p16-CyclinD1-CDK4/6-pRb通路在非小细胞肺癌中表达及其与预后关系的研究
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摘要
目的：通过检测、分析正常肺组织和非小细胞肺癌(non-small-cell lung cancer, NSCLC)中多肿瘤抑制基因(multipletumor-suppressor1, MTS1又称p16),细胞周期蛋白(CyclinDl)和视网膜母细胞瘤基因(Retinoblastoma gene, Rb),探讨p16-CyclinDl-CDK4/6-Rb通路在非小细胞肺癌(NSCLC)发病机制中的作用及与预后的关系。
方法：运用免疫组化、分子生物学技术(PCR, PCR-SSCP, MSP,DNA测序和DPCR技术等)和病理学技术对人体正常肺组织,非小细胞肺癌癌组织中细胞周期相关基因p16, cyclinDl和Rb,从蛋白质和DNA水平改变及其相互关系进行研究,并结合临床病理资料和随访资料进行分析。
结果：
1.应用免疫组化技术检测p16、CyclinDl和Rb的表达,结果显示NSCLC中p16-CyclinD1-Rb通路总异常率为97.6%(82/84)：p16、RB和CyclinDl的异常表达率分别为38.1%,51.2%和54.8%：提示p16-cyclinDl-Rb通路异常与NSCLC发病机制密切相关,三种蛋白的异常可单独或共同发挥作用。p16与Rb表达呈明显的负相关关系(P<0.01)；而CyclinDl与RB表达呈正相关(P<0.05)。Rb表达与NSCLC的分化程度呈负相关(P<0.05),提示其可能在肿瘤的演进中发挥作用。
2.应用PCR-SSCP, MSP和DNA测序技术检测p16基因状态。共发现24/76例(31.6%)LMS中有p16基因异常,其中18例(23.7%)发生启动子区5’CpG岛甲基化,4例发生基因突变(2例在第2外显子编码区,2例在第2外显子与内含子接头处),2例存在纯合缺失。24例p16基因异常的NSCLC中p16蛋白阴性20例,弱阳性4例.研究结果提示p16基因失活与NSCLC的发病机制有关。启动子区5’CpG岛的甲基化是NSCLC中p16基因失活的主要方式,但也有少量点突变和缺失。
3.应用DPCR技术检钡CCND1基因扩增。结果显示16/76例(21.1%)NSCLC存在CCND1基因扩增,均伴CyclinD1过表达。但仍有32/48例(66.7%) cyclinD1过表达的病例未检测至JCCND1扩增。实验结果提示CCND1基因扩增在中NSCLC较为常见,是引起CyclinD1过表达的原因之一,可能与NSCLC发病机制有关。
4.本研究回访率51.2%,中位生存期为24个月。采用Cox比例风险回归模型评估各因素。单因素分析发现患者年龄、肿瘤大小、分化程度、组织类型CyclinD1表达以及转移与患者死亡率相关,是有意义的预后因素。多因素分析则仅发现p16表达、肿瘤大小和有无转移是独立的预后指标。P16、CyclinD1和Rb联合检测对NSCLC进展及预后的评估有一定的临床价值。
结论：p16-cyclinD-pRB通路异常与NSCLC发病机制密切相关。启动子区5'CpG岛甲基化是NSCLC中p16基因失活的主要方式。CCND1基因扩增在NSCLC中较为常见,是引起cyclinD1过表达的原因之一,可能与NSCLC发病机制有关。P16、肿瘤大小和有无转移是判断NSCLC患者预后的有用指标。
The p16-cyclinD1-CDK4/6-Rb pathway plays a very important role in the cell cycle regulation. Progression through the G1-S phase of the cell cycle is mediated by phosphorylation of the Rb resulting in the release of essential transcription factors such as E2F-1.The phosphorylation of Rb is regulated positively by cyclinDl/CDK4and negatively by CDK inhibitors, such as p16(CDKN2/MTS-1/INK4A). Rb and p16are known as tumor surpressors, and cyclinDl is regarded as oncoprotein. It has been shown that he p16-cyclinD-Rb pathway is closely related to tumorigenesis. Many tumor types display a high frequency of inactivation of at least one component of this pathway. The majority of the scientific studies that have analyzed the occurrence of cell cycle regulator aberrations within lung cancer have dealt with different tumors. Data concerning single class of sarcomas are very limited. In order to determine contributions of these three components to the progression of lung cancer, we studied here in84cases of lung cancer by analyzing protein alteration of p16, cyclinD1and Rb, and gene aberration of p16and CCND1. In addition, prognostic analysis was made on the basis of follow-up. The results were summarized as follows:
1.Immunohistochemistry was performed to detect p16,cyclinDl and Rb expression. Aberrations involving the p16-cyclinD1-Rb pathway were observed in82/84(97.6%) cases. Abnormal expression frequency of p16, cyclinD1and Rb was38.7%,51.2%,54.8%,respectively.The p16-cyclinD-Rb pathway therefore emerges as the preferred target for molecular abnormalities in non-small-cell lung cancer. There was a significant inverse correlation between Rb and p16expression (P<0.01) and a direct correlation between Rb and cyclinDl expression (P<0.05). A clinico-pathologic survey indicated that negative expression of Rb was associated with poorly diferentiated lung cancer (P<0.05),suggesting the loss of Rb expression might play a role in malignant progression of lung cancer.
