：29-31.
[36]Siddik ZH. Cisplatin:mode of cytotoxic action and molecular basis of resistance [J]. Oncogene,2003,22(47):7265-7279.
[37]Arriagada R, Bergman B, Dunant A, et al. Vansteenkiste J. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer [J]. New Engl J Med,2004,350(4):351-360.
[38]Olanssen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy [J]. New Engl J Med,2006,355(10): 983-991.
[39]Kwon HC, Roh M, Oh S, et al. Prognostic value of expression of ERCC1, thymidylate synthase, and glutathione S-transferase P1 for 5-fluorouracil/oxaliptin chemotherapy in advanced gastric cancer [J]. Ann Oncol,2007,18(3):504-509.
[40]Lord RV, Brabender J, Gandara D, et al. Low ERCC1 expression correlates with rolonged survival aftere cisplatin plus gemeitabine chemotherapy in non small cell lung cancer [J]. Clin Cancer Res,2002,8(7):2286-2291.
[41]逯晓波,王雪莲,李晓霞,等.实时定量PCR测定大肠癌细胞系中ERCC1mRNA水平及草酸铂药物抵抗的关联性分析[J].沈阳药科大学学报,2008,25(5)：404-405.
[42]Liu GY, Qu QX, Mi RR, et al. Relationship between nucleotide excision repair gene ERCC1 and resistance to cisplatin in ovarian cancer [J]. Zhonghua Zhong Liu Za Zhi,2008,30(3): 184-187.
[43]Bellmunt J, Paz-ares L, Cuello M, et al. Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy [J]. Ann Oncol,2007,18 (3):522-528.
[44]Sun Kyung Baek, Si-Young Kim, Jae Jin Lee, et al. Inereased ERCC1 expression correlates with improved outcome of patients with cisplatin as an adjuvant therapy for curatively resected gastric cancer [J]. Cancer Res Treat,2006,38(1):19-24.
[45]Polyak K, Kato JY, Solomon MJ, et al. P27kip1, a cyclin-Cdk inhibitor, inks transforming growth factor-bata and contact inhibition to cell cycle arrest[J]. Genes Dev,1994,8(1):9-22.
[46]Caldon CE, Daly RJ, Sutherland RL, et al. Cell cycle control in breast cancer cells [J]. Cell Biochem,2006,97 (2):261-274.
[47]Assoian RK. Stopping and going with p27kipl [J]. Dev Cell,2004,6(4):458-459.
[48]Vemon AE, Devine C, Philpott A, et al. The cdk inhibitor p27kip1 is required for differentiation of primary neurones in Xenopus [J]. Development,2003,130(1):85-92.
[49]Ohtani M, Isoiak i H, Fujii K, et al. Impact of the apoptosis in tumor cell the overall survival of patients with non-early stage gastric carcinoma [J]. Cancer,1999,85(8):1711-1718.
[50]Mcallister SS, Becker-hapak M, Pintucci G, et al. Novel P27kipl terminal scatter domain mediates Rac-dependent cell migration independent of cell cyclin arrest functions [J]. Mol cell Biol,2003,23(1):216-221.
[51]Nitti D, Belluco C, Mammano E, et al. Low level of p27 (kip1) protein expression in gastric adenocarcinoma is associated with disease progression and poor outcome [J]. J Surg Oncol, 2002,81(4):175-176.
[52]Li JQ, Miki H, Wu F, et al. CyclinA correlates with carcinogenesis and metastasis, and p27 (kipl) correlates with lymphatic invasion, in colorectal neoplasms [J]. Hum Pathol,2002, 33(10):1006-1015.
[53]Auld CA, Fenandes KM, Morrison RF, et al. Skp2-mediated p27 (Kip1) degradation during S/G2 phase p rogression of a dipocyte hyperp lasia [J]. J Cell Physiol,2007,211 (1): 101-111.
[54]Wu FY, Wang SE, SandersME, et al. Reduction of cytosolic p27 (Kipl) inhibits cancer cell motility, survival, and tumorigenicity [J]. Cancer Res,2006,66 (4):2162-2172.
[55]Porter PL, Barlow WE, Yeh IT, et al. p27 Kipl and cyclin E expression and breast cancer survival after treatment with adjuvant chemotherapy[J]. J Nat Cancer Inst,2006,98 (23): 1723-1731.
