P27~(kip1)、Cyclin D1与Skp2在基底细胞癌及其临床病理特征中的表达
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摘要
目的:检测激酶抑制蛋白-1(kinase inhibition protein-1, P27~(kip1))、周期素D1(Cyclin D1)与S期激酶相关蛋白-2(S-phase kinase-associated protein-2, Skp2)在基底细胞癌(Basal cell carcinoma, BCC)中的表达,探讨三者在BCC发生发展中的作用及其相关性,及与BCC临床病理特征的关系;并初步研究P27~(kip1)、Cyclin D1与Skp2在BCC临床分型中的作用,尤以硬化型中的作用为主。
方法:取皮肤基底细胞癌病理蜡块26例,7例为硬化型基底细胞癌组(即侵袭性基底细胞癌组,IBCCs) 19例结节型及浅表型组(即非侵袭性基底细胞癌组,NIBCCs),应用免疫组织化学染色SP二步法检测26例BCC及20例正常皮肤组织对照组中P27~(kip1)、Cyclin D1与Skp2的表达情况,并结合患者的年龄、性别及有无复发等进行综合分析。所有资料均运用SPSS13.0进行统计分析,采用卡方检验,以P<0.05为差异有显著性,P<0.01为差异有非常显著性。BCC组别间及IBCCs内相关性检验采用Phi相关分析等。
结果:
1.P27~(kip1)与Cyclin D1阳性表达均定位于胞核,而Skp2阳性表达定位于胞核或胞浆。
2.P27~(kip1)在BCC阳性表达率为65.4%(17/26),在正常皮肤组织中为95.0%(19/20),在两者之间的表达有显著的差异(P<0.05);P27~(kip1)在IBCCs阳性表达率为28.6%(2/7),在NIBCCs为78.9% (15/19),在组间的表达也有显著差异(P<0.05)。
3.Cyclin D1在BCC阳性表达率为38.5%(10/26),在正常皮肤组织中为5% (1/20),在两者之间的表达有显著的差异(P<0.05);Cyclin D1在IBCCs阳性表达率为85.7%(6/7),在NIBCCs为21.2%(4/19),在组间的表达也有显著差异(P<0.05)。
4.Skp2在BCC阳性表达率为46.2%(12/26),在正常皮肤组织中为10% (2/20),在两者之间的表达有非常显著的差异(P<0.01);Skp2在IBCCs阳性表达率为85.7%(6/7),在NIBCCs为31.6%(6/19),在组间的表达也有显著差异(P<0.05)。
5.P27~(kip1)、Cyclin D1与Skp2表达与患者性别、年龄等因素均无关(P>0.05)。
6.经Phi相关分析发现: BCC中,Cyclin D1与P27~(kip1)阳性表达成负相关,相关系数r= -0.422,P<0.05; BCC中,Skp2与P27~(kip1)阳性表达成负相关,相关系数r= -0.624,P<0.05; BCC中,Cyclin D1与Skp2阳性表达成正相关,相关系数r= 0.695,P<0.05。
7.IBCCs中,这些蛋白均无相关性(P<0.05)。
结论:
1.P27~(kip1)蛋白定位与肿瘤的恶性程度也有很大相关性,其蛋白的胞核定位对其在细胞周期中生长抑制功能是必须的。
2.在BCC中存在P27~(kip1)的低表达,Cyclin D1与Skp2的高表达,提示三者在BCC的发生、发展起重要作用。在IBCCs组间,P27~(kip1)的低表达,Cyclin D1与Skp2的高表达,提示三者在BCC分型中可起到相当重要的地位。
3.在BCC中,Cyclin D1及Skp2两个蛋白与P27~(kip1)阳性表达率均成负相关,提示在BCC的浸润、转移等中存在协同作用或相互调节机制,共同促进肿瘤的发生发展;而Cyclin D1与Skp2阳性表达率成正相关,提示在BCC的浸润、转移等中存在拮抗作用,可能共同抑制肿瘤的发生发展。
4.P27~(kip1)、Cyclin D1与Skp2在BCC中的表达与临床病理特征无关,如性别、年龄等因素;三者在IBCCs中也无相关性,考虑可能与例数少或者检测方法受限所致,需进一步完善。
本研究初步探讨了细胞周期调控因子P27~(kip1)、Cyclin D1与Skp2在BCC发生发展中的作用,深入研究了它们与BCC临床病理特征的关系及组别间和IBCCs中的作用,提示三者的检测可作为BCC的诊断及评价分析恶性程度的重要参考指标,有可能为将来的治疗提供靶点,同时也揭示出BCC的发生发展是多基因相互协同或拮抗的结果,联合检测可参与皮肤BCC的分型,并有可能成为BCC分型的预测因子,从而为不同类型BCC手术切缘的设计提供依据。
Objective: To investigate the expression of P27~(kip1), Cyclin D1, Skp2 and their relationship with the clinicopathologic features in basal cell carcinoma(BCC) . To explore their expression between with the subtypes of BCC of skin especially in morpheaform BCC subtype(IBCCs).
