非小细胞肺癌中抑癌基因PTEN突变、表达及相关信号通路与肿瘤发生发展及预后的相关性研究
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摘要
前言
肺癌是最常见、最具有危险性的恶性肿瘤之一,五年生存率较低,而80%肺癌为非小细胞肺癌(non-small cell of lung cancer, NSCLC),其发生、发展是多因素多步骤参与的过程。由PTKs(蛋白质酪氨酸激酶)和PTPs(蛋白质酪氨酸磷酸酶)精确调控的蛋白质酪氨酸磷酸化水平在此过程中起重要作用。而很多PTKs都是由原癌基因或癌基因编码的,因此某些PTPs可能在体内起抑癌基因的作用,这个结论直到PTEN/MMAC1/TEPl(后简称PTEN)基因发现后才得到证实。作为第一个编码PTPs的抑癌基因即第10号染色体同源丢失性磷酸酶-张力蛋白基因(phoshatase and tension homology deleted on chromosome ten, PTEN),自1997年3月以来先后被国际上三个科研小组分别克隆后立即成为分子生物学、细胞信号转导和肿瘤病理等领域的研究热点,一些研究已经证明它与肿瘤的形成,尤其进展有关。Li和Steck等首先对为数不多的脑肿瘤、前列腺癌及乳腺癌肿瘤细胞株和一些原发肿瘤进行该基因的初步检测,均发现了不同形式的体细胞性突变(somatic mutation)。然而对于非小细胞肺癌发生、发展过程中是否有PTEN基因的突变报道较少,至于其蛋白水平的改变,结论尚不一致。
方法
收集有完整随访资料的61例非小细胞肺癌及20例癌旁正常肺组织蜡块,其中30例非小细胞肺癌组织抽提DNA, PCR扩增PTEN基因第3、5、7、8外显子,琼脂糖凝胶电泳鉴定扩增产物,有条带者DNA测序；所有蜡块均使用免疫组化SP法检测组织中PTEN、PI3K和P-Akt蛋白的表达情况；计数资料采用率表示,不同组间比较用x2检验,生存分析采用Kaplan-Meier法进行单因素分析及Log-rank检验,并用Cox比例风险模型进行多因素分析。
结果
测序结果显示,仅1例标本(临床Ⅳ期、低分化、T3N2M1期、术后生存12个月)发生了PTEN基因外显子5、7、8的纯和性丢失。余29例NSCLC标本中发现了2类2例突变位点的存在,这2类突变均位于内含子中：第7外显子3'-侧翼下游46bp处检测到的一个G→A(116033)点突变,在第8外显子5'-侧翼上游2bp和3bp之间(11859-11860)插入了一个T。
免疫组化结果显示：NSCLC组织标本中PTEN蛋白的表达低于癌旁正常肺组织；肺腺癌标本中PTEN蛋白表达较高；PTEN蛋白表达随NSCLC患者最初发现时临床分期的增加及出现淋巴结转移而降低；PTEN蛋白在术后生存期≥4年的患者中表达较高(P<0.05)。PTEN蛋白表达在不同年龄组及不同分化程度组的NSCLC组织中差异无显著性(P>0.05)
Spearson相关性检验显示：NSCLC组织中PTEN与PI3K/Akt蛋白表达成负相关,证实了PTEN和PI3K/Akt信号通路的负向调控关系。
Cox比例风险模型显示：在众多的影响因子中仅吸烟和PTEN阴性表达为影响NSCLC患者预后的危险因子。
结论
本研究结果显示：PTEN基因的改变、蛋白的表达水平下调及PTEN-PI3K/Akt信号通路的失衡在NSCLC的发生发展中起到了一定的作用,维持了肿瘤的恶性生物学行为,促进了肿瘤的进展。表明PTEN基因有可能通过降低NSCLC的恶性表型成为NSCLC基因治疗的一个有效靶基因。
Introdution
Lung Cancer is one of the most common and maligant tumors in the world and the patients have poor prognosis. About 80%of lung cancer is non small cell of lung cancer (NSCLC). Just like some tumors, the development of NSCLC is a complex process involving many genes and factors. The phosphorylation level of protein tyrosine, precisely regulated by PTKs and PTPs, plays an important role in the cellular signal transduction and cell cycle progression. As many PTKs are encoded by pro-oncogenes, it has been postulated that some of PTPs may act as tumor suppressor gene for a long time. But this assumption is not testified until the discovery ofPTEN tumor suppressor gene.Since characterized and cloned seperatedly by Jing Li, Peter A. steck and DaMing Li. in 1997, PTEN has been found to be inactivated by point mutations or homozygous deletions in many malignant tumors such as glioblastoma, protate carcinoma and breast carcinoma. Although much work has been done on the relationships between PTEN gene and some other tumors, there are few reports on the relationship between PTEN mutation and NSCLC. And so far, to our knowledge there is no unified view on PTEN protein expression during the occurrence and development ofNSCLC.
Methods
In the study, we collected 61 NSCLC samples with complete follow-up data and 20 cases near cancer tissue as control. At first, we extracted 30 cases of NSCLC tissue s DNA, then designed primers of PTEN 3.5.7,8 exons.consequently got the amplification production by PCR and identified by agarose gel electrophoresis.The next step, we sended the ones which have amplification productions to the detecting company, then we could obtain the sequence result. We also used immunohistochemistry to detect PTEN,PI3K and P-Akt protein expression in all samples. At last, we usedχ2 test to analyze the mutation and protein expression outcomes and analyzed survival aspects by single factor Kaplan-Meier assay and Cox-Model.
Results
It was shown that two kinds of novel point mutations and one case of PTEN EXON5,7 and 8 loss of homozygosity in NSCLC samples used were identified by PCR and DNA sequencing methods. Among them, one case of base substitutions was found in 7-intron region(46bp of downstream of exon73'-flanking region,116033 G→A), while other 1 case of point mutation localized in 7-intron region(between 2 bp and 3 bp of upstream of exon85-flanking region insert a T,11859-11860).
By immunohistochemistry, the expression level of PTEN protein in NSCLC were significantly lower than in tumor-sorrounding lung tissues(P<0.05). Besides the low expression level of PTEN protein was significantly associated with squamous cancer, late clinical stage,lymphangitic metastases and short survival time after operation(P< 0.05). However no significant relationship was found with age and histological grading(P>0.05).
Spearman correlation test showed that the expression level of PTEN protein was signicantly positive correlation with PI3K and Akt protein expression. Now, it demonstrated the negative regulation between PTEN and PI3K/Akt signal pathway.
Cox multiple factor proportion risk model showed that among many factors, only smoking and loss expression of PTEN were risk factors of patients survival time after operation.
Conclusions
Our results suggest that mutation,loss expression of PTEN gene and the disbalance between PTEN and PI3K/Akt signal pathway may be involved in the occurrence and development of NSCLC. which sustained the malignant phenotype of tumor and facilitated tumor development. Then we believe that PTEN may be implicated in the genetherapy of NSCLC.
