Μελέτες σχετικά με το ρόλο της P21/ WAF 1 στην ανάπτυξη του καρκίνου

Abstract

GHRH (Growth Hormone Releasing Hormone) is released by the hypothalamus and through specific receptors located in the anterior pituitary gland, induces the release of growth hormone (GH). Along with this physiological role, GHRH was also found to play an extremely significant role in the development of several types of cancers such as those of the lungs, thick bowel (colon), prostate and others. It is also expressed in other normal tissues such as the placenta, ovaries, testis and lymphocytes as well. Ectopic expression of this hormone has been reported in primary tumors and in cultivated cancer cell lines derived from patients with diagnosed cancer of the lungs, prostate and pancreas and from women with neoplasia of the genital tract. Several studies reported a mitotogenic role of regionally produced GHRH in the proliferation of cancer cells in culture, while GHRH antagonists produce the opposite effect on the same cells. These findings are indicative of a possible autocrine/paracrine role of GHRH on human cancers. GHRH antagonists are peptides with important anticancer activity reported by many studies based on several experimental tumors and other cancer cells. The exact mechanism of these substances is still under investigation, but the most accepted hypothesis so far is that they act through inhibition of the endocrine pathway of GH release by the pituitary gland and subsequently IGF-1 production mostly by the liver. It seems that they act through receptors (SV1) that share similar cytoplasmic and transmembrane regions with GHRH receptors (GHRH-R) and exist in the cancer cells of some tumors. In our study, we investigated GHRH expression along with SV1 expression on primary human melanomas and human dysplastic nevi by using immunochemical assays. To our knowledge, this is the very first study showing the pathophysiology of GHRH/SV1 activating loop interference in the pathogenesis of melanoma and that also suggests that the transition from the dysplastic stage to that of malignancy is accompanied by SV1 receptor expression. Furthermore, the possible role of p21/waf1 in the mediation of the effects of GHRH on A549 epithelial cells of lung cancer in humans was also investigated. Exposure of A549 cells to the GHRH antagonist, JMR-132, resulted in a significant inhibition of cell proliferation. In A549 epithelial cells of lung cancer, HT29 cancer cells of colon cancer and in non-modified KS483 mice osteoblasts, GHRH reduced while JMR-132 elevated p21 expression in a dose-dependent manner. The purpose of the study was to illuminate the molecular mechanism of GHRH antagonist JMR-132 action on tumor tissues. Our results suggest that the antineoplastic role of GHRH antagonists could be considered for the therapy of cancers, especially those expressing p21.%%%%Η GHRH (eκλυτική ορμόνη της αυξητικής ορμόνης) eκκρίνeται από τον υποθάλαμο και μέσω eιδικών υποδοχέων που βρίσκονται στην πρόσθια υπόφυση eπάγeι την έκκριση της αυξητικής ορμόνης από αυτήν. Eπιπρόσθeτα μe την φυσιολογική της αυτή δράση έχeι βρeθeί ότι…