人p27kiplcDNA克隆及其对人舌癌细胞系Tca8113细胞生物学作用的研究
|
摘要
目的：舌鳞状细胞癌是口腔颌面部最常见的恶性肿瘤之一，它生长快，浸润强，早期常有淋巴结转移，治疗效果不够理想。近年来，随着分子生物学的快速发展，基因治疗在肿瘤治疗中表现出不可估量的作用。
本实验以体外培养的人舌鳞状细胞癌细胞Tca8113为研究对象。将克隆的人p27kip1基因连接到pcDNA3载体上，通过脂质体介导转染Tca8113细胞。探讨其对人舌癌细胞系Tca8113细胞的生物学作用。
方法：从正常肝组织中，提取组织中的总RNA。应用RT-PCR将RNA逆转录为cDNA。参照Gene Bank中人p27kip1 cDNA序列，设计2个引物，应用PCR扩增p27kip1 cDNA。将PCR产物行TA克隆进行测序。测序后选择真核表达载体pcDNA3构建重组表达质粒。将pcDNA3-p27kip1和pcDNA3质粒DNA分别用脂质体包裹转染培养细胞，而后通过G418培养液进行筛选，应用PCR法鉴定p27kip1基因转染的Tca8113细胞株。采用流式细胞术检测p27kip1蛋白的表达；凋亡相关蛋白Bcl-2的表达；细胞周期及细胞凋亡。用MTT法检测p27kip1基因转染对Tca8113细胞生长的影响；检测化疗药物对p27kip1基因转染的Tca8113细胞生长的影响。
结果：
1.经测序我们所获得的p27kip1cDNA与Gene Bank登录的序列一致为具有完整阅读框架的p27kip1基因。成功地构建了pcDNA3-p27kip1重组表达质粒，pcDNA3-p27kip1重组表达质粒经酶切鉴定正确。筛选出了抗G418阳性细胞克隆，建立二个新的细胞株。分别命名为：转染质粒pcDNA3-p27kip1的细胞株为Tca-P27；转染空载体pcDNA3的细胞株为Tca-P3。应用PCR鉴定，pcDNA3-p27kip1质粒转染的Tca8113细胞基因组DNA出现p27kip1cDNA扩增带，Tca8113细胞和转染空载体pcDNA3的Tca-P3细胞基因组DNA的PCR产物为阴性。证明了pcDNA3-p27kip1质粒成功地转染入Tca8113细胞。
2.流式细胞术检测p27kip1蛋白的表达结果以p27kip1蛋白表达的阳性细胞百分数表示。Tca-P27细胞p27kip1蛋白表达的阳性细胞百分数明显高于Tca-P3、Tca8113细胞，差异显著（P<0.05）。Tca8113与Tca-P3细胞p27kip1蛋白阳性细胞百分数无显著性差异（P>0.05）。显示转染p27kip1基因的
Tca8113细胞获得了p27kip1蛋白的高表达。
3.MTT法检测Tca8113细胞、Tca-P3细胞、Tca-P27细胞24h(小时)、48h、72h、96h OD值，以OD值代表细胞相对数量，结果Tca-P27细胞增殖速度明显低于Tca8113细胞和Tca-P3细胞。24h、48h，Tca-P27细胞比Tca8113、Tca-P3细胞增殖速度慢，72h、96h时，Tca-P27细胞出现增殖下降。而Tca8113、Tca-P3细胞在24h、48h、72h、96h呈持续增殖状态，三者增殖速度差异显著（P<0.05）。显示转染p27kip1基因后抑制了Tca8113细胞生长。
4.流式细胞术检测细胞周期 结果Tca-P27细胞G0/G1期占细胞百分数明显高于Tca-P3和Tca8113细胞G0/G1期细胞百分数，显著差异（P<0.05）。Tca-P27细胞出现了G0/G1期阻滞。表明转染外源性p27kip1基因在Tca8113细胞中的高表达抑制了细胞周期向S期过渡，使细胞阻滞于G0/G1期，抑制了细胞的增殖。
G2/M和S期所占细胞百分数Tca-P27细胞明显低于Tca8113细胞和Tca-P3细胞所占的细胞百分数（P<0.05）。通过计算细胞的增殖指数，Tca-P27细胞增殖指数明显低于Tca-P3细胞和Tca8113细胞的增殖指数。三者增殖指数比较差异显著（P<0.05）。显示了转染外源性p27kip1基因，使Tca8113细胞出现G0/G1期阻滞，细胞增殖下降，抑制了细胞生长。
5.流式细胞术检测凋亡结果 在G1期前Tca-P27细胞出现了凋亡峰，表明Tca-P27细胞出现了凋亡。Tca8113细胞没有明显凋亡峰出现；Tca-P3细胞也没有明显凋亡峰出现，Tca-P27细胞凋亡指数明显高于Tca8113细胞和Tca-P3细胞的凋亡指数，差异显著（P<0.05）。显示了转染p27kip1基因由于p27kip1基因的高表达，诱导了Tca8113细胞出现了凋亡。
6.流式细胞术检测Bcl-2蛋白的表达结果以Bcl-2蛋白表达阳性细胞百分数表示，Tca-P27细胞阳性细胞百分数明显低于Tca8113细胞和Tca-P3细胞阳性细胞百分数，差异显著（P<0.05）。Tca8113细胞与Tca-P3细胞阳性细胞百分数比较无显著差异（P>.05）。显示了转染p27kip1基因由于p27kip1基因的高表达，引起了凋亡相关蛋白Bcl-2的表达的下调。Bcl-2是一种抗凋亡蛋白，推测转染外源p27kip1基因诱导了Tca8113细胞的凋亡，可能与Bcl-2蛋白表达下调有关。
7.用MTT法对8种化疗药作用Tca-P27细胞、Tca-P3细胞、Tca8113细胞，24h、48h测OD值计算化疗药对三组细胞的生长抑制率。结果顺铂、丝裂霉素、氟尿嘧啶对三组细胞都有明显的抑制作用。平阳 霉素对三组细胞有一定的抑制作用，但以上化疗药对三组细胞的抑制率比较无显著差异（P>0.05）均未显示出转染p27kip1基因有提高以上化疗药对Tca8113细胞的生长抑制作用。环磷酰胺、甲氨蝶呤、阿霉素对三组细胞无明显抑制作用。长春新碱对Tca-P27细胞抑制率明显高于Tca8113细胞和Tca-P3细胞，差异显著（P<0.05）。随时间的增加，细胞抑制率增高（P<0.05）。显示出转染p27kip1基因提高了长春新碱对Tca8113细胞的生长抑制作用。长春新碱使
转染外源p27kip1基因的Tca8113细胞抑制率增加，推测可能因长春新碱作用于M期及其干扰细胞肌醇磷脂代谢而影响细胞增殖。同
Objective: Tongue squamous cell carcinoma (TSCC) is one of the most common malignancies in oral and maxillofacial region. It grows fast and invades tissues beside soon. It often has lymph nodes transfer in earlier period and has a bad therapeutic efficacy. Recently, with the rapid development of molecular biology, gene therapy exhibits an immeasurable role in tumor therapy.
Our investigative object is the human TSCC cell Tca8113 that cultured in vitro. We linked cloned human p27Kip1 gene to pcDNA3 vector and transfected it to Tca8113 cells mediated by liposomes. We discussed the biological action of p27Kip1 gene in TSCC cell line Tca8113.
Methods: Extracts the RNA of the normal liver tissue. Reverse transcription the RNA to cDNA by RT-PCR method. Design the two primers in accordance with the cDNA sequence of p27Kip1 gene in Gene Bank and make PCR to amplify p27Kip1 cDNA. Undertake TA clone with the production of PCR and sequencing. Constructed the recombinated expression plasmid with eukaryon expression vector pcDNA3 after sequencing. Coating the pcDNA3-p27Kip1 and pcDNA3 plasmid DNA with liposomes separately and transfected them to Tca8113 cells. Selected the transfected cell in G418 culture medium and evaluated the Tca8113 cells strain transfected by p27Kip1 gene with PCR. We used flow cytometer to detect the expression of p27Kip1 protein, apoptosis related protein Bcl-2, cell cycle and cell apoptosis. Detected the effects on the growth of Tca8113 cells that transfected by p27Kip1 gene with MTT method. Detected the effects of chemical therapy medicine on the growth of Tca8113 cells transfected by p27Kip1 gene.
Results:
1. The sequence of p27Kip1 cDNA that we obtained was confirmed coincide with the sequence of Gene Bank. This result proved that it was the p27Kip1 gene with integrated read framework. We constructed the recombination expression plasmid pcDNA3-p27Kip1 successfully and it was correct after of enzyme cut. We screened positive cell clone that anti-G418 and established two new cell strains that we called them Tca-P27 and Tca-P3. Tca-P27 is the cell strain that transfected
by pcDNA3-p27Kip1and Tca-P3 is the cell strain that transfected by empty vector pcDNA3. Evaluated by PCR, the genome DNA of Tca8113 cells transfected by pcDNA3-p27Kip1 plasmid appeared p27Kip1 cDNA amplification strip. The PCR production of genome DNA of Tca8113 cells and Tca-P3 cells transfected empty vector pcDNA3 were negative. This proved the pcDNA3- p27Kip1 plasmid transfected to Tca8113 cells successfully.
2. We detected the expression of p27Kip1 protein with flow cytometry and registered the results by the percentage of the positive cells that expressed the p27Kip1 protein. The percentage of the positive cells that expressed the p27Kip1 protein in Tca-P27 cells is higher than Tca-P3 cells and Tca8113 cells distinctly and the difference was prominence（P<0.05）. There was no prominent difference (P>.05) in the percentage of the positive cells that expressed the p27Kip1 protein in Tca-P3 cells and Tca8113 cells. These results indicated that the Tca8113 cells transfected by p27Kip1 gene obtained the high expression of p27Kip1 protein.
3. Measure the OD value of Tca8113 cells, Tca-P3 cells and Tca-P27 cells with MTT method at 24 hours, 48 hours, 72 hours and 96 hours. The OD value represents the cell relative number. The results indicated that the proliferative speed of Tca-P27 cells was slower than Tca8113 cells and Tca-P3 cells distinctly. The proliferative speed of Tca-P27 cells was slower than Tca8113 cells and Tca-P3 cells at 24 hours and 48 hours. Tca-P27 cells appeared a state of descending of proliferation at 72 hours and 96 hours. Tca8113 cells and Tca-P3 cells proliferated continually at 24 hours, 48 hours, 72 hours and 96 hours and the difference was prominence（P<0.05）in the speed of proliferation among them. This investigation shown that the growth of Tca8113 cells was inhibited after transfected by p27Kip1 gene and the proliferation of Tca8113 cells presented stasis.