肺癌是最常见、最具有危险性的恶性肿瘤之一,五年生存率较低,而80%肺癌为非小细胞肺癌(non-small cell of lung cancer, NSCLC),其发生、发展是多因素多步骤参与的过程。由PTKs(蛋白质酪氨酸激酶)和PTPs(蛋白质酪氨酸磷酸酶)精确调控的蛋白质酪氨酸磷酸化水平在此过程中起重要作用。而很多PTKs都是由原癌基因或癌基因编码的,因此某些PTPs可能在体内起抑癌基因的作用,这个结论直到PTEN/MMAC1/TEPl(后简称PTEN)基因发现后才得到证实。作为第一个编码PTPs的抑癌基因即第10号染色体同源丢失性磷酸酶-张力蛋白基因(phoshatase and tension homology deleted on chromosome ten, PTEN),自1997年3月以来先后被国际上三个科研小组分别克隆后立即成为分子生物学、细胞信号转导和肿瘤病理等领域的研究热点,一些研究已经证明它与肿瘤的形成,尤其进展有关。Li和Steck等首先对为数不多的脑肿瘤、前列腺癌及乳腺癌肿瘤细胞株和一些原发肿瘤进行该基因的初步检测,均发现了不同形式的体细胞性突变(somatic mutation)。然而对于非小细胞肺癌发生、发展过程中是否有PTEN基因的突变报道较少,至于其蛋白水平的改变,结论尚不一致。
方法
收集有完整随访资料的61例非小细胞肺癌及20例癌旁正常肺组织蜡块,其中30例非小细胞肺癌组织抽提DNA, PCR扩增PTEN基因第3、5、7、8外显子,琼脂糖凝胶电泳鉴定扩增产物,有条带者DNA测序；所有蜡块均使用免疫组化SP法检测组织中PTEN、PI3K和P-Akt蛋白的表达情况；计数资料采用率表示,不同组间比较用x2检验,生存分析采用Kaplan-Meier法进行单因素分析及Log-rank检验,并用Cox比例风险模型进行多因素分析。
结果
测序结果显示,仅1例标本(临床Ⅳ期、低分化、T3N2M1期、术后生存12个月)发生了PTEN基因外显子5、7、8的纯和性丢失。余29例NSCLC标本中发现了2类2例突变位点的存在,这2类突变均位于内含子中：第7外显子3'-侧翼下游46bp处检测到的一个G→A(116033)点突变,在第8外显子5'-侧翼上游2bp和3bp之间(11859-11860)插入了一个T。
免疫组化结果显示：NSCLC组织标本中PTEN蛋白的表达低于癌旁正常肺组织；肺腺癌标本中PTEN蛋白表达较高；PTEN蛋白表达随NSCLC患者最初发现时临床分期的增加及出现淋巴结转移而降低；PTEN蛋白在术后生存期≥4年的患者中表达较高(P<0.05)。PTEN蛋白表达在不同年龄组及不同分化程度组的NSCLC组织中差异无显著性(P>0.05)
Spearson相关性检验显示：NSCLC组织中PTEN与PI3K/Akt蛋白表达成负相关,证实了PTEN和PI3K/Akt信号通路的负向调控关系。
Cox比例风险模型显示：在众多的影响因子中仅吸烟和PTEN阴性表达为影响NSCLC患者预后的危险因子。
结论
本研究结果显示：PTEN基因的改变、蛋白的表达水平下调及PTEN-PI3K/Akt信号通路的失衡在NSCLC的发生发展中起到了一定的作用,维持了肿瘤的恶性生物学行为,促进了肿瘤的进展。表明PTEN基因有可能通过降低NSCLC的恶性表型成为NSCLC基因治疗的一个有效靶基因。
Introdution
Lung Cancer is one of the most common and maligant tumors in the world and the patients have poor prognosis. About 80%of lung cancer is non small cell of lung cancer (NSCLC). Just like some tumors, the development of NSCLC is a complex process involving many genes and factors. The phosphorylation level of protein tyrosine, precisely regulated by PTKs and PTPs, plays an important role in the cellular signal transduction and cell cycle progression. As many PTKs are encoded by pro-oncogenes, it has been postulated that some of PTPs may act as tumor suppressor gene for a long time. But this assumption is not testified until the discovery ofPTEN tumor suppressor gene.Since characterized and cloned seperatedly by Jing Li, Peter A. steck and DaMing Li. in 1997, PTEN has been found to be inactivated by point mutations or homozygous deletions in many malignant tumors such as glioblastoma, protate carcinoma and breast carcinoma. Although much work has been done on the relationships between PTEN gene and some other tumors, there are few reports on the relationship between PTEN mutation and NSCLC. And so far, to our knowledge there is no unified view on PTEN protein expression during the occurrence and development ofNSCLC.
Methods
In the study, we collected 61 NSCLC samples with complete follow-up data and 20 cases near cancer tissue as control. At first, we extracted 30 cases of NSCLC tissue s DNA, then designed primers of PTEN 3.5.7,8 exons.consequently got the amplification production by PCR and identified by agarose gel electrophoresis.The next step, we sended the ones which have amplification productions to the detecting company, then we could obtain the sequence result. We also used immunohistochemistry to detect PTEN,PI3K and P-Akt protein expression in all samples. At last, we usedχ2 test to analyze the mutation and protein expression outcomes and analyzed survival aspects by single factor Kaplan-Meier assay and Cox-Model.
Results
It was shown that two kinds of novel point mutations and one case of PTEN EXON5,7 and 8 loss of homozygosity in NSCLC samples used were identified by PCR and DNA sequencing methods. Among them, one case of base substitutions was found in 7-intron region(46bp of downstream of exon73'-flanking region,116033 G→A), while other 1 case of point mutation localized in 7-intron region(between 2 bp and 3 bp of upstream of exon85-flanking region insert a T,11859-11860).
By immunohistochemistry, the expression level of PTEN protein in NSCLC were significantly lower than in tumor-sorrounding lung tissues(P<0.05). Besides the low expression level of PTEN protein was significantly associated with squamous cancer, late clinical stage,lymphangitic metastases and short survival time after operation(P< 0.05). However no significant relationship was found with age and histological grading(P>0.05).
Spearman correlation test showed that the expression level of PTEN protein was signicantly positive correlation with PI3K and Akt protein expression. Now, it demonstrated the negative regulation between PTEN and PI3K/Akt signal pathway.
Cox multiple factor proportion risk model showed that among many factors, only smoking and loss expression of PTEN were risk factors of patients survival time after operation.
Conclusions
Our results suggest that mutation,loss expression of PTEN gene and the disbalance between PTEN and PI3K/Akt signal pathway may be involved in the occurrence and development of NSCLC. which sustained the malignant phenotype of tumor and facilitated tumor development. Then we believe that PTEN may be implicated in the genetherapy of NSCLC.
引文
1 Shen WH., A. S. Balajee, J.Wang, et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell,2007,128(1):157-170.
2 Trotman LC., X. Wang, A. Alimonti, et al. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell,2007,128(1):141-156.
3 Gallus S, Altieri A, Bosetti C, et al. Cigarette tar yield and risk of upper digestive tract cancers:case-control studies from Italy and Switzerland.Ann Oncol,2003,14 (2):209-213.
