ILK、HIF-1α、E-钙粘蛋白和p16在宫颈癌组织中的表达及临床意义
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摘要
目的：探讨整合素连接激酶(ILK)、缺氧诱导因子-1α(HIF-1α)、上皮型钙粘蛋白(E-cadherin)及p16在正常宫颈黏膜上皮、宫颈上皮内瘤变(CIN)及宫颈癌组织中的表达及临床意义。
方法：采用免疫组化技术(SP法)对空军总医院病理科2005年1月～2009年8月宫颈活检及手术切除的病理标本112例,其中CINⅠ级16例,CINⅡ～Ⅲ级38例,浸润癌38例,行ILK、HIF、1α、E-钙粘蛋白和p16蛋白的检测。
结果：①从正常宫颈黏膜上皮到CIN再到浸润癌,ILK阳性表达率呈渐进性增高。宫颈癌组织中ILK阳性率明显高于CINⅡ～Ⅲ级,CINⅠ级阳性率明显高于正常宫颈黏膜上皮(P<0.05)。ILK在宫颈癌组织中的表达与患者年龄、FIGO分期、分化程度及有无淋巴结转移无相关性(P>0.05),可能与病例数量偏少及实验假阳性有关。
②从正常宫颈黏膜上皮到CIN再到浸润癌,HIF-1α阳性表达率呈渐进性增高,在正常宫颈组织中基本无表达,CINⅠ中显著低于CINⅡ～Ⅲ(P＜0.05),而CINⅡ～Ⅲ又显著低于浸润癌(P<0.01)。HIF-1α的表达与年龄无关,与FIGO分期、分化程度及有无淋巴结转移相关。Ⅲ、Ⅳ期、中低分化及有淋巴结转移的宫颈癌组织中HIF-1α的表达水平均明显高于Ⅰ、Ⅱ期、高分化和的无淋巴结转移的组织(P<0.01)。
③E-钙粘蛋白在正常宫颈组织、CINⅠ、CINⅡ-Ⅲ、浸润癌中的阳性表达率呈递减趋势,在正常宫颈组织表达显著高于CINⅠ(P＜0.05),CINⅠ显著高于浸润癌(P<0.05)。随着临床期别的增加,E-钙粘蛋白的阳性表达率呈下降趋势,按不同分化程度比较,癌细胞分化越差,E-钙粘蛋白的阳性率越低。此外,无淋巴结转移宫颈癌中的阳性表达率也显著高于有淋巴结转移(P<0.01)。对于年龄因素,E-钙粘蛋白在宫颈癌中的表达与其无关(P>0.05)。
④p16在正常宫颈、CINⅠ、CINⅡ-Ⅲ及宫颈癌组织中表达呈递增趋势,且正常宫颈组织p16蛋白阳性表达率显著低于CINⅠ(P＜0.05), CINⅠ显著低于浸润癌(P<0.05)。p16蛋白在宫颈癌患者年龄组、FIGO分期组和有无淋巴结转移组各组内的阳性表达率均无显著性差异(P>0.05)。在不同分化程度宫颈癌组织中,宫颈癌组织分化程度越低,p16的阳性表达率就越高。
⑤ILK、HIF-1α及p16蛋白等信号分子的阳性表达率均与E-钙粘蛋白的阳性表达率呈现负相关。
结论：①ILK作为一项较好的细胞增殖标记物,对区分宫颈正常黏膜与各级CIN病变及浸润癌有一定参考价值,但其是否与宫颈癌的生物学行为和恶性程度有关,以及是否有助于临床评估宫颈癌患者的预后,这方面还需要做进一步的研究随访。
②对HIF-1α蛋白的检测和研究将有助于宫颈癌的早期诊断及鉴别诊断,并能够预测肿瘤的发展趋势和转移潜能,有望成为一种新的临床诊断指标和肿瘤标记物；宫颈癌中同样存在着HIF-1α/E-钙粘蛋白途径,进一步对HIF-1α/E-钙粘蛋白表达调控机制的研究将为宫颈癌的诊治提供重要线索。
③E-钙粘蛋白的异常表达参与了宫颈癌的发生,宫颈癌中E-钙粘蛋白的降表达与ILK、HIF-1α及p16等信号分子过表达均相关,说明多种信号分子和E-钙粘蛋白在宫颈癌变过程中协同发挥细胞恶性转化作用,联合检测多种信号分子及E-钙粘蛋白的表达对了解宫颈癌发生、发展的机制有一定意义。
④p16蛋白在宫颈癌的表达明显高于正常宫颈黏膜组织,且在肿瘤早期即发生改变,是一类早期事件。将p16检测作为宫颈癌前病变的辅助筛查,可帮助我们判定宫颈病变是否已经达到CIN,减少宫颈癌的漏诊率,从而进行早期及时的治疗。
Objective:To study the expression and clinical significance of ILK, HIF-1α, E-cadherin and p16 in normal cervical epithelium, cervical intraepithelial neoplasia(CIN) and cervical carcinoma.
Methods:The expression of ILK, HIF-1α, E-cadherin and p16 in 112 pathological specimens was detected by Immunohistochemistry. The specimens were all obtained by cervical biopsy or excision, including 16 cases of CINⅠ,38 cases of CINⅡ～Ⅲand 38 cases of cervical carcinoma.
Results:①From normal cervical epithelium to CIN and then to cervical carcinoma, the positive expression rate of ILK showed gradual increase. The rate in cervical carcinoma was apparently higher than in CINⅡ～Ⅲ, and that in CINⅠwas apparently higher than in normal cervical epithelium(P＜0.05). The expression of ILK did not correlate with the patients' age, FIGO staging, degree of differentiation and lymph node metastasis(P＞0.05). The reason might be related to the insufficient cases and false-positive results.