4. The results of cell cycle detected
本实验以体外培养的人舌鳞状细胞癌细胞Tca8113为研究对象。将克隆的人p27kip1基因连接到pcDNA3载体上，通过脂质体介导转染Tca8113细胞。探讨其对人舌癌细胞系Tca8113细胞的生物学作用。
方法：从正常肝组织中，提取组织中的总RNA。应用RT-PCR将RNA逆转录为cDNA。参照Gene Bank中人p27kip1 cDNA序列，设计2个引物，应用PCR扩增p27kip1 cDNA。将PCR产物行TA克隆进行测序。测序后选择真核表达载体pcDNA3构建重组表达质粒。将pcDNA3-p27kip1和pcDNA3质粒DNA分别用脂质体包裹转染培养细胞，而后通过G418培养液进行筛选，应用PCR法鉴定p27kip1基因转染的Tca8113细胞株。采用流式细胞术检测p27kip1蛋白的表达；凋亡相关蛋白Bcl-2的表达；细胞周期及细胞凋亡。用MTT法检测p27kip1基因转染对Tca8113细胞生长的影响；检测化疗药物对p27kip1基因转染的Tca8113细胞生长的影响。
结果：
1.经测序我们所获得的p27kip1cDNA与Gene Bank登录的序列一致为具有完整阅读框架的p27kip1基因。成功地构建了pcDNA3-p27kip1重组表达质粒，pcDNA3-p27kip1重组表达质粒经酶切鉴定正确。筛选出了抗G418阳性细胞克隆，建立二个新的细胞株。分别命名为：转染质粒pcDNA3-p27kip1的细胞株为Tca-P27；转染空载体pcDNA3的细胞株为Tca-P3。应用PCR鉴定，pcDNA3-p27kip1质粒转染的Tca8113细胞基因组DNA出现p27kip1cDNA扩增带，Tca8113细胞和转染空载体pcDNA3的Tca-P3细胞基因组DNA的PCR产物为阴性。证明了pcDNA3-p27kip1质粒成功地转染入Tca8113细胞。
2.流式细胞术检测p27kip1蛋白的表达结果以p27kip1蛋白表达的阳性细胞百分数表示。Tca-P27细胞p27kip1蛋白表达的阳性细胞百分数明显高于Tca-P3、Tca8113细胞，差异显著（P<0.05）。Tca8113与Tca-P3细胞p27kip1蛋白阳性细胞百分数无显著性差异（P>0.05）。显示转染p27kip1基因的
Tca8113细胞获得了p27kip1蛋白的高表达。
3.MTT法检测Tca8113细胞、Tca-P3细胞、Tca-P27细胞24h(小时)、48h、72h、96h OD值，以OD值代表细胞相对数量，结果Tca-P27细胞增殖速度明显低于Tca8113细胞和Tca-P3细胞。24h、48h，Tca-P27细胞比Tca8113、Tca-P3细胞增殖速度慢，72h、96h时，Tca-P27细胞出现增殖下降。而Tca8113、Tca-P3细胞在24h、48h、72h、96h呈持续增殖状态，三者增殖速度差异显著（P<0.05）。显示转染p27kip1基因后抑制了Tca8113细胞生长。
4.流式细胞术检测细胞周期 结果Tca-P27细胞G0/G1期占细胞百分数明显高于Tca-P3和Tca8113细胞G0/G1期细胞百分数，显著差异（P<0.05）。Tca-P27细胞出现了G0/G1期阻滞。表明转染外源性p27kip1基因在Tca8113细胞中的高表达抑制了细胞周期向S期过渡，使细胞阻滞于G0/G1期，抑制了细胞的增殖。
G2/M和S期所占细胞百分数Tca-P27细胞明显低于Tca8113细胞和Tca-P3细胞所占的细胞百分数（P<0.05）。通过计算细胞的增殖指数，Tca-P27细胞增殖指数明显低于Tca-P3细胞和Tca8113细胞的增殖指数。三者增殖指数比较差异显著（P<0.05）。显示了转染外源性p27kip1基因，使Tca8113细胞出现G0/G1期阻滞，细胞增殖下降，抑制了细胞生长。
5.流式细胞术检测凋亡结果 在G1期前Tca-P27细胞出现了凋亡峰，表明Tca-P27细胞出现了凋亡。Tca8113细胞没有明显凋亡峰出现；Tca-P3细胞也没有明显凋亡峰出现，Tca-P27细胞凋亡指数明显高于Tca8113细胞和Tca-P3细胞的凋亡指数，差异显著（P<0.05）。显示了转染p27kip1基因由于p27kip1基因的高表达，诱导了Tca8113细胞出现了凋亡。
6.流式细胞术检测Bcl-2蛋白的表达结果以Bcl-2蛋白表达阳性细胞百分数表示，Tca-P27细胞阳性细胞百分数明显低于Tca8113细胞和Tca-P3细胞阳性细胞百分数，差异显著（P<0.05）。Tca8113细胞与Tca-P3细胞阳性细胞百分数比较无显著差异（P>.05）。显示了转染p27kip1基因由于p27kip1基因的高表达，引起了凋亡相关蛋白Bcl-2的表达的下调。Bcl-2是一种抗凋亡蛋白，推测转染外源p27kip1基因诱导了Tca8113细胞的凋亡，可能与Bcl-2蛋白表达下调有关。
7.用MTT法对8种化疗药作用Tca-P27细胞、Tca-P3细胞、Tca8113细胞，24h、48h测OD值计算化疗药对三组细胞的生长抑制率。结果顺铂、丝裂霉素、氟尿嘧啶对三组细胞都有明显的抑制作用。平阳 霉素对三组细胞有一定的抑制作用，但以上化疗药对三组细胞的抑制率比较无显著差异（P>0.05）均未显示出转染p27kip1基因有提高以上化疗药对Tca8113细胞的生长抑制作用。环磷酰胺、甲氨蝶呤、阿霉素对三组细胞无明显抑制作用。长春新碱对Tca-P27细胞抑制率明显高于Tca8113细胞和Tca-P3细胞，差异显著（P<0.05）。随时间的增加，细胞抑制率增高（P<0.05）。显示出转染p27kip1基因提高了长春新碱对Tca8113细胞的生长抑制作用。长春新碱使
转染外源p27kip1基因的Tca8113细胞抑制率增加，推测可能因长春新碱作用于M期及其干扰细胞肌醇磷脂代谢而影响细胞增殖。同
Objective: Tongue squamous cell carcinoma (TSCC) is one of the most common malignancies in oral and maxillofacial region. It grows fast and invades tissues beside soon. It often has lymph nodes transfer in earlier period and has a bad therapeutic efficacy. Recently, with the rapid development of molecular biology, gene therapy exhibits an immeasurable role in tumor therapy.
Our investigative object is the human TSCC cell Tca8113 that cultured in vitro. We linked cloned human p27Kip1 gene to pcDNA3 vector and transfected it to Tca8113 cells mediated by liposomes. We discussed the biological action of p27Kip1 gene in TSCC cell line Tca8113.
Methods: Extracts the RNA of the normal liver tissue. Reverse transcription the RNA to cDNA by RT-PCR method. Design the two primers in accordance with the cDNA sequence of p27Kip1 gene in Gene Bank and make PCR to amplify p27Kip1 cDNA. Undertake TA clone with the production of PCR and sequencing. Constructed the recombinated expression plasmid with eukaryon expression vector pcDNA3 after sequencing. Coating the pcDNA3-p27Kip1 and pcDNA3 plasmid DNA with liposomes separately and transfected them to Tca8113 cells. Selected the transfected cell in G418 culture medium and evaluated the Tca8113 cells strain transfected by p27Kip1 gene with PCR. We used flow cytometer to detect the expression of p27Kip1 protein, apoptosis related protein Bcl-2, cell cycle and cell apoptosis. Detected the effects on the growth of Tca8113 cells that transfected by p27Kip1 gene with MTT method. Detected the effects of chemical therapy medicine on the growth of Tca8113 cells transfected by p27Kip1 gene.
Results:
1. The sequence of p27Kip1 cDNA that we obtained was confirmed coincide with the sequence of Gene Bank. This result proved that it was the p27Kip1 gene with integrated read framework. We constructed the recombination expression plasmid pcDNA3-p27Kip1 successfully and it was correct after of enzyme cut. We screened positive cell clone that anti-G418 and established two new cell strains that we called them Tca-P27 and Tca-P3. Tca-P27 is the cell strain that transfected
by pcDNA3-p27Kip1and Tca-P3 is the cell strain that transfected by empty vector pcDNA3. Evaluated by PCR, the genome DNA of Tca8113 cells transfected by pcDNA3-p27Kip1 plasmid appeared p27Kip1 cDNA amplification strip. The PCR production of genome DNA of Tca8113 cells and Tca-P3 cells transfected empty vector pcDNA3 were negative. This proved the pcDNA3- p27Kip1 plasmid transfected to Tca8113 cells successfully.
2. We detected the expression of p27Kip1 protein with flow cytometry and registered the results by the percentage of the positive cells that expressed the p27Kip1 protein. The percentage of the positive cells that expressed the p27Kip1 protein in Tca-P27 cells is higher than Tca-P3 cells and Tca8113 cells distinctly and the difference was prominence（P<0.05）. There was no prominent difference (P>.05) in the percentage of the positive cells that expressed the p27Kip1 protein in Tca-P3 cells and Tca8113 cells. These results indicated that the Tca8113 cells transfected by p27Kip1 gene obtained the high expression of p27Kip1 protein.
3. Measure the OD value of Tca8113 cells, Tca-P3 cells and Tca-P27 cells with MTT method at 24 hours, 48 hours, 72 hours and 96 hours. The OD value represents the cell relative number. The results indicated that the proliferative speed of Tca-P27 cells was slower than Tca8113 cells and Tca-P3 cells distinctly. The proliferative speed of Tca-P27 cells was slower than Tca8113 cells and Tca-P3 cells at 24 hours and 48 hours. Tca-P27 cells appeared a state of descending of proliferation at 72 hours and 96 hours. Tca8113 cells and Tca-P3 cells proliferated continually at 24 hours, 48 hours, 72 hours and 96 hours and the difference was prominence（P<0.05）in the speed of proliferation among them. This investigation shown that the growth of Tca8113 cells was inhibited after transfected by p27Kip1 gene and the proliferation of Tca8113 cells presented stasis.
4. The results of cell cycle detected
引文
1. Zhou BB, Elledge SJ. The DNA damage response: putting checkpoints in perspective. Nature. 2000,408(6811):433-439
2. Hoeijmakers JH. Genome maintenance mechanisms for preventing cancer. Nature. 2001, 411(6835):366-374
3. Evans –T, Rosenthal -E-T, Youngbloom –J, et al. Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division.cell. 1983, 33(2): 389-96
4. Zhou P, Zhou P, Jiang W, et al. Antisense to cyclinD1 inhibits growth and reverses the transformed phenotype of human esophageul cancer cells. Oncogene. 1995, 11(3): 571-580
5. Bartkova J, Lukas J, Muner H, et al. cyclin D1 protein expression and function in human breast cancer. Int J Cancer. 1994,57(3): 353
6. Gansauge S, Gansauge F, Rsmadani M, et al. Over expression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis. Cancer Res. 1997, 57(9): 1634-1637
7. Zhang YJ, Jiang W, chen CJ, et al. Amplification and over expression of cyclin D1 in human hepatocellufter carcinoma. Bio chem. Biopsy’s ReQcommun. 1993,196(2): 1010
8. Nishida N, Fukuda Y, Komeda T, et al. Amplificafion and over expression of cyclinD1 gene ingressive human hepatocelluar Carcinoma. Cancer Res. 1994,54(12): 3107 -3110
9. Yu Jin Jung, Kee-Ho lee. Dong-Wook choo Reciprocal expressions of cycin E and cycinD1 in hepatocelluar carcinoma. Cancer letters .2001,68:57-63.