4 Tselepis C, Morris CD, Wakelin D, et al. Upregulation of the oncogene c-myc in Barrett's adenocarcinoma:induction of c-myc by acidified bile acid in vitro.Gut,2003,52(2):174-180.
5 Jone GJ, Heiss NS, Veale RB, et al. Amplification and expression of the TGF-alpha, EGF receptor and c-myc genes in four human oesophageal squamous cell carcinoma lines. Biosci Rep,1993,13(5):303-312.
6 Mathew R, Arora S, Khanna R, et al. Alteractions in p53 and pRb pathways and their prognostic significane in oesophageal cancer. Eur J Cancer,2002,38(6):832-841.
7 Freitas S, Moore DH, Michael H, et al. Studies of apurine/apyrimidition endonueclease/ref-1 expression in epithelial ovarian cancer:correlations with tumor progression and platinum resistance. Clin Cancer Res,2003,9:4689-4694.
8 Li J, Yen C, LiawD, et al. PTEN a putive protein tyrosine phoshatage gene mutated in human brain, breast and prostate cancer. Science,1997,275(5308):1943-1947.
9 Steck PA, Pershonse MA, Jasser SA, et al. Identification of a candidate tumor Suppressor gene, MMAC1, at chromasome 10q23.3 that is mutated in multiple advanced cancers. Nature Genetics,1997,15 (4):356-359.
10 Li DM, Sun H. Tepl, encoded by a candidate tumor suppressor Locus, is a novel protein tyrosine phosphatease regulated by transforming growth factor β1, Cancer Res,1997,57(11):2124-2130.
11 Denu J, Stuckey JA, Saper D, et al. Form and function in protein dephosphorylation.
Cell,1996,87(3):361-364.
12 Chen JW, Li SX, Yang ZR, et al. Correlation between NDRG1 and PTEN expression in endometrial carcinoma. Cancer Sci,2008,99(4):706-710.
13 Ali IU, Schriml LM, Dean M. Mutational spectra of PTEN/MMAC1 gene:a tumor supp ressor with lip id phosphatase activity. J Natl Cancer Inst,1999,91(22): 1922-1932.
14 Jiang BH, Liu LZ. PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochim Biophys Acta,2008,1784(1):150-158.
15 Ferraro B, Bepler G, et al. EGR1 predicts PTEN and survival in patients with non-small cell lung cancer. Clin Oncol,2005,23(9):1921-1926.
16 Christine Grill, Christian Guelly, Birgit Ebner, et al. Loss of PTEN/MMAC1 activity is a rare and late event in the pathogenesis of nephroblastomas. Human Pathology,2010, In Press.
17 Bepler G, Sharma S, Cantor A, et al. RRM1 and PTEN as prognostic parameters for overall and disease-free survival in patients with non small cell lung cancer. J Clin Oncol,2004,22(10):1878.
18 Zhang Y, Yu D, Li X, et al. Reduced expression of PTEN protein and its prognostic significance in the gastrointestinal stromal tumor. J Huazhong Univ Sci Technolog Med Sci.2010,30(2):165-169.
19 Salmena L, Carracedo A,Pandolfi P P. Tenets of PTEN tumor suppression. Cell,2008,133(3):403-414.
20 李厚文.肺癌的基础与临床,第一版.沈阳：辽宁科学技术出版社,1984,266.
21 Tian XX, Pang JC, To SS, et al. Restoration of wild-type PTEN expression leads to apoptosis, induces differentiation, and reduces telomerase activity in human glioma cells. Neuropathol Exp Neurol.1999,58(5):472-479.
22 Ghosh AK, Grigorieva I, Steele R, et al. PTEN transcriptionally modulates c-myc gene expression in human breast carcinoma cells and is involved in cell growth regulation. Gene,1999,22,235(1-2):85-91.
23 Lu Y, Lin YZ, LaPushin R, et al. The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cnacer cells. Oncogene, 1999,18:7034-7045.
24 Schwartzbauer G, Robbins J. The tumor suppressor gene PTEN can regulate cardiac hypertrophy and survival. J Biol Chen,2001,276:35786-35793.
25 Uzuki A, Hayashida M, et al. Hepatocyte growth factor promotes cell survival from fas-mediates cell death in hepatocellular carcinoma cells via Akt action and Fas-death-inducing signaling complex suppression. Hepatology,2000,32:796-802.
26 Kurose K, Zhou XP, et al. Frequent loss of PTEN expression is linked to elevated phosphorylated Akt levels but not associated with p27 and cyclin D1 expression, in primary epithelial ovarian carcinomas.Am J Pathol,2001,158:2097-2106.
27 Abal M, Planaguma J, Gil-Moreno A, et al. Molecular pathology of endometrial carcinoma:transcriptional signature in endometrioid tumors. Histopathol,2006, 21(2):197-204.
28 Erkanli S, Kayaselcuk F, Kuscu E, et al. Expression of surviving, PTEN and p27 in normal, hyperplastic, and carcinomatous endometrium. Int J Gynecol Cancer,2006, 16(3):1412-1418.
29 Foster K, Wang Y, Zhou D, et al. Dependence on PI3K/Akt signaling for malignant rhabdoid tumor cell survival. Cancer Chemother Pharmacol,2009,63(5):783-791.
30 Park KK, Liu K, Hu Y, et al. Promoting axon regeneration in the adult CN by modulation of the PTEN/Mtor pathway. Science,2008,322(5903):963-966.
31 Bertram J, Peacock JW, Tan C, et al. Inhibition of the phosphatidylinositol3'-kinase pathway promotes autocrine Fas-induced death of phosphatase and tension homologue-deficient prostate cancer cells. Cancer Res,2006,66(9):4781-8.
32 Petrocelli T, Slingerland JM. PTEN deficiency:a role in mammary carcinogenesis. Breast Cancer Res,2001,3(6):356-360.
33 Dianren X, Harish S, Young HA, et al. Mitogen-activated protein kinase-4 promotes cell survival by decreasing PTEN expression through an NF-Kβdependent pathway. J
Biol Chem,2007,282(6):3507-3519.
34 Paweletz CP, Charboneau L, Bichsel VE, et al. Reverse phase protein microarrays which capture disease progression show activation of prosurvival pathways at the cancer invasion front. Oncogene,2001,20(16):1981-1989.
35 L.Zhang, N.Yang, D. Katsaros, et al. The oncogene phosphatidlinositol 3,-kinse catalytic subunit alpha promotes angiogenesis via vascular endothelial growth factor in ovarian carcinoma. Cancer Res.2003,63 (14),4225-4231.
36 Shukla S, Maclennan GT, Hartman DJ, et al. Activation of PI3K-Akt signaling pathway promotes prostate cancer cell invasion. Int J Cancer.2007,121 (7):1424-1432.