Methods: Twenty-six BCCs were divided into two groups(seven in morpheaform BCC subtype, IBCCs; nineteen in superficial and nodular BCC subtype, NIBCCs). We used streptavidin-biotin peroxidase(SP) method of immunohistochemical staining for observing the expression of P27~(kip1), Cyclin D1 and Skp2 in 50 cases of BCC and 30 cases with normal tissues of skin in control group. The expression level was analyzed combined with clinicopathological features of age, gender and subtypes of tumor. Tissue sections were observed under optical microscope. All the data were conducted by spss13.0, chisquare test was used, P<0.05 was refered to statistically significant difference, P<0.01 was refered to statistically significant difference extremely. The relations of the three marks in BCC subtypes and IBCCs were conducted by Phi correlation analysis.
Results:
1.P27~(kip1) and Cyclin D1 positive products located in nucleus. Skp2 positive products located in cytoplasm or nucleus.
2.The rate of positive expression of P27~(kip1) in BCC was 65.4%(17/26), in normal skin tissues was 95.0%(19/20)(P<0.05); P27~(kip1) in IBCCs was 28.6%(2/7), in NIBCCs was 78.9% (15/19) (P<0.05).
3.The rate of positive expression of Cyclin D1 in BCC was 38.5%(10/26), in normal skin tissues was 5% (1/20)(P<0.05); Cyclin D1 in IBCCs was 85.7%(6/7), in NIBCCs was 21.2%(4/19) (P<0.05).
4.The rate of positive expression of Skp2 in BCC was 46.2%(12/26), in normal skin tissues was 10% (2/20)(P<0.01); Skp2 in IBCCs was 85.7%(6/7), in NIBCCs was 31.6%(6/19) (P<0.05).
5.The rate of positive expression of P27~(kip1), Cyclin D1, Skp2 were no significant differences in age and sex of tumor(P>0.05).
6.Phi correlation analysis showed that: Cyclin D1 expression in BCC had negative correlation with P27~(kip1) expression. Correlation coefficient: r= -0.422,P<0.05;
Skp2 expression in BCC had negative correlation with P27~(kip1) expression. Correlation coefficient: r= -0.624,P<0.05;
Cyclin D1 expression in BCC had positive correlation with Skp2 expression. Correlation coefficient: r= 0.695,P<0.05.
7. There were no correlated with each other of the three marks in IBCCs(P>0.05).
Conclusions:
1.There is significant relationship between the location of P27~(kip1) and the grade of malignancy in certain human tumours.
2.Low expression of P27~(kip1) and high expression of Cyclin D1 and Skp2 was in BCC, which indicate three of them may play an important role in carcinogenesis and the development of BCC. The expression of P27~(kip1) in IBCCs was lower than it in NIBCCs, but Cyclin D1 and Skp2 were reverse with P27~(kip1), which imply that they may play an important role in BCC subtypes.
3.Cyclin D1 and Skp2 expression were negatively correlated with P27~(kip1), which indicates that Cyclin D1 and Skp2 are coordinating or co-regulating in the saturation and transference of tumor and promoting the occurrence and development of tumor together with P27~(kip1). Cyclin D1 expression was positively correlated with Skp2 in BCC, which indicates that there is reverse role in BCC.
4. There were no significant differences in age and gender of tumor.And they are not associated with each other in IBCCs, due to fewer cases of this experiment can not be proven relation with IBCCs. We will keep working on it.