②From normal cervical epithelium to CIN and then to cervical carcinoma, the positive expression rate of HIF-la increased gradually. There was almost no expression of HIF-1αin normal cervical epithelium. The expression in CINⅠwas apparently lower than in CINⅡ～Ⅲ(P＜0.05), while that in CINⅡ～Ⅲwas apparently lower than in cervical carcinoma(P＜0.01). And the expression of HIF-1αdid not correlate with the patients' age, but did with FIGO staging, degree of differentiation and lymph node metastasis. The expression in the cervical carcinoma StageⅢandⅣ, moderately or poorly differentiated and with lymph node metastasis was apparently higher than in that StageⅠandⅡ, well differentiated and without lymph node metastasis(P＜0.01).
③The positive expression rate of E-cadherin showed a decreasing trend in turn in normal cervical tissues, CINⅠ, CINⅡ～Ⅲand cervical carcinoma. The rate in normal cervical tissues was apparently higher than in CINⅠ(P＜0.05), and in CINⅠapparently higher than in cervical carcinoma(P＜0.05). With the clinical stage increased, the positive expression rate of E-cadherin decreased. By comparison of different degree of differentiation, the positive rate was lower with the poorer differentiation of the cancer cells. Besides, the positive expression rate in the cervical carcinoma with lymph node metastasis was apparently higher than without(P＜0.01). For the age factor, it had no correlation with the expression(P＞0.05).
④The expression of p16 showed a increasing trend in turn in normal cervical tissues, CINⅠ, CINⅡ～Ⅲand cervical carcinoma. The positive expression rate in normal cervical tissues was apparently lower than in CINⅠ(P＜0.05), and in CINⅠwas apparently lower than in cervical carcinoma(P＜0.05). There was no significant difference within each of the groups of age, FIGO staging and lymph node metastasis(P＞0.05). In the cervical carcinoma with different degree of differentiation, the poorer the degree was, the higher the positive expression rate of p16 was.
⑤The positive expression rate of ILK, HIF-1αand p16 had negative correlation with that of E-cadherin.
Conclusion:①As a better cell proliferation marker, ILK has certain reference value for the discrimination of normal cervical epithelium, CIN at all levels and cervical carcinoma. But whether it has correlation with the biological behaviour and the degree of malignancy of cervical carcinoma, and whether it helps clinical assessment of prognosis of patients with cervical cancer, needs to further research and follow-up.
②The detection and research of HIF-1αwould contribute to early and differential diagnosis of cervical carcinoma, and predict the development trend and metastatic potential of tumors. It is expected to be a new clinical diagnostic criteria and tumor marker. HIF-la/E-cadherin pathway also exists in cervical carcinoma, and further research on the expression and regulation mechanism of HIF-1α/E-cadherin will provide important clues to the diagnosis and treatment of cervical carcinoma.
③Abnormal expression of E-cadherin has a hand in the occurrence of cervical carcinoma. Reduced expression of E-cadherin in cervical carcinoma correlates with the over expression of ILK, HIF-1α, p16 and such signaling molecules. This shows that a variety of signaling molecules together with E-cadherin play a part in malignant transformation of cell during the cancerization of cervix. To detect the expression of various signaling molecules together with E-cadherin makes sense to understand the occurrence and development mechanism of cervical carcinoma.
④The expression of p16 in cervical carcinoma is apparently higher than that in normal cervical mucosa. And it changes early in the tumor, so it is an early event. To regard detection of p16 as a secondary screening for precancerous lesions of uterine cervix, would help us to judge CIN, to reduce the rate of misdiagnosis of cervical cancer, and so to take early and timely treatment.
方法：采用免疫组化技术(SP法)对空军总医院病理科2005年1月～2009年8月宫颈活检及手术切除的病理标本112例,其中CINⅠ级16例,CINⅡ～Ⅲ级38例,浸润癌38例,行ILK、HIF、1α、E-钙粘蛋白和p16蛋白的检测。
结果：①从正常宫颈黏膜上皮到CIN再到浸润癌,ILK阳性表达率呈渐进性增高。宫颈癌组织中ILK阳性率明显高于CINⅡ～Ⅲ级,CINⅠ级阳性率明显高于正常宫颈黏膜上皮(P<0.05)。ILK在宫颈癌组织中的表达与患者年龄、FIGO分期、分化程度及有无淋巴结转移无相关性(P>0.05),可能与病例数量偏少及实验假阳性有关。
②从正常宫颈黏膜上皮到CIN再到浸润癌,HIF-1α阳性表达率呈渐进性增高,在正常宫颈组织中基本无表达,CINⅠ中显著低于CINⅡ～Ⅲ(P＜0.05),而CINⅡ～Ⅲ又显著低于浸润癌(P<0.01)。HIF-1α的表达与年龄无关,与FIGO分期、分化程度及有无淋巴结转移相关。Ⅲ、Ⅳ期、中低分化及有淋巴结转移的宫颈癌组织中HIF-1α的表达水平均明显高于Ⅰ、Ⅱ期、高分化和的无淋巴结转移的组织(P<0.01)。
③E-钙粘蛋白在正常宫颈组织、CINⅠ、CINⅡ-Ⅲ、浸润癌中的阳性表达率呈递减趋势,在正常宫颈组织表达显著高于CINⅠ(P＜0.05),CINⅠ显著高于浸润癌(P<0.05)。随着临床期别的增加,E-钙粘蛋白的阳性表达率呈下降趋势,按不同分化程度比较,癌细胞分化越差,E-钙粘蛋白的阳性率越低。此外,无淋巴结转移宫颈癌中的阳性表达率也显著高于有淋巴结转移(P<0.01)。对于年龄因素,E-钙粘蛋白在宫颈癌中的表达与其无关(P>0.05)。
④p16在正常宫颈、CINⅠ、CINⅡ-Ⅲ及宫颈癌组织中表达呈递增趋势,且正常宫颈组织p16蛋白阳性表达率显著低于CINⅠ(P＜0.05), CINⅠ显著低于浸润癌(P<0.05)。p16蛋白在宫颈癌患者年龄组、FIGO分期组和有无淋巴结转移组各组内的阳性表达率均无显著性差异(P>0.05)。在不同分化程度宫颈癌组织中,宫颈癌组织分化程度越低,p16的阳性表达率就越高。
⑤ILK、HIF-1α及p16蛋白等信号分子的阳性表达率均与E-钙粘蛋白的阳性表达率呈现负相关。
结论：①ILK作为一项较好的细胞增殖标记物,对区分宫颈正常黏膜与各级CIN病变及浸润癌有一定参考价值,但其是否与宫颈癌的生物学行为和恶性程度有关,以及是否有助于临床评估宫颈癌患者的预后,这方面还需要做进一步的研究随访。
②对HIF-1α蛋白的检测和研究将有助于宫颈癌的早期诊断及鉴别诊断,并能够预测肿瘤的发展趋势和转移潜能,有望成为一种新的临床诊断指标和肿瘤标记物；宫颈癌中同样存在着HIF-1α/E-钙粘蛋白途径,进一步对HIF-1α/E-钙粘蛋白表达调控机制的研究将为宫颈癌的诊治提供重要线索。
③E-钙粘蛋白的异常表达参与了宫颈癌的发生,宫颈癌中E-钙粘蛋白的降表达与ILK、HIF-1α及p16等信号分子过表达均相关,说明多种信号分子和E-钙粘蛋白在宫颈癌变过程中协同发挥细胞恶性转化作用,联合检测多种信号分子及E-钙粘蛋白的表达对了解宫颈癌发生、发展的机制有一定意义。
④p16蛋白在宫颈癌的表达明显高于正常宫颈黏膜组织,且在肿瘤早期即发生改变,是一类早期事件。将p16检测作为宫颈癌前病变的辅助筛查,可帮助我们判定宫颈病变是否已经达到CIN,减少宫颈癌的漏诊率,从而进行早期及时的治疗。
Objective:To study the expression and clinical significance of ILK, HIF-1α, E-cadherin and p16 in normal cervical epithelium, cervical intraepithelial neoplasia(CIN) and cervical carcinoma.