10. Jiang W, zhang YJ, Kahn SM, et al. Altered expression of the cyclinD1 and retinablastoma gene in human esophageal cancer. Proc Natal Aced Sci USA. 1993,90(19): 9026-9030
11. Mate JL, Ariza A, Aracil C, et al. CyclinD1 over expression in non Small cell lung carcinoma correlation with Ki-67 labeling index and poor cytoplasmic differentiation. Pathol. 1996,180(4): 395-399
12. Arbet N, Hidshoosh Moss SF, et al. Increased expression of cyclinD1 is an early event in multistage colorectal carcinogenesis. Gastroenterology. 1996,
110(3): 669-674
13. Worsley SD, Ponder BA, Davies BR. Over expression of cyclinD1 in epithelial ovarian Cancers. Gynecoloncol. 1997,64(2): 189-195
14. Haas K, Johannes C, Geisen C, et al. Malignant transformation by cyclinE and Ha-Ras correlates with lower sensitivity towards induction of cell death but requires functional Myc and CDK4. Oncogene. 1997,15(21): 2615-23
15. Geng Y, Eaton EN, Picon M, et al. Regulation of cyclin E transcripti-on by E2Fs and retinoblastoma protein. Oncogene. 1996,12(6): 1173-1180
16. Koff A, Giordano A, Desai D, et al. Formation and activation of a cyclinE-cdk2 complex during the G1 phase of the human cell cycle. Scienc-e.1992, 257:1689-1694
17. Akama Y, Yasui W, Yokozaki H, et al. Frequent amplitication of the cycinE gene in human qastric carcinoma. J Ph Cancer Res .1995,86:617-621
18. Pines J, Hunter T. Hunman cyclinA is adenovirus EIA-associated protein p60 and behaves differently from cyclin B. Nature. 1990,346:760-763
19. Pagano M, pepperkok R, Verde F, et al. Cyclin A is required at two points in the human cell cycle. EMBO J. 1992,11:961-971
20. Muller C, Yang R, Beckvon PL, et al. Cloning of the cyclinA1 qenomic structure and characterization of the promoter region GC boxes are essential for cell cycle regulated transcription of cyclinA1 gene. J Boils Chem. 1999,274:11220-11228
21. Yang R, Nakamaki T, Lubbert M, et al. CyclinA expression in leukemia and normal hematopietic cells. Blood. 1999,93:2067-2074
22. Handak YM, Takeda H, et al. Expression of cell cycle markers in colorectal carcinoma: superiority of cyclinA as a indicators of poor prognosis. Int J Cancer. 1999,84(3):225—233
23. Alatomaas, Lipponenp, Ala opas M, et al. Expression of cyclinA and p21 proteins in renal cell cancers and the relation to clinic pathological variables and patients survival. Br J Cancer. 1990,80(12): 2001-2007
24. Amon A, Irniger S, Nasmyth K. Closing the cell cycle circle in yeast: G2 cyclin proteolysis initiated at mitosis persists until the activation of G1 cyclins in the next cycle. Cell .1994,7:1037-1050
25. Dunphy WG. The decision to enter mitosis. Trends Cell Biol. 1994,4: 202-207
26. Morgan D.Principles of CDK regulation. Nature.1995,374: 131-134
27. Nana, Kohzato A, Youyi, Dong B, Li Sui C. Ove rexpression of cyclinE and cyclin-dependent kinase 2 is correlated with development of hepatocellular carcinomas. Hepatology Research.2001,21: 27-39
28. Kawana H, Tamaru J, Tanaka T, et al. Role of p27kip1 and cyclin-dependent kinase 2 in the proliferation of non-small cell lung cancer. Am J Pathol. 1998,153:505-13
29. Sasano H, Frost AR, Saitoh R, et al. Immunolocalization of cyclins D and E and cyclin-dependent kinase (cdk) 2 and 4 in human breast carcinoma. Anticancer Res. 1997,17:3685-90
30. Kim JH, Kang MJ, Park CU, et al. Amplified CDK2 and cdc2 activities in primary colorectal carcinoma. Cancer .1999,85:546-53
31. Matsumoto M, Furihata M, Ishikawa T, et al, Comparison of deregulated expression of cyclinD1 and cyclinE with that of cyclin-dependent kinase 4(CDK4) and CDK2 in human esophageal squamous cell carcinoma. Br J Cancer.1999, 80: 256-61
32. Hinds PW, Mittnacht S, Dulic V, et al. Regulation of retinoblastoma protein function by entopic expression of human cyclins. Cell .1992,70:990-1006
33. Kato J, Matsushime H, Hiebert SW, et al. Direct binding of cyclinD to the retinohlastoma gene product (pRb), pRb phosphorylation by the cyclinD-dependent kinase CDK4. Gene Rev. 1993,7:331-342
34. Cannon-Albright LA, Goldgar DE, Meyer LJ. Assignment of a locus for familiar lmelanoma MLM to chromosome 9p13-p22. Science. 1992, 258: 1148-1152
35. Serrano M, Hannon GL, Beach D. A new regulatory motifin cell cycle control causing specific inhibition of cyclinD/CDK4. Nature. 1993,366:704-707
36. He J, Olson JJ, James CD. Lack of p16IN4 or Rentinoblastom a gene alterations in hepatocellular carcinomas induced by N-nitrosodiethylamine or a cholined decently-amino acid-defined diet in rats. Cancer Letters.2000, 152: 71-77
37. Kita Y, Nishida N, Fukuda Y. Infrequent alteration of the p16 INK4a gene in liver cancer. Int J Cncer .1996,67:176-180
38. Biden K, Young J, Buttenshaw R. Frequency of mutation and deletion of the tumor suppressor gene CDKN2a (MST1/p16) in hepatocellular carcino-ma from an Australian population. Hepatology. 1997,25:593-597
39. Hui AM, Sakamoto M, Kanai Y. Inactivation of p16INK4 in hepatoc-ellular carcinoma. Hepatology .1996,24: 575-579
40. Caldas C, Hahns A, Dacostal T, et al. Frequent somatic mutations and homozygous deletions of the p16 (NTS1) gene in the pancreaticadeno carcinoma. Nat Genet .1994,8:27-32
41. Mori T, Miura K, Aoki T, et al. Frequent Somatic mutation of the MST/CDK4I (multiple tumor suppressor/cyclin dependent kinase4 inhibit gene)
in esophageal squamous cell carcinoma. Cancer Res .1994,54: 3396-3397
42. Okamoto A, Hussain SP, Hagiwara K, et al. Mutation in the p16INK4/MTS1/CDKN2 p15INK4B/MTS2 and p18 gene in primary and metastasis lung Cancer. Cancer Res .1995,55: 1448-1451
43. Gonzales ZM, Shibata A, Ohneseit PF, et al. High frequency of chromosome 9 pallelicloss and CDKN2 tumor suppressor gene alteration in squamous cell carcinoma of the bladder. Natal Cancer Inst. 1995,87: 1383-1393
44. Fizzott M, Cimino G, Pisegna S, et al. Detection of homozygous deletion of the cyclin dependent Kinase4 inhibitor (p16) gene in acute lymphoblastic leukemia and association with advance prognostic features. Blood .1995,85: 2685
45. Wu CL, Roz L, Mcknow S, et al. DNA studies understimate the major role of CDKN2a inactivation in oral and oropharyngeal squamous cell carcinomas. Genes Chromosomes Cancer. 1999,25(1): 16-25
46. Kato H, Yoshikawa M, Fukai Y, et al. An immunohistochemical study of p16 pRb p21 and p53 Proteins in human esophageal cancer. Anticancer Res. 2000, 20(14): 345-349
47. Reed AL, Califano J, Cairns P, et al. High frequency of p16 (CDKN2/MTS-1/lnk4A) in activation in had and neck squamous cell carcinoma. Cancer Res 1996,56(16): 3630-3633
48. Sartor M, Steingrimsdottir H, Elamin F, et al. Role of p16/MTS1, cyclinD1 and RB in primary oral cancer and oral cancer cell lines. British J Cancer. 1999,80(1/2) 79-86
49. Feng XH, Liu X, Derynek R. Smad2 smad3 and smad4 cooeperate with sp1 to induce p15 transcription in response to TGF-beta. EMBO J. 2000,19(9): 5178-5193
50. Fuxe J, Akusjarvi G. Adenovirus-mediated over expression of p15INK4B inhibis human glioma cell growth induces replicative senescence and inhibits telomerase activity similarly to p16INK4A. Cell Growth. 2000,11:373-384
51. Liu J, Tong YK, Liu HT. Effect of p15INK4b expression on the cell cycle and G1 phase regulated regulatory genes in human melanoma cells. Pro Nat Sci. 2001,11:40—45
52. Blais A, Labrie Y, Pouliot F, et al. Structure of the gene encoding the human cyclin-dependent inhibitor p18 and mutation al analysis in breast cancer. Biochem Biophys Res Com-mun .1998,247(1):146-153
53. Jeffrey PD, Tong L, Pavletich NP. Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors. Gent Dev .2000,14(24): 3115-3125
54. Morse L, Chen D, Franklin D, et al. Induction of cell cycle arrest sand B cell terminal differentiation by CDK4 inhibitor p18 (INK4c) and IL-6. Immunity. 1997,6:47-56
55. Tao W, Levine AJ. p19(ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2 . Proc Nat1 Acad Sci USA. 1999,96(12): 6937-6941
56. Adachi M, Roussel MF, Havenith Kand, et al. Features of macrophage differentiation induced by p19INK4d: a specific inhibitor of cyclinD-dependent kinases. Blood. 1997,90: 126—137.
57. Kannan K, Muniraian AK, Krishnamurthy J, et al. The p16INK4 alpha/p19ARF gene mutations are in freguent and are mutually exclusive to p53 mutations in Indian oral squamous cell carcinomas. Int J Oncol. 2000,16 (3): 585-590.
58. 刘习强.INK4家族与头颈肿瘤研究新进展.国外医学口腔医学分册.2002,20(1): 19-20
59. Hirama T, Koeffler HP. Role of the cyclin-dependent kinase inhibiters in the development of cancer. Blood .1995, 86(3):841-854
60. Harper JW, Elledge ST, Keyomarsi K, et al. Inhibiti of cyclin-dependent kinase by p21. Mol Biol cell. 1995,6:387-400
61. Umar A, Buermeyer AB, Simon TA, et al. Requirement for PCNA in DNA mismatch repair at a step preceding DNA resynthesis. Cell.1996, 87: 65-73
62. Hui AM, Kanai Y, Sakamoto M. Reduced p21 WAF1/CIP1 expression and p53 mutation in hepatocellular carcinomas. Hepatology. 1997,25:575-579
63. Kokunai T, Izawai I, Tamaki N. Overexpression of p21WAF1/CIP1 induces cell differentiation and growth inhibition in a human glioma cell line. Int J Cancer. 1998,75(4): 643-648
64. Lee MH, Reynisdottir I, Massague J. Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribut-ion. Genes Dev. 1995,9(6): 639-49
65. Matsuoka S, Edwards MC, Bai C, et al. p57KIP2, a structurally distinct member of the p21CIP1 CDK inhibitor family, is a candidate tumor suppressor gene. Genes-Dev. 1995,9(6): 650-62
66. Yan Y, Frisen J, Lee MH, et al. Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development. Genes-Dev. 1997,11(8): 973-83
67. Hatada I, Ohashi, H, Fukushima Y, et al. An imprinted gene p57KIP2 is mutated in Beckwith-Wiedemann syndrome. Nat Genet. 1996,14(2): 171-3
68. Kondo M, Matsuoka S, Uchida K, et al. Selective maternal-allele loss
in human lung cancers of the maternally expressed p57KIP2 gene at 11p15.5. Oncogene. 1996,12(6): 1365-8
69. Polyak K, kato JY, Solomon M, et al.p27kip1 a cyclin-CDK inhibitor links transforming growth factor beta and contact inhibition to cell cycle arrest. Genes Dev .1994,8(5): 9-22
70. Toyoshima H. p27 novel inhibitor of G1 cyclin-cdk protein kinase activity is rlated to p21. Hunter J Cell. 1994,78(1)67-74
71. Ponce-Castaneda MV, Lee MH, Latres E, et al. p27kip1 chromosomal mapping to 12p12-12p13.1 and abence of mutations in human tumors. Cancer Res .1995, 55:1211
72. Bullrich F, Maclachlan TK, Sang N, et al. Chromosomal map-ping of members of the cdc2 family of protein kinases cdk3 CDK6 POSSLRE and PJTALER and a cdk inhibitor p27kip1 to regions involved in human Cacer. Cancer Res .1995,55:1199
73. Rivard N, Bartek J, Pouyssegur J, et al. Abrogation of p27kip1 by cDNA antisense suppresses quiescence (Go State) in fibroblasts. J Biol Chem. 1996, 71:18337-18341
74. Sgambato AA, Cittadini A, Weinstein IB, et al. Multiple functions of p27kip1 and its alterations in tumor cells. J Cell Physiol .2000,183 (1): 18-27
75. Toyoshima H, Hunter T.p27 a novel inhibitor of G1 cyclin-cdk protein kinase activity is related to p21. Cell.1994, 78: 67-74
76. 陈广理. p27的生物学功能及其在中耳胆脂瘤研究中的进展. 国外医学耳鼻咽喉科学. 2002,26(3)：137-138
77. Coppock DL, Buffolino P, Kopman C, et al. Inhibition of the melamoma cellcycle and regulatioatthe at the G1/S trans by12-0 tetradecanoy-lphorbol-13-acetate (TPA) by modulation of CDK2 activity. Exp Cell Res. 1995,221:92-102
78. Depoortere F, pirson I, Bartek J, et al. Transforming growth factor beta (1) selectively inhibits the cyclin Amp-dependenp proliferation of primary thyroid epithelial cells by preventing the association of cyclinD3-cdk4 with nuclear p27kip1. Mol Biol cell, 2000,11:1061-1076
79. Resnitzky D, Hengst L, Reed S, et al. Cyclin-A-associated kinase activity is rate limiting for entranceinto S phase and is negatively regulated in G1 by p27kip1. Mol Cell Biol. 1995,15:4347-4352
80. Bleler RT, Martin R, Nucleo-cytoplasmic translocation of histone H1 during the Hela cell cycle. Chromosoma. 1999,108:308-316
81. Gardner LB, Li Q, Park MS, et al. Hypoxia inhibits G1/S transition through regulation of p27 expression. J Biol Chem. 2001,276(11):7919-7926.
