β-catenin和DKK-1在宫颈鳞癌中的表达及意义
摘要
目的：
检测宫颈鳞癌及癌前病变患者病理组织中β-catenin、DKK-1的表达,探讨其与宫颈鳞癌发生发展、临床病理各参数之间的关系。
方法：
1.收集在我院经临床和病理确诊宫颈鳞癌组44例、CIN组30例、慢性宫颈炎组30例病理组织标本,采用免疫组化SABC法检测β-catenin、DKK-1的表达。
2.分析β-catenin、DKK-1的表达与宫颈鳞癌发生、发展及患者年龄,临床分期,组织学分级,肌层浸润程度、淋巴结转移、高危型HPV感染的关系,并分析β-catenin、DKK-1表达的相关性。
结果：
1.β-catenin在慢性宫颈炎组织中均为细胞膜着色；在CIN及宫颈癌组织中表现为膜表达减弱或缺失,呈现异位表达(胞质或胞核着色)；其在慢性宫颈炎、CINⅠ、CINⅡ-Ⅲ、宫颈鳞癌中异常表达率分别为0,15.4%,52.9%,79.5%,四组比较差异有显著性(P＜0.05)。
2.DKK-1阳性表达定位于胞浆中,在慢性宫颈炎、CINⅠCINⅡ-Ⅲ、宫颈鳞癌中阳性表达率依次降低,其阳性表达率分别为：83.3%,76.9%,35.3%,11.4%,四组比较差异有显著性(P＜0.05)。
3.β-catenin在各病理分级中的异常表达率随组织学分级的升高而上升,其阳性表达率分别为：G1-G2：66.7%,G3：91.3%,差异有显著性(P＜0.05)；在高危型HPV感染阳性组及阴性组的异常表达率分别为：83.3%,0,差异有显著性(P<0.05)。DKK-1的阳性表达率随着组织学分级的升高而降低,其阳性表达率分别为：G1-G2：23.8%,G3：0,差异有显著性(P<0.05)；在高危型HPV感染阳性组及阴性组的阳性表达率分别为：7.1%,100.0%,差异有显著性(P＜0.051。
4.β-catenin在FIGO分期中Ⅰbl-Ⅰb、Ⅱ2a期的异常表达率分别为76.0%,84.2%,差异无显著性(P>0.05)；在浅、深肌层浸润组的异常表达率分别为75.0%,82.1%,差异无显著性(P>0.05)；<40岁组和≥40岁组的异常表达率分别为77.3%,81.8%,差异无显著性(P>0.05)；有淋巴结转移组及无淋巴结转移组的异常表达率分别为90.0%,76.5%,差异无显著性(P>0.05)。
5.DKK-1在Ⅰb1-Ⅰb2、Ⅱa期的阳性表达率分别为16.0%,5.3%,差异无显著性(P>0.05)；在浅、深肌层浸润组的阳性表达率分别为18.8%,7.1%,差异无显著性(P>0.05)；<40岁组和≥40岁组的阳性表达率分别为13.6%,11.1%,差异亦无显著性(P>0.05)；在有淋巴结转移组及无淋巴结转移组的阳性表达率分别为10.0%，11.8%,差异无显著性(P>0.05)。
6.宫颈癌中β-catenin和DKK-1的表达存在负相关,相关系数为r=-0.706,P=0.000。
结论：
1.在宫颈鳞状上皮恶性转化的过程中,随着病变程度的增加,β-catenin的异常表达率逐渐增高,DKK-1阳性表达率逐渐降低,提示β-catenin、DKK-1可能在宫颈鳞癌的发生过程中起一定作用。
2.β-catenin、DKK-1的表达与宫颈鳞癌组织病理分级有关,提示β-catenin、DKK-1表达水平可能在一定程度上反映了宫颈鳞癌的恶性程度；两者的表达与高危型HPV感染有关,提示两者的异常表达可能协同高危型HPV在宫颈鳞癌的发生过程中起作用。
3.宫颈癌中β-catenin和DKK-1的表达存在负相关,提示DKK-1的表达缺失可能促进了β-catenin异常表达。
OBJECTIVE
To detect the expression of P-catenin and DKK-1 in chronic cervicitis, CIN,cervical squamous carcinoma,to explore the relationship between the expression of P-catenin or DKK-1 and the genesis,clinic pathological parameters of cervical squamous carcinoma and to explore the function of P-catenin and DKK-1 in the genesis and development of cervical squamous carcinoma.