2. The p16gene status of76cases of NSCLC was analysised by PCR-SSCP, MSP and DNA sequence.Of76cases of NSCLC,18(23.7%) showed5'CpG island Hypermethylation in p16gene;4(5.3%) showed point mutations(two G→T)missence mutation in exon2and two G→T mutation in exon-intron junction,as confirmed by DNA sequencing and2(2.6%) showed homozygous deletion. The total frequency of alteration in p16gene was31.6%(24/76).The results suggest both genetic and epigenetic events play an important role in oncogenic processes.
3. The relationship between the CCND1gene amplification with non-small cell lung cancer was explored by PCR.CCND1gene amplification was detected in16/76cases(21.1%)by DPCR, accompanied by cyclinD1overexpression.However, there were still32/48cases (66.7%) of NSCLC, in which cyclinD1was overexpressed, showed no CCND1gene amplification.CCND1gene amplification was detected in14/34cases (41.2%)of Rb Positive NSCLC; CCND1gene amplification was detected in2/42cases of Rb negative NSCLC. There is statistically significant in the two groups(P<0.05).
4. A Cox proportional hazard regression model was used for statistical evaluation of the prognostic factors; And Kaplan-Meier method was used to draw the survival curves, log-rank test was used to compare survival curves.The follow-up was available in43(51.2%) patients. Median survival time was24months.Age of the patient, volume of tumor, pathologic parameters,metastasis and abnormal cyclinD1expression were prognostic factors for overall survival. p16was an independent prognostic factors (P<0.01). Abnormal cyclinDl expression (P<0.05) andmetastasis(P<0.05),were determined to be significant prognostic factors for NSCLC.
As the results mentioned above,we suggest that aberrations involving p16-cyclin D-pRB pathway play a very important role in pathogenesis of NSCLC.5'C pG-island hypermethylation in p16gene is a major way to inactive p16gene. CCND1gene amplification is common in NSCLC,which is one of the mechanisms leading to cyclinDl and may be responsible for the loss of cell cycle control in a fraction of NSCLC. p16expression, volume of the tumor and metastasis are valuable prognostic factors for NSCLC patients.
方法：运用免疫组化、分子生物学技术(PCR, PCR-SSCP, MSP,DNA测序和DPCR技术等)和病理学技术对人体正常肺组织,非小细胞肺癌癌组织中细胞周期相关基因p16, cyclinDl和Rb,从蛋白质和DNA水平改变及其相互关系进行研究,并结合临床病理资料和随访资料进行分析。
结果：
1.应用免疫组化技术检测p16、CyclinDl和Rb的表达,结果显示NSCLC中p16-CyclinD1-Rb通路总异常率为97.6%(82/84)：p16、RB和CyclinDl的异常表达率分别为38.1%,51.2%和54.8%：提示p16-cyclinDl-Rb通路异常与NSCLC发病机制密切相关,三种蛋白的异常可单独或共同发挥作用。p16与Rb表达呈明显的负相关关系(P<0.01)；而CyclinDl与RB表达呈正相关(P<0.05)。Rb表达与NSCLC的分化程度呈负相关(P<0.05),提示其可能在肿瘤的演进中发挥作用。
2.应用PCR-SSCP, MSP和DNA测序技术检测p16基因状态。共发现24/76例(31.6%)LMS中有p16基因异常,其中18例(23.7%)发生启动子区5’CpG岛甲基化,4例发生基因突变(2例在第2外显子编码区,2例在第2外显子与内含子接头处),2例存在纯合缺失。24例p16基因异常的NSCLC中p16蛋白阴性20例,弱阳性4例.研究结果提示p16基因失活与NSCLC的发病机制有关。启动子区5’CpG岛的甲基化是NSCLC中p16基因失活的主要方式,但也有少量点突变和缺失。
3.应用DPCR技术检钡CCND1基因扩增。结果显示16/76例(21.1%)NSCLC存在CCND1基因扩增,均伴CyclinD1过表达。但仍有32/48例(66.7%) cyclinD1过表达的病例未检测至JCCND1扩增。实验结果提示CCND1基因扩增在中NSCLC较为常见,是引起CyclinD1过表达的原因之一,可能与NSCLC发病机制有关。
4.本研究回访率51.2%,中位生存期为24个月。采用Cox比例风险回归模型评估各因素。单因素分析发现患者年龄、肿瘤大小、分化程度、组织类型CyclinD1表达以及转移与患者死亡率相关,是有意义的预后因素。多因素分析则仅发现p16表达、肿瘤大小和有无转移是独立的预后指标。P16、CyclinD1和Rb联合检测对NSCLC进展及预后的评估有一定的临床价值。
结论：p16-cyclinD-pRB通路异常与NSCLC发病机制密切相关。启动子区5'CpG岛甲基化是NSCLC中p16基因失活的主要方式。CCND1基因扩增在NSCLC中较为常见,是引起cyclinD1过表达的原因之一,可能与NSCLC发病机制有关。P16、肿瘤大小和有无转移是判断NSCLC患者预后的有用指标。