This research investigats the roles of the regulation factors P27~(kip1), Cyclin D1 and Skp2 of cell cycle in the occurrence of BCC, and their relation with the clinopathological charaters and with the role in IBCCs, indicating that the examination of the three factors can be taken as important indicators for diagnosis and evaluation of the malignancy degree of BCC, and also make targets to treat it. It also reveals that the occurrence and development of BCC is due to the coordinated work or antagonism of many genes, and a joint test will help the accurate evaluation in the diagnosis and prognosis, can be useful factors to predict the subtypes of the tumor, also determine surgical margin for BCC cases.
方法:取皮肤基底细胞癌病理蜡块26例,7例为硬化型基底细胞癌组(即侵袭性基底细胞癌组,IBCCs) 19例结节型及浅表型组(即非侵袭性基底细胞癌组,NIBCCs),应用免疫组织化学染色SP二步法检测26例BCC及20例正常皮肤组织对照组中P27~(kip1)、Cyclin D1与Skp2的表达情况,并结合患者的年龄、性别及有无复发等进行综合分析。所有资料均运用SPSS13.0进行统计分析,采用卡方检验,以P<0.05为差异有显著性,P<0.01为差异有非常显著性。BCC组别间及IBCCs内相关性检验采用Phi相关分析等。
结果:
1.P27~(kip1)与Cyclin D1阳性表达均定位于胞核,而Skp2阳性表达定位于胞核或胞浆。
2.P27~(kip1)在BCC阳性表达率为65.4%(17/26),在正常皮肤组织中为95.0%(19/20),在两者之间的表达有显著的差异(P<0.05);P27~(kip1)在IBCCs阳性表达率为28.6%(2/7),在NIBCCs为78.9% (15/19),在组间的表达也有显著差异(P<0.05)。
3.Cyclin D1在BCC阳性表达率为38.5%(10/26),在正常皮肤组织中为5% (1/20),在两者之间的表达有显著的差异(P<0.05);Cyclin D1在IBCCs阳性表达率为85.7%(6/7),在NIBCCs为21.2%(4/19),在组间的表达也有显著差异(P<0.05)。
4.Skp2在BCC阳性表达率为46.2%(12/26),在正常皮肤组织中为10% (2/20),在两者之间的表达有非常显著的差异(P<0.01);Skp2在IBCCs阳性表达率为85.7%(6/7),在NIBCCs为31.6%(6/19),在组间的表达也有显著差异(P<0.05)。
5.P27~(kip1)、Cyclin D1与Skp2表达与患者性别、年龄等因素均无关(P>0.05)。
6.经Phi相关分析发现: BCC中,Cyclin D1与P27~(kip1)阳性表达成负相关,相关系数r= -0.422,P<0.05; BCC中,Skp2与P27~(kip1)阳性表达成负相关,相关系数r= -0.624,P<0.05; BCC中,Cyclin D1与Skp2阳性表达成正相关,相关系数r= 0.695,P<0.05。
7.IBCCs中,这些蛋白均无相关性(P<0.05)。
结论:
1.P27~(kip1)蛋白定位与肿瘤的恶性程度也有很大相关性,其蛋白的胞核定位对其在细胞周期中生长抑制功能是必须的。
2.在BCC中存在P27~(kip1)的低表达,Cyclin D1与Skp2的高表达,提示三者在BCC的发生、发展起重要作用。在IBCCs组间,P27~(kip1)的低表达,Cyclin D1与Skp2的高表达,提示三者在BCC分型中可起到相当重要的地位。
3.在BCC中,Cyclin D1及Skp2两个蛋白与P27~(kip1)阳性表达率均成负相关,提示在BCC的浸润、转移等中存在协同作用或相互调节机制,共同促进肿瘤的发生发展;而Cyclin D1与Skp2阳性表达率成正相关,提示在BCC的浸润、转移等中存在拮抗作用,可能共同抑制肿瘤的发生发展。
4.P27~(kip1)、Cyclin D1与Skp2在BCC中的表达与临床病理特征无关,如性别、年龄等因素;三者在IBCCs中也无相关性,考虑可能与例数少或者检测方法受限所致,需进一步完善。
本研究初步探讨了细胞周期调控因子P27~(kip1)、Cyclin D1与Skp2在BCC发生发展中的作用,深入研究了它们与BCC临床病理特征的关系及组别间和IBCCs中的作用,提示三者的检测可作为BCC的诊断及评价分析恶性程度的重要参考指标,有可能为将来的治疗提供靶点,同时也揭示出BCC的发生发展是多基因相互协同或拮抗的结果,联合检测可参与皮肤BCC的分型,并有可能成为BCC分型的预测因子,从而为不同类型BCC手术切缘的设计提供依据。
Objective: To investigate the expression of P27~(kip1), Cyclin D1, Skp2 and their relationship with the clinicopathologic features in basal cell carcinoma(BCC) . To explore their expression between with the subtypes of BCC of skin especially in morpheaform BCC subtype(IBCCs).
