PTEN、CDK4蛋白在膀胱移行细胞癌中的表达及其临床意义
摘要
目的：探讨PTEN、CDK4蛋白表达与膀胱移行细胞癌的发生、发展的关系。
方法：采用免疫组化S-P法，测定10例正常膀胱粘膜及40例膀胱移行细胞癌标本中的PTEN、CDK4蛋白的表达情况。
结果：1. PTEN蛋白在正常膀胱粘膜和膀胱移行细胞癌组织中的阳性表达率分别为100%、67.50%，差异有显著性（P<0.05）。2. PTEN蛋白在G1、G2、G3中的阳性表达率依次为89.47%、53.85％、37.50％，G1与G2 或/和G3相比较，差异有显著性（P<0.05）；在Tis -T1中PTEN阳性表达率为80.00%，明显高于T2-T4中的46.67%（P<0.05）。PTEN的表达随病理分级、临床分期的增高而明显下降。3. CDK4蛋白在正常膀胱粘膜和膀胱移行细胞癌组织中的阳性表达率分别为0.00%、52.50%，差异有显著性（P<0.05）。4. CDK4蛋白在G1、G2、G3中的阳性表达率依次为36.84%、61.54％、75.00％，组间比较，差异无显著性（P>0.05）；在在Tis -T1中CDK4阳性表达率为40.00%，明显低于T2-T4中的73.33%（P<0.05）。CDK4的表达随与临床分期密切相关。5. PTEN与CDK4相关性分析显示，二者的表达不相关。
结论：PTEN蛋白表达缺失及CDK4的过度表达可能在膀胱移行细胞癌的发生、发展中具有重要作用，PTEN、CDK4蛋白可成为反映膀胱移行细胞癌恶性程度及预后估计的参考指标。
Objective: To investigate the expression of PTEN, CDK4 protein in bladder transitional cell carcinoma ( BTCC ) and the relation between their expression and carcinogensis, progression and clinical pathological parameters.
Methods: A specifically and sensitively immunohistochemical S-P assay was used to detect the expression of PTEN and CDK4 in paraffin-embedded sections of 40 cases of BTCC and 10 normal bladder mucosa.
Result: 1. The positive rates of PTEN protein expression were 67.50% in BTCC tissues and 100% in normal bladder mucosa tissues. There was significant difference between them（P<0.05）.2. The positive rates of PTEN protein expression in G1, G2 and G3 were 89.47%, 53.85％, 37.50％，respectively; and the difference was statistically significant between G1 and G2 or G3（P<0.05）.The positive rate of PTEN protein expression in Tis-T1 was significantly higher than that in T2-T4（P<0.05）. The PTEN protein expression deletion rates in BTCC were significantly associated with histological grades and clinical stages. 3. The positive rates of CDK4 protein expression were 52.50% in BTCC tissues and 0.00% in normal bladder mucosa tissues, and the difference was statistically significant between them（P<0.05）. 4. The positive rates of CDK4 protein expression in G1, G2 and G3 were 36.84%, 61.54％,75.00％,respectively; and there wasn’t statistically significant difference among the three groups （P>0.05）.The positive rate of CDK4 protein expression in Tis -T1 was significantly lower than that in T2-T4（P<0.05）. The CDK4 protein overexpression rates in BTCC were significantly associated with clinical stages.
Conclusion: PTEN protein expression deletion and CDK4 protein overexpression are closely related to the occurrence and development of BTCC. To detect PTEN and CDK4 protein together is an important method for the evaluation of the malignancy and prognosis of BTCC.
方法：采用免疫组化S-P法，测定10例正常膀胱粘膜及40例膀胱移行细胞癌标本中的PTEN、CDK4蛋白的表达情况。
结果：1. PTEN蛋白在正常膀胱粘膜和膀胱移行细胞癌组织中的阳性表达率分别为100%、67.50%，差异有显著性（P<0.05）。2. PTEN蛋白在G1、G2、G3中的阳性表达率依次为89.47%、53.85％、37.50％，G1与G2 或/和G3相比较，差异有显著性（P<0.05）；在Tis -T1中PTEN阳性表达率为80.00%，明显高于T2-T4中的46.67%（P<0.05）。PTEN的表达随病理分级、临床分期的增高而明显下降。3. CDK4蛋白在正常膀胱粘膜和膀胱移行细胞癌组织中的阳性表达率分别为0.00%、52.50%，差异有显著性（P<0.05）。4. CDK4蛋白在G1、G2、G3中的阳性表达率依次为36.84%、61.54％、75.00％，组间比较，差异无显著性（P>0.05）；在在Tis -T1中CDK4阳性表达率为40.00%，明显低于T2-T4中的73.33%（P<0.05）。CDK4的表达随与临床分期密切相关。5. PTEN与CDK4相关性分析显示，二者的表达不相关。
结论：PTEN蛋白表达缺失及CDK4的过度表达可能在膀胱移行细胞癌的发生、发展中具有重要作用，PTEN、CDK4蛋白可成为反映膀胱移行细胞癌恶性程度及预后估计的参考指标。
Objective: To investigate the expression of PTEN, CDK4 protein in bladder transitional cell carcinoma ( BTCC ) and the relation between their expression and carcinogensis, progression and clinical pathological parameters.