82. Durand B, Gao FB, Raff MA. Accumulation of the cyclin dependent kinase inhibitor p27kip and the timing of oligodendrocyte differentiation. EMBO J. 1997, 16: 306
83. Robker RL, Richards JS. Hormone-induced proliferation and differentiation of granulosa cells: a coordinated balance of the cell cycle regulators cyclinD2 and p27kip1. Mol-Endocrinol. 1998,12(7): 924-40
84. Nakayama K, Ishida N, shirand M, et al. Mice lacking p27kip1 display increased body size multiple organ hyperplasia and piuity tumors [J]. Cell 1996;85: 707
85. Muraoka RS, Lenferink AE, Simpson J, et al. Cyclin-dependent kinase inhibitor p27(kip1) is required for mouse mammary gland morphogenesis and function[J]. J Cell Biol .2001,153(5): 917-932
86. Muraoka RS, Lenferink AE, Law B, et al. ErbB2/Neu-induced. Cyclin D1-Dependent transformation is accelerated in p27-haploinsuffi-cient mammary epithelial cells but impaired in p27-null cells. Mol cell Biol. 2002,22(7): 2204-2219
87. Alexander K, Hinds PW. Requirement for p27(kip1) in retinoblasto-ma protein-mediated sensecence[J]. Mol Cell Biol. 2001,21(11): 3616-3631
88. Katayose Y, Kim M, Rakkar AN, et al. Promoting apoptosis: A novel activity associated with the cyclin-dependent kinase inhibitor p27 [J]. Cancer Res. 1997,57:5441-5445
89. Fujieda S, Inuzuka M, Tanaka N, et al. Expression of p27 is associated with Bax expression and spontaneous apoptosis in oral and oropharyngeal carcinoma [J]. Int J Cancer .1999, 84:315.
90. Naruse I, Hoshino H, Dobashi K, et al. Over-expression of p27kip1 induces growth arrest and apoptosis mediated by changes of pRb expression in lung cancer cell [J]. Int J Cancer. 2000,88(3): 377-383
91. Barata T, Cardoso AA, Nadler LM, et al. Interleukin-7 promotes survival and cell cycle progression of T-cell acute lymphoblastic leukemia cells by down-regulating the cyclin-dependent kinase inhibitor p27 (kip1). Blood. 2001, 98(5): 1524
92. Yang Q, Sakurai T, Yoshimura G, et al. Overexpression of p27 protein in human breast cancer correlates with in vitro resistance to doxorubicin and mitomycin C. Anticancer Res 2000,20:4319
93. Oshita F, Kameda Y, Nishio K, et al. Increased expression levels of cyclin-dependent Kinase inhibitor p27 correlare with good responses to platinum-based chemotherapy in non-small cell lung cancer [J]. Oncol Rep 2000, 7(3): 491-495
94. Mendelsohn J. The epidermal growth factor receptor as a tar-get for cancer therapy [J]. Endor Relat Cancer. 2001,8:3-9
95. Valeria M, Grabiella F, Bruna P, et al. p27 expression is associated with chinical out come in advanced epithelial ovarian cancer: Muitivariate analysis. Clin Cancer Res. 2000,6:4816-4822
96. Goff BA, Paley PJ, Greer BE, et al. Evaluation of chemoresistance markers in women with epithelial ovarian carcinoma [J]. Gynecol Oncol. 2001, 81:18-24
97. Krtolica A, Krucher NA, Ludiow JW. Molecular analysis of selected cell cycle regulatory proteins during gerobie and hypoxic Maintenance of human ovarian Carcinoma cells. Br J Cancer 1999,80:1873-1875
98. St Croix B, Florenes VA, Rak JW, et al. Impact of the cyclin-dependent kinase inhibitor p27 on resistance of tumor cells to anti-Cancer agents [J]. Nature Med. 1996,2:1204-1210
99. Lloyd RV, Erickson LA, Jin L, et al. p27kip1:a multifunc-tional cyclin-dependent kinase inhibitor with prognostic signifi-cance in human cancers[J]. Am J pathol. 1999,154:313
100. Yao J, Eu KW, Seow Choen F, et al. Down-regulatien of p27 is a significant predictor of poor overall survival and may facilitate metastasis in colorectal carcinomal. Int J Cancer. 2000,20:213-216
101. George VT, Kinga S, Michael M, et al. Down-regulation of p27 is associated with development of colorectal adenocarcinoma metastases [J]. Am J Pathol.1998,153: 681-687
102. St Croix B, Sheehan C, Rak JW, et al. PE-Cadherin-dependent growth suppression is mediated by the cyclin-dependent kinase inhihitor p27 [J]. J Cell Biol. 1998,142:557-571
103. Takata T, Kudo Y, Zhao M, et al. Reduced expression of p27 (KiP1) Protein in relation to salivary adenoid cystic carcinoma metastasis [J]. Cancer. 1999,86:928
104. Kuo MY, Hsu HY, Kok SH, et al. Prognostic role of p27kip1 expression in oral squamous cell carcinoma in Taiwan [J]. Oral Oncol. 2002,38(2): 172-178
105. Singh SP, Lipman J, Goldman H, et al. Loss or altered subcellular localization of p27 in Barretts associated adenocarcinoma [J]. Cancer Res. 1998,58:1730-1735
106. Yang HY, Zhou BP, Hung MC, et al. Oncogenic signals of HER-2/neu in regulating the stability of the cyclin-dependent kinase inhibitor p27 J. Biol Chem. 2000,275:24735-24739
107. Sherr CJ.The pezcoller Iecture: Cancer cell cycles revisited [J]. Cancer Res. 2000,60:3689-3695
108. King RW. How proteolysis drives the cell cycle. Science. 1996,274(5293): 1652-1659
109. Hengst L, Reed SI. TranIational Control of p27kip1 accumulation during the cell cycle [J]. Science. 1996,271(5257): 1861-1864
110. Loda M, Cukor B, Tam SW, et al. Increased proteasome dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive Colorectal Carcinomas [J]. Nature Med .1997,3(2): 231-234
111. Hochstrasser M. Ubiquitin proteasomes and the regulation of intracellular protein degradation [J]. Curr opin cell Biol. 1995,7(2): 215-223
112. Slingerland J. Regulation of the cdk inhibit p27 and its deregulation in cancer. J Cell Phys. 2000,18:10
113. De Paola F. p27kip1 expression in normal epithelium benign and neoplastic breast. J Pathol .2002; 196(1):26
114. Koguchi K, Nakatsuji K. Modulation of astrocyte proliferation by cyclin-dependent kinase inhibitor p27kip1 [J]. Glia .2002, 37(2): 93-104
115. Sakai H, Yamane T, Yanai T, et al. Expression of cyclin kinase inhibitor p27 (kip1) in skin tumours of dogs [J]. Comp Pathol. 2001, 125(2-3): 153-158
116. Ellis FH, Xuox JR, Kulke MH, et al. Malignant transformation of the esophageal mucosa is enhanced in p27 knockout mice [J] .J Thorac Cardiovasc Surg. 2001,122(4): 809-814
117. Yang HY, Shao R, Hung MC, et al. p27kip1 inhibits HER2/neu-mediated cell growth and tumorigenesis [J]. Oncogene. 2001,20(28): 3695-3702
118. Hayashi H, Ito T, Yazawa T, et al. Reduced expression of p27kip1 is associated with the development of pulmonary adenocarcinom [J]. J Pathol. 2000,192(1): 26-31
119. Saito T, Nakajima T, Mogi K. Immunohistochemical analysis of cell cycle-associated proteins p16 pRb p53 p27 and Ki-67 in oral cancer and precancer with special reference to verrucous carcinomas. J Oral Pathol Med. 1999,28(5): 226-32
120. Pietenpol JA, Bohlander SK, Sato Y. Assignment of the p27kip1 gene to 12p13 and its analysis in leukemias. Cancer Res .1995,55:1206-1210
121. Ferrando A, Balbion M, Pendas AM. Mutational analysis of the human cyclin-dependent kinase inhibitor p27kip in primary breast carcinomas. Hum Genet. 1996,97:91-94
122. Catzavelos C, Bhattacharya N, Ung YC. Decreased levels of the cell-cycle inhibitor p27kip1 protein: prognostic implications in primary breast cancer. Nat Med .1997,3:227-230
123. Porter PL, Malone KE, Heagerty PJ. Expression of cell-cycle regulators p27kip1 and cyclin E alone and incombination correlate with survival in young breast cancer patients. Nat Med. 1997,3:222-225
124. Loda M, Cukor B, Tam SW. Increased proteasome dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med. 1997,3:231-234
125. Fradersdorf S, Burns J, Milne AM. High level expression of p27kip1 and cyclinD1 in Some human breast cancer cells: inverse correlation between the expression of p27kip1 and degree of malignancy in human breast and colorectal cancers. Prol Natl Acad Sci USA. 1997,94:6380-6385
126. Ai-Min Hui, Lin Sun, Yae kana. Reduced p27kip1 expression in hepatocellular carcinomas. Cancer Letters. 1998,132:67-73
127. 张政华, 张引成, 刘军. 粘液表皮样癌中热休克蛋白70和细胞周期调节蛋白p27表达与预后的研究. 中华口腔医学杂志. 2001,36(6):467-470
128. 汤炜, 王炼, 李声伟. 颊面粘膜癌中p27kip基因的蛋白质表达及临床意义.口腔颌面处科杂志. 2001, (1):49-52
129. 司晓辉, 金岩, 杨连甲. 颌骨骨肉瘤中p27的表达及意义.口腔医学. 2000,20(4): 174-175
130. Mineta H, Miura K, Suzuki I, et al. Low p27expression correlates with poor prognosis for patients with oral tongue squamous cell carcinoma[J]. Cancer. 1999, 85:1011
131. Tamura N, Dong Y, Sui L, et al. Cyclin-dependent kinase inhibitor p27 is related to cell proliferation and prognosis in laryngeal squamous cell carcinomas[J]. J Laryngol Otol. 2001,115:400
132. Kuo MY, Hsu HY,Kok SH,et al. Prognostic role of p27kip1 expression in oral squamous cell carcinoma in Taiwan [J]. Oral Oncol 2002,38(2): 172-178
133. Okabe M, Inagaki H, Murase J, et al. Prognostic significance of p27 and Ki-67 expression in mucoepidermoid carcinoma of the intraoral minor salivary gland. Mod Pathol. 2001,14(10): 1008-14