37 Che G, Chen J, Liu L, et al. Transfection of nm23-H1 increased expression of beta-Catenin, E-cadherin and TIMP-1 and decreased the expression of MMP-2, CD44v6 and VEGF and inhibited the metastatic potential of human non-small cell lung cancer cell line L9981. Neoplasma.2006,53(6):530-537.
38 史惠蓉,张瑞涛.P53、 P21WAF1.和CDK1在卵巢癌上皮性癌组织中的表达及意义.癌症,2009,28(8)：882-885.
39 Gort EH, Suijkerbuijk KP, Roothaan SM, et al. Methylation of the TWIST promoter, TWIST1 mRNA levels,and immunohistochemical expression of TWIST in breast cancer. Cancer Epidemiol Biomarkers Pres,2008,17(12):3325-3330.
40 Yuen HF, Kwork WK, Chan KK, et al. TWIST modulates prostate cancer cell-mediate bone cell activity and is upregulated by osteogenic induction. Cancinogenesis, 2008,29(8):1509-1518.
41 Fendrich V, Waldmann J, Feldmann G, et al. Unique expression pattern of the EMT markers Snail, Twist and E-cadherin in benign and malignant parathyroid neoplasia. Eur J Endocrinol,2009,160(4):695-703.
42 Wang C, Yang R, Yue D, et al. Expression of FAK and PTEN in bronchioloalveolar carcinoma and lung adenocarcinoma. Lung,2009,87(2):104-109.
43 Greenwald P, Dunn BK. Landmarks in the history of cancer epidemiology.Cancer Res,2009,69(6):2151-2162.
1 Li DM,Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res,1997,57(11):2124-2129.
2 Lee JO, Yang MM, Georgescu A. D, et al. Crystal structure of the PTEN tumor Suppressor:implication for its phosphoinositide phosphatase activity and membrane association.Cell,1999,99(3):323-334.
3 Tamguney T, Stokoe D. New insight into PTEN. Cell Science,2007,120 (23):4071-4079.
4 Planchon SM.Waite KA, Eng C. The nuclear affairs of PTEN. Cell Science,2008, 121 (3):249-253.
5 Liu JL, Mao ZY, Lafortune TA, et al. Cell cycle-dependent nuclear export of phosphatase and tesin homologue tumor suppressor is regulated by the phosphoinositide-3-kinase signaling cascade. Cancer Res,2007,67(22): 110542-11063.
6 Fridberg M, Servin A, Anagnostaki L, et al. Protein expression and cellular localization in two prognostic subgroups of diffuse large B-cell lymphoma: Higher expression of ZAP70 and PKC-beta II in t he non-germinal center group and poor survival in patient deficient in nuclear PTEN. Leuk Lympho,2007,48 (11): 2221-2232.
7 Shen WH, A. S. Balajee, J. Wang, et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 2007,128(1):157-170.
8 Trotman L C, X. Wang, A. Alimonti, et al. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 2007,128(1):141-156.
9 Ginn Pease ME, Eng C. Increase nuclear phosphtase and tensinhomologue deleted on chromosome 10 is associated with GOG1 in MCF27 cells. Cancer Res,2003,63 (2):282-286.
10 Kadel ES, Skeen J, Majewski N, et al. Activation of Akt/proteion kinase B over comes a G(2)/M cell cycle check point indued by DNA damage. Mol Cell m,
Biol,2002,22(22):7831-7841.
11 Stewart AL, Mhashilka AM, Yang XH, et al. PI3kinase blockade by Ad-PTEN inhibits invasion and induces apoptosis in RGP and metastatic melanoma cells. Mol Med,2002,8(8):451-461.
12 Li AG, Piluso L G, Cai X, et al. Mechanistic insight s into maintenance of high P53 acetylation by PTEN.Mol Cell,2006,23(4):575-587.
13 An HJ, Shim JY, Kim SJ, et al. Alteration of PTEN expression in endometrial carcinoma is associated with down-regulation of cyclin-dependent kinase inhibitor, p27. Histopathology,2002,41(5):437-445.
14 Cheney IW, Neuteboom ST, Vaillancourt MT, et al. Adenovirusmediated gene transfer of MMAC1/PTEN to glioblastoma cells inhibits S phase entry by the recruitment of p27 Kipl into cyclin E/CDK2 complexes.Cancer res,1999,59(10):2318-2323.
15 Koul D, Shen R, Garyali A, et al. MMAC1/PTEN tumor suppressor gene regulates vascular endothelial growth factor mediated angiogenesis in prostate cancer. Int J Oncol,2002,21(3):469-475.
16 Yanagi S, Kishimoto H, Kawahara K, et al. Pten controls lung morphogenesis, bronchioalveolar stem cells, and onset of lung adenocarcinomas in mice. J Clin Invest.2007,117(10):2929-2940.
17 Myers MP, Pass I, Batty IH, et al. The lipid phosphatase activity of PTEN is critical for its tumor suppressor fuction. Proc Natl Acad Sci USA, 1998,95(23):13513-13518.
18 Kandasamy K, Srivastava RK. Role of the phosphatdylionsitol 3-kinase/PTEN/AKT kinase pathway in tumor necrosis facto-related apoptosis-inducing ligand-induced apoptosis in non-small cell lung cancer cells. Cancer Res,2002, 62(17):4929-4937.
19 Lee HY, Srinivas H, Xia D, et al. Evidence that phosphatidylinositol 3-kinase and motogen-activated protein kinase-4/c-jun NH2-terminal kinase-dependent pathways cooperate to maintain lung cancer cell survival. J Biol Che2003,278
(26):23630-23638.
20 Yu J, Ni M, Xu J, et al. Methylation profiling of twenty promoter CpG islands of genes which may contribute to hepatocelluar carcinogenesis. BMC Cancer,2002,15(2):29.
21 Ali IU, Schriml LM, Dean M. Mutational spectra of PTEN/MMAC1 gene:a tumor suppressor with lip id phosphatase activity. JNatl Cancer Inst,1999,91 (22): 1922-1932.
220 kam i K, W uu L, R iggins G, et al. Analysis of PTEN6MMAC1 alterations in aero digestive tract tumors. Cancer R es,1998; 58 (3):509-511.
23 Kanamori Y, Kigawa J, Itamochi H, et al. Correlation between loss of PTEN exp ression and A KT phosphorylation in endomet rial carcinoma. Clin Cancer Res, 2001,7(4):892-895.
24 Soria JC, Lee HY, Lee JI, et al. Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation. Clin Cancer Res,2002,8 (5): 1178-1184.
25 Tamura M, Gu J, Matsumoto K, et al. Inhibition of cell migration, spreading and focal adhesions by tumor suppressor PTEN. Science,1998,280:1614-1617.
26 Bepler G, Sharma S, Cator A, et al. RRMland PTEN as prognostic parameters for overall and disease-free survival in patients with non-small-cell lung cancer. J Clin Oncol.2004,22(10):1878-1885.
27 Frisk T, Foukakis T, Dwight T, et al. Silencing of the PTEN tumor suppressor gene in anaplastic thyoid cancer, Genes Chromosomes Cancer,2002,35:74-80.