METHODS
1.There are 30 patients with chronic cervicitis,30patients with CIN, and 44 patients with FIGO stageⅠb1 toⅡa.The expression of P-catenin and DKK-1 were deteced by immunohistochemistry technique.
2.Analysing the relationship between the expression ofβ-catenin or DKK-1 and the age of patients,surgical stage,myometrial invasion,patho-logical grading or lymphatic metastasis; exploring the function ofβ-catenin and DKK-1 in the genesis and development of cervical squamous carcinoma; analysing the correlation betwwen the expression ofβ-catenin and DKK-1.
RESULTS
1.β-catenin showed nomal expression in 30 chronic cervicitic tissues,and showed abnomal expression(cytoplasic expression) in the tissues of cervical intraepithelial neoplasia and cervical squamous carcinoma. The abnomal expression rates ofβ-catenin in the chronic cervical tissues, CINⅠ,CINⅡ-Ⅲand cervical squmaous careinoma were respectively 0,15.4%,52.9%,79.5%. There was signifieantly dieffrence respectively(P＜0.05).
2.DKK-1 expressed in cytoplasic. The positive expression rates of DKK-1 in the chronic cervical tissues, CINⅠ,CINⅡ-Ⅲand cervical squmaous careinoma were respectively 83.3%,76.9%,35.3%,11.4%. There was signifieantly dieffrence respectively(P<0.05).
3. The abnomal expression rate ofβ-catenin and the positive expression rate of DKK-1 were significantly associated with the tumor diefferntiation stuats and high-risk human papillomavirus infection (P<0.05).
4.The abnomal expression rate of P-catenin in FIGO stageⅠb1-Ⅰb2 andⅡa were respectively 76.0%,84.2%.There was no signifieantly dieffrence(P<0.05). The abnomal expression rate of P-catenin were not associated with myometrial invasion, the age of patients, pelvic lymph node metastases. (P<0.05)
5.The positive expression rate of DKK-1 in FIGO stageⅠb1-Ⅰb2 andⅡa were respectively 16.0%,5.3%.There was also no signifieantly dieffrence (P＜0.05). The positive expression rate of DKK-1 were not associated with myometrial invasion, the age of patients, pelvic lymph node metastases. (P＜0.05)
6.There is significant negative correlation between the expression ofβ-catenin and DKK-1.(r=-0.706, P=0.000)
Conclusion
1.In cervieal squarnous cell malignant transformation process, with the lesions inerease,the abnomal expression rate ofβ-catenin increased, and the positive expression rate of DKK-1 decrese. They may play an important role in carcinogenesis.
2. The abnomal expression rate ofβ-catenin and the positive expression rate of DKK-1 were significantly associated with the tumor diefferntiation stuats and high-risk human papillomavirus infection. They may reflect the malignant degree of cervical tissues, and play an important role in carcinogenesis collaborating with high-risk human papillomavirus infection.
3. There is significant negative correlation between the expression ofβ-catenin and DKK-1.(r=-0.706, P=0.000) The loss of DKK-1 may promote the abnomal expression of P-catenin, so as to lead to the occurrence and development of cervical cancer.