Methods:The expression of ILK, HIF-1α, E-cadherin and p16 in 112 pathological specimens was detected by Immunohistochemistry. The specimens were all obtained by cervical biopsy or excision, including 16 cases of CINⅠ,38 cases of CINⅡ～Ⅲand 38 cases of cervical carcinoma.
Results:①From normal cervical epithelium to CIN and then to cervical carcinoma, the positive expression rate of ILK showed gradual increase. The rate in cervical carcinoma was apparently higher than in CINⅡ～Ⅲ, and that in CINⅠwas apparently higher than in normal cervical epithelium(P＜0.05). The expression of ILK did not correlate with the patients' age, FIGO staging, degree of differentiation and lymph node metastasis(P＞0.05). The reason might be related to the insufficient cases and false-positive results.
②From normal cervical epithelium to CIN and then to cervical carcinoma, the positive expression rate of HIF-la increased gradually. There was almost no expression of HIF-1αin normal cervical epithelium. The expression in CINⅠwas apparently lower than in CINⅡ～Ⅲ(P＜0.05), while that in CINⅡ～Ⅲwas apparently lower than in cervical carcinoma(P＜0.01). And the expression of HIF-1αdid not correlate with the patients' age, but did with FIGO staging, degree of differentiation and lymph node metastasis. The expression in the cervical carcinoma StageⅢandⅣ, moderately or poorly differentiated and with lymph node metastasis was apparently higher than in that StageⅠandⅡ, well differentiated and without lymph node metastasis(P＜0.01).
③The positive expression rate of E-cadherin showed a decreasing trend in turn in normal cervical tissues, CINⅠ, CINⅡ～Ⅲand cervical carcinoma. The rate in normal cervical tissues was apparently higher than in CINⅠ(P＜0.05), and in CINⅠapparently higher than in cervical carcinoma(P＜0.05). With the clinical stage increased, the positive expression rate of E-cadherin decreased. By comparison of different degree of differentiation, the positive rate was lower with the poorer differentiation of the cancer cells. Besides, the positive expression rate in the cervical carcinoma with lymph node metastasis was apparently higher than without(P＜0.01). For the age factor, it had no correlation with the expression(P＞0.05).
④The expression of p16 showed a increasing trend in turn in normal cervical tissues, CINⅠ, CINⅡ～Ⅲand cervical carcinoma. The positive expression rate in normal cervical tissues was apparently lower than in CINⅠ(P＜0.05), and in CINⅠwas apparently lower than in cervical carcinoma(P＜0.05). There was no significant difference within each of the groups of age, FIGO staging and lymph node metastasis(P＞0.05). In the cervical carcinoma with different degree of differentiation, the poorer the degree was, the higher the positive expression rate of p16 was.
⑤The positive expression rate of ILK, HIF-1αand p16 had negative correlation with that of E-cadherin.
Conclusion:①As a better cell proliferation marker, ILK has certain reference value for the discrimination of normal cervical epithelium, CIN at all levels and cervical carcinoma. But whether it has correlation with the biological behaviour and the degree of malignancy of cervical carcinoma, and whether it helps clinical assessment of prognosis of patients with cervical cancer, needs to further research and follow-up.
②The detection and research of HIF-1αwould contribute to early and differential diagnosis of cervical carcinoma, and predict the development trend and metastatic potential of tumors. It is expected to be a new clinical diagnostic criteria and tumor marker. HIF-la/E-cadherin pathway also exists in cervical carcinoma, and further research on the expression and regulation mechanism of HIF-1α/E-cadherin will provide important clues to the diagnosis and treatment of cervical carcinoma.
③Abnormal expression of E-cadherin has a hand in the occurrence of cervical carcinoma. Reduced expression of E-cadherin in cervical carcinoma correlates with the over expression of ILK, HIF-1α, p16 and such signaling molecules. This shows that a variety of signaling molecules together with E-cadherin play a part in malignant transformation of cell during the cancerization of cervix. To detect the expression of various signaling molecules together with E-cadherin makes sense to understand the occurrence and development mechanism of cervical carcinoma.
④The expression of p16 in cervical carcinoma is apparently higher than that in normal cervical mucosa. And it changes early in the tumor, so it is an early event. To regard detection of p16 as a secondary screening for precancerous lesions of uterine cervix, would help us to judge CIN, to reduce the rate of misdiagnosis of cervical cancer, and so to take early and timely treatment.