Methods: Twenty-six BCCs were divided into two groups(seven in morpheaform BCC subtype, IBCCs; nineteen in superficial and nodular BCC subtype, NIBCCs). We used streptavidin-biotin peroxidase(SP) method of immunohistochemical staining for observing the expression of P27~(kip1), Cyclin D1 and Skp2 in 50 cases of BCC and 30 cases with normal tissues of skin in control group. The expression level was analyzed combined with clinicopathological features of age, gender and subtypes of tumor. Tissue sections were observed under optical microscope. All the data were conducted by spss13.0, chisquare test was used, P<0.05 was refered to statistically significant difference, P<0.01 was refered to statistically significant difference extremely. The relations of the three marks in BCC subtypes and IBCCs were conducted by Phi correlation analysis.
Results:
1.P27~(kip1) and Cyclin D1 positive products located in nucleus. Skp2 positive products located in cytoplasm or nucleus.
2.The rate of positive expression of P27~(kip1) in BCC was 65.4%(17/26), in normal skin tissues was 95.0%(19/20)(P<0.05); P27~(kip1) in IBCCs was 28.6%(2/7), in NIBCCs was 78.9% (15/19) (P<0.05).
3.The rate of positive expression of Cyclin D1 in BCC was 38.5%(10/26), in normal skin tissues was 5% (1/20)(P<0.05); Cyclin D1 in IBCCs was 85.7%(6/7), in NIBCCs was 21.2%(4/19) (P<0.05).
4.The rate of positive expression of Skp2 in BCC was 46.2%(12/26), in normal skin tissues was 10% (2/20)(P<0.01); Skp2 in IBCCs was 85.7%(6/7), in NIBCCs was 31.6%(6/19) (P<0.05).
5.The rate of positive expression of P27~(kip1), Cyclin D1, Skp2 were no significant differences in age and sex of tumor(P>0.05).
6.Phi correlation analysis showed that: Cyclin D1 expression in BCC had negative correlation with P27~(kip1) expression. Correlation coefficient: r= -0.422,P<0.05;
Skp2 expression in BCC had negative correlation with P27~(kip1) expression. Correlation coefficient: r= -0.624,P<0.05;
Cyclin D1 expression in BCC had positive correlation with Skp2 expression. Correlation coefficient: r= 0.695,P<0.05.
7. There were no correlated with each other of the three marks in IBCCs(P>0.05).
Conclusions:
1.There is significant relationship between the location of P27~(kip1) and the grade of malignancy in certain human tumours.
2.Low expression of P27~(kip1) and high expression of Cyclin D1 and Skp2 was in BCC, which indicate three of them may play an important role in carcinogenesis and the development of BCC. The expression of P27~(kip1) in IBCCs was lower than it in NIBCCs, but Cyclin D1 and Skp2 were reverse with P27~(kip1), which imply that they may play an important role in BCC subtypes.
3.Cyclin D1 and Skp2 expression were negatively correlated with P27~(kip1), which indicates that Cyclin D1 and Skp2 are coordinating or co-regulating in the saturation and transference of tumor and promoting the occurrence and development of tumor together with P27~(kip1). Cyclin D1 expression was positively correlated with Skp2 in BCC, which indicates that there is reverse role in BCC.
4. There were no significant differences in age and gender of tumor.And they are not associated with each other in IBCCs, due to fewer cases of this experiment can not be proven relation with IBCCs. We will keep working on it.
This research investigats the roles of the regulation factors P27~(kip1), Cyclin D1 and Skp2 of cell cycle in the occurrence of BCC, and their relation with the clinopathological charaters and with the role in IBCCs, indicating that the examination of the three factors can be taken as important indicators for diagnosis and evaluation of the malignancy degree of BCC, and also make targets to treat it. It also reveals that the occurrence and development of BCC is due to the coordinated work or antagonism of many genes, and a joint test will help the accurate evaluation in the diagnosis and prognosis, can be useful factors to predict the subtypes of the tumor, also determine surgical margin for BCC cases.