检测宫颈鳞癌及癌前病变患者病理组织中β-catenin、DKK-1的表达,探讨其与宫颈鳞癌发生发展、临床病理各参数之间的关系。
方法：
1.收集在我院经临床和病理确诊宫颈鳞癌组44例、CIN组30例、慢性宫颈炎组30例病理组织标本,采用免疫组化SABC法检测β-catenin、DKK-1的表达。
2.分析β-catenin、DKK-1的表达与宫颈鳞癌发生、发展及患者年龄,临床分期,组织学分级,肌层浸润程度、淋巴结转移、高危型HPV感染的关系,并分析β-catenin、DKK-1表达的相关性。
结果：
1.β-catenin在慢性宫颈炎组织中均为细胞膜着色；在CIN及宫颈癌组织中表现为膜表达减弱或缺失,呈现异位表达(胞质或胞核着色)；其在慢性宫颈炎、CINⅠ、CINⅡ-Ⅲ、宫颈鳞癌中异常表达率分别为0,15.4%,52.9%,79.5%,四组比较差异有显著性(P＜0.05)。
2.DKK-1阳性表达定位于胞浆中,在慢性宫颈炎、CINⅠCINⅡ-Ⅲ、宫颈鳞癌中阳性表达率依次降低,其阳性表达率分别为：83.3%,76.9%,35.3%,11.4%,四组比较差异有显著性(P＜0.05)。
3.β-catenin在各病理分级中的异常表达率随组织学分级的升高而上升,其阳性表达率分别为：G1-G2：66.7%,G3：91.3%,差异有显著性(P＜0.05)；在高危型HPV感染阳性组及阴性组的异常表达率分别为：83.3%,0,差异有显著性(P<0.05)。DKK-1的阳性表达率随着组织学分级的升高而降低,其阳性表达率分别为：G1-G2：23.8%,G3：0,差异有显著性(P<0.05)；在高危型HPV感染阳性组及阴性组的阳性表达率分别为：7.1%,100.0%,差异有显著性(P＜0.051。
4.β-catenin在FIGO分期中Ⅰbl-Ⅰb、Ⅱ2a期的异常表达率分别为76.0%,84.2%,差异无显著性(P>0.05)；在浅、深肌层浸润组的异常表达率分别为75.0%,82.1%,差异无显著性(P>0.05)；<40岁组和≥40岁组的异常表达率分别为77.3%,81.8%,差异无显著性(P>0.05)；有淋巴结转移组及无淋巴结转移组的异常表达率分别为90.0%,76.5%,差异无显著性(P>0.05)。
5.DKK-1在Ⅰb1-Ⅰb2、Ⅱa期的阳性表达率分别为16.0%,5.3%,差异无显著性(P>0.05)；在浅、深肌层浸润组的阳性表达率分别为18.8%,7.1%,差异无显著性(P>0.05)；<40岁组和≥40岁组的阳性表达率分别为13.6%,11.1%,差异亦无显著性(P>0.05)；在有淋巴结转移组及无淋巴结转移组的阳性表达率分别为10.0%，11.8%,差异无显著性(P>0.05)。
6.宫颈癌中β-catenin和DKK-1的表达存在负相关,相关系数为r=-0.706,P=0.000。
结论：
1.在宫颈鳞状上皮恶性转化的过程中,随着病变程度的增加,β-catenin的异常表达率逐渐增高,DKK-1阳性表达率逐渐降低,提示β-catenin、DKK-1可能在宫颈鳞癌的发生过程中起一定作用。
2.β-catenin、DKK-1的表达与宫颈鳞癌组织病理分级有关,提示β-catenin、DKK-1表达水平可能在一定程度上反映了宫颈鳞癌的恶性程度；两者的表达与高危型HPV感染有关,提示两者的异常表达可能协同高危型HPV在宫颈鳞癌的发生过程中起作用。
3.宫颈癌中β-catenin和DKK-1的表达存在负相关,提示DKK-1的表达缺失可能促进了β-catenin异常表达。
OBJECTIVE
To detect the expression of P-catenin and DKK-1 in chronic cervicitis, CIN,cervical squamous carcinoma,to explore the relationship between the expression of P-catenin or DKK-1 and the genesis,clinic pathological parameters of cervical squamous carcinoma and to explore the function of P-catenin and DKK-1 in the genesis and development of cervical squamous carcinoma.
METHODS
1.There are 30 patients with chronic cervicitis,30patients with CIN, and 44 patients with FIGO stageⅠb1 toⅡa.The expression of P-catenin and DKK-1 were deteced by immunohistochemistry technique.