引文
[1]Bonlter E, van Obberghen-Schilling E. Integrin-linked kinase and its partners: a modular platform regulating cell-matrix adhesion dynamics and cytosceletal organization[J].Eur J Cell Biol.2006,85(3-4):255-263.
[2]Oloumi A, Mcphee T, Dedhar S. Regulation of E-cadherin expression and β-catenin/Tcf transcriptional activity by the integrin-linked kinase[J]. Bioc Hem Biophys Acta.2004,1691(1):1-15.
[3]Edwards L, Shabbits J, Bally M, et al. Integrin-linked kinase(ILK) in combination molecular targeting[J]. Cancer Treat Res.2004,119(6):59-75.
[4]李胜水,张凤梅,孙德飞,等.整合素连接激酶在宫颈上皮内瘤变及宫颈癌组织中的表达及临床意义[J].中国实用妇科与产科杂志.2009,25(1)：58-59.
[5]Kung AL, Zabludoff SD, France DS, et al. Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway[J]. Cancer Cell.2004,6(1):33-43.
[6]Klaes R, Friedrich T, Spitkovsky D, et al. Overexpression of p16(INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri[J]. Int J Cancer.2001,92(2):276-284.
[7]Tringler B, Gup CJ, Singh M, et al. Evaluation of p16 INK4a and pRb expression in cervical squamous and glandular neoplasia[J]. Hum Pathol.2004, 35(6):689-696.
[8]Zhong H, Semenza GL, Simons JW, et al. Up-regulation of hypoxia-inducible factor 1 alpha is an early event in prostate carcinogenesis[J]. Cancer Detect Prev. 2004,28(2):88-93.
[9]Joshi MB, Ivanov D, Philippova M, et al. Integrin-linked kinase is an essential mediator for T-cadherin-dependent signaling via Akt and GSK3 beta in endothelial cells[J]. Faseb J.2007,21(12):3083-3095.
[10]林梁.整合素连接激酶与肿瘤[J].国外医学：肿瘤学分册.2002,29(2)：98-101.
[11]Wong RP, Ng P, Dedhar S, et al. The role of integrin-linked kinase in melanoma cell migration, invasion and tumor growth[J]. Mol Cancer Ther.2007, 6(6):1602-1700.
[12]Okamura M, Yamaji S, Nagashima Y, et al. Prognostic value of integrin betal-ILK-pAkt signaling pathway in non-small cell lung cancer[J]. Hum Pathol. 2007,38(7):1081-1091.
[13]Liu BC, Xia HL, Wu JN, et al. Influence of irbesartan on expression of ILK and its relationship with epithelial-mesenchymal transition in mice with unilateral ureteral obstruction[J]. Acta Pharmacol Sin.2007,28(11):1810-1808.
[14]Korinek V, Barker N, Morin PJ, et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma[J]. Science.1997, 275(5307):1784-1787.
[15]Wu C, Keightley SY, Leung-Hagesteijn C, et al. Integrin-linked protein kinase regulates fibronectin matrix assembly, E-cadherin expression, and tumorigenicity[J]. J Biol Chem.1998,273(1):528-536.
[16]Kelly BD, Hackett SF, Hirota K, et al. Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1 [J]. Circ Res.2003,93(11):1074-1081.
[17]Bos R, Zhong H, Hanrahan CF, et al. Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis[J]. J Natl Cancer Inst.2001,93(4):309-314.
[18]Imai T, Horiuchi A, Wang C, et al. Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells[J]. Am J Pathol. 2003,163(4):1437-1447.
[19]Serrano M, Hannon GJ, Beach D, et al. A new regulatory motif in cell-cycle control causing specific inhibition of cyclinD/CDK4[J]. Nature(Lond).1993, 366(16):704-707.
[20]Marx J. New tumor suppressor may rival p53[J]. Science.1994,264(5157): 344-345.
[21]Kamb A, Gruis NA, Weaver-Feldhaus J, et al. A cell cycle regulator potentially involved in genesis of many tumor types[J]. Science.1994,264(5157): 436-440.
[22]戴淑真,李旭日,王宁,等.宫颈癌组织中P16和HPV16/18E7的表达和意义[J].齐鲁医学杂志.2004,19：283-286.
[23]Kelly MJ, Otterson GA, Kaye FJ, et al. CDKN2 in HPV-negative cervical-carcinoma cell lines[J]. Int J Cancer.1995,63:226-230.
[24]Hirama T, Miller CW, Wilczynski SP. P16(CDKN2/cyclin-dependent kinase-4 inhibitor/multiple tumor suppressor1) gene is not altered in uterine cervical carcinomas or cell lines[J]. Modern Pathol.1996,9:26-31.
[25]Tam SW, Shay JW, Pagano M. Differential expression and cell cycle regulation of the cyclin dependent kinase-4 inhibitor p16INK4[J]. Cancer Res. 1995,54(22):5816-5820.
[26]Schorge JO, Lea JS, Elias KJ, et al. P16 as a molecular biomarker of cervical adenocarcinoma[J]. Am J Obstet Gynecol.2004,190(3):668-673.
[27]Tringler B, Gup CJ, Singh M, et al. Evaluation of p16INK4a and pRb expression in cervical squamous and glandular neoplasia[J]. Hum Pathol.2004, 35(6):689-696.
[1]Hannigan GE, Leung-Hagesteijn C, Fitz-Gibbon L, et al. Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase[J]. Nature.1996,379(6560):91-96.
[2]Joshi MB, Ivanov D, Philippova M, et al. Integrin-linked kinase is an essential mediator for T-cadherin-dependent signaling via Akt and GSK3beta in endothelial cells[J]. Faseb J.2007,21(12):3083-3095.
[3]Stanchi F, Grashoff C, Nguemeni Yonga CF, et al. Molecular dissection of the ILK-PINCH-parvin triad reveals a fundamental role for the ILK kinase domain in the late stages of focal-adhesion maturation[J]. J Cell Sci.2009,122(11): 1800-1811.
