losartan-potassium and Uterine-Cervical-Dysplasia

The blood plasma erythropoietin content, erythropoietin content, erythropoietin and cellular renovation markers expression in exocervical epithelium in reproductive aged women with normal peripheral red blood values were studied. It was determined that erythropoietin expression increased in exocervical epithelium activity (cervical intraepithelial neoplasia 1 and 2), combined with the increase of blood plasma erythropoietin level, activation of pro- and antiapoptosis programs and cellular proliferation processes in cervical epithelium.

Topics: Adolescent; Adult; Apoptosis; Cell Proliferation; Cervix Uteri; Chronic Disease; Epithelium; Erythropoietin; Female; Humans; Middle Aged; Uterine Cervical Dysplasia; Uterine Cervicitis

Malignant phenotypic traits are caused by microenvironmental selection pressures during carcinogenesis. Hypoxia can drive a tumor toward a more aggressive malignant phenotype. The objective was to better understand the role of the hypoxia-regulated genes in cervical carcinogenesis.. We analyzed the expression of the hypoxia-regulated genes, including hypoxia-inducible factor-1alpha (HIF-1alpha), erythropoietin (Epo), vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT1), carbonic anhydrase IX (CAIX), and MET, in cervical cell lines and human tissue samples of cervical intraepithelial neoplasia (CIN I-III) and invasive squamous cell carcinoma (ISCC).. CAIX and MET were expressed in cervical carcinoma cell lines, but not in normal or human papillomavirus-immortalized cervical cells. In clinical tissue samples, Epo, VEGF, GLUT1, and CAIX were not detected in normal