Objective: To investigate the relationship between PTEN promoter methylation and protein expression, and the possible involvement of the PTEN gene in development of gestational trophoblasts and the pathogenesis of hydatidjform moles.
Methods: DNA was extracted from choria of normal early placentas, partial hydatidtform moles, complete hydatidiform moles, and invasive moles, and overdigested by methylation-sensitive endonuclease HpaII. The PTEN promoter was amplifcated by polymerase chain reaction. PTEN protein expression was detected by immunohistochemistry.
Results: In partial and complete hydatidiform moles, the PTEN promoter methylation rate was significantly higher than in early placentas (72%, 59.4%, 14.3%; P = .000, .002, respectively), and the PTEN protein expression rate was significantly lower than in early placentas (9.1%, 4.5%, 90.5%; P = .000, .000, respectively). However, partial hydatidiform moles, complete hydatidiform moles, and invasive moles were not significant different in terms of PTEN promoter methylation and protein expression.
Conclusions: These findings suggest that the regulation of PTEN expression may play an important role in the development of the early gestational trophoblast and in the pathogenesis of hydatidiform mole, but not in its malignant transformation.
1. Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science1997;275:1943-1947.
2.
2. Myers MP, Stolarov JP, Eng C, et al. P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci U S A1997;94:9052-9057.
3.
3. Suzuki A, de la Pompa JL, Stambolic V, et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol1998;8:1169-1178.
4.
4. Pianetti S, Arsura M, Romieu-Mourez R, Coffey RJ, Sonenshein GE. Her-2/neu overexpression induces NF-kappaB via a P13-kinase/Akt pathway involving calpain-mediated degradation of IkappaB-alpha that can be inhibited by the tumor suppressor PTEN. Oncogene2001;20:1287-1299.
5.
5. Pararmio JM, Navarro M, Segrelles C, Gomez-Casero E, Jorcano JL. PTEN tumour suppressor is linked to the cell cycle control through the retinoblastoma protein. Oncogene1999;18:7462-7468.
6.
6. Tamura M, Gu J, Takino T, Yamada KM. Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: Differential involvement of focal adhesion kinase and p130Cas. Cancer Res1999;59:442-449.
7.
7. Nadav L, Katz BZ. The molecular effects of oncogenesis on cell-extracellular matrix adhesion. Int J Oncol2001;19:237-246.
8.
8. Hwang PH, Yi HK, Kim DS, Nam SY, Kim JS, Lee DY. Suppression of tumorigenicity and metastasis in B16F10 cells by PTEN/MMAC1/TEP1 gene. Cancer Lett2001;172:83-91.
9.
9. Guldberg P, Thor Straten P, Birck A, Ahrenkiel V, Kirkin AF, Zeuthen J. Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res1997;57:3660-3663.
10.
10. Tashiro H, Blazes MS, Wu R, et al. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res1997;57:393539-40.
11.
11. Salvesen HB, MacDonald N, Ryan A, et al. PTEN methylation is associated with advanced stage and microsatellite instability in endometrial carcinoma. Int J Cancer2001;91:22-26.
12.
12. Kang YH, Lee HS, Kim WH. Promoter methylation and silencing of PTEN in gastric carcinoma. Lab Invest2002;82:285-291.
13.
13. Kane MF, Loda M, Gaida GM, et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res1997;57:808-811.
14.
14. Torres J, Navarro S, Rogla I, et al. Heterogeneous lack of expression of the tumour suppressor PTEN protein in human neoplastic tissues. Eur J Cancer2001;37:114-121.
15.
15. Fromowitz FB, Viola MV, Chao S, et al. ras p21 expression in the progression of breast cancer. Hum Pathol1987;18:1268-1275.
16.
16. Dahia PL. PTEN, a unique tumor suppressor gene. Endocr Relat Cancer2000;7:115-129.
17.
17. McGrath J, Solter D. Completion of mouse embryogenesis requires both the maternal and patemal genomes. Cell1982;37:179-183.
18.
18. Ariel I, de Groot N, Hochberg A. Imprinted H19 gene expression in embryogenesis and human cancer: The oncofetal connection. Am J Med Genet2000;91:46-50.
19.
19. Walsh C, Miller SJ, Flam F, Fisher RA, Ohlsson R. Paternally derived H19 is differentially expressed in malignant and nonmalignant trophoblast. Cancer Res1995;55:1111-1116.
20.
20. Steenman MJ, Rainier S, Dobry CJ, et al. Loss of imprinting of IGF2 is linked to reduced expression and abnormal methylation of H19 in Wilms' tumour. Nat Genet1994;7:433-439.
21.
21. Ariel I, Lustig O, Oyer CE, et al. Relaxation of imprinting in trophoblastic disease. Gynecol Oncol1994;53:212-219.
22.
22. Tuncer ZS, Vegh GL, Fulop V, Genest DR, Mok SC, Berkowitz RS. Expression of epidermal growth factor receptor-related family products in gestational trophoblastic diseases and normal placenta and its relationship with development of postmolar tumor. Gynecol Oncol2000;77:389-393.
23.
23. Stambolic V, MacPherson D, Sas D, et al. Regulation of PTEN transcription by p53. Mol Cell2001;8:317-325.
24.
24. Persaud V, Ganjei P, Nadji M, et al. Cell proliferative activity and mutation of P53 suppressor gene in human gestational trophoblastic disease. West Indian Med J1993;42:142-143.