[4]Wu C. PINCH, N(i)ck and the ILK:network wiring at cell-matrix adhesions[J]. Trends Cell Biol.2005,15(9):460-466.
[5]Cho HJ, Youn SW, Cheon SI, et al. Regulation of endothelial cell and endothelial progenitor cell survival and vasculogenesis by integrin-linked kinase[J]. Arterioscler Thromb Vasc Biol.2005,25(6):1154-1160.
[6]蹇华.整合素连接激酶(ILK)在肿瘤中的作用[J].中国现代医药杂志.2006,8(7)：148-150.
[7]Wong RP, Ng P, Dedhar S, et al. The role of integrin-linked kinase in melanoma cell migration, invasion and tumor growth[J]. Mol Cancer Ther.2007, 6(6):1602-1700.
[8]Okamura M, Yamaji S, Nagashima Y, et al. Prognostic value of integrin betal-ILK-pAkt signaling pathway in non-small cell lung cancer[J]. Hum Pathol. 2007,38(7):1081-1091.
[9]Haase M, Gmach CC, Eke I, et al. Expression of integrin-linked kinase is increased in differentiated cells[J]. J Histochem Cytochem.2008,56(9):819-829.
[10]Liu BC, Xia HL, Wu JN, et al. Influence of irbesartan on expression of ILK and its relationship with epithelial-mesenchymal transition in mice with unilateral ureteral obstruction[J]. Acta Pharmacol Sin.2007,28(11):1810-1818.
[11]Bonlter E, Van Obberghen-Schilling E. Integrin-linked kinase and its partners: a modular platform regulating cell-matrix adhesion dynamics and cytoskeletal organization[J]. Eur J Cell Biol.2006,85(3-4):255-263.
[12]Mi Z, Guo H, Wai PY, et al. Integrin-linked kinase regulates osteopontin-dependent MMP-2 and uPA expression to convey metastatic function in murine mammary epithelial cancer cells[J]. Carcinogenesis.2006,27(6): 1134-1145.
[13]Fan Y, Gong Y, Ghosh PK, et al. Spatial coordination of actin polymerization and ILK-Akt2 activity during endothelial cell migration[J]. Dev Cell,2009.16(5): 661-674.
[14]Qian Y, Zhong X, Flynn DC, et al. ILK mediates actin filament rearrangements and cell migration and invasion through PI3K/Akt/Rac1 signaling[J]. Oncogene.2005,24(19):3154-3165.
[15]Edwards LA, Woo J, Huxham LA, et al. Suppression of VEGF secretion and changes in glioblastoma multiforme microenvironment by inhibition of integrin-linked kinase (ILK)[J]. Mol Cancer Ther.2008,7(1):59-70..
[16]Ito R, Oue N, Zhu X, et al. Expression of integrin-linked kinase is closely correlated with invasion and metastasis of gastric carcinoma[J]. Virchows Arch. 2003,442(2):118-123.
[17]Bravou V, Klironomos G, Papadaki E, et al. ILK over-expression in human colon cancer progression correlates with:activation of beta-catenin, down-regulation of E-cadherin and activation of the Akt-FKHR pathway[J]. J Pathol.2006,208(1):91-99.
[18]Driver GA, Veale RB. Modulation of integrin-linked kinase (ILK) expression in human oesophageal squamous cell carcinoma cell lines by the EGF and TGFbetal growth factors[J]. Cancer Cell Int.2006,6:12.
[19]Graff JR, Deddens JA, Konicek BW, et al. Integrin-linked kinase expression increases with prostate tumor grade[J]. Clin Cancer Res.2001,7(7):1987-1991.
[20]Kieffer N, Schmitz M, Plancon S, et al. ILK as a potential marker gene to ascertain specific adenocarcinoma cell mRNA isolation from frozen prostate biopsy tissue sections. Int J Oncol.2005,26(6):1549-1558.
[21]Takanami I. Increased expression of integrin-linked kinase is associated with shorter survival in non-small cell lung cancer[J]. BMC Cancer.2005,5:1.
[22]Schmitz M, Grignard G, Margue C, et al. Complete loss of PTEN expression as a possible early prognostic marker for prostate cancer metastasis. Int J Cancer. 2007,120(6):1284-1292.
[23]Persad S, Attwell S, Gray V, et al. Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cell[J]. Proc Natl Acad Sci USA.2000, 97(7):3207-3212.
[24]Tan C, Cruet-Hennequart S, Troussard A, et al. Regulation of tumor angiogenesis by integrin-linked kinase (ILK)[J]. Cancer Cell.2004,5(1):79-90.
[25]Ahmed N, Oliva K, Rice GE, et al. Cell-free 59 kDa immunoreactive integrin-linked kinase:a novel marker for ovarian carcinoma[J]. Clin Cancer Res. 2004,10(7)：2415-2420.
[26]于翠珍,李双标,孙德飞.整合素连接激酶在卵巢肿瘤组织中的表达及意义[J].中国实用妇科与产科杂志.2007,23(9)：712-713.
[27]朱明艳,冯虹,万冰,等.ILK与P-PKB蛋白在卵巢肿瘤组织中的表达及意义[J].中国实用医药.2008,3(29)：64-66.
[28]李胜水,张凤梅,孙德飞,等.整合素连接激酶在宫颈上皮内瘤变及宫颈癌组织中的表达及临床意义[J].中国实用妇科与产科杂志.2009,25(1)：58-59.
[1]Lee JW, Bae SH, Jeong JW, et al. Hypoxia-inducible factor (HIF-1)alpha:its protein stability and biological functions[J]. Exp Mol Med.2004,36(1):1-12.
[2]Krishnamachary B, Berg-Dixon S, Kelly B, et al. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1[J]. Cancer Res.2003,63(5): 1138-1143.
[3]Pili R, Donehower RC. Is HIF-1 alpha a valid therapeutic target[J]? J Natl Cancer Inst.2003,95(7):498-499.
[4]Acs G, Zhang PJ, McGrath CM, et al. Hypoxia-inducible erythropoietin signaling in squamous dysplasia and squamous cell carcinoma of the uterine cervix and its potential role in cervical carcinogenesis and tumor progression[J]. Am J Pathol.2003,162(6):1789-1806.