134. Ishihara S, Minato K, Hoshino H, et al. The cyclin-dependent kinase inhibitor p27 as a prognostic factor in advanced non-small cell lung cancer: its immunohistochemical evaluation using biopsy specimens [J]. Lung Cancer. 1999,26(3): 187-194
135. Tsukamoto S, Sugio K, sakada T, et al. Reduced expression of
cell-cyclin regulator p27 (kip1) correlates with a shortened survival in non-small cell lung cancer[J]. Lung Cancer. 2001,34(1): 83-90
136. Shige-masa K, Shiroyama Y, Sawasaki T, et al. Underexpression of cyclin-depentent kinase inhibitor p27 is associated with poor prognosis in serous ovarian carcinomas [J]. Int J Oncool .2001,18(5): 953-958
137. 李华, 金兴香, 张祖训.p27kip蛋白表达与舌鳞癌颈淋巴结转移的关系. 中华实用医学. 2002, 4(12): 38-39
138. Park KH, Seol JY, Yoo CG, et al. Adenovirus expression p27(kip1)induces growth arrest of lung cancer cell lines and suppresses the growth of established lung cancer xenografts[J]. Lung Cancer. 2001,31(2-3): 149-155
139. Katner AL, Gootam P, Hoang QB, et al. A recombinant adenivirns expressing p27kip1 induces cell cycle arrest and apoptosis in human 786-0 renal carcinome cells. J Urol. 2002,168(2): 766-773
140. 王刚, 薛兆英, 张志文.p27kip1基因过度表达对人膀胱癌细胞系EJ的抑制作用. 中华泌尿外科杂志. 1999,20(12): 729-731
141. 潘晓明, 章卫平, 吴宗贵. 人p27kip1重组腺病毒载体的构建及其介导的p27kip1表达. 中华肿瘤杂志。 2000; 22(2): 120-123
142. 罗昆仑,马宽生, 何振平. p27kip1真核表达载体的构建及其对胆管癌细胞生长的影响. 中国肿瘤临床. 2001,28(6): 405-409
143. 张运涛,刘凡, 姜茹. 抑癌基因p27对肾癌细胞系GRC-1生长的抑制作用.第四军医大学学报. 2001,22(7): 1566-1568
144. 宝全,胡祥. p27kip基因逆转录病毒载体的构建及其对胃癌细胞系生长抑制作用的研究. 中华现代普通外科进展. 2002,5(5): 149-151
145. 周勇安,谷仲平,王云杰. 外源性p27kip对肺癌细胞系A549的影响. 中国肺癌杂志. 2002，5(37):180-183
146. 郑建勇,李开学,王为忠. p27kip基因过表达诱导HCC-9204细胞在G1期阻滞并导致凋亡. 中华普通外科杂志. 2002, 17(9): 536-538
147. Dublin EA, Patel NK, Ginet CE. Retinoblastoma and p16 Proteins in mammary carcinoma their relationship to cyclinD1 and histopathological parameters Int J Cancer. 1998,79:71-75
148. Quesnel B, perudhomme C, Fenaux P. p16InK4, a gene and hematological lm- alignancies. Leuklymphoma 1996,22:11-24
149. Cote RJ, Dunn MD, Chatterijee SJ. Elevated and absent pRb expression is associated with bladder cancer progression and has cooperative effects with p53. Cancer Res. 1998, 58:1090-1094
150. Ai-Min Hui, Ya-zhou Shi, Xin Li. Loss of p16 InK4 protein alone and together with loss of petinoblastoma protein correlate with hepatocellular
carcinoma progression. Cancer Letters.2000,154:93-99
151. Otterson GA, Rratzke RA, Coxon A. Absence of p16INK4 protein is restricted to the subset of lung cancer lines that retains wildtype RB. Oncogene 1994,9: 3375-3378
152. Shapiro GI, Edwards CD, Kobzik L. Reciprocal Rb inactivation and p16 expression in primary lung cancers and cell lines. Cancer Res 1995, 55:505-509
153. Ueki K, Yono JW.Henson. CDK2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. Cancer Res. 1996,56:150-153
154. Fang X, Jin X, Xu HJ. Expression of p16 induces transcriptional down regulation of the RB gene. Oncogene 1998,16:1-8
155. Tokino T, Nakamura Y. The role of p53 target genes in human Cancer[J]. Crit Rev Oncol Hematol. 2000,33:16-22
156. Hollstein M, Sidransky S, Vogelstein B, et al. p53 mutation in human cancer. Science 1991,253:49-53
157. Levine A, Monmand J, Finay CA. The p53 tumor suppressor gene. Nature. 1991,351:453-456
158. Harris CC. p53: at the crossroads of molecular carcinogenesis and risk a assessment. Science. 1993,262:1980-1981
159. Blagosklonny MV, pardee AB. Exploiting cancer cell cycling for selective protection of normal cells [J]. Cancer Res. 2001, 1(11): 4301-4305
160. Zwacka RM, Dunlop MG. Gene therapy for colon cancer [J]. Hematol oncol clin North Am. 1998, 12(3): 595-615
161. Gore ME, Collins MK.Gene therapy for cancer [J].Eur cancer. 1994,30A(8): 1047-1049
162. Dubensky TW, Lin MA, Vlmer JB. Delivery systems for gene-based Vaccines. Mol Med .2000,6(9): 723-732
163. Morsy MA, Caskey CT. Expanded-capacity adenoviral Vector the helper-dependent vectors. Mol Med Today. 1999,5:18-24
164. During MJ, Nacgele JR, Mallerkl O, et al. Long-term behavioral recovery in pakinsonian rats by an HSV vector expression tyrosine hydroxylase. Science. 1994,266:1399-1403
165. Nabel GT. Development of optimized vectors for gene therapy. Proc Natl Acad Sci USA. 1999,96:324-326
166. Li S, Rizzoma MA, Bhattacharya S, et al. Characterization of cationic lipid-protamine-DNA (LPD) Complexes for intravenous gene delivery. Gene Ther. 1998,5(7): 930-937
167. Li S, Huang L. Nonviral gene therapy: promises and challenges. Gene Ther. 2000,7(1): 31-34
168. Takayanagi A, chen J, Gamou S, et al. Targeting delivery of theraputic gene using monoclonal antibody immunogene approach. Nippon Rinsho. 1998,56:731-736
169. Elliott G, O Hare P. Intercellular trafficking and protein delivery by a herpes virus structural protein. J Cell. 1997, 88: 223-233
170. Prochiantz A. Messenger proteins: homeoproteins, TAT and others. Curr Opin Cell Boil.2000, 12(4): 400-6
171. Xi Li Fu, Gene Feng, Fan Yan Rong, et al. Bifidobacterium abolescentis as a delivery system of endostatin for cancer gene therapy selective inhibitor of angiogenesis and hypoxic tumor growth cancer. Gene Ther. 2003,10: 105-111
172. Rogulsk KR, Zhang K, Koiozsvary A. Pronounced antitumor effects and tumor radiosensitization of double suicide gene therapy. Clin Cancer Res. 1997,31(11): 2081-2088
173. Uckert W, Kammertons T, Haack K, et al. Double suicide gene (cytosine deaminase and herpes simplex virus thymidine kinase) but not single gene transfer allows reliable elimination of tumor cells in Vivo. Hum Gene Ther. 1998,9(6): 955-865
174. Gao Z, Fields JZ, Bomon BM. Co-transfection of MDR1 and MRP antisense RNAs abolishes the drug resistance in multidrug-resistant human lung cancer cells. Anticancer Res. 1998,18(4C): 3073-3076
175. Rahman Z, Kavanagh J, champlin R, et al. Chemotherapy immediately following autologous stemocell transplantation in patients with advanced breast cancer. Clin cancer Res. 1998,7(11): 2717-2721
176. 吴焱. 肿瘤抑制基因在恶性肿瘤基因治疗中的应用. 国外医学遗传分册. 2001,24(1):17-21
177. 王翰章主编. 中华口腔科学. 北京:人民卫生出版社. 2001, 2591-3104
178. 温玉明,华成舸,王昌美等. 口腔癌的综合治疗.中华口腔医学杂志.2003,38(1): 73-75
179. 郭锡久,严中福,阮兴朝. 顺铂联合术前诱导化疗治疗口腔颌面部癌肿的近期疗效. 实用口腔医学杂志. 2000,6(6):460-462
180. 邱蔚六.中国口腔颌面肿瘤学进展50年.中华口腔医学杂志.2002,37(3)161-164
181. 陈万涛, 何荣根, 周晓健. 维甲酸受体-β基因联合维甲酸对Tca8113细胞的凋亡诱导作用. 口腔颌面外科杂志. 2000,10(3):214-218
182. 黄洪章, 王安训. 腺病毒介导的HSV-TK/GCV系统治疗舌癌的实验研究.中华口腔医学杂志. 2001,36(6):457-460
183. 王安训, 黄洪章. 全反式维甲酸提高HSV-TK/GCV系统治疗舌癌旁观者效应的研究. 中华口腔医学杂志. 2003,38(1): 24-26
184. 周峻, 杨连甲, 何勇. 细胞周期蛋白A正反义基因对人舌癌细胞增殖的影响. 中华口腔医学杂志. 2001,36(2): 124-127
185. 王安训,黄洪章. 腺病毒介导CD/5-FC系统治疗舌癌的实验研究.华西口腔医学杂志. 2002,20(4): 279-282
186. 高振南, 李声伟, 高家让. 人肿瘤坏死因子-a基因转染对舌癌细胞的抑制作用.华西口腔医学杂志.2002,20(1): 52-54
187. 高振南, 李声伟, 高家让. 人肿瘤坏死因子-a基因转染与干扰素-γ联合应用对舌癌细胞生长的影响.华西口腔医学杂志.2002,20(1): 55-57
188. 余优成, 顾章愉, 陈万涛. p53/p21融合基因的克隆及其对Tca8113的细胞生长的影响. 中华口腔医学杂志. 2003,38(2):116-118
189. Wakasa T, Inoue T, Kawai N, et al. The combination of ionizing radiation and expression of a wild type p53 gene via recombinant adenovirus induced a prominent tumour suppressing effect in human oral squamous cell carcinoma. Br J Radiol. 2002,75(896): 657-62
190. 何荣根，徐秀祺，周晓健.人舌鳞状细胞癌Tca8113细胞系的建立及其生物学特性. 肿瘤. 1983,3(3): 97-100
191. Kim -W-H, Ghil -K-C, Lee -J-H. Involvement of p27kip1 in ceramide mediated apoptosis in HL-60 cell. Cancer Lett.2000, Apr3. 151(1): 39-48
192. 谢斌，何双梧，王代科. 长春新碱对5肽胃泌素促人结肠癌细胞SW480增殖的影响及其临床意义. 中国普外基础与临床杂志. 2000,7（1）: 3-5
193. Weng LP, Brown JL, Eng C. PTEN coordinates G1 arrest by down-regulating cyclinD3 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a brease cancer model. Hum Mol Genet.2001, 10: 599-604
2. Hoeijmakers JH. Genome maintenance mechanisms for preventing cancer. Nature. 2001, 411(6835):366-374
3. Evans –T, Rosenthal -E-T, Youngbloom –J, et al. Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division.cell. 1983, 33(2): 389-96
4. Zhou P, Zhou P, Jiang W, et al. Antisense to cyclinD1 inhibits growth and reverses the transformed phenotype of human esophageul cancer cells. Oncogene. 1995, 11(3): 571-580
5. Bartkova J, Lukas J, Muner H, et al. cyclin D1 protein expression and function in human breast cancer. Int J Cancer. 1994,57(3): 353
6. Gansauge S, Gansauge F, Rsmadani M, et al. Over expression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis. Cancer Res. 1997, 57(9): 1634-1637
7. Zhang YJ, Jiang W, chen CJ, et al. Amplification and over expression of cyclin D1 in human hepatocellufter carcinoma. Bio chem. Biopsy’s ReQcommun. 1993,196(2): 1010
8. Nishida N, Fukuda Y, Komeda T, et al. Amplificafion and over expression of cyclinD1 gene ingressive human hepatocelluar Carcinoma. Cancer Res. 1994,54(12): 3107 -3110
9. Yu Jin Jung, Kee-Ho lee. Dong-Wook choo Reciprocal expressions of cycin E and cycinD1 in hepatocelluar carcinoma. Cancer letters .2001,68:57-63.