Methods: A specifically and sensitively immunohistochemical S-P assay was used to detect the expression of PTEN and CDK4 in paraffin-embedded sections of 40 cases of BTCC and 10 normal bladder mucosa.
Result: 1. The positive rates of PTEN protein expression were 67.50% in BTCC tissues and 100% in normal bladder mucosa tissues. There was significant difference between them（P<0.05）.2. The positive rates of PTEN protein expression in G1, G2 and G3 were 89.47%, 53.85％, 37.50％，respectively; and the difference was statistically significant between G1 and G2 or G3（P<0.05）.The positive rate of PTEN protein expression in Tis-T1 was significantly higher than that in T2-T4（P<0.05）. The PTEN protein expression deletion rates in BTCC were significantly associated with histological grades and clinical stages. 3. The positive rates of CDK4 protein expression were 52.50% in BTCC tissues and 0.00% in normal bladder mucosa tissues, and the difference was statistically significant between them（P<0.05）. 4. The positive rates of CDK4 protein expression in G1, G2 and G3 were 36.84%, 61.54％,75.00％,respectively; and there wasn’t statistically significant difference among the three groups （P>0.05）.The positive rate of CDK4 protein expression in Tis -T1 was significantly lower than that in T2-T4（P<0.05）. The CDK4 protein overexpression rates in BTCC were significantly associated with clinical stages.
Conclusion: PTEN protein expression deletion and CDK4 protein overexpression are closely related to the occurrence and development of BTCC. To detect PTEN and CDK4 protein together is an important method for the evaluation of the malignancy and prognosis of BTCC.
引文
1 Steck PA, Pershouse MA, Jasser SA, et al. Identification of a candidate tumor suppressor gene,MMAC1,at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nature Genetics,1997 Apr;15(4):357-62.
2 Cheney IW,Johnson DE,Vaillancourt MT,et al. Suppression of tumorigenicity of glioblastoma cells by adenovirus-mediated MMAC1/PTEN gene transfer. Cancer Res. 1998 Jun 1;58(11):2331-4.
3 Davies MA, Koul D, Dhesi H, et al. Regulation of Akt/PKB activity, cellular growth, and apoptosis in prostate carcinoma cells by MMAC/PTEN. Cancer Res 1999 Jun 1; 59(11): 2551-6.
4 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 cancer cells. Oncogene. 1999 Nov 25; 18(50): 7034-45.
5 汤钊猷主编. 现代肿瘤学. 第二版.上海：上海医科大学出版社，2001.
6 Wang YL, Uhara H, Yamazaki Y, et al. Immunohistochemical detection of CDK4 and P16INK4 protein in cutaneous malignant melanoma. Bri J Dermatol,1996 Feb;134(2):269-75.
7 He J, Olson JJ, James CD. Lack of p16INK4 or retinoblastoma protein (pRb), or amplification-associated overexpression of cdk4 is observed in distinct subsets of malignant glial tumors and cell lines. : Cancer Res. 1995 Nov 1;55(21):4833-6.
8 Zhang T, Nanney LB, Luongo C, et al. Concurrent overexpression of cyclin D1 and cyclin-dependent kinase 4 (Cdk4) in intestinal adenomas from multiple intestinal neoplasia (Min) mice and human familial adenomatous polyposis patients. Cancer Res. 1997 Jan 1;57(1):169-75.
9 刘坤平, 冯伟勋, 谢芝香. 大肠癌CDK4、Ki-67表达与CyclinD1、P16蛋白表达的相关性及临床意义. 中国肿瘤临床与康复,2001;8(4):9-11
10 Pilotti S, Della Torre G, Mezzelani A, et al. The expression of MDM2/CDK4 gene product in the differential diagnosis of well differentiated liposarcoma and large deep-seated lipoma. Br J Cancer. 2000 Apr;82(7):1271-5.