[5]Kaio E, Tanaka S, Kitadai Y, Kaio E, Clinical significance of angiogenic factor expression at the deepest invasive site of advanced colorectal carcinoma[J]. Oncology.2003,64(1):61-73.
[6]Jubb AM, Pham TQ, Hanby AM, et al. Expression of vascular endothelial growth factor, hypoxia inducible factor 1 alpha, and carbonic anhydrase IX in human tumours[J]. J Clin Pathol.2004,57(5):504-512.
[7]Fujimoto J, Alam SM, Jahan I, et al. Plausible linkage of hypoxia inducible factor-1alpha in uterine cervical cancer[J]. Cancer Sci.2006,97(9):861-867.
[8]Jones A, Fujiyama C, Blanche C, et al. Relation of vascular endothelial growth factor production to expression and regulation of hypoxia-inducible factor-1 alpha and hypoxia-inducible factor-2 alpha in human bladder tumors and cell lines[J]. Clin Cancer Res.2001,7(5):1263-1272.
[9]Kung AL, Wang S, Klco JM, et al. Suppression of tumor growth through disruption of hypoxia-inducible transcription[J]. Nat Med.2000,6(12): 1335-1340.
[10]Yeo EJ, Chun YS, Cho YS, et al. YC-1:a potential anticancer drug targeting hypoxia-inducible factor 1[J]. J Natl Cancer Inst.2003,95(7):516-525.
[11]Zhang Q, Tang X, Lu Q, et al. Green tea extract and (-)-epigallocatechin-3-gallate inhibit hypoxia-and serum-induced HIF-1alpha protein accumulation and VEGF expression in human cervical carcinoma and hepatoma cells[J]. Mol Cancer Ther.2006,5(5):1227-1238.
[12]Schwock J, Geddie WR, Hedley DW. Analysis of hypoxia-inducible factor-1alpha accumulation and cell cycle in geldanamycin-treated human cervical carcinoma cells by laser scanning cytometry[J]. Cytometry A.2005,68(2):59-70.
[13]徐军,施红旗,刘庆伟,等.HIF-1α、VEGF在宫颈鳞癌中的表达及临床意义[J].浙江实用医学,2006,11(1)：6-8.
[14]Haugland HK, Vukovic V, Pintilie M, Expression of hypoxia-inducible factor-1alpha in cervical carcinomas:correlation with tumor oxygenation[J]. Int J Radiat Oncol Biol Phys.2002,53(4):854-861.
[15]Sivridis E, Giatromanolaki A, Gatter KC, et al. Association of hypoxia-inducible factors 1alpha and 2alpha with activated angiogenic pathways and prognosis in patients with endometrial carcinoma[J]. Cancer.2002,95(5): 1055-1063.
[16]Acs G, Xu X, Chu C, et al. Prognostic significance of erythropoietin expression in human endometrial carcinoma[J]. Cancer.2004,100(11): 2376-2386.
[17]Wong C, Wellman TL, Lounsbury KM. VEGF and HIF-1 alpha expression are increased in advanced stages of epithelial ovarian cancer[J]. Gynecol Oncol.2003, 91(3):513-517.
[2]Oloumi A, Mcphee T, Dedhar S. Regulation of E-cadherin expression and β-catenin/Tcf transcriptional activity by the integrin-linked kinase[J]. Bioc Hem Biophys Acta.2004,1691(1):1-15.
[3]Edwards L, Shabbits J, Bally M, et al. Integrin-linked kinase(ILK) in combination molecular targeting[J]. Cancer Treat Res.2004,119(6):59-75.
[4]李胜水,张凤梅,孙德飞,等.整合素连接激酶在宫颈上皮内瘤变及宫颈癌组织中的表达及临床意义[J].中国实用妇科与产科杂志.2009,25(1)：58-59.
[5]Kung AL, Zabludoff SD, France DS, et al. Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway[J]. Cancer Cell.2004,6(1):33-43.
[6]Klaes R, Friedrich T, Spitkovsky D, et al. Overexpression of p16(INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri[J]. Int J Cancer.2001,92(2):276-284.
[7]Tringler B, Gup CJ, Singh M, et al. Evaluation of p16 INK4a and pRb expression in cervical squamous and glandular neoplasia[J]. Hum Pathol.2004, 35(6):689-696.
[8]Zhong H, Semenza GL, Simons JW, et al. Up-regulation of hypoxia-inducible factor 1 alpha is an early event in prostate carcinogenesis[J]. Cancer Detect Prev. 2004,28(2):88-93.
[9]Joshi MB, Ivanov D, Philippova M, et al. Integrin-linked kinase is an essential mediator for T-cadherin-dependent signaling via Akt and GSK3 beta in endothelial cells[J]. Faseb J.2007,21(12):3083-3095.
[10]林梁.整合素连接激酶与肿瘤[J].国外医学：肿瘤学分册.2002,29(2)：98-101.
[11]Wong RP, Ng P, Dedhar S, et al. The role of integrin-linked kinase in melanoma cell migration, invasion and tumor growth[J]. Mol Cancer Ther.2007, 6(6):1602-1700.
[12]Okamura M, Yamaji S, Nagashima Y, et al. Prognostic value of integrin betal-ILK-pAkt signaling pathway in non-small cell lung cancer[J]. Hum Pathol. 2007,38(7):1081-1091.
[13]Liu BC, Xia HL, Wu JN, et al. Influence of irbesartan on expression of ILK and its relationship with epithelial-mesenchymal transition in mice with unilateral ureteral obstruction[J]. Acta Pharmacol Sin.2007,28(11):1810-1808.
[14]Korinek V, Barker N, Morin PJ, et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma[J]. Science.1997, 275(5307):1784-1787.
[15]Wu C, Keightley SY, Leung-Hagesteijn C, et al. Integrin-linked protein kinase regulates fibronectin matrix assembly, E-cadherin expression, and tumorigenicity[J]. J Biol Chem.1998,273(1):528-536.