10. Jiang W, zhang YJ, Kahn SM, et al. Altered expression of the cyclinD1 and retinablastoma gene in human esophageal cancer. Proc Natal Aced Sci USA. 1993,90(19): 9026-9030
11. Mate JL, Ariza A, Aracil C, et al. CyclinD1 over expression in non Small cell lung carcinoma correlation with Ki-67 labeling index and poor cytoplasmic differentiation. Pathol. 1996,180(4): 395-399
12. Arbet N, Hidshoosh Moss SF, et al. Increased expression of cyclinD1 is an early event in multistage colorectal carcinogenesis. Gastroenterology. 1996,
110(3): 669-674
13. Worsley SD, Ponder BA, Davies BR. Over expression of cyclinD1 in epithelial ovarian Cancers. Gynecoloncol. 1997,64(2): 189-195
14. Haas K, Johannes C, Geisen C, et al. Malignant transformation by cyclinE and Ha-Ras correlates with lower sensitivity towards induction of cell death but requires functional Myc and CDK4. Oncogene. 1997,15(21): 2615-23
15. Geng Y, Eaton EN, Picon M, et al. Regulation of cyclin E transcripti-on by E2Fs and retinoblastoma protein. Oncogene. 1996,12(6): 1173-1180
16. Koff A, Giordano A, Desai D, et al. Formation and activation of a cyclinE-cdk2 complex during the G1 phase of the human cell cycle. Scienc-e.1992, 257:1689-1694
17. Akama Y, Yasui W, Yokozaki H, et al. Frequent amplitication of the cycinE gene in human qastric carcinoma. J Ph Cancer Res .1995,86:617-621
18. Pines J, Hunter T. Hunman cyclinA is adenovirus EIA-associated protein p60 and behaves differently from cyclin B. Nature. 1990,346:760-763
19. Pagano M, pepperkok R, Verde F, et al. Cyclin A is required at two points in the human cell cycle. EMBO J. 1992,11:961-971
20. Muller C, Yang R, Beckvon PL, et al. Cloning of the cyclinA1 qenomic structure and characterization of the promoter region GC boxes are essential for cell cycle regulated transcription of cyclinA1 gene. J Boils Chem. 1999,274:11220-11228
21. Yang R, Nakamaki T, Lubbert M, et al. CyclinA expression in leukemia and normal hematopietic cells. Blood. 1999,93:2067-2074
22. Handak YM, Takeda H, et al. Expression of cell cycle markers in colorectal carcinoma: superiority of cyclinA as a indicators of poor prognosis. Int J Cancer. 1999,84(3):225—233
23. Alatomaas, Lipponenp, Ala opas M, et al. Expression of cyclinA and p21 proteins in renal cell cancers and the relation to clinic pathological variables and patients survival. Br J Cancer. 1990,80(12): 2001-2007
24. Amon A, Irniger S, Nasmyth K. Closing the cell cycle circle in yeast: G2 cyclin proteolysis initiated at mitosis persists until the activation of G1 cyclins in the next cycle. Cell .1994,7:1037-1050
25. Dunphy WG. The decision to enter mitosis. Trends Cell Biol. 1994,4: 202-207
26. Morgan D.Principles of CDK regulation. Nature.1995,374: 131-134
27. Nana, Kohzato A, Youyi, Dong B, Li Sui C. Ove rexpression of cyclinE and cyclin-dependent kinase 2 is correlated with development of hepatocellular carcinomas. Hepatology Research.2001,21: 27-39
28. Kawana H, Tamaru J, Tanaka T, et al. Role of p27kip1 and cyclin-dependent kinase 2 in the proliferation of non-small cell lung cancer. Am J Pathol. 1998,153:505-13
29. Sasano H, Frost AR, Saitoh R, et al. Immunolocalization of cyclins D and E and cyclin-dependent kinase (cdk) 2 and 4 in human breast carcinoma. Anticancer Res. 1997,17:3685-90
30. Kim JH, Kang MJ, Park CU, et al. Amplified CDK2 and cdc2 activities in primary colorectal carcinoma. Cancer .1999,85:546-53
31. Matsumoto M, Furihata M, Ishikawa T, et al, Comparison of deregulated expression of cyclinD1 and cyclinE with that of cyclin-dependent kinase 4(CDK4) and CDK2 in human esophageal squamous cell carcinoma. Br J Cancer.1999, 80: 256-61
32. Hinds PW, Mittnacht S, Dulic V, et al. Regulation of retinoblastoma protein function by entopic expression of human cyclins. Cell .1992,70:990-1006
33. Kato J, Matsushime H, Hiebert SW, et al. Direct binding of cyclinD to the retinohlastoma gene product (pRb), pRb phosphorylation by the cyclinD-dependent kinase CDK4. Gene Rev. 1993,7:331-342
34. Cannon-Albright LA, Goldgar DE, Meyer LJ. Assignment of a locus for familiar lmelanoma MLM to chromosome 9p13-p22. Science. 1992, 258: 1148-1152
35. Serrano M, Hannon GL, Beach D. A new regulatory motifin cell cycle control causing specific inhibition of cyclinD/CDK4. Nature. 1993,366:704-707
36. He J, Olson JJ, James CD. Lack of p16IN4 or Rentinoblastom a gene alterations in hepatocellular carcinomas induced by N-nitrosodiethylamine or a cholined decently-amino acid-defined diet in rats. Cancer Letters.2000, 152: 71-77
37. Kita Y, Nishida N, Fukuda Y. Infrequent alteration of the p16 INK4a gene in liver cancer. Int J Cncer .1996,67:176-180
38. Biden K, Young J, Buttenshaw R. Frequency of mutation and deletion of the tumor suppressor gene CDKN2a (MST1/p16) in hepatocellular carcino-ma from an Australian population. Hepatology. 1997,25:593-597
39. Hui AM, Sakamoto M, Kanai Y. Inactivation of p16INK4 in hepatoc-ellular carcinoma. Hepatology .1996,24: 575-579
40. Caldas C, Hahns A, Dacostal T, et al. Frequent somatic mutations and homozygous deletions of the p16 (NTS1) gene in the pancreaticadeno carcinoma. Nat Genet .1994,8:27-32
41. Mori T, Miura K, Aoki T, et al. Frequent Somatic mutation of the MST/CDK4I (multiple tumor suppressor/cyclin dependent kinase4 inhibit gene)
in esophageal squamous cell carcinoma. Cancer Res .1994,54: 3396-3397
42. Okamoto A, Hussain SP, Hagiwara K, et al. Mutation in the p16INK4/MTS1/CDKN2 p15INK4B/MTS2 and p18 gene in primary and metastasis lung Cancer. Cancer Res .1995,55: 1448-1451
43. Gonzales ZM, Shibata A, Ohneseit PF, et al. High frequency of chromosome 9 pallelicloss and CDKN2 tumor suppressor gene alteration in squamous cell carcinoma of the bladder. Natal Cancer Inst. 1995,87: 1383-1393
44. Fizzott M, Cimino G, Pisegna S, et al. Detection of homozygous deletion of the cyclin dependent Kinase4 inhibitor (p16) gene in acute lymphoblastic leukemia and association with advance prognostic features. Blood .1995,85: 2685
45. Wu CL, Roz L, Mcknow S, et al. DNA studies understimate the major role of CDKN2a inactivation in oral and oropharyngeal squamous cell carcinomas. Genes Chromosomes Cancer. 1999,25(1): 16-25
46. Kato H, Yoshikawa M, Fukai Y, et al. An immunohistochemical study of p16 pRb p21 and p53 Proteins in human esophageal cancer. Anticancer Res. 2000, 20(14): 345-349
47. Reed AL, Califano J, Cairns P, et al. High frequency of p16 (CDKN2/MTS-1/lnk4A) in activation in had and neck squamous cell carcinoma. Cancer Res 1996,56(16): 3630-3633
48. Sartor M, Steingrimsdottir H, Elamin F, et al. Role of p16/MTS1, cyclinD1 and RB in primary oral cancer and oral cancer cell lines. British J Cancer. 1999,80(1/2) 79-86
49. Feng XH, Liu X, Derynek R. Smad2 smad3 and smad4 cooeperate with sp1 to induce p15 transcription in response to TGF-beta. EMBO J. 2000,19(9): 5178-5193
50. Fuxe J, Akusjarvi G. Adenovirus-mediated over expression of p15INK4B inhibis human glioma cell growth induces replicative senescence and inhibits telomerase activity similarly to p16INK4A. Cell Growth. 2000,11:373-384
51. Liu J, Tong YK, Liu HT. Effect of p15INK4b expression on the cell cycle and G1 phase regulated regulatory genes in human melanoma cells. Pro Nat Sci. 2001,11:40—45
52. Blais A, Labrie Y, Pouliot F, et al. Structure of the gene encoding the human cyclin-dependent inhibitor p18 and mutation al analysis in breast cancer. Biochem Biophys Res Com-mun .1998,247(1):146-153
53. Jeffrey PD, Tong L, Pavletich NP. Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors. Gent Dev .2000,14(24): 3115-3125
54. Morse L, Chen D, Franklin D, et al. Induction of cell cycle arrest sand B cell terminal differentiation by CDK4 inhibitor p18 (INK4c) and IL-6. Immunity. 1997,6:47-56
55. Tao W, Levine AJ. p19(ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2 . Proc Nat1 Acad Sci USA. 1999,96(12): 6937-6941
56. Adachi M, Roussel MF, Havenith Kand, et al. Features of macrophage differentiation induced by p19INK4d: a specific inhibitor of cyclinD-dependent kinases. Blood. 1997,90: 126—137.
57. Kannan K, Muniraian AK, Krishnamurthy J, et al. The p16INK4 alpha/p19ARF gene mutations are in freguent and are mutually exclusive to p53 mutations in Indian oral squamous cell carcinomas. Int J Oncol. 2000,16 (3): 585-590.