2.Analysing the relationship between the expression ofβ-catenin or DKK-1 and the age of patients,surgical stage,myometrial invasion,patho-logical grading or lymphatic metastasis; exploring the function ofβ-catenin and DKK-1 in the genesis and development of cervical squamous carcinoma; analysing the correlation betwwen the expression ofβ-catenin and DKK-1.
RESULTS
1.β-catenin showed nomal expression in 30 chronic cervicitic tissues,and showed abnomal expression(cytoplasic expression) in the tissues of cervical intraepithelial neoplasia and cervical squamous carcinoma. The abnomal expression rates ofβ-catenin in the chronic cervical tissues, CINⅠ,CINⅡ-Ⅲand cervical squmaous careinoma were respectively 0,15.4%,52.9%,79.5%. There was signifieantly dieffrence respectively(P＜0.05).
2.DKK-1 expressed in cytoplasic. The positive expression rates of DKK-1 in the chronic cervical tissues, CINⅠ,CINⅡ-Ⅲand cervical squmaous careinoma were respectively 83.3%,76.9%,35.3%,11.4%. There was signifieantly dieffrence respectively(P<0.05).
3. The abnomal expression rate ofβ-catenin and the positive expression rate of DKK-1 were significantly associated with the tumor diefferntiation stuats and high-risk human papillomavirus infection (P<0.05).
4.The abnomal expression rate of P-catenin in FIGO stageⅠb1-Ⅰb2 andⅡa were respectively 76.0%,84.2%.There was no signifieantly dieffrence(P<0.05). The abnomal expression rate of P-catenin were not associated with myometrial invasion, the age of patients, pelvic lymph node metastases. (P<0.05)
5.The positive expression rate of DKK-1 in FIGO stageⅠb1-Ⅰb2 andⅡa were respectively 16.0%,5.3%.There was also no signifieantly dieffrence (P＜0.05). The positive expression rate of DKK-1 were not associated with myometrial invasion, the age of patients, pelvic lymph node metastases. (P＜0.05)
6.There is significant negative correlation between the expression ofβ-catenin and DKK-1.(r=-0.706, P=0.000)
Conclusion
1.In cervieal squarnous cell malignant transformation process, with the lesions inerease,the abnomal expression rate ofβ-catenin increased, and the positive expression rate of DKK-1 decrese. They may play an important role in carcinogenesis.
2. The abnomal expression rate ofβ-catenin and the positive expression rate of DKK-1 were significantly associated with the tumor diefferntiation stuats and high-risk human papillomavirus infection. They may reflect the malignant degree of cervical tissues, and play an important role in carcinogenesis collaborating with high-risk human papillomavirus infection.
3. There is significant negative correlation between the expression ofβ-catenin and DKK-1.(r=-0.706, P=0.000) The loss of DKK-1 may promote the abnomal expression of P-catenin, so as to lead to the occurrence and development of cervical cancer.
引文
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[12]TETSU O, MCCORMICK F. Bete-catenin regulates expression of cyclin Dl in colon carcinoma cells[J]. Nature,1999,398:422-426.
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[15]Gordon M, Nusse R. Wnt signaling:multiple pathways,multiple receptors, and multipletranscription factors[J]. Biol Chem.2006,281:22429-22433.
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[17]Heasman J. Maternal determinants of embryonic cell fate[J]. Semi Cell Dev Biol, 2006,17:93-98.
[18]Yamaguchi T. Heads or tails:Wnts and anterior-posterior patterning[J]. Curr Biol, 2001,11:713-724.
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[27]Yamabuki T, Takano A, Hayama S, et al. Dikkopf-1 as a novel serologic and p rognostic biomarker for lung and esophageal carcinomas[J]. Cancer Res,2007, 67:2517-2525.
[28]Glinka A, WuW, Delius H, et al. Dickkopf-1 is a member of a new family of secreted p roteins and functions in head induction[J]. Nature,1998,391 (6665): 357-362.
[29]Krupnik VE, Sharp JD, Jiang C, etal. Functional and structural diversity of the human Dickkopf gene family. Gene.1999,238(2):301-313.