28 An Q, LiuY, Gao Y, et al. Deletion of tumor suppressor genes in Chinese non-small cell lung cancer.Cancer Lett,2002,184(2):189-195.
29 HosoyaY, Gemma A, SeikeM, et al. Alteration of the PTEN/MMAC Gene locus in primary lung cancer with distant metastasis. Lung Cancer,1999,25:87-93.
30 Kohno T, Takahashi M, Manda R, et al. Inactivation of the PTEN/MMAC1/TEP1 gene in human lung cancer. Oncogene,1998,22(2):152-156,
31 Yokomizo A, Tindall DJ, Drabkin H, et al. PTEN/MMAC1 mutations identified in small cell, but not in non-small cell lung cancers. Oncogene,1998,17(4):475-479.
32 Kim SK, Sulk, Oh Y, et al. Alterations of PTEN/MMAC1, a candidate tumor suppressor gene, and its homologue, PTH2, in small cell lung cancer cell lines. Oncogene,1998,16(1):89-93.
33 Forgacs E, Biesterveld EJ, Sekido Y, et al. Mutation analysis of the PTEN/MMAC1 gene in lung cancer. Oncogene,1998,17(12):1557-1565.
34 Zhang L, Liu T, Liu H, et al. Loss and inactivation of PTEN/MMAC1/TEP1 gene in lung cancer. Zhonghua Bing Li Xe Za Zhi,2000,29(2):8588.
35 Hosoya Y, Gemma A, Seike M, et al. Alteration of the PTEN/MMAC1 gene locus on primary lung cancer with distant metastasis. Lung Cancer,1999,25(2):87-93.
36 An Q, Liu Y, Huang J. Comparison of tumor suppressor gene deletion between squamous cell carcinoma and adenocarcinoma lung cancer in Chinese. zhonghua Zhong Liu Za Zhi,2001,23(6):470-472.
37 Petersen S, Rudolf J, Bock muhl U, et al. Distinct regions of allelic imbalance on chromosome 10q22-q26 in squamous cell carcinomas of the lung. Oncogenec,1998,17(4):449-454.
38 Sakurada A, Suzuki A, Sato M, et al. Infrequent genetic alterations of the PTEN/MMAC1 gene in Japanese patients with primary cancers of the breast, lung, pancreas, kidney and ovary. Jpn J Cancer Res,1997,88(11):1025-1028.
39 Tsujiuchi T, Sasaki Y, Tsutsumi M, et al.Absense of PTEN/MMAC1 gene mutations in lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine in rats. Cancer Lett,2001,162(2):207-211.
40 Tamura M, Gu J, Takino, et al. Tumor suppressor PTEN inhibition of cell I nvision, migration,and growth:differential involvement of focal adhesion kinase and p130Cas. Cancer Res,1999,59(2):442-449.
41 Kanamori Y, Kigawa J, Itamochi H, et al. Correlation between loss of PTEN expression and Akt phosphosphorylation in endometrial carcinoma. Clin Cancer
Res,2001,7(4):892-895.
42 Li DM, Sun H. PTEN/MMAC1/TEP1 suppresses the tumorigenicity and inducees G1 cell cycle arrest in human glioblastoma cells. Proc Natl Acad Sci USA,1998,95(26):15406-15411.
43 Tamura M, Gu J, Danen EH, et al. PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatinositol 3-kinase/Akt cell survival pathway. J Biol Chem,1999,274(29):20693-20703.
44 A. Denley, S. Kang, U. Karst, et al. Oncogenic signaling of class I PI3K isoforms. Oncogene 2008,27(18),2561-2574.
45 S. Kang, A. Denley, B. Vanhaesebroeck, et al. Oncogenic transformation induced by the pllObeta,-gamma, and-delta isoforms of class I phosphoinositide 3-kinase. Proc. Natl. Acad. Sci. USA 2006,103(5):1289-1294.
46 Q. Meng, C. Xia, J. Fang, et al. Role of PI3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70S6Kl pathway. Cell Signal,2006,18(12):2262-2271.
47 Chun KH, Kosemeder II JW, Sun S, et al. Effects of deguelin on the phosphatidylinositol3-kinase/Akt pathway and apoptosis in premalignant human bronchial epithelial cells. J Natl Cancer Inst 2003:95(4):291—302.
48 Paweletz CP, Charboneau L, Bichsel VE, et al. Reverse phase protein microarrays which capture disease progression show activation of prosurvival pathways at the cancer invasion front. Oncogene,2001,20(16):1981-1989.
49 Osaki M, Kase S, Adachi K, et al. Inhibition of the PI3K-AKT siganaling pathway enhances the sensitivity of Fas-mediated apoptosis in human gastric carcinoma cell line,MKN-45. J Cancer Res Clin Oncol,2004,130(1):8-14.
50 Yong Geon Kim, MIji Kim, et al. ICAM-3-induced cancer cell proliferation through the PI3K/AKT pathway.Cancer Letters 2006,239(1):103-110.
51 Kaarbo M, Klokk TI, Saatcioglu F. Androgen signaling and its interactions with other signaling pathways in prostate cancer. Bioessays.2007,29(12):1227
-1238.
52 Shen MM, Abate-Shen C. Pten inactivation and the emergence of androgen-independent prostate cancer. Cancer Res.2007,67(14):6535-6538.
53 L.Zhang, N.Yang, D. Katsaros, et al. The oncogene phosphatidlinositol 3,-kinse catalytic subunit alpha promotes angiogenesis via vascular endothelial growth factor in ovarian carcinoma. Cancer Res.2003,63(14),4225-4231.
54 Shukla S, Maclennan GT, Hartman DJ, et al. Activation of PI3K-Akt signaling pathway promotes prostate cancer cell invasion. Int J Cancer.2007,121(7):1424-1432.
55 Qian Y, Corum L, Meng Q, et al. PI3K induced actin filament remodeling through AKT and p70S6K1;implication of essential role in cell migration. Am J Physiol,2004,286(9):C153-163.
56 Liaw D, Marsh DJ, Li J, et al. Germline mutation of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet,1997,16 (1):64-67.
57 赵军,刘晓谦,张军等.脑胶质瘤组织PTEN基因异常及其蛋白表达.第四军医大学学报,2009,30(9)：843-845.
58 Lin H, Bondy ML, Lanford LA, et al. Allelic deletion analyses of MMAC1/PTEN and DMBT1 loci in gliomas:relation to prognostic significance. Clin Cancer Res,1998,4(10):2447-2454.
59 Soheila S, Narges IM, Kambiz S, et al. Altered PTEN expression:a diagnostic marker for differentiating normal, hyperpastic and neoplastic endometrium. Diagn Pathol,2009,4:41.
60 Taranger-Charpin C, Carpentier S, Dales JP, et al. Immunohistochemical expres sion expression of PTEN antigen:a new tool for diagnosis of early endometrial neoplasia. Bulletin de 1'Academie national de medicine 2004,188(3)415-427.