58. 刘习强.INK4家族与头颈肿瘤研究新进展.国外医学口腔医学分册.2002,20(1): 19-20
59. Hirama T, Koeffler HP. Role of the cyclin-dependent kinase inhibiters in the development of cancer. Blood .1995, 86(3):841-854
60. Harper JW, Elledge ST, Keyomarsi K, et al. Inhibiti of cyclin-dependent kinase by p21. Mol Biol cell. 1995,6:387-400
61. Umar A, Buermeyer AB, Simon TA, et al. Requirement for PCNA in DNA mismatch repair at a step preceding DNA resynthesis. Cell.1996, 87: 65-73
62. Hui AM, Kanai Y, Sakamoto M. Reduced p21 WAF1/CIP1 expression and p53 mutation in hepatocellular carcinomas. Hepatology. 1997,25:575-579
63. Kokunai T, Izawai I, Tamaki N. Overexpression of p21WAF1/CIP1 induces cell differentiation and growth inhibition in a human glioma cell line. Int J Cancer. 1998,75(4): 643-648
64. Lee MH, Reynisdottir I, Massague J. Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribut-ion. Genes Dev. 1995,9(6): 639-49
65. Matsuoka S, Edwards MC, Bai C, et al. p57KIP2, a structurally distinct member of the p21CIP1 CDK inhibitor family, is a candidate tumor suppressor gene. Genes-Dev. 1995,9(6): 650-62
66. Yan Y, Frisen J, Lee MH, et al. Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development. Genes-Dev. 1997,11(8): 973-83
67. Hatada I, Ohashi, H, Fukushima Y, et al. An imprinted gene p57KIP2 is mutated in Beckwith-Wiedemann syndrome. Nat Genet. 1996,14(2): 171-3
68. Kondo M, Matsuoka S, Uchida K, et al. Selective maternal-allele loss
in human lung cancers of the maternally expressed p57KIP2 gene at 11p15.5. Oncogene. 1996,12(6): 1365-8
69. Polyak K, kato JY, Solomon M, et al.p27kip1 a cyclin-CDK inhibitor links transforming growth factor beta and contact inhibition to cell cycle arrest. Genes Dev .1994,8(5): 9-22
70. Toyoshima H. p27 novel inhibitor of G1 cyclin-cdk protein kinase activity is rlated to p21. Hunter J Cell. 1994,78(1)67-74
71. Ponce-Castaneda MV, Lee MH, Latres E, et al. p27kip1 chromosomal mapping to 12p12-12p13.1 and abence of mutations in human tumors. Cancer Res .1995, 55:1211
72. Bullrich F, Maclachlan TK, Sang N, et al. Chromosomal map-ping of members of the cdc2 family of protein kinases cdk3 CDK6 POSSLRE and PJTALER and a cdk inhibitor p27kip1 to regions involved in human Cacer. Cancer Res .1995,55:1199
73. Rivard N, Bartek J, Pouyssegur J, et al. Abrogation of p27kip1 by cDNA antisense suppresses quiescence (Go State) in fibroblasts. J Biol Chem. 1996, 71:18337-18341
74. Sgambato AA, Cittadini A, Weinstein IB, et al. Multiple functions of p27kip1 and its alterations in tumor cells. J Cell Physiol .2000,183 (1): 18-27
75. Toyoshima H, Hunter T.p27 a novel inhibitor of G1 cyclin-cdk protein kinase activity is related to p21. Cell.1994, 78: 67-74
76. 陈广理. p27的生物学功能及其在中耳胆脂瘤研究中的进展. 国外医学耳鼻咽喉科学. 2002,26(3)：137-138
77. Coppock DL, Buffolino P, Kopman C, et al. Inhibition of the melamoma cellcycle and regulatioatthe at the G1/S trans by12-0 tetradecanoy-lphorbol-13-acetate (TPA) by modulation of CDK2 activity. Exp Cell Res. 1995,221:92-102
78. Depoortere F, pirson I, Bartek J, et al. Transforming growth factor beta (1) selectively inhibits the cyclin Amp-dependenp proliferation of primary thyroid epithelial cells by preventing the association of cyclinD3-cdk4 with nuclear p27kip1. Mol Biol cell, 2000,11:1061-1076
79. Resnitzky D, Hengst L, Reed S, et al. Cyclin-A-associated kinase activity is rate limiting for entranceinto S phase and is negatively regulated in G1 by p27kip1. Mol Cell Biol. 1995,15:4347-4352
80. Bleler RT, Martin R, Nucleo-cytoplasmic translocation of histone H1 during the Hela cell cycle. Chromosoma. 1999,108:308-316
81. Gardner LB, Li Q, Park MS, et al. Hypoxia inhibits G1/S transition through regulation of p27 expression. J Biol Chem. 2001,276(11):7919-7926.
82. Durand B, Gao FB, Raff MA. Accumulation of the cyclin dependent kinase inhibitor p27kip and the timing of oligodendrocyte differentiation. EMBO J. 1997, 16: 306
83. Robker RL, Richards JS. Hormone-induced proliferation and differentiation of granulosa cells: a coordinated balance of the cell cycle regulators cyclinD2 and p27kip1. Mol-Endocrinol. 1998,12(7): 924-40
84. Nakayama K, Ishida N, shirand M, et al. Mice lacking p27kip1 display increased body size multiple organ hyperplasia and piuity tumors [J]. Cell 1996;85: 707
85. Muraoka RS, Lenferink AE, Simpson J, et al. Cyclin-dependent kinase inhibitor p27(kip1) is required for mouse mammary gland morphogenesis and function[J]. J Cell Biol .2001,153(5): 917-932
86. Muraoka RS, Lenferink AE, Law B, et al. ErbB2/Neu-induced. Cyclin D1-Dependent transformation is accelerated in p27-haploinsuffi-cient mammary epithelial cells but impaired in p27-null cells. Mol cell Biol. 2002,22(7): 2204-2219
87. Alexander K, Hinds PW. Requirement for p27(kip1) in retinoblasto-ma protein-mediated sensecence[J]. Mol Cell Biol. 2001,21(11): 3616-3631
88. Katayose Y, Kim M, Rakkar AN, et al. Promoting apoptosis: A novel activity associated with the cyclin-dependent kinase inhibitor p27 [J]. Cancer Res. 1997,57:5441-5445
89. Fujieda S, Inuzuka M, Tanaka N, et al. Expression of p27 is associated with Bax expression and spontaneous apoptosis in oral and oropharyngeal carcinoma [J]. Int J Cancer .1999, 84:315.
90. Naruse I, Hoshino H, Dobashi K, et al. Over-expression of p27kip1 induces growth arrest and apoptosis mediated by changes of pRb expression in lung cancer cell [J]. Int J Cancer. 2000,88(3): 377-383
91. Barata T, Cardoso AA, Nadler LM, et al. Interleukin-7 promotes survival and cell cycle progression of T-cell acute lymphoblastic leukemia cells by down-regulating the cyclin-dependent kinase inhibitor p27 (kip1). Blood. 2001, 98(5): 1524
92. Yang Q, Sakurai T, Yoshimura G, et al. Overexpression of p27 protein in human breast cancer correlates with in vitro resistance to doxorubicin and mitomycin C. Anticancer Res 2000,20:4319
93. Oshita F, Kameda Y, Nishio K, et al. Increased expression levels of cyclin-dependent Kinase inhibitor p27 correlare with good responses to platinum-based chemotherapy in non-small cell lung cancer [J]. Oncol Rep 2000, 7(3): 491-495
94. Mendelsohn J. The epidermal growth factor receptor as a tar-get for cancer therapy [J]. Endor Relat Cancer. 2001,8:3-9
95. Valeria M, Grabiella F, Bruna P, et al. p27 expression is associated with chinical out come in advanced epithelial ovarian cancer: Muitivariate analysis. Clin Cancer Res. 2000,6:4816-4822
96. Goff BA, Paley PJ, Greer BE, et al. Evaluation of chemoresistance markers in women with epithelial ovarian carcinoma [J]. Gynecol Oncol. 2001, 81:18-24
97. Krtolica A, Krucher NA, Ludiow JW. Molecular analysis of selected cell cycle regulatory proteins during gerobie and hypoxic Maintenance of human ovarian Carcinoma cells. Br J Cancer 1999,80:1873-1875
98. St Croix B, Florenes VA, Rak JW, et al. Impact of the cyclin-dependent kinase inhibitor p27 on resistance of tumor cells to anti-Cancer agents [J]. Nature Med. 1996,2:1204-1210
99. Lloyd RV, Erickson LA, Jin L, et al. p27kip1:a multifunc-tional cyclin-dependent kinase inhibitor with prognostic signifi-cance in human cancers[J]. Am J pathol. 1999,154:313
100. Yao J, Eu KW, Seow Choen F, et al. Down-regulatien of p27 is a significant predictor of poor overall survival and may facilitate metastasis in colorectal carcinomal. Int J Cancer. 2000,20:213-216
101. George VT, Kinga S, Michael M, et al. Down-regulation of p27 is associated with development of colorectal adenocarcinoma metastases [J]. Am J Pathol.1998,153: 681-687
102. St Croix B, Sheehan C, Rak JW, et al. PE-Cadherin-dependent growth suppression is mediated by the cyclin-dependent kinase inhihitor p27 [J]. J Cell Biol. 1998,142:557-571
103. Takata T, Kudo Y, Zhao M, et al. Reduced expression of p27 (KiP1) Protein in relation to salivary adenoid cystic carcinoma metastasis [J]. Cancer. 1999,86:928
104. Kuo MY, Hsu HY, Kok SH, et al. Prognostic role of p27kip1 expression in oral squamous cell carcinoma in Taiwan [J]. Oral Oncol. 2002,38(2): 172-178
105. Singh SP, Lipman J, Goldman H, et al. Loss or altered subcellular localization of p27 in Barretts associated adenocarcinoma [J]. Cancer Res. 1998,58:1730-1735
106. Yang HY, Zhou BP, Hung MC, et al. Oncogenic signals of HER-2/neu in regulating the stability of the cyclin-dependent kinase inhibitor p27 J. Biol Chem. 2000,275:24735-24739
107. Sherr CJ.The pezcoller Iecture: Cancer cell cycles revisited [J]. Cancer Res. 2000,60:3689-3695
108. King RW. How proteolysis drives the cell cycle. Science. 1996,274(5293): 1652-1659
109. Hengst L, Reed SI. TranIational Control of p27kip1 accumulation during the cell cycle [J]. Science. 1996,271(5257): 1861-1864
110. Loda M, Cukor B, Tam SW, et al. Increased proteasome dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive Colorectal Carcinomas [J]. Nature Med .1997,3(2): 231-234
111. Hochstrasser M. Ubiquitin proteasomes and the regulation of intracellular protein degradation [J]. Curr opin cell Biol. 1995,7(2): 215-223
112. Slingerland J. Regulation of the cdk inhibit p27 and its deregulation in cancer. J Cell Phys. 2000,18:10
113. De Paola F. p27kip1 expression in normal epithelium benign and neoplastic breast. J Pathol .2002; 196(1):26
114. Koguchi K, Nakatsuji K. Modulation of astrocyte proliferation by cyclin-dependent kinase inhibitor p27kip1 [J]. Glia .2002, 37(2): 93-104
115. Sakai H, Yamane T, Yanai T, et al. Expression of cyclin kinase inhibitor p27 (kip1) in skin tumours of dogs [J]. Comp Pathol. 2001, 125(2-3): 153-158
116. Ellis FH, Xuox JR, Kulke MH, et al. Malignant transformation of the esophageal mucosa is enhanced in p27 knockout mice [J] .J Thorac Cardiovasc Surg. 2001,122(4): 809-814
117. Yang HY, Shao R, Hung MC, et al. p27kip1 inhibits HER2/neu-mediated cell growth and tumorigenesis [J]. Oncogene. 2001,20(28): 3695-3702
118. Hayashi H, Ito T, Yazawa T, et al. Reduced expression of p27kip1 is associated with the development of pulmonary adenocarcinom [J]. J Pathol. 2000,192(1): 26-31