[30]Aravind L, Koonin EV. A colipase fold in the carboxy-tenninal domain of the Wnt antagonists-the Dickkopfs..CurrBiol.1998,8(14):R477-478.
[31]Niehrs C. Oneogene. Function and biologieal roles of the Dickkopf family of Wnt modulators.2006,25(57):7469-7481.
[32]Gonzalez-Sancho JM, Aguilera O, Garcia JM etal. The Wnt antagonist DKK-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer. Oneogene,2005,24(6):1098-1103.
[33]Ohnaka K, Taniguchi H, Kawate H etal. Glucocorticoid enhances the expres-sion of DKK-1 in human osteoblasts:novel mechanism of glucocortieoid induced osteoporosis.Bioehem Biophys Res Commun.2004,318(1):259-264.
[34]Wang FS, Ko JY, Lin CL. Nocking down DKK-1 alleviat esestroge deficiency induction of bone lose. A histomorphological study in ovariectomizedrats.2007, 40(2):485-492.
[35]Shou J, Ali-Osman F, Multani AS. Human DKK-1, a gene encoding a Wnt anta-gonist, responds to DNA damage and its over expression sensitizes braintumor cells to apoptosis following alkylation damage of DNA. Oneogene.2002,21(6): 878-889.
[36]腊蕾、班武、饶进军,等.Wnt通路抑制因子Dickkopf-1的表达作用[J].中国医院药学杂志,2007,27(5)：629-632。
[37]Bhat RV, Budd Haeberlein SL, Avila J, et al. Glycogen synthase kinase 3:a drug target for CNS therapies. J Neurochem,2004,89:1313-1317.
[38]Wang J, Shou J, Chen X. DKK-1, an inhibitor of the Wnt signaling Pathway is indueed by P53. Oncogene,2000,19(14):1843-1848.
[39]Pollheimer J, Loregger T, Sonderegger S, etal. Activation of the Canonieal Wing-less/T-Cell Factor Signaling Pathway Promotes Invasive Differeniiation of Hu-man Trophoblast. Am J Pathol.2006,168(4):1134-1137.
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[41]KuPhal S, LodermeyerS, BatailleF, et al, Expression of DICKKOPF genes is strongly reduced inmalignant melanoma.Oncogene.2006; 25(36):5027-5036.
[42]Mikata R, Yokosuka O, Fukal K, et al. Analysis of genes upregulated by the demethylating agents 5-aza-2-deoxycytidine in gastric cancer cell lines.Int J Cancer.2006;119(7):1616-1622.
[43]伊诺,廖秦平,李挺等.子宫内膜癌Dickkopfl表达及对内膜癌侵袭力的影响.现代妇产科进展.2009,18(2)：113-116.
[44]Li L, Mao J, Sun L, et al. Second cysteine 2rich domain of Dickkopf-2 activates canonical Wnt signaling pathway via LRP26 independently of dishevelled[J]. J B iol Chem,2002,277(8):5977-5981.
[45]Roman-Gomez J, Jimenez-Velasco A, Agirre X, et al. Transcriptional silencing of the Dickkopfs-3(DKK-3)gene by CpG hypermethylation in acute lymphoblas-tic leukaem ia[J]. B r J Cancer,2004,91(4):707-713.
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[47]Khalida M, Huilgol NG, HongyoT, etal. Mutations in cervieal caneeras predietive factors for radiotherapy. International Congress Series,2002,1236(7): 459-461.
[48]UedaM, Gelnrnill RM, West J, etal. Mutations of the beta-and ganllna-catenin genes are uneommon inhumanlung, breast, kidney, cervical and ovarian carcinomas. Br J Caneer,2001,85(1):64-68.
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[50]Fadare O, Reddy H, Wang J, etal. E-cadherin and β-catenin expression in early stage cervical careinoma:a tissue mieroarray study of 147cases.World J Surg Oncol,2005,3(1):38-48.
[51]龚玲玲,李红英,曾俊.宫颈癌中α/β-连接素的联合表达及意义.临床与实验病理学杂志,2005,21(1)：62-65.
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