[16]Kelly BD, Hackett SF, Hirota K, et al. Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1 [J]. Circ Res.2003,93(11):1074-1081.
[17]Bos R, Zhong H, Hanrahan CF, et al. Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis[J]. J Natl Cancer Inst.2001,93(4):309-314.
[18]Imai T, Horiuchi A, Wang C, et al. Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells[J]. Am J Pathol. 2003,163(4):1437-1447.
[19]Serrano M, Hannon GJ, Beach D, et al. A new regulatory motif in cell-cycle control causing specific inhibition of cyclinD/CDK4[J]. Nature(Lond).1993, 366(16):704-707.
[20]Marx J. New tumor suppressor may rival p53[J]. Science.1994,264(5157): 344-345.
[21]Kamb A, Gruis NA, Weaver-Feldhaus J, et al. A cell cycle regulator potentially involved in genesis of many tumor types[J]. Science.1994,264(5157): 436-440.
[22]戴淑真,李旭日,王宁,等.宫颈癌组织中P16和HPV16/18E7的表达和意义[J].齐鲁医学杂志.2004,19：283-286.
[23]Kelly MJ, Otterson GA, Kaye FJ, et al. CDKN2 in HPV-negative cervical-carcinoma cell lines[J]. Int J Cancer.1995,63:226-230.
[24]Hirama T, Miller CW, Wilczynski SP. P16(CDKN2/cyclin-dependent kinase-4 inhibitor/multiple tumor suppressor1) gene is not altered in uterine cervical carcinomas or cell lines[J]. Modern Pathol.1996,9:26-31.
[25]Tam SW, Shay JW, Pagano M. Differential expression and cell cycle regulation of the cyclin dependent kinase-4 inhibitor p16INK4[J]. Cancer Res. 1995,54(22):5816-5820.
[26]Schorge JO, Lea JS, Elias KJ, et al. P16 as a molecular biomarker of cervical adenocarcinoma[J]. Am J Obstet Gynecol.2004,190(3):668-673.
[27]Tringler B, Gup CJ, Singh M, et al. Evaluation of p16INK4a and pRb expression in cervical squamous and glandular neoplasia[J]. Hum Pathol.2004, 35(6):689-696.
[1]Hannigan GE, Leung-Hagesteijn C, Fitz-Gibbon L, et al. Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase[J]. Nature.1996,379(6560):91-96.
[2]Joshi MB, Ivanov D, Philippova M, et al. Integrin-linked kinase is an essential mediator for T-cadherin-dependent signaling via Akt and GSK3beta in endothelial cells[J]. Faseb J.2007,21(12):3083-3095.
[3]Stanchi F, Grashoff C, Nguemeni Yonga CF, et al. Molecular dissection of the ILK-PINCH-parvin triad reveals a fundamental role for the ILK kinase domain in the late stages of focal-adhesion maturation[J]. J Cell Sci.2009,122(11): 1800-1811.
[4]Wu C. PINCH, N(i)ck and the ILK:network wiring at cell-matrix adhesions[J]. Trends Cell Biol.2005,15(9):460-466.
[5]Cho HJ, Youn SW, Cheon SI, et al. Regulation of endothelial cell and endothelial progenitor cell survival and vasculogenesis by integrin-linked kinase[J]. Arterioscler Thromb Vasc Biol.2005,25(6):1154-1160.
[6]蹇华.整合素连接激酶(ILK)在肿瘤中的作用[J].中国现代医药杂志.2006,8(7)：148-150.
[7]Wong RP, Ng P, Dedhar S, et al. The role of integrin-linked kinase in melanoma cell migration, invasion and tumor growth[J]. Mol Cancer Ther.2007, 6(6):1602-1700.
[8]Okamura M, Yamaji S, Nagashima Y, et al. Prognostic value of integrin betal-ILK-pAkt signaling pathway in non-small cell lung cancer[J]. Hum Pathol. 2007,38(7):1081-1091.
[9]Haase M, Gmach CC, Eke I, et al. Expression of integrin-linked kinase is increased in differentiated cells[J]. J Histochem Cytochem.2008,56(9):819-829.
[10]Liu BC, Xia HL, Wu JN, et al. Influence of irbesartan on expression of ILK and its relationship with epithelial-mesenchymal transition in mice with unilateral ureteral obstruction[J]. Acta Pharmacol Sin.2007,28(11):1810-1818.
[11]Bonlter E, Van Obberghen-Schilling E. Integrin-linked kinase and its partners: a modular platform regulating cell-matrix adhesion dynamics and cytoskeletal organization[J]. Eur J Cell Biol.2006,85(3-4):255-263.
[12]Mi Z, Guo H, Wai PY, et al. Integrin-linked kinase regulates osteopontin-dependent MMP-2 and uPA expression to convey metastatic function in murine mammary epithelial cancer cells[J]. Carcinogenesis.2006,27(6): 1134-1145.
[13]Fan Y, Gong Y, Ghosh PK, et al. Spatial coordination of actin polymerization and ILK-Akt2 activity during endothelial cell migration[J]. Dev Cell,2009.16(5): 661-674.
[14]Qian Y, Zhong X, Flynn DC, et al. ILK mediates actin filament rearrangements and cell migration and invasion through PI3K/Akt/Rac1 signaling[J]. Oncogene.2005,24(19):3154-3165.
[15]Edwards LA, Woo J, Huxham LA, et al. Suppression of VEGF secretion and changes in glioblastoma multiforme microenvironment by inhibition of integrin-linked kinase (ILK)[J]. Mol Cancer Ther.2008,7(1):59-70..
[16]Ito R, Oue N, Zhu X, et al. Expression of integrin-linked kinase is closely correlated with invasion and metastasis of gastric carcinoma[J]. Virchows Arch. 2003,442(2):118-123.
[17]Bravou V, Klironomos G, Papadaki E, et al. ILK over-expression in human colon cancer progression correlates with:activation of beta-catenin, down-regulation of E-cadherin and activation of the Akt-FKHR pathway[J]. J Pathol.2006,208(1):91-99.