2 Trotman LC., X. Wang, A. Alimonti, et al. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell,2007,128(1):141-156.
3 Gallus S, Altieri A, Bosetti C, et al. Cigarette tar yield and risk of upper digestive tract cancers:case-control studies from Italy and Switzerland.Ann Oncol,2003,14 (2):209-213.
4 Tselepis C, Morris CD, Wakelin D, et al. Upregulation of the oncogene c-myc in Barrett's adenocarcinoma:induction of c-myc by acidified bile acid in vitro.Gut,2003,52(2):174-180.
5 Jone GJ, Heiss NS, Veale RB, et al. Amplification and expression of the TGF-alpha, EGF receptor and c-myc genes in four human oesophageal squamous cell carcinoma lines. Biosci Rep,1993,13(5):303-312.
6 Mathew R, Arora S, Khanna R, et al. Alteractions in p53 and pRb pathways and their prognostic significane in oesophageal cancer. Eur J Cancer,2002,38(6):832-841.
7 Freitas S, Moore DH, Michael H, et al. Studies of apurine/apyrimidition endonueclease/ref-1 expression in epithelial ovarian cancer:correlations with tumor progression and platinum resistance. Clin Cancer Res,2003,9:4689-4694.
8 Li J, Yen C, LiawD, et al. PTEN a putive protein tyrosine phoshatage gene mutated in human brain, breast and prostate cancer. Science,1997,275(5308):1943-1947.
9 Steck PA, Pershonse MA, Jasser SA, et al. Identification of a candidate tumor Suppressor gene, MMAC1, at chromasome 10q23.3 that is mutated in multiple advanced cancers. Nature Genetics,1997,15 (4):356-359.
10 Li DM, Sun H. Tepl, encoded by a candidate tumor suppressor Locus, is a novel protein tyrosine phosphatease regulated by transforming growth factor β1, Cancer Res,1997,57(11):2124-2130.
11 Denu J, Stuckey JA, Saper D, et al. Form and function in protein dephosphorylation.
Cell,1996,87(3):361-364.
12 Chen JW, Li SX, Yang ZR, et al. Correlation between NDRG1 and PTEN expression in endometrial carcinoma. Cancer Sci,2008,99(4):706-710.
13 Ali IU, Schriml LM, Dean M. Mutational spectra of PTEN/MMAC1 gene:a tumor supp ressor with lip id phosphatase activity. J Natl Cancer Inst,1999,91(22): 1922-1932.
14 Jiang BH, Liu LZ. PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochim Biophys Acta,2008,1784(1):150-158.
15 Ferraro B, Bepler G, et al. EGR1 predicts PTEN and survival in patients with non-small cell lung cancer. Clin Oncol,2005,23(9):1921-1926.
16 Christine Grill, Christian Guelly, Birgit Ebner, et al. Loss of PTEN/MMAC1 activity is a rare and late event in the pathogenesis of nephroblastomas. Human Pathology,2010, In Press.
17 Bepler G, Sharma S, Cantor A, et al. RRM1 and PTEN as prognostic parameters for overall and disease-free survival in patients with non small cell lung cancer. J Clin Oncol,2004,22(10):1878.
18 Zhang Y, Yu D, Li X, et al. Reduced expression of PTEN protein and its prognostic significance in the gastrointestinal stromal tumor. J Huazhong Univ Sci Technolog Med Sci.2010,30(2):165-169.
19 Salmena L, Carracedo A,Pandolfi P P. Tenets of PTEN tumor suppression. Cell,2008,133(3):403-414.
20 李厚文.肺癌的基础与临床,第一版.沈阳：辽宁科学技术出版社,1984,266.
21 Tian XX, Pang JC, To SS, et al. Restoration of wild-type PTEN expression leads to apoptosis, induces differentiation, and reduces telomerase activity in human glioma cells. Neuropathol Exp Neurol.1999,58(5):472-479.
22 Ghosh AK, Grigorieva I, Steele R, et al. PTEN transcriptionally modulates c-myc gene expression in human breast carcinoma cells and is involved in cell growth regulation. Gene,1999,22,235(1-2):85-91.
23 Lu Y, Lin YZ, LaPushin R, et al. The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cnacer cells. Oncogene, 1999,18:7034-7045.
24 Schwartzbauer G, Robbins J. The tumor suppressor gene PTEN can regulate cardiac hypertrophy and survival. J Biol Chen,2001,276:35786-35793.
25 Uzuki A, Hayashida M, et al. Hepatocyte growth factor promotes cell survival from fas-mediates cell death in hepatocellular carcinoma cells via Akt action and Fas-death-inducing signaling complex suppression. Hepatology,2000,32:796-802.
26 Kurose K, Zhou XP, et al. Frequent loss of PTEN expression is linked to elevated phosphorylated Akt levels but not associated with p27 and cyclin D1 expression, in primary epithelial ovarian carcinomas.Am J Pathol,2001,158:2097-2106.
27 Abal M, Planaguma J, Gil-Moreno A, et al. Molecular pathology of endometrial carcinoma:transcriptional signature in endometrioid tumors. Histopathol,2006, 21(2):197-204.
28 Erkanli S, Kayaselcuk F, Kuscu E, et al. Expression of surviving, PTEN and p27 in normal, hyperplastic, and carcinomatous endometrium. Int J Gynecol Cancer,2006, 16(3):1412-1418.
29 Foster K, Wang Y, Zhou D, et al. Dependence on PI3K/Akt signaling for malignant rhabdoid tumor cell survival. Cancer Chemother Pharmacol,2009,63(5):783-791.
30 Park KK, Liu K, Hu Y, et al. Promoting axon regeneration in the adult CN by modulation of the PTEN/Mtor pathway. Science,2008,322(5903):963-966.
31 Bertram J, Peacock JW, Tan C, et al. Inhibition of the phosphatidylinositol3'-kinase pathway promotes autocrine Fas-induced death of phosphatase and tension homologue-deficient prostate cancer cells. Cancer Res,2006,66(9):4781-8.
32 Petrocelli T, Slingerland JM. PTEN deficiency:a role in mammary carcinogenesis. Breast Cancer Res,2001,3(6):356-360.
33 Dianren X, Harish S, Young HA, et al. Mitogen-activated protein kinase-4 promotes cell survival by decreasing PTEN expression through an NF-Kβdependent pathway. J
Biol Chem,2007,282(6):3507-3519.
34 Paweletz CP, Charboneau L, Bichsel VE, et al. Reverse phase protein microarrays which capture disease progression show activation of prosurvival pathways at the cancer invasion front. Oncogene,2001,20(16):1981-1989.
35 L.Zhang, N.Yang, D. Katsaros, et al. The oncogene phosphatidlinositol 3,-kinse catalytic subunit alpha promotes angiogenesis via vascular endothelial growth factor in ovarian carcinoma. Cancer Res.2003,63 (14),4225-4231.
36 Shukla S, Maclennan GT, Hartman DJ, et al. Activation of PI3K-Akt signaling pathway promotes prostate cancer cell invasion. Int J Cancer.2007,121 (7):1424-1432.