11 Dong Y, Sui L, Sugimoto K, et al. Cyclin D1-CDK4 complex, a possible critical factor for cell proliferation and prognosis in laryngeal squamous cell carcinomas. Int J Cancer. 2001 Jul 20;95(4):209-15.
12 Fromowitz FB, Voila MV, Chao S, et al. Ras p21 expression in the progression of brest cancer. Human pathol,1987,18:1268-1275.
13 Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997 Mar 28;275(5308):1943-7.
14 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 Jun 1;57(11):2124-9.
15 Di Cristofano A, Pesce B, Cordon-Cardo C, et al. Pten is essential for embryonic development and tumour suppression. Nat Genet. 1998 Aug;19(4):348-55.
16 Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4240-5.
17 Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1,dephosphory-
lates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.
J Biol Chem. 1998 May 29;273(22):13375-8.
18 Tamura M, Gu J, Matsumoto K, et al. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science. 1998 Jun 5;280(5369):1614-7.
19 Gu J, Tamura M, Yamada KM. Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling pathways. J Cell Biol. 1998 Nov 30;143(5):1375-83.
20 Gimm O, Attie-Bitach T, Lees JA, et al. Expression of the PTEN tumour suppressor protein during human development. Hum Mol Genet. 2000 Jul 1;9(11):1633-9.
21 Perren A, Weng LP, Boag AH, et al. Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. Am J Pathol. 1999 Oct;155(4):1253-60.
22 Fults D, Pedone C. Immunocytochemical mapping of the phosphatase and tensin homolog (PTEN/MMAC1) tumor suppressor protein in human gliomas. Neuro-oncol. 2000 Apr;2(2):71-9.
23 Liu J, Babaian DC, Liebert M, et al. Inactivation of MMAC1 in bladder transitional-cell carcinoma cell lines and specimens. Mol Carcinog. 2000 Nov;29(3):143-50.
24 Cairns P, Evron E, Okami K, et al. Point mutation and homozygous deletion of PTEN/MMAC1 in primary bladder cancers. Oncogene. 1998 Jun 18;16(24):3215-8.
25 Aveyard JS, Skilleter A, Habuchi T, et al. Somatic mutation of PTEN in bladder carcinoma. Br J Cancer. 1999 May;80(5-6):904-8.
26 Wang DS, Rieger-Christ K, Latini JM, et al. Molecular analysis of PTEN and MXI1 in primary bladder carcinoma. Int J Cancer. 2000 Nov 15;88(4):620-5.
27 Whang YE, Wu X, Suzuki H, et al . Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5246-50.
28 Salvesen HB, MacDonald N, Ryan A, et al. PTEN methylation is associated with advanced stage and microsatellite instability in endometrial carcinoma. Int J Cancer. 2001 Jan 1;91(1):22-6.
29 Harbour JW, Luo RX, Dei Santi A, et al. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell. 1999 Sep 17;98(6):859-69.
30 Nurse P. A long twentieth century of the cell cycle and beyond. Cell. 2000 Jan 7;100(1):71-8.
31 De Bondt HL, Rosenblatt J, Jancarik J, et al. Crystal structure of cyclin-dependent kinase 2. Nature. 1993 Jun 17;363(6430):595-602.
32 Maelandsmo GM, Berner JM, Florenes VA, et al. Homozygous deletion frequency and expression levels of the CDKN2 gene in human sarcomas--relationship to amplification and mRNA levels of CDK4 and CCND1. Br J Cancer. 1995 Aug;72(2):393-8.
33 李甘地主编. 病理学（七年制）.第一版. 北京：人民卫生出版社，2001.
34 Ewen ME, Sluss HK, Whitehouse LL, et al. TGF beta inhibition of Cdk4
synthesis is linked to cell cycle arrest. Cell. 1993 Sep 24;74(6):1009-20.
35 Khatib ZA, Matsushime H, Valentine M,et al. Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. Cancer Res. 1993 Nov 15;53(22):5535-41.
36 Rane SG, Cosenza SC, Mettus RV, et al. Germ line transmission of the Cdk4(R24C) mutation facilitates tumorigenesis and escape from cellular senescence. Mol Cell Biol. 2002 Jan;22(2):644-56.
37 戴文斌，任占平，陈蔚麟，等. 鼻咽癌及癌前病变组织CDK4和P16蛋白的表达. 诊断病理学杂志，2001，8（5）：290-292.
38 An HX, Beckmann MW, Reifenberger G, et al. Gene amplification and overexpression of CDK4 in sporadic breast carcinomas is associated with high tumor cell proliferation. Am J Pathol. 1999 Jan;154(1):113-8.