119. Saito T, Nakajima T, Mogi K. Immunohistochemical analysis of cell cycle-associated proteins p16 pRb p53 p27 and Ki-67 in oral cancer and precancer with special reference to verrucous carcinomas. J Oral Pathol Med. 1999,28(5): 226-32
120. Pietenpol JA, Bohlander SK, Sato Y. Assignment of the p27kip1 gene to 12p13 and its analysis in leukemias. Cancer Res .1995,55:1206-1210
121. Ferrando A, Balbion M, Pendas AM. Mutational analysis of the human cyclin-dependent kinase inhibitor p27kip in primary breast carcinomas. Hum Genet. 1996,97:91-94
122. Catzavelos C, Bhattacharya N, Ung YC. Decreased levels of the cell-cycle inhibitor p27kip1 protein: prognostic implications in primary breast cancer. Nat Med .1997,3:227-230
123. Porter PL, Malone KE, Heagerty PJ. Expression of cell-cycle regulators p27kip1 and cyclin E alone and incombination correlate with survival in young breast cancer patients. Nat Med. 1997,3:222-225
124. Loda M, Cukor B, Tam SW. Increased proteasome dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med. 1997,3:231-234
125. Fradersdorf S, Burns J, Milne AM. High level expression of p27kip1 and cyclinD1 in Some human breast cancer cells: inverse correlation between the expression of p27kip1 and degree of malignancy in human breast and colorectal cancers. Prol Natl Acad Sci USA. 1997,94:6380-6385
126. Ai-Min Hui, Lin Sun, Yae kana. Reduced p27kip1 expression in hepatocellular carcinomas. Cancer Letters. 1998,132:67-73
127. 张政华, 张引成, 刘军. 粘液表皮样癌中热休克蛋白70和细胞周期调节蛋白p27表达与预后的研究. 中华口腔医学杂志. 2001,36(6):467-470
128. 汤炜, 王炼, 李声伟. 颊面粘膜癌中p27kip基因的蛋白质表达及临床意义.口腔颌面处科杂志. 2001, (1):49-52
129. 司晓辉, 金岩, 杨连甲. 颌骨骨肉瘤中p27的表达及意义.口腔医学. 2000,20(4): 174-175
130. Mineta H, Miura K, Suzuki I, et al. Low p27expression correlates with poor prognosis for patients with oral tongue squamous cell carcinoma[J]. Cancer. 1999, 85:1011
131. Tamura N, Dong Y, Sui L, et al. Cyclin-dependent kinase inhibitor p27 is related to cell proliferation and prognosis in laryngeal squamous cell carcinomas[J]. J Laryngol Otol. 2001,115:400
132. Kuo MY, Hsu HY,Kok SH,et al. Prognostic role of p27kip1 expression in oral squamous cell carcinoma in Taiwan [J]. Oral Oncol 2002,38(2): 172-178
133. Okabe M, Inagaki H, Murase J, et al. Prognostic significance of p27 and Ki-67 expression in mucoepidermoid carcinoma of the intraoral minor salivary gland. Mod Pathol. 2001,14(10): 1008-14
134. Ishihara S, Minato K, Hoshino H, et al. The cyclin-dependent kinase inhibitor p27 as a prognostic factor in advanced non-small cell lung cancer: its immunohistochemical evaluation using biopsy specimens [J]. Lung Cancer. 1999,26(3): 187-194
135. Tsukamoto S, Sugio K, sakada T, et al. Reduced expression of
cell-cyclin regulator p27 (kip1) correlates with a shortened survival in non-small cell lung cancer[J]. Lung Cancer. 2001,34(1): 83-90
136. Shige-masa K, Shiroyama Y, Sawasaki T, et al. Underexpression of cyclin-depentent kinase inhibitor p27 is associated with poor prognosis in serous ovarian carcinomas [J]. Int J Oncool .2001,18(5): 953-958
137. 李华, 金兴香, 张祖训.p27kip蛋白表达与舌鳞癌颈淋巴结转移的关系. 中华实用医学. 2002, 4(12): 38-39
138. Park KH, Seol JY, Yoo CG, et al. Adenovirus expression p27(kip1)induces growth arrest of lung cancer cell lines and suppresses the growth of established lung cancer xenografts[J]. Lung Cancer. 2001,31(2-3): 149-155
139. Katner AL, Gootam P, Hoang QB, et al. A recombinant adenivirns expressing p27kip1 induces cell cycle arrest and apoptosis in human 786-0 renal carcinome cells. J Urol. 2002,168(2): 766-773
140. 王刚, 薛兆英, 张志文.p27kip1基因过度表达对人膀胱癌细胞系EJ的抑制作用. 中华泌尿外科杂志. 1999,20(12): 729-731
141. 潘晓明, 章卫平, 吴宗贵. 人p27kip1重组腺病毒载体的构建及其介导的p27kip1表达. 中华肿瘤杂志。 2000; 22(2): 120-123
142. 罗昆仑,马宽生, 何振平. p27kip1真核表达载体的构建及其对胆管癌细胞生长的影响. 中国肿瘤临床. 2001,28(6): 405-409
143. 张运涛,刘凡, 姜茹. 抑癌基因p27对肾癌细胞系GRC-1生长的抑制作用.第四军医大学学报. 2001,22(7): 1566-1568
144. 宝全,胡祥. p27kip基因逆转录病毒载体的构建及其对胃癌细胞系生长抑制作用的研究. 中华现代普通外科进展. 2002,5(5): 149-151
145. 周勇安,谷仲平,王云杰. 外源性p27kip对肺癌细胞系A549的影响. 中国肺癌杂志. 2002，5(37):180-183
146. 郑建勇,李开学,王为忠. p27kip基因过表达诱导HCC-9204细胞在G1期阻滞并导致凋亡. 中华普通外科杂志. 2002, 17(9): 536-538
147. Dublin EA, Patel NK, Ginet CE. Retinoblastoma and p16 Proteins in mammary carcinoma their relationship to cyclinD1 and histopathological parameters Int J Cancer. 1998,79:71-75
148. Quesnel B, perudhomme C, Fenaux P. p16InK4, a gene and hematological lm- alignancies. Leuklymphoma 1996,22:11-24
149. Cote RJ, Dunn MD, Chatterijee SJ. Elevated and absent pRb expression is associated with bladder cancer progression and has cooperative effects with p53. Cancer Res. 1998, 58:1090-1094
150. Ai-Min Hui, Ya-zhou Shi, Xin Li. Loss of p16 InK4 protein alone and together with loss of petinoblastoma protein correlate with hepatocellular
carcinoma progression. Cancer Letters.2000,154:93-99
151. Otterson GA, Rratzke RA, Coxon A. Absence of p16INK4 protein is restricted to the subset of lung cancer lines that retains wildtype RB. Oncogene 1994,9: 3375-3378
152. Shapiro GI, Edwards CD, Kobzik L. Reciprocal Rb inactivation and p16 expression in primary lung cancers and cell lines. Cancer Res 1995, 55:505-509
153. Ueki K, Yono JW.Henson. CDK2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. Cancer Res. 1996,56:150-153
154. Fang X, Jin X, Xu HJ. Expression of p16 induces transcriptional down regulation of the RB gene. Oncogene 1998,16:1-8
155. Tokino T, Nakamura Y. The role of p53 target genes in human Cancer[J]. Crit Rev Oncol Hematol. 2000,33:16-22
156. Hollstein M, Sidransky S, Vogelstein B, et al. p53 mutation in human cancer. Science 1991,253:49-53
157. Levine A, Monmand J, Finay CA. The p53 tumor suppressor gene. Nature. 1991,351:453-456
158. Harris CC. p53: at the crossroads of molecular carcinogenesis and risk a assessment. Science. 1993,262:1980-1981
159. Blagosklonny MV, pardee AB. Exploiting cancer cell cycling for selective protection of normal cells [J]. Cancer Res. 2001, 1(11): 4301-4305
160. Zwacka RM, Dunlop MG. Gene therapy for colon cancer [J]. Hematol oncol clin North Am. 1998, 12(3): 595-615
161. Gore ME, Collins MK.Gene therapy for cancer [J].Eur cancer. 1994,30A(8): 1047-1049
162. Dubensky TW, Lin MA, Vlmer JB. Delivery systems for gene-based Vaccines. Mol Med .2000,6(9): 723-732
163. Morsy MA, Caskey CT. Expanded-capacity adenoviral Vector the helper-dependent vectors. Mol Med Today. 1999,5:18-24
164. During MJ, Nacgele JR, Mallerkl O, et al. Long-term behavioral recovery in pakinsonian rats by an HSV vector expression tyrosine hydroxylase. Science. 1994,266:1399-1403
165. Nabel GT. Development of optimized vectors for gene therapy. Proc Natl Acad Sci USA. 1999,96:324-326
166. Li S, Rizzoma MA, Bhattacharya S, et al. Characterization of cationic lipid-protamine-DNA (LPD) Complexes for intravenous gene delivery. Gene Ther. 1998,5(7): 930-937
167. Li S, Huang L. Nonviral gene therapy: promises and challenges. Gene Ther. 2000,7(1): 31-34
168. Takayanagi A, chen J, Gamou S, et al. Targeting delivery of theraputic gene using monoclonal antibody immunogene approach. Nippon Rinsho. 1998,56:731-736
169. Elliott G, O Hare P. Intercellular trafficking and protein delivery by a herpes virus structural protein. J Cell. 1997, 88: 223-233
170. Prochiantz A. Messenger proteins: homeoproteins, TAT and others. Curr Opin Cell Boil.2000, 12(4): 400-6
171. Xi Li Fu, Gene Feng, Fan Yan Rong, et al. Bifidobacterium abolescentis as a delivery system of endostatin for cancer gene therapy selective inhibitor of angiogenesis and hypoxic tumor growth cancer. Gene Ther. 2003,10: 105-111
172. Rogulsk KR, Zhang K, Koiozsvary A. Pronounced antitumor effects and tumor radiosensitization of double suicide gene therapy. Clin Cancer Res. 1997,31(11): 2081-2088
173. Uckert W, Kammertons T, Haack K, et al. Double suicide gene (cytosine deaminase and herpes simplex virus thymidine kinase) but not single gene transfer allows reliable elimination of tumor cells in Vivo. Hum Gene Ther. 1998,9(6): 955-865
174. Gao Z, Fields JZ, Bomon BM. Co-transfection of MDR1 and MRP antisense RNAs abolishes the drug resistance in multidrug-resistant human lung cancer cells. Anticancer Res. 1998,18(4C): 3073-3076
175. Rahman Z, Kavanagh J, champlin R, et al. Chemotherapy immediately following autologous stemocell transplantation in patients with advanced breast cancer. Clin cancer Res. 1998,7(11): 2717-2721
176. 吴焱. 肿瘤抑制基因在恶性肿瘤基因治疗中的应用. 国外医学遗传分册. 2001,24(1):17-21
177. 王翰章主编. 中华口腔科学. 北京:人民卫生出版社. 2001, 2591-3104
178. 温玉明,华成舸,王昌美等. 口腔癌的综合治疗.中华口腔医学杂志.2003,38(1): 73-75
179. 郭锡久,严中福,阮兴朝. 顺铂联合术前诱导化疗治疗口腔颌面部癌肿的近期疗效. 实用口腔医学杂志. 2000,6(6):460-462
180. 邱蔚六.中国口腔颌面肿瘤学进展50年.中华口腔医学杂志.2002,37(3)161-164
181. 陈万涛, 何荣根, 周晓健. 维甲酸受体-β基因联合维甲酸对Tca8113细胞的凋亡诱导作用. 口腔颌面外科杂志. 2000,10(3):214-218
182. 黄洪章, 王安训. 腺病毒介导的HSV-TK/GCV系统治疗舌癌的实验研究.中华口腔医学杂志. 2001,36(6):457-460
183. 王安训, 黄洪章. 全反式维甲酸提高HSV-TK/GCV系统治疗舌癌旁观者效应的研究. 中华口腔医学杂志. 2003,38(1): 24-26
184. 周峻, 杨连甲, 何勇. 细胞周期蛋白A正反义基因对人舌癌细胞增殖的影响. 中华口腔医学杂志. 2001,36(2): 124-127
185. 王安训,黄洪章. 腺病毒介导CD/5-FC系统治疗舌癌的实验研究.华西口腔医学杂志. 2002,20(4): 279-282
186. 高振南, 李声伟, 高家让. 人肿瘤坏死因子-a基因转染对舌癌细胞的抑制作用.华西口腔医学杂志.2002,20(1): 52-54
187. 高振南, 李声伟, 高家让. 人肿瘤坏死因子-a基因转染与干扰素-γ联合应用对舌癌细胞生长的影响.华西口腔医学杂志.2002,20(1): 55-57
188. 余优成, 顾章愉, 陈万涛. p53/p21融合基因的克隆及其对Tca8113的细胞生长的影响. 中华口腔医学杂志. 2003,38(2):116-118
189. Wakasa T, Inoue T, Kawai N, et al. The combination of ionizing radiation and expression of a wild type p53 gene via recombinant adenovirus induced a prominent tumour suppressing effect in human oral squamous cell carcinoma. Br J Radiol. 2002,75(896): 657-62
190. 何荣根，徐秀祺，周晓健.人舌鳞状细胞癌Tca8113细胞系的建立及其生物学特性. 肿瘤. 1983,3(3): 97-100
191. Kim -W-H, Ghil -K-C, Lee -J-H. Involvement of p27kip1 in ceramide mediated apoptosis in HL-60 cell. Cancer Lett.2000, Apr3. 151(1): 39-48
192. 谢斌，何双梧，王代科. 长春新碱对5肽胃泌素促人结肠癌细胞SW480增殖的影响及其临床意义. 中国普外基础与临床杂志. 2000,7（1）: 3-5
193. Weng LP, Brown JL, Eng C. PTEN coordinates G1 arrest by down-regulating cyclinD3 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a brease cancer model. Hum Mol Genet.2001, 10: 599-604