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The protein p16INK4a as a reliable indicator of the HPV-induced carcinogenesisстатья
- Авторы: Volgareva G.M., Zavalishina LE Golovina DA, Andreeva YY, Petrov AN, Ermilova VD, Petrenko A.A., Katargin A.N., Bateva M.V., Kisseljova N.P., Frank G.A.
- Сборник: New Research on Cervical Cancer (Rolland GZ, ed.)
- Год издания: 2006
- Издательство: Nova Science Pub.
- Местоположение издательства: Hauppauge, N.Y.,
- Первая страница: 129
- Последняя страница: 147
- Аннотация: The protein p16INK4a, an inhibitor of cycline-dependent kinases CDKs 4/6, is encoded by the tumor suppressor gene INK4a. INK4a belongs to the RB signal pathway. In the human papillomavirus (HPV) – induced cervical carcinomas cells uncontrollably pass to the S- cell cycle stage owing to the pRb inactivation by the HPV E7 oncoprotein. As far as p16INK4a acts upstream of pRb in HPV-positive cervical dysplasia and carcinoma p16INK4a loses the role of the G1/S check-point controller. The content of p16INK4a increases drastically. The feed-back loop between pRb inactivation by E7 and the sharp growth of the p16INK4a amount had been demonstrated in in vitro systems. Details of this feed-back loop in primary dysplasia and carcinoma remain not quite clear. None the less the given phenomenon was taken as the basis for use of the p16INK4a detecting in early diagnostics of cervical cancer. The trend is being formed to apply the p16INK4a immunocytochemical detection for specification of the Pap-test data in screening of large women groups. As other research groups we had demonstrated formerly that the share of p16INK4a-positive cells increases in the row: LSIL→ HSIL→ invasive carcinoma. The merits of the test are reviewed herein. However some ambiguities still arise in the course of the test data interpreting. In line with some other investigators we had registered samples of HSIL and invasive squamous carcinomas which contained very small numbers of p16INK4a-positive cells or fully lacked them. The number of such specimens would decrease if the HSILs and carcinomas with the predominantly or exclusively cytoplasmic p16INK4a location are scored as positive. To contribute to the validation of the test we further addressed correspondence of expression of the HPV E7 oncogene and cellular gene INK4a in squamous cervical carcinomas (including those which had been shown to express p16INK4a predominantly in a cytoplasm). It was done at two levels, m-RNA and protein. The results obtained prove that the HPV E7 oncogene does influence the gene INK4a transcription activation in cervical cancer in vivo; transcription of the gene INK4a is strongly up-regulated in cervical cancer which may lead to specific overexpression of its protein product p16INK4a ; INK4a transcription in specimens with a predominantly cytoplasmic location of p16INK4a is not less active than that in the carcinomas expressing p16INK4a in majority of nuclei. Both variants of staining with p16INK4a-specific antibodies, - nuclear and cytoplasmic, are likely to be regarded as p16INK4a-positive. However there exist rare cervical carcinomas harboring HPV DNA and expressing the oncogene E7 at both the m-RNA and the protein level while fully lacking the INK4a expression at the both levels. The sum total of these findings further proves the value of the p16INK4a-directed immunochemistry for cervical cancer diagnostics.
- Добавил в систему: Волгарева Галина Михайловна