39 Oya M, Schmidt B, Schmitz-Drager BJ, et al. Expression of G1-->S transition regulatory molecules in human urothelial cancer. Jpn J Cancer Res. 1998 Jul;89(7):719-26.
40 Simon R, Struckmann K, Schraml P, et al. Amplification pattern of 12q13-q15 genes (MDM2, CDK4, GLI) in urinary bladder cancer. Oncogene. 2002 Apr 11;21(16):2476-83.
41 谢庆祥，汪鸿，缪友仁，等.膀胱癌中CDK4和细胞周期素D1表达的意义. 中华实验外科杂志，2000，17(4)：368.
42 熊华淇，邹桂华，吴绮明，等. 膀胱移行细胞癌组织中cyclin D1和CDK4的表达及其与临床病理的关系. 实用癌症杂志，2000，15(3):232-4.
43 吴绮明, 熊华淇, 邹桂华, 等. T24细胞系中CyclinD1、CDK4、P16和PCNA的表达状态及其意义. 江西医学院学报，2001；41(4):5-8.
44 Tanaka M, Koul D, Davies MA, et al. MMAC1/PTEN inhibits cell growth and induces chemosensitivity to doxorubicin in human bladder cancer cells. Oncogene. 2000 Nov 9;19(47):5406-12.
2 Cheney IW,Johnson DE,Vaillancourt MT,et al. Suppression of tumorigenicity of glioblastoma cells by adenovirus-mediated MMAC1/PTEN gene transfer. Cancer Res. 1998 Jun 1;58(11):2331-4.
3 Davies MA, Koul D, Dhesi H, et al. Regulation of Akt/PKB activity, cellular growth, and apoptosis in prostate carcinoma cells by MMAC/PTEN. Cancer Res 1999 Jun 1; 59(11): 2551-6.
4 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 cancer cells. Oncogene. 1999 Nov 25; 18(50): 7034-45.
5 汤钊猷主编. 现代肿瘤学. 第二版.上海：上海医科大学出版社，2001.
6 Wang YL, Uhara H, Yamazaki Y, et al. Immunohistochemical detection of CDK4 and P16INK4 protein in cutaneous malignant melanoma. Bri J Dermatol,1996 Feb;134(2):269-75.
7 He J, Olson JJ, James CD. Lack of p16INK4 or retinoblastoma protein (pRb), or amplification-associated overexpression of cdk4 is observed in distinct subsets of malignant glial tumors and cell lines. : Cancer Res. 1995 Nov 1;55(21):4833-6.
8 Zhang T, Nanney LB, Luongo C, et al. Concurrent overexpression of cyclin D1 and cyclin-dependent kinase 4 (Cdk4) in intestinal adenomas from multiple intestinal neoplasia (Min) mice and human familial adenomatous polyposis patients. Cancer Res. 1997 Jan 1;57(1):169-75.
9 刘坤平, 冯伟勋, 谢芝香. 大肠癌CDK4、Ki-67表达与CyclinD1、P16蛋白表达的相关性及临床意义. 中国肿瘤临床与康复,2001;8(4):9-11
10 Pilotti S, Della Torre G, Mezzelani A, et al. The expression of MDM2/CDK4 gene product in the differential diagnosis of well differentiated liposarcoma and large deep-seated lipoma. Br J Cancer. 2000 Apr;82(7):1271-5.
11 Dong Y, Sui L, Sugimoto K, et al. Cyclin D1-CDK4 complex, a possible critical factor for cell proliferation and prognosis in laryngeal squamous cell carcinomas. Int J Cancer. 2001 Jul 20;95(4):209-15.
12 Fromowitz FB, Voila MV, Chao S, et al. Ras p21 expression in the progression of brest cancer. Human pathol,1987,18:1268-1275.
13 Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997 Mar 28;275(5308):1943-7.
14 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 Jun 1;57(11):2124-9.
15 Di Cristofano A, Pesce B, Cordon-Cardo C, et al. Pten is essential for embryonic development and tumour suppression. Nat Genet. 1998 Aug;19(4):348-55.
16 Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4240-5.
17 Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1,dephosphory-
lates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.
J Biol Chem. 1998 May 29;273(22):13375-8.
18 Tamura M, Gu J, Matsumoto K, et al. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science. 1998 Jun 5;280(5369):1614-7.
19 Gu J, Tamura M, Yamada KM. Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling pathways. J Cell Biol. 1998 Nov 30;143(5):1375-83.
20 Gimm O, Attie-Bitach T, Lees JA, et al. Expression of the PTEN tumour suppressor protein during human development. Hum Mol Genet. 2000 Jul 1;9(11):1633-9.