The p16-cyclinD1-CDK4/6-Rb pathway plays a very important role in the cell cycle regulation. Progression through the G1-S phase of the cell cycle is mediated by phosphorylation of the Rb resulting in the release of essential transcription factors such as E2F-1.The phosphorylation of Rb is regulated positively by cyclinDl/CDK4and negatively by CDK inhibitors, such as p16(CDKN2/MTS-1/INK4A). Rb and p16are known as tumor surpressors, and cyclinDl is regarded as oncoprotein. It has been shown that he p16-cyclinD-Rb pathway is closely related to tumorigenesis. Many tumor types display a high frequency of inactivation of at least one component of this pathway. The majority of the scientific studies that have analyzed the occurrence of cell cycle regulator aberrations within lung cancer have dealt with different tumors. Data concerning single class of sarcomas are very limited. In order to determine contributions of these three components to the progression of lung cancer, we studied here in84cases of lung cancer by analyzing protein alteration of p16, cyclinD1and Rb, and gene aberration of p16and CCND1. In addition, prognostic analysis was made on the basis of follow-up. The results were summarized as follows:
1.Immunohistochemistry was performed to detect p16,cyclinDl and Rb expression. Aberrations involving the p16-cyclinD1-Rb pathway were observed in82/84(97.6%) cases. Abnormal expression frequency of p16, cyclinD1and Rb was38.7%,51.2%,54.8%,respectively.The p16-cyclinD-Rb pathway therefore emerges as the preferred target for molecular abnormalities in non-small-cell lung cancer. There was a significant inverse correlation between Rb and p16expression (P<0.01) and a direct correlation between Rb and cyclinDl expression (P<0.05). A clinico-pathologic survey indicated that negative expression of Rb was associated with poorly diferentiated lung cancer (P<0.05),suggesting the loss of Rb expression might play a role in malignant progression of lung cancer.
2. The p16gene status of76cases of NSCLC was analysised by PCR-SSCP, MSP and DNA sequence.Of76cases of NSCLC,18(23.7%) showed5'CpG island Hypermethylation in p16gene;4(5.3%) showed point mutations(two G→T)missence mutation in exon2and two G→T mutation in exon-intron junction,as confirmed by DNA sequencing and2(2.6%) showed homozygous deletion. The total frequency of alteration in p16gene was31.6%(24/76).The results suggest both genetic and epigenetic events play an important role in oncogenic processes.
3. The relationship between the CCND1gene amplification with non-small cell lung cancer was explored by PCR.CCND1gene amplification was detected in16/76cases(21.1%)by DPCR, accompanied by cyclinD1overexpression.However, there were still32/48cases (66.7%) of NSCLC, in which cyclinD1was overexpressed, showed no CCND1gene amplification.CCND1gene amplification was detected in14/34cases (41.2%)of Rb Positive NSCLC; CCND1gene amplification was detected in2/42cases of Rb negative NSCLC. There is statistically significant in the two groups(P<0.05).
4. A Cox proportional hazard regression model was used for statistical evaluation of the prognostic factors; And Kaplan-Meier method was used to draw the survival curves, log-rank test was used to compare survival curves.The follow-up was available in43(51.2%) patients. Median survival time was24months.Age of the patient, volume of tumor, pathologic parameters,metastasis and abnormal cyclinD1expression were prognostic factors for overall survival. p16was an independent prognostic factors (P<0.01). Abnormal cyclinDl expression (P<0.05) andmetastasis(P<0.05),were determined to be significant prognostic factors for NSCLC.
As the results mentioned above,we suggest that aberrations involving p16-cyclin D-pRB pathway play a very important role in pathogenesis of NSCLC.5'C pG-island hypermethylation in p16gene is a major way to inactive p16gene. CCND1gene amplification is common in NSCLC,which is one of the mechanisms leading to cyclinDl and may be responsible for the loss of cell cycle control in a fraction of NSCLC. p16expression, volume of the tumor and metastasis are valuable prognostic factors for NSCLC patients.
引文
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