[18]Driver GA, Veale RB. Modulation of integrin-linked kinase (ILK) expression in human oesophageal squamous cell carcinoma cell lines by the EGF and TGFbetal growth factors[J]. Cancer Cell Int.2006,6:12.
[19]Graff JR, Deddens JA, Konicek BW, et al. Integrin-linked kinase expression increases with prostate tumor grade[J]. Clin Cancer Res.2001,7(7):1987-1991.
[20]Kieffer N, Schmitz M, Plancon S, et al. ILK as a potential marker gene to ascertain specific adenocarcinoma cell mRNA isolation from frozen prostate biopsy tissue sections. Int J Oncol.2005,26(6):1549-1558.
[21]Takanami I. Increased expression of integrin-linked kinase is associated with shorter survival in non-small cell lung cancer[J]. BMC Cancer.2005,5:1.
[22]Schmitz M, Grignard G, Margue C, et al. Complete loss of PTEN expression as a possible early prognostic marker for prostate cancer metastasis. Int J Cancer. 2007,120(6):1284-1292.
[23]Persad S, Attwell S, Gray V, et al. Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cell[J]. Proc Natl Acad Sci USA.2000, 97(7):3207-3212.
[24]Tan C, Cruet-Hennequart S, Troussard A, et al. Regulation of tumor angiogenesis by integrin-linked kinase (ILK)[J]. Cancer Cell.2004,5(1):79-90.
[25]Ahmed N, Oliva K, Rice GE, et al. Cell-free 59 kDa immunoreactive integrin-linked kinase:a novel marker for ovarian carcinoma[J]. Clin Cancer Res. 2004,10(7)：2415-2420.
[26]于翠珍,李双标,孙德飞.整合素连接激酶在卵巢肿瘤组织中的表达及意义[J].中国实用妇科与产科杂志.2007,23(9)：712-713.
[27]朱明艳,冯虹,万冰,等.ILK与P-PKB蛋白在卵巢肿瘤组织中的表达及意义[J].中国实用医药.2008,3(29)：64-66.
[28]李胜水,张凤梅,孙德飞,等.整合素连接激酶在宫颈上皮内瘤变及宫颈癌组织中的表达及临床意义[J].中国实用妇科与产科杂志.2009,25(1)：58-59.
[1]Lee JW, Bae SH, Jeong JW, et al. Hypoxia-inducible factor (HIF-1)alpha:its protein stability and biological functions[J]. Exp Mol Med.2004,36(1):1-12.
[2]Krishnamachary B, Berg-Dixon S, Kelly B, et al. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1[J]. Cancer Res.2003,63(5): 1138-1143.
[3]Pili R, Donehower RC. Is HIF-1 alpha a valid therapeutic target[J]? J Natl Cancer Inst.2003,95(7):498-499.
[4]Acs G, Zhang PJ, McGrath CM, et al. Hypoxia-inducible erythropoietin signaling in squamous dysplasia and squamous cell carcinoma of the uterine cervix and its potential role in cervical carcinogenesis and tumor progression[J]. Am J Pathol.2003,162(6):1789-1806.
[5]Kaio E, Tanaka S, Kitadai Y, Kaio E, Clinical significance of angiogenic factor expression at the deepest invasive site of advanced colorectal carcinoma[J]. Oncology.2003,64(1):61-73.
[6]Jubb AM, Pham TQ, Hanby AM, et al. Expression of vascular endothelial growth factor, hypoxia inducible factor 1 alpha, and carbonic anhydrase IX in human tumours[J]. J Clin Pathol.2004,57(5):504-512.
[7]Fujimoto J, Alam SM, Jahan I, et al. Plausible linkage of hypoxia inducible factor-1alpha in uterine cervical cancer[J]. Cancer Sci.2006,97(9):861-867.
[8]Jones A, Fujiyama C, Blanche C, et al. Relation of vascular endothelial growth factor production to expression and regulation of hypoxia-inducible factor-1 alpha and hypoxia-inducible factor-2 alpha in human bladder tumors and cell lines[J]. Clin Cancer Res.2001,7(5):1263-1272.
[9]Kung AL, Wang S, Klco JM, et al. Suppression of tumor growth through disruption of hypoxia-inducible transcription[J]. Nat Med.2000,6(12): 1335-1340.
[10]Yeo EJ, Chun YS, Cho YS, et al. YC-1:a potential anticancer drug targeting hypoxia-inducible factor 1[J]. J Natl Cancer Inst.2003,95(7):516-525.
[11]Zhang Q, Tang X, Lu Q, et al. Green tea extract and (-)-epigallocatechin-3-gallate inhibit hypoxia-and serum-induced HIF-1alpha protein accumulation and VEGF expression in human cervical carcinoma and hepatoma cells[J]. Mol Cancer Ther.2006,5(5):1227-1238.
[12]Schwock J, Geddie WR, Hedley DW. Analysis of hypoxia-inducible factor-1alpha accumulation and cell cycle in geldanamycin-treated human cervical carcinoma cells by laser scanning cytometry[J]. Cytometry A.2005,68(2):59-70.
[13]徐军,施红旗,刘庆伟,等.HIF-1α、VEGF在宫颈鳞癌中的表达及临床意义[J].浙江实用医学,2006,11(1)：6-8.
[14]Haugland HK, Vukovic V, Pintilie M, Expression of hypoxia-inducible factor-1alpha in cervical carcinomas:correlation with tumor oxygenation[J]. Int J Radiat Oncol Biol Phys.2002,53(4):854-861.
[15]Sivridis E, Giatromanolaki A, Gatter KC, et al. Association of hypoxia-inducible factors 1alpha and 2alpha with activated angiogenic pathways and prognosis in patients with endometrial carcinoma[J]. Cancer.2002,95(5): 1055-1063.
[16]Acs G, Xu X, Chu C, et al. Prognostic significance of erythropoietin expression in human endometrial carcinoma[J]. Cancer.2004,100(11): 2376-2386.
[17]Wong C, Wellman TL, Lounsbury KM. VEGF and HIF-1 alpha expression are increased in advanced stages of epithelial ovarian cancer[J]. Gynecol Oncol.2003, 91(3):513-517.