21 Perren A, Weng LP, Boag AH, et al. Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. Am J Pathol. 1999 Oct;155(4):1253-60.
22 Fults D, Pedone C. Immunocytochemical mapping of the phosphatase and tensin homolog (PTEN/MMAC1) tumor suppressor protein in human gliomas. Neuro-oncol. 2000 Apr;2(2):71-9.
23 Liu J, Babaian DC, Liebert M, et al. Inactivation of MMAC1 in bladder transitional-cell carcinoma cell lines and specimens. Mol Carcinog. 2000 Nov;29(3):143-50.
24 Cairns P, Evron E, Okami K, et al. Point mutation and homozygous deletion of PTEN/MMAC1 in primary bladder cancers. Oncogene. 1998 Jun 18;16(24):3215-8.
25 Aveyard JS, Skilleter A, Habuchi T, et al. Somatic mutation of PTEN in bladder carcinoma. Br J Cancer. 1999 May;80(5-6):904-8.
26 Wang DS, Rieger-Christ K, Latini JM, et al. Molecular analysis of PTEN and MXI1 in primary bladder carcinoma. Int J Cancer. 2000 Nov 15;88(4):620-5.
27 Whang YE, Wu X, Suzuki H, et al . Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5246-50.
28 Salvesen HB, MacDonald N, Ryan A, et al. PTEN methylation is associated with advanced stage and microsatellite instability in endometrial carcinoma. Int J Cancer. 2001 Jan 1;91(1):22-6.
29 Harbour JW, Luo RX, Dei Santi A, et al. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell. 1999 Sep 17;98(6):859-69.
30 Nurse P. A long twentieth century of the cell cycle and beyond. Cell. 2000 Jan 7;100(1):71-8.
31 De Bondt HL, Rosenblatt J, Jancarik J, et al. Crystal structure of cyclin-dependent kinase 2. Nature. 1993 Jun 17;363(6430):595-602.
32 Maelandsmo GM, Berner JM, Florenes VA, et al. Homozygous deletion frequency and expression levels of the CDKN2 gene in human sarcomas--relationship to amplification and mRNA levels of CDK4 and CCND1. Br J Cancer. 1995 Aug;72(2):393-8.
33 李甘地主编. 病理学（七年制）.第一版. 北京：人民卫生出版社，2001.
34 Ewen ME, Sluss HK, Whitehouse LL, et al. TGF beta inhibition of Cdk4
synthesis is linked to cell cycle arrest. Cell. 1993 Sep 24;74(6):1009-20.
35 Khatib ZA, Matsushime H, Valentine M,et al. Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. Cancer Res. 1993 Nov 15;53(22):5535-41.
36 Rane SG, Cosenza SC, Mettus RV, et al. Germ line transmission of the Cdk4(R24C) mutation facilitates tumorigenesis and escape from cellular senescence. Mol Cell Biol. 2002 Jan;22(2):644-56.
37 戴文斌，任占平，陈蔚麟，等. 鼻咽癌及癌前病变组织CDK4和P16蛋白的表达. 诊断病理学杂志，2001，8（5）：290-292.
38 An HX, Beckmann MW, Reifenberger G, et al. Gene amplification and overexpression of CDK4 in sporadic breast carcinomas is associated with high tumor cell proliferation. Am J Pathol. 1999 Jan;154(1):113-8.
39 Oya M, Schmidt B, Schmitz-Drager BJ, et al. Expression of G1-->S transition regulatory molecules in human urothelial cancer. Jpn J Cancer Res. 1998 Jul;89(7):719-26.
40 Simon R, Struckmann K, Schraml P, et al. Amplification pattern of 12q13-q15 genes (MDM2, CDK4, GLI) in urinary bladder cancer. Oncogene. 2002 Apr 11;21(16):2476-83.
41 谢庆祥，汪鸿，缪友仁，等.膀胱癌中CDK4和细胞周期素D1表达的意义. 中华实验外科杂志，2000，17(4)：368.
42 熊华淇，邹桂华，吴绮明，等. 膀胱移行细胞癌组织中cyclin D1和CDK4的表达及其与临床病理的关系. 实用癌症杂志，2000，15(3):232-4.
43 吴绮明, 熊华淇, 邹桂华, 等. T24细胞系中CyclinD1、CDK4、P16和PCNA的表达状态及其意义. 江西医学院学报，2001；41(4):5-8.
44 Tanaka M, Koul D, Davies MA, et al. MMAC1/PTEN inhibits cell growth and induces chemosensitivity to doxorubicin in human bladder cancer cells. Oncogene. 2000 Nov 9;19(47):5406-12.