37 Che G, Chen J, Liu L, et al. Transfection of nm23-H1 increased expression of beta-Catenin, E-cadherin and TIMP-1 and decreased the expression of MMP-2, CD44v6 and VEGF and inhibited the metastatic potential of human non-small cell lung cancer cell line L9981. Neoplasma.2006,53(6):530-537.
38 史惠蓉,张瑞涛.P53、 P21WAF1.和CDK1在卵巢癌上皮性癌组织中的表达及意义.癌症,2009,28(8)：882-885.
39 Gort EH, Suijkerbuijk KP, Roothaan SM, et al. Methylation of the TWIST promoter, TWIST1 mRNA levels,and immunohistochemical expression of TWIST in breast cancer. Cancer Epidemiol Biomarkers Pres,2008,17(12):3325-3330.
40 Yuen HF, Kwork WK, Chan KK, et al. TWIST modulates prostate cancer cell-mediate bone cell activity and is upregulated by osteogenic induction. Cancinogenesis, 2008,29(8):1509-1518.
41 Fendrich V, Waldmann J, Feldmann G, et al. Unique expression pattern of the EMT markers Snail, Twist and E-cadherin in benign and malignant parathyroid neoplasia. Eur J Endocrinol,2009,160(4):695-703.
42 Wang C, Yang R, Yue D, et al. Expression of FAK and PTEN in bronchioloalveolar carcinoma and lung adenocarcinoma. Lung,2009,87(2):104-109.
43 Greenwald P, Dunn BK. Landmarks in the history of cancer epidemiology.Cancer Res,2009,69(6):2151-2162.
1 Li DM,Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res,1997,57(11):2124-2129.
2 Lee JO, Yang MM, Georgescu A. D, et al. Crystal structure of the PTEN tumor Suppressor:implication for its phosphoinositide phosphatase activity and membrane association.Cell,1999,99(3):323-334.
3 Tamguney T, Stokoe D. New insight into PTEN. Cell Science,2007,120 (23):4071-4079.
4 Planchon SM.Waite KA, Eng C. The nuclear affairs of PTEN. Cell Science,2008, 121 (3):249-253.
5 Liu JL, Mao ZY, Lafortune TA, et al. Cell cycle-dependent nuclear export of phosphatase and tesin homologue tumor suppressor is regulated by the phosphoinositide-3-kinase signaling cascade. Cancer Res,2007,67(22): 110542-11063.
6 Fridberg M, Servin A, Anagnostaki L, et al. Protein expression and cellular localization in two prognostic subgroups of diffuse large B-cell lymphoma: Higher expression of ZAP70 and PKC-beta II in t he non-germinal center group and poor survival in patient deficient in nuclear PTEN. Leuk Lympho,2007,48 (11): 2221-2232.
7 Shen WH, A. S. Balajee, J. Wang, et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 2007,128(1):157-170.
8 Trotman L C, X. Wang, A. Alimonti, et al. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 2007,128(1):141-156.
9 Ginn Pease ME, Eng C. Increase nuclear phosphtase and tensinhomologue deleted on chromosome 10 is associated with GOG1 in MCF27 cells. Cancer Res,2003,63 (2):282-286.
10 Kadel ES, Skeen J, Majewski N, et al. Activation of Akt/proteion kinase B over comes a G(2)/M cell cycle check point indued by DNA damage. Mol Cell m,
Biol,2002,22(22):7831-7841.
11 Stewart AL, Mhashilka AM, Yang XH, et al. PI3kinase blockade by Ad-PTEN inhibits invasion and induces apoptosis in RGP and metastatic melanoma cells. Mol Med,2002,8(8):451-461.
12 Li AG, Piluso L G, Cai X, et al. Mechanistic insight s into maintenance of high P53 acetylation by PTEN.Mol Cell,2006,23(4):575-587.
13 An HJ, Shim JY, Kim SJ, et al. Alteration of PTEN expression in endometrial carcinoma is associated with down-regulation of cyclin-dependent kinase inhibitor, p27. Histopathology,2002,41(5):437-445.
14 Cheney IW, Neuteboom ST, Vaillancourt MT, et al. Adenovirusmediated gene transfer of MMAC1/PTEN to glioblastoma cells inhibits S phase entry by the recruitment of p27 Kipl into cyclin E/CDK2 complexes.Cancer res,1999,59(10):2318-2323.
15 Koul D, Shen R, Garyali A, et al. MMAC1/PTEN tumor suppressor gene regulates vascular endothelial growth factor mediated angiogenesis in prostate cancer. Int J Oncol,2002,21(3):469-475.
16 Yanagi S, Kishimoto H, Kawahara K, et al. Pten controls lung morphogenesis, bronchioalveolar stem cells, and onset of lung adenocarcinomas in mice. J Clin Invest.2007,117(10):2929-2940.
17 Myers MP, Pass I, Batty IH, et al. The lipid phosphatase activity of PTEN is critical for its tumor suppressor fuction. Proc Natl Acad Sci USA, 1998,95(23):13513-13518.
18 Kandasamy K, Srivastava RK. Role of the phosphatdylionsitol 3-kinase/PTEN/AKT kinase pathway in tumor necrosis facto-related apoptosis-inducing ligand-induced apoptosis in non-small cell lung cancer cells. Cancer Res,2002, 62(17):4929-4937.
19 Lee HY, Srinivas H, Xia D, et al. Evidence that phosphatidylinositol 3-kinase and motogen-activated protein kinase-4/c-jun NH2-terminal kinase-dependent pathways cooperate to maintain lung cancer cell survival. J Biol Che2003,278
(26):23630-23638.
20 Yu J, Ni M, Xu J, et al. Methylation profiling of twenty promoter CpG islands of genes which may contribute to hepatocelluar carcinogenesis. BMC Cancer,2002,15(2):29.
21 Ali IU, Schriml LM, Dean M. Mutational spectra of PTEN/MMAC1 gene:a tumor suppressor with lip id phosphatase activity. JNatl Cancer Inst,1999,91 (22): 1922-1932.
220 kam i K, W uu L, R iggins G, et al. Analysis of PTEN6MMAC1 alterations in aero digestive tract tumors. Cancer R es,1998; 58 (3):509-511.
23 Kanamori Y, Kigawa J, Itamochi H, et al. Correlation between loss of PTEN exp ression and A KT phosphorylation in endomet rial carcinoma. Clin Cancer Res, 2001,7(4):892-895.
24 Soria JC, Lee HY, Lee JI, et al. Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation. Clin Cancer Res,2002,8 (5): 1178-1184.
25 Tamura M, Gu J, Matsumoto K, et al. Inhibition of cell migration, spreading and focal adhesions by tumor suppressor PTEN. Science,1998,280:1614-1617.
26 Bepler G, Sharma S, Cator A, et al. RRMland PTEN as prognostic parameters for overall and disease-free survival in patients with non-small-cell lung cancer. J Clin Oncol.2004,22(10):1878-1885.
27 Frisk T, Foukakis T, Dwight T, et al. Silencing of the PTEN tumor suppressor gene in anaplastic thyoid cancer, Genes Chromosomes Cancer,2002,35:74-80.