[56]Doganavsargil B, Simsir A, Boyacioglu H, et al. a comparison of p21 and p27 immunoexpression in benign glands, prostatic intraepithelial neop lasia and prostate adenocarcinoma[J]. BJU Intern,2006,97 (3):644-648.
[57]Kim JY, Lim SJ, Kim HJ, et al. Clinical Significance of p27 and Skp2 Protein Expression in Uterine CervicalNeop lasm[J]. Intern J Gynecol Pathol,2007,26 (3):242-247.
[58]Nowee ME, Dorsman JC, Piek JMJ, et al. HER-2/neu and p27Kip1 in progression of Fallopian tube carcinoma:an immunohis-tochemical and array comparativegenomic hybridization study [J]. Histopathology,2007,51 (5):666-673.
[59]Galizia G, Lieto E, Ferraraccio F, et al. Determination of molecular marker expression can predict clinical outcome in colon carcinomas [J]. Clin Cancer Res,2004,10(10):3490-3499.
[60]Tchernev G, Orfanos CE. Downregulation of cell cycle modulators p21, p27, p53, Rb and proapoptotic Bcl2-related proteins Bax and Bak in cutaneous melanoma is associated with worse patient prognosis:preliminary findings [J]. J Cutan Pathol,2007,34 (3):247-256.
[61]Rabbani F, Kopp ie TM, Charytonowicz E, et al. Prognostic significance of p27Kip1 expression in bladder cancer [J]. BJU Intern,2007,100 (2):259-263.
[62]Galizia G, Ferraraccio F, Lieto E, et al. p27 Downregulation and metallothionein overexpression in gastric cancer patients are associated with a poor survival rate [J]. J Surg Oncol,2006,93 (3):241-252.
[63]Shin JY, Kim HS, Park J, et al. Mechanism for inactivation of the KIP family cyclin-dependent kinase inbitior genes in gastric cancer cell[J] C. ancer Res,2000,60(2): 262-265.
[64]Jan-Patrik, Wiksten, Johan Lundi, et al. The prognostic value of p27 in gastric cancer [J]. Oncology,2002,63(2):180-184.
[65]李志琴,章静波.细胞周期调控与肿瘤[J].癌症进展杂志,2004,2(1)：70-75.
[66]Murray AW, Mark D. Can sequencing shed light on cell cycling [J]. Nature,2001,294 (5540):173-177.
[67]石玉宝,李勇,范立侨,等.CyclinE和P27kipl蛋白表达与胃癌临床生物学行为关系的研究[J].中国现代医学杂志,2009,19(20)：3087-3090.
[68]Mussman JG, Horn HF, Carroll DE, et al. Synergistic induction of centrosome hyperamplification by loss of p53 and cyclinE overexpression [J]. Oncogene,2000,19(13): 1635-1646.
[69]丁俊,李可为,王坚,等.P27、CyclinD、CyclinE在原发性胆囊癌中的表达及临床意义[J].肝胆胰外科杂志,2009,21(3)：191-195.
[70]郭静,唐仁泉.CyclinE和p27在乳腺癌中的表达及临床意义[J].当代医学,2009,15(7)：130-131.
[1]Jemal A, Siegel R, Ward E, et al. Cancer statistics, CA Cancer [J]. Clin 2008,58(2):71-96.
[2]D'Angelica M, Gonen M, Brennan MF, et al. Patterns of initial recurrence in completely resected gastric adenocarcinoma. Ann Surg 2004,240(5):808-816.
[3]Janunger KG, Hafstrom L, Glimelius B. Chemotherapy in gastric cancer. a review and updated meta-analysis. Eur J Surg 2002,168(11):597-608.
[4]Wilson MD, Ruttan CC, Koop BF, et al. ERCC1:a comparative genomic perspective. Environ Mol Mutagen,2001,38(2-3):209-215.
[5]Konstantinos Tripsianes, Gert E, Folkers, et al. Analysis of the XPA and cDNA-binding surfaces on the central domain of human ERCC1 reveals evidence for subfunctionalization [J]. Nucleic Acids Research,2007,35(17):5789-5798.
