The Study On Expression Of Hif-1 α And Related Genes In Hamster Buccal Pouch Carcinogenesis

Hypoxia inducible factor 1 (HIF-1),composed of HIF-1α and HIF-1β subunits,is a heterodimeric transcriptional activator, recently found to exist extensively in mammals under hypoxia conditions.HIF-1α , as a master regulator of oxygen homeostasis, is more dependent on oxygen level. Hypoxia is one of basic characters of most human solid tumors. Under hypoxia conditions, over 40 kinds of HIF-1 target genes have been identified thus far, the encoded proteins of which play roles in critical development and physiological processes including angiogenesis, glyeolysis, erythropoiesis,cell proliferation/survival, vascular remodeling and so on,which contribute to the metabolic adaptation and oxygen transportation in tumors under hypoxia conditions.It has been reported that HIF-1α overexpressed in many kinds of tumors and mediated its corresponding biological behavior.So far, there has no report on the study of HIF-1α in oral mucosal carcinogenesis. In this study, we tested the expression of HIF-1α and its related genes in the evolution of hamster buccal carcinogenesis,further discuss the development and progression mechanisms of oral carcinogenesis,and wish to supply a new valid therapeutic target for oral carcinoma.ObjectivesTo observe the changes of HIF-1 a ? 1NOS and Fas in the evolution of hamster buccal carcinogenesis,and to discuss the roles of them in oral carcinogenesis. MethodsEstablishing golden hamster buccal carcinigenesis model, we used the specimens of hamster' s oral buccal pouch.The specimens were divided into two parts: in one part, the specimens were placed into liquid nitrogen immediately and stored in -80°C.The expression of HIF-1 a and iNOS were detected by RT-PCR technology.In the other part,the specimens were embedded by paraffin traditionally, dyed with hematoxylin-eosin, and then cytopathological grades were done.The expression of Fas was tested using immunohistochemical method.The results were statistically analyzed with SPSS Software \2. 0.Chi-squre test,Fisher's test, Kruskal-Wallis test, Mann-Whitney test, Spearman' s correlation coefficient were performed./7 value of <0.05 was considered significantly. Results(1) The expression results of HIF-1 a mRNA: HIF-1 a tnRNA was only overexpressed in the groups of severe dysplasia and oral squamous ceil carcinoma(OSCC), and there was no significant difference between them in positive expression rate (/*>(). 05). No expression of HIF-1 a was found in the groups of normal,hyperkeratosis, mild epithelial dysplasia and moderate dysplasia.(2) The expression results of iNOSmRNA: iNOSmRNA was overexpressed in dysplasia and OSCC groups,and no expression was found in the normal and hyperkeratosis groups.Significant difference was found i n mild , moderate dysplasia and OSCC groups (/)0.05).C3) The expression results Fas:In the evolution of hamster buccal carcinogenesis, the expression of Fas was significantly down-regulated,which was negative correlation with the grades of hamster oral carcinogenesis'pathology.Positive expression was mainly located in membrane and cytoplasm,especially in membrane.While in OSCC the expression of Fas was in cells of cancer nests,especially in keratin pearls, and most located in cytoplasm, which was different from premalignant lesions. Significant differences were found in the groups of moderate, severe dysplasia, OSCC and normal mucosa(/'< 0. 05), but no differences in OSCC and moderate, severe dysplasia groups (P>0. 05). There were no significances in the groups of mild dysplasia,the normal and hyperkeratosis(/°>0. 05). Conclusions(1) The overexpression of HIF-1a may be an early event in oral mucosa carcinogenesis, and earlier than angiogenesis and tumor invasion in histology. Furthermore,HIF-1 a can accelerate the malignant transformation of tumors. There was no significant differences between severe dysplasia and OSCC groups, which suggests that HIF-1 a play roles during premalignance to the development and progression of oral cancer.(2) The expression of iNOSmRNA was consistent with the expression of its protein, and retains highly in the evolution of hamster buccal carcinogenesis, which indicates that iNOS is involved in the development and progression of oral cancer.(3) Oral cancer cells are in an attempt to escape from immune surveillance and the destruction of activated cytotoxic T cells by down-regulation of Fas expression and translocation of expressionposition.