28 An Q, LiuY, Gao Y, et al. Deletion of tumor suppressor genes in Chinese non-small cell lung cancer.Cancer Lett,2002,184(2):189-195.
29 HosoyaY, Gemma A, SeikeM, et al. Alteration of the PTEN/MMAC Gene locus in primary lung cancer with distant metastasis. Lung Cancer,1999,25:87-93.
30 Kohno T, Takahashi M, Manda R, et al. Inactivation of the PTEN/MMAC1/TEP1 gene in human lung cancer. Oncogene,1998,22(2):152-156,
31 Yokomizo A, Tindall DJ, Drabkin H, et al. PTEN/MMAC1 mutations identified in small cell, but not in non-small cell lung cancers. Oncogene,1998,17(4):475-479.
32 Kim SK, Sulk, Oh Y, et al. Alterations of PTEN/MMAC1, a candidate tumor suppressor gene, and its homologue, PTH2, in small cell lung cancer cell lines. Oncogene,1998,16(1):89-93.
33 Forgacs E, Biesterveld EJ, Sekido Y, et al. Mutation analysis of the PTEN/MMAC1 gene in lung cancer. Oncogene,1998,17(12):1557-1565.
34 Zhang L, Liu T, Liu H, et al. Loss and inactivation of PTEN/MMAC1/TEP1 gene in lung cancer. Zhonghua Bing Li Xe Za Zhi,2000,29(2):8588.
35 Hosoya Y, Gemma A, Seike M, et al. Alteration of the PTEN/MMAC1 gene locus on primary lung cancer with distant metastasis. Lung Cancer,1999,25(2):87-93.
36 An Q, Liu Y, Huang J. Comparison of tumor suppressor gene deletion between squamous cell carcinoma and adenocarcinoma lung cancer in Chinese. zhonghua Zhong Liu Za Zhi,2001,23(6):470-472.
37 Petersen S, Rudolf J, Bock muhl U, et al. Distinct regions of allelic imbalance on chromosome 10q22-q26 in squamous cell carcinomas of the lung. Oncogenec,1998,17(4):449-454.
38 Sakurada A, Suzuki A, Sato M, et al. Infrequent genetic alterations of the PTEN/MMAC1 gene in Japanese patients with primary cancers of the breast, lung, pancreas, kidney and ovary. Jpn J Cancer Res,1997,88(11):1025-1028.
39 Tsujiuchi T, Sasaki Y, Tsutsumi M, et al.Absense of PTEN/MMAC1 gene mutations in lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine in rats. Cancer Lett,2001,162(2):207-211.
40 Tamura M, Gu J, Takino, et al. Tumor suppressor PTEN inhibition of cell I nvision, migration,and growth:differential involvement of focal adhesion kinase and p130Cas. Cancer Res,1999,59(2):442-449.
41 Kanamori Y, Kigawa J, Itamochi H, et al. Correlation between loss of PTEN expression and Akt phosphosphorylation in endometrial carcinoma. Clin Cancer
Res,2001,7(4):892-895.
42 Li DM, Sun H. PTEN/MMAC1/TEP1 suppresses the tumorigenicity and inducees G1 cell cycle arrest in human glioblastoma cells. Proc Natl Acad Sci USA,1998,95(26):15406-15411.
43 Tamura M, Gu J, Danen EH, et al. PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatinositol 3-kinase/Akt cell survival pathway. J Biol Chem,1999,274(29):20693-20703.
44 A. Denley, S. Kang, U. Karst, et al. Oncogenic signaling of class I PI3K isoforms. Oncogene 2008,27(18),2561-2574.
45 S. Kang, A. Denley, B. Vanhaesebroeck, et al. Oncogenic transformation induced by the pllObeta,-gamma, and-delta isoforms of class I phosphoinositide 3-kinase. Proc. Natl. Acad. Sci. USA 2006,103(5):1289-1294.
46 Q. Meng, C. Xia, J. Fang, et al. Role of PI3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70S6Kl pathway. Cell Signal,2006,18(12):2262-2271.
47 Chun KH, Kosemeder II JW, Sun S, et al. Effects of deguelin on the phosphatidylinositol3-kinase/Akt pathway and apoptosis in premalignant human bronchial epithelial cells. J Natl Cancer Inst 2003:95(4):291—302.
48 Paweletz CP, Charboneau L, Bichsel VE, et al. Reverse phase protein microarrays which capture disease progression show activation of prosurvival pathways at the cancer invasion front. Oncogene,2001,20(16):1981-1989.
49 Osaki M, Kase S, Adachi K, et al. Inhibition of the PI3K-AKT siganaling pathway enhances the sensitivity of Fas-mediated apoptosis in human gastric carcinoma cell line,MKN-45. J Cancer Res Clin Oncol,2004,130(1):8-14.
50 Yong Geon Kim, MIji Kim, et al. ICAM-3-induced cancer cell proliferation through the PI3K/AKT pathway.Cancer Letters 2006,239(1):103-110.
51 Kaarbo M, Klokk TI, Saatcioglu F. Androgen signaling and its interactions with other signaling pathways in prostate cancer. Bioessays.2007,29(12):1227
-1238.
52 Shen MM, Abate-Shen C. Pten inactivation and the emergence of androgen-independent prostate cancer. Cancer Res.2007,67(14):6535-6538.
53 L.Zhang, N.Yang, D. Katsaros, et al. The oncogene phosphatidlinositol 3,-kinse catalytic subunit alpha promotes angiogenesis via vascular endothelial growth factor in ovarian carcinoma. Cancer Res.2003,63(14),4225-4231.
54 Shukla S, Maclennan GT, Hartman DJ, et al. Activation of PI3K-Akt signaling pathway promotes prostate cancer cell invasion. Int J Cancer.2007,121(7):1424-1432.
55 Qian Y, Corum L, Meng Q, et al. PI3K induced actin filament remodeling through AKT and p70S6K1;implication of essential role in cell migration. Am J Physiol,2004,286(9):C153-163.
56 Liaw D, Marsh DJ, Li J, et al. Germline mutation of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet,1997,16 (1):64-67.
57 赵军,刘晓谦,张军等.脑胶质瘤组织PTEN基因异常及其蛋白表达.第四军医大学学报,2009,30(9)：843-845.
58 Lin H, Bondy ML, Lanford LA, et al. Allelic deletion analyses of MMAC1/PTEN and DMBT1 loci in gliomas:relation to prognostic significance. Clin Cancer Res,1998,4(10):2447-2454.
59 Soheila S, Narges IM, Kambiz S, et al. Altered PTEN expression:a diagnostic marker for differentiating normal, hyperpastic and neoplastic endometrium. Diagn Pathol,2009,4:41.
60 Taranger-Charpin C, Carpentier S, Dales JP, et al. Immunohistochemical expres sion expression of PTEN antigen:a new tool for diagnosis of early endometrial neoplasia. Bulletin de 1'Academie national de medicine 2004,188(3)415-427.