引文
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[36]、郭剑锋,陈富进,管志伟,等.荧光定量PCR技术检测喉鳞状细胞癌标本中Skp2基因表达.临床耳鼻咽喉头颈外科杂志,2008,22(12):547-550.
[37]、Dong Y,Sui L,Watanabe Y,et al. S-phase kinase-associated protein 2 expression in laryngeal squamous cell carcinoma and its prognostic implications. Oncol Rep,2003,10(2):321-325.
[38]、高俊霞,王纯波,吕强. Cyclin D1、p27kip1及幽门螺旋杆菌在胃息肉和胃癌中的表达及相关性探索.医学综述,2010,16(16):2520-2523.
[39]、Motti ML,Califano D,Troncone G,et al. Complex regulation of the cyclin-dependent kinase inhibitor p27kip1 in thyroid cancer cells by the P13K/AKT pathway: regulation of p27kip1 expression and localization. Am J Pathol,2005,166(3):737-749.
[1]、Stralton SP. Prevention of non-melanoma skin cancer. Curr Oncol Rep,2001,3(4):295-300.
[2]、Allali J,D’Hermies F,Renard G. Basal cell carcinomas of the eyelids. Ophthalmologica,2005,219(2):57-71.
[3]、Dazard JE,Gal H,Amariglio N,et al. Genomewide comparison of human keratinocyte and squamous cell carcinoma response to UVB irradiation:implication for skin and epithelial cancer. Oncogene,2003,22(19):2993-3006.
[4]、Saari KM,Paavilainen V,Tuominen J,et al. Epidemiology of basal cell carcinoma of the eyelid in south-western Finland. Graefes Arch Clin Exp Ophthalmol,2001,239(3):230-233.
[5]、Ragge NK,Salt A,Collin JR,et al. Gorlin syndrome:the PTCH gene links ocular developmental defects and tumour formation. Br J Ophthalmol,2005,89(8):988-991.
[6]、Zhang H,Ping XL,Lee PK,et al.Role of PTCH and P53 Genes in Early-Onset basal Cell Carcinoma.Am J Pathol,2001,158(2):381-385.
[7]、Hahn H,Wicking c,Zaphiropoulous PG,et al. Mutations of the Human Homolog of Drosophila Patched in the Nevoid Basal Carcinoma Syndrome. Cell,1996,85(5):841-851.
[8]、Thibert C,Teillet MA,Lapointe F,et al. Inhibition of neuroepithelial patched-induced apoptosis by sonic hedgehog. Science,2003,301(5634):843-846.
[9]、Barnes EA,Kong M,Ollendorff V,et al. Patched interacts with cyclin B1 to regulate cell cycle progression. EMBO J,2001,20(9):2212-2223.
[10]、Bergstein I,Leopold PL,Sato N,et al. In vivo enhanced expression of patched dampens the sonic hedgehog pathway. Mol Ther,2002,6(2):258-264.
[11]、Casali A,Struhl G. Reading the Hedgehog morphogen gradient by measuring the ratio of bound to unbound Patched protein. Nature,2004,431(7004):76-80.
[12]、Heitzer E,Lassacher A,Quehenberger F,et al. UV fingerprints predominate in the PTCH mutation spectraof basal cell carcinomas independent of clinical phenotype. J Invest Dermatol,2007,127(12):2872-2881.
[13]、Dicker AJ,Serewko MM,Russell T,et al. Isolation (from a basal cell carcinoma ) of a functionally distinct fibroblast—like cell type that overexpresses PTCH. J Invest De rmatol,2002,118(5):859.
[14]、Akkiprik M,Celikel CA,Dü?ünceli F,et al. Relationship between overexpression of ras P21 oncoprotein and K-ras codon 12 and 13 mutations in Trukish colorectal cancer patients. Turk J Gastroenterol,2008,19(1):22-27.
[15]、Haigis KM,Kendall KR,Wang Y,et al. Differential effects of oncogenic K-ras and N-ras on proliferation, differentiation and tumor progression in the colon. Nature Genetics,2008,40(5):600-608.