[6]Jaspers NG, Raams A, Silengo MC, et al. First reported patient with human ERCC1 deficiency has cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure [J]. Am. J. Hum. Genet,2007,80(2): 457-466.
[7]Chikako Kiyohara, Kouichi Yoshimasu. Genetic polymorphisms in the nucleotide excision repair pathway and lung cancer risk:A meta-analysis [J]. Int J Med Sci,2007,4(2):59-71.
[8]Zhou W, Liu G, Park S, et al. Gene-smoking interaction associations for the ERCC1 polymorphisms in the risk of lung cancer [J]. Cancer Epidermal Biomarkers Prev,2005,1(2): 491-496.
[9]Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer [J]. N Engl J Med,2004,350(4): 351-360.
[10]龚玮华,丁红华,王理伟等.切除修复交叉互补基因1的研究进展[J]. World Health Digest,2008,5(5):305-308.
[11]Ahaha R, Liang X, YU J J, et al. Excision repair cross comp lamenting-group 1:gene expression and platinum resistance [J]. Int J MolMed,2004,14 (6):959-970.
[12]林莉,刘晓晴.DNA损伤修复与铂类耐药研究进展[J].中国肿瘤,2006,15(1)：29-31.
[13]Siddik ZH. Cisplatin:mode of cytotoxic action and molecular basis of resistance [J]. Oncogene,2003,22(47):7265-7279.
[14]Olaussen KA, Mountzios G, Soria JC, et al. ERCC1 as a risk stratifier in platinum-based chemotherapy for non-small-cell lung cancer [J]. CurrOp in Pulm Med,2007,13 (4): 284-289.
[15]Kwon HC, Roh M, Oh S, et al. Prognostic value of expression of ERCC1, thymidylate synthase, and glutathione S-transferase P1 for 5-Fu/Oxaliplatin chemotherapy in advanced gastric cancer [J]. Ann oncol,2007,18(3):504-509.
[16]Olaussen KA, Dunant A. DNA repair by ERCC1 in NSCLC and cisplatin-based adjuvant chemotherapy [J]. N Eng J MED,2006,335(10):983-991.
[17]Park DJ, Lenz HJ. Determination of chemosensitivity in gastric cancer [J]. Curr Opin Pharmacol,2006,6(4):337-344.
[18]刘晓芳.顺铂对ERCCI在293细胞中表达的影响[J].中国公共卫生,2003,19(4)：441-442.
[19]Fujii.t. ERCC1 protein expression predicts the response of cisplatin-based neoadjuvant chemotherapy in non-small-cell lung cancer [J]. Lung cancer,2008,59(3):377-384.
[20]International adjuvant lung cancer trial collaborative group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer [J]. N Eng I J Med,2004,350(4):351-360.
[21]Pare L, Marcuello E, Altes A, et al. Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving oxaliplatin/5-fluorouracil as first-line chemotherapy [J]. Br J Cancer,2008,99(7):1050.
[22]Bellmunt J, Paz-ares L, Cuello M, et al. Gene expression of ERCC1 as a novel p rognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy [J]. Ann Oncol,2007,18 (3):522-528.
[23]唐琳,梁军,李玉军.上皮性卵巢癌ERCC1表达与顺铂化疗耐药的关系[J].齐鲁医学杂志,2009,24(5)：388-390.
[24]刘静,瞿全新.RNA干扰ERCC1基因表达对卵巢癌细胞耐药的影响[J].河北医学,2006,12(9)：893-895.
[25]Polyak K, KatoJY, Solomon MJ, et al. P27, a cyclin-CDK Inhibitor links transforming growth factor beta Ond contact Inhibitor to cell cycle arrest [J]. GenesDev,1994,8(1):9-10.
[26]Vemon AE, Devine C, Philpott A. The cdk inhibitor p27Xicl is required for differentiation of primary neurones in Xenopus [J]. Development,2003,130(1):85-92.
[27]KatnerAL, Gootam P, Hoang QB, et al. A recombinant adenovirus expressing p27kip1 induces cell cycle arrest and apoptosis in human renal carcinoma cell [J]. JUrol,2002,168(2): 766-769.
[28]殷敏智,张忠德.肾盂输尿管癌中p27及Ki-67表达的临床意义[J].重庆医学,2003,32(1)：1726-1728.