[16]、Amstad PA,Cerutti PA. Ultraviolet-B-light-induced mutagencsis of C-H-Ras codons 11 and 12 in human skin flbroblasts. Int J Cancer,1995,63(1):136-139.
[17]、Hussein MR. Ultraviolet radiation and skin cancer:molecular mechanisms. J Cutan Pathol,2005,32(3):191-205.
[18]、Murphy N,Ring M,Killalea AG,et al. p16INK4a as a marker for cervical dyskaryosis:CIN and cGIN in cervical biopsies and ThinPrep smears. Clin Pathol,2003,56(1):56-63.
[19]、Haferkamp S , Becker TM , Scurr LL , et al. p16(INK4a)-induced senescence is disabled by melanoma-associated mutations. Aging Cell,2008,7(5):733-745.
[20]、Khoo CM, Carrasco DR, Bosenberg MW,et al. Ink4a/Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse. Proc Natl Acad Sci USA,2007,104(10):3931-3936.
[21]、Nemtsova MV,Zemliakova VV,Kuznetsova EV. Correlation of p16/INK4a gene damages and protein expression in the tumor tissue of sporadic breast cancer. Arkh Pathol,2008,70(4):6-9.
[22]、Blokx WA,Lesterhuis JJ,Andriessen MP,et al. CDKN2A INK4A-ARF mutation analysis to distinguish cutaneous melanoma metastasis from a second primary melanoma. Am J Surg Pathol,2007,31(4):637-641.
[23]、Saridaki Z,Koumantaki E,Liloglon T,et al. High frequency of loss of heterozygosity on chromosome region 9p21-p22 but lack of P16INK4a/p19ARF mutations in greek patients with basal cell carcinoma of the skin. J Invest Dermatol,2000,115(4):719-725.
[24]、Niu Y,Liu F,Menf X,et al. A Study on the Expression of P16 Protein and Bcl-2 Protein in Cutaneous Eyelid Tumors. Chin J Ophthalmol,2000,36(4):259-262.
[25]、Liu Fuling,Niu YingjLtn,Wang Hongyun,et al. Expression of P16 and CD44v6 in basal cell carcinomas of eyelid. Clin Ophthal Res,2005,23(1):63-65.
[26]、Rajabi MA,Rajabi P,Afshar-Moghaddam N. Determination of P53 expression in basal cell carcinoma tissues and adjacent nontumoral epidermis from sun-exposed areas of the head and neck. Arch Iran Med,2006,9(1):46-48.
[27]、Reszec J,Sulkowski S. The expression of P53 protein and infection of human papilloma virus in conjunctival and eyelid neoplasms. Int J Mol Med,2005,16(4):559-564.
[28]、Tsai KY,TsaoH. The genetics of skin cancer. Am J Med Genet C Semin Med Genet,2004,131(1):82-92.
[29]、Brash DE,Ziegler A,Jonason AS,et al. Sunlight and sunburn in human skin cancer p53 apoptosis and tumor promotion. J invest Dermatol Symp Proc,1996,1(2):136-142.
[30]、Ahmed MM,Alcock RA,Chendil D ,et al. Restoration of Transforming Growth Factor-βSignaling Enhances Radiosensitivity by Altering the Bcl-2/Bax Ratio in the p53 Mutant Pancreatic Cancer Cell Line MIA PaCa-2. J Biol Chem,2002,277(3):2234-2246.
[31]、Bolshakov S, Walker CM, Strom SS,et al. P53 mutations in human aggressive and nonaggressive basal and squamous cell carcinomas. Clin Cancer Res,2003,9(1):228-234.
[32]、Demirkan NC,Colakoglu N,Duzcan E. Value of P53 portein in biological behavior of basal cell carcinoma and in normal epithelia adjacent to carcinomas. Pathol Oncol Res,2000,6(4): 272-274.
[33]、Liefer KM,Koster MI. Down Regulation of P63 is Required for Epidermal U-V-B induced Apoptosis. Cancer Res,2000,60(15):4016-4020.
[34]、王良君,李超英,孙玉芬,等. Nm23H1和NF-kBP65在眼睑BCC中的表达及意义.山东大学基础医学院报,2005,19(1):49-51.
[35]、Kanitakis J,Euvrard S,Bourchany D,et al. Expression of the nm23 metastasis-suppressor gene product in skin tumors. J Cutan Pathol,1997,24(3):151-156.
[36]、Ramdial PK, Madaree A,Reddy R,et al. Bcl-2 protein expression in aggressive and non- aggressive basal cell carcinomas. J Cutan Pathol,2000,27(6):283-291.
[37]、Bozdogan O,Erkek E,Atasoy P,et al. Bcl-2-related proteins,alpha-smooth muscle actin and amyloid deposits in aggressive and non-aggressive basal cell carcinomas. Acta Derm Venereal,2002,82(6):423-427.
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[39]、Motti ML,Califano D,Troncone G,et al. Complex regulation of the cyclin-dependent kinase inhibitor p27kip1 in thyroid cancer cells by the P13K/AKT pathway: regulation of p27kip1 expression and localization. Am J Pathol,2005,166(3):737-749.
[1]、Stralton SP. Prevention of non-melanoma skin cancer. Curr Oncol Rep,2001,3(4):295-300.
[2]、Allali J,D’Hermies F,Renard G. Basal cell carcinomas of the eyelids. Ophthalmologica,2005,219(2):57-71.
[3]、Dazard JE,Gal H,Amariglio N,et al. Genomewide comparison of human keratinocyte and squamous cell carcinoma response to UVB irradiation:implication for skin and epithelial cancer. Oncogene,2003,22(19):2993-3006.
[4]、Saari KM,Paavilainen V,Tuominen J,et al. Epidemiology of basal cell carcinoma of the eyelid in south-western Finland. Graefes Arch Clin Exp Ophthalmol,2001,239(3):230-233.
[5]、Ragge NK,Salt A,Collin JR,et al. Gorlin syndrome:the PTCH gene links ocular developmental defects and tumour formation. Br J Ophthalmol,2005,89(8):988-991.
[6]、Zhang H,Ping XL,Lee PK,et al.Role of PTCH and P53 Genes in Early-Onset basal Cell Carcinoma.Am J Pathol,2001,158(2):381-385.
[7]、Hahn H,Wicking c,Zaphiropoulous PG,et al. Mutations of the Human Homolog of Drosophila Patched in the Nevoid Basal Carcinoma Syndrome. Cell,1996,85(5):841-851.
[8]、Thibert C,Teillet MA,Lapointe F,et al. Inhibition of neuroepithelial patched-induced apoptosis by sonic hedgehog. Science,2003,301(5634):843-846.
[9]、Barnes EA,Kong M,Ollendorff V,et al. Patched interacts with cyclin B1 to regulate cell cycle progression. EMBO J,2001,20(9):2212-2223.
[10]、Bergstein I,Leopold PL,Sato N,et al. In vivo enhanced expression of patched dampens the sonic hedgehog pathway. Mol Ther,2002,6(2):258-264.
[11]、Casali A,Struhl G. Reading the Hedgehog morphogen gradient by measuring the ratio of bound to unbound Patched protein. Nature,2004,431(7004):76-80.
[12]、Heitzer E,Lassacher A,Quehenberger F,et al. UV fingerprints predominate in the PTCH mutation spectraof basal cell carcinomas independent of clinical phenotype. J Invest Dermatol,2007,127(12):2872-2881.
[13]、Dicker AJ,Serewko MM,Russell T,et al. Isolation (from a basal cell carcinoma ) of a functionally distinct fibroblast—like cell type that overexpresses PTCH. J Invest De rmatol,2002,118(5):859.
[14]、Akkiprik M,Celikel CA,Dü?ünceli F,et al. Relationship between overexpression of ras P21 oncoprotein and K-ras codon 12 and 13 mutations in Trukish colorectal cancer patients. Turk J Gastroenterol,2008,19(1):22-27.
[15]、Haigis KM,Kendall KR,Wang Y,et al. Differential effects of oncogenic K-ras and N-ras on proliferation, differentiation and tumor progression in the colon. Nature Genetics,2008,40(5):600-608.
[16]、Amstad PA,Cerutti PA. Ultraviolet-B-light-induced mutagencsis of C-H-Ras codons 11 and 12 in human skin flbroblasts. Int J Cancer,1995,63(1):136-139.
[17]、Hussein MR. Ultraviolet radiation and skin cancer:molecular mechanisms. J Cutan Pathol,2005,32(3):191-205.