[29]Fujieda S, Inuzuka M, Tanaka N, et al. Expression of p27 is associated with Bax expression and spontaneous apoptosis in oral an doropharyngeal carcinoma [J]. IntJ Cancer,1999,84(3): 315-318.
[30]张欣,张志刚.p27基因和蛋白表达的调控及其在肿瘤发生机制中的作用[J]. International Journal of Pathology and Clinical Medicine,2009,29(2):170-174.
[31]Nitti D, Belluco C, Mammano E, et al. Low level of p27 porotein expression in gastric adenlocarcinomais associated with disease progression and poor outcome [J]. Sting Oncol, 2002,81(4):167-175.
[32]Gelen MT, Elpek GO, Aksoy NH, et al. P27 expression and pro liferation in gastrointestinal tromaltumors[J]. Turk-J-Gastro-entero,2003,14(2):132-137.
[33]Langner C, Von WR, Ratschek M, et al. Biological significance of P27kip1 and Skp2 expression in renal cell carcinpma.A systrmatic analysis of primary and metastatic tumor tissues using a tissue microarray technique[J]. Virchows Arch,2004, 445(6):631-636.
[34]Lebe B, Saroglu S, Soken S, et al. The clinical significance of p53, p21 and p27 expressions in rectal carcinoma [J]. Appl Immunohistochem MolMorphol,2005,13 (1):38-44.
[35]阎庆辉,任鹏涛,王凤安,等.大肠癌中p21,p27及c-Met的表达[J].中华实验外科杂志,2005,22(9)：1030.
[36]Koff Cross F, Fisher A, Schumacher J, et al. Roberts JM. Human cyclinE, a new cyclin that interacts with two members of the CDC2 gene family [J]. cpff,1991,66(6):1217-1228.
[37]Nakayama K, Nagahama H, Minamishima YA, et al. arrgeted disrup-tion of SKP2 results in accumulation of cyclin E and p27(kipl), polyploidy and centrosome overduplication[J]. EMBO J,2000,19(9):2069-2081.
[38]Hinchcliffe EH, Lj C, Thompson EA, et al. Requirement of CDK2/cyclinE activity for repeated centrosome reproduction in xenoPus egg extracts [J]. Science,1999,283(5043): 851-854.
[39]MussmanJ G, Horn HF, Carroll DE, et al. Synergistic indoction of centrosome hyPeramPlification by loss of p53 and cyclinE overexpression[J]. Oncogene,2000,19 (13): 1635-1646.
[40]周彦明,李玉民,朱有全,等.Cyclin E和P27蛋白在胆囊癌组织中的表达及其意义[J].中国普外基础与临床杂志,2004,11(2)：148-150.
[41]Oya M, Yao T, TsuneyoshiM. Expressions of cell-cycl regul atory gene products in conventional gastric adenomas:possible immunohistochemical markers of malignant transformation [J]. Hum Pathol,2000,31 (3):279-287.
[42]丁俊,李可为,王坚,等.P27、CyclinD、CyclinE在原发性胆囊癌中的表达及临床意义[J].肝胆胰外科杂志,2009,21(3)：191-195.
[43]Lindahl T. Over expression of cyclinE protein is associated with specific mutation types in p53 gene and poor survival in human breast cancer [J]. Car-cinogenesis,2004,25 (3):375.
[44]Takano Y, Kato Y, van Diest P J, et al. CyclinD2 overexpression and lack of p27 correlate positively and cyclinE inverse1y with a poor prognosis in gastric cancer cases [J]. AmJ Pathol,2000,156 (2):585-594.
[45]Yasui W, Kudo Y. Reduced expression of cyclin-dependent kinase inhibitor p27kipl is associated with advanced stage and invasiveness of gastric carcinomas [J]. Jpnj Cancer Res, 1997,88(6):625-629.
[46]刘勇,路名芝.细胞周期调控因子p27, cyclinE和Ki-67在早期胃癌中的表达[J].九江医学,2002,17(2)：233-235.
[47]陈清波,常青,夏和顺.CyclinE、p27蛋白表达及Hp感染与胃癌发生关系的研究[J].中华实用医学,2005,4(5)：222-225.