[18]、Murphy N,Ring M,Killalea AG,et al. p16INK4a as a marker for cervical dyskaryosis:CIN and cGIN in cervical biopsies and ThinPrep smears. Clin Pathol,2003,56(1):56-63.
[19]、Haferkamp S , Becker TM , Scurr LL , et al. p16(INK4a)-induced senescence is disabled by melanoma-associated mutations. Aging Cell,2008,7(5):733-745.
[20]、Khoo CM, Carrasco DR, Bosenberg MW,et al. Ink4a/Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse. Proc Natl Acad Sci USA,2007,104(10):3931-3936.
[21]、Nemtsova MV,Zemliakova VV,Kuznetsova EV. Correlation of p16/INK4a gene damages and protein expression in the tumor tissue of sporadic breast cancer. Arkh Pathol,2008,70(4):6-9.
[22]、Blokx WA,Lesterhuis JJ,Andriessen MP,et al. CDKN2A INK4A-ARF mutation analysis to distinguish cutaneous melanoma metastasis from a second primary melanoma. Am J Surg Pathol,2007,31(4):637-641.
[23]、Saridaki Z,Koumantaki E,Liloglon T,et al. High frequency of loss of heterozygosity on chromosome region 9p21-p22 but lack of P16INK4a/p19ARF mutations in greek patients with basal cell carcinoma of the skin. J Invest Dermatol,2000,115(4):719-725.
[24]、Niu Y,Liu F,Menf X,et al. A Study on the Expression of P16 Protein and Bcl-2 Protein in Cutaneous Eyelid Tumors. Chin J Ophthalmol,2000,36(4):259-262.
[25]、Liu Fuling,Niu YingjLtn,Wang Hongyun,et al. Expression of P16 and CD44v6 in basal cell carcinomas of eyelid. Clin Ophthal Res,2005,23(1):63-65.
[26]、Rajabi MA,Rajabi P,Afshar-Moghaddam N. Determination of P53 expression in basal cell carcinoma tissues and adjacent nontumoral epidermis from sun-exposed areas of the head and neck. Arch Iran Med,2006,9(1):46-48.
[27]、Reszec J,Sulkowski S. The expression of P53 protein and infection of human papilloma virus in conjunctival and eyelid neoplasms. Int J Mol Med,2005,16(4):559-564.
[28]、Tsai KY,TsaoH. The genetics of skin cancer. Am J Med Genet C Semin Med Genet,2004,131(1):82-92.
[29]、Brash DE,Ziegler A,Jonason AS,et al. Sunlight and sunburn in human skin cancer p53 apoptosis and tumor promotion. J invest Dermatol Symp Proc,1996,1(2):136-142.
[30]、Ahmed MM,Alcock RA,Chendil D ,et al. Restoration of Transforming Growth Factor-βSignaling Enhances Radiosensitivity by Altering the Bcl-2/Bax Ratio in the p53 Mutant Pancreatic Cancer Cell Line MIA PaCa-2. J Biol Chem,2002,277(3):2234-2246.
[31]、Bolshakov S, Walker CM, Strom SS,et al. P53 mutations in human aggressive and nonaggressive basal and squamous cell carcinomas. Clin Cancer Res,2003,9(1):228-234.
[32]、Demirkan NC,Colakoglu N,Duzcan E. Value of P53 portein in biological behavior of basal cell carcinoma and in normal epithelia adjacent to carcinomas. Pathol Oncol Res,2000,6(4): 272-274.
[33]、Liefer KM,Koster MI. Down Regulation of P63 is Required for Epidermal U-V-B induced Apoptosis. Cancer Res,2000,60(15):4016-4020.
[34]、王良君,李超英,孙玉芬,等. Nm23H1和NF-kBP65在眼睑BCC中的表达及意义.山东大学基础医学院报,2005,19(1):49-51.
[35]、Kanitakis J,Euvrard S,Bourchany D,et al. Expression of the nm23 metastasis-suppressor gene product in skin tumors. J Cutan Pathol,1997,24(3):151-156.
[36]、Ramdial PK, Madaree A,Reddy R,et al. Bcl-2 protein expression in aggressive and non- aggressive basal cell carcinomas. J Cutan Pathol,2000,27(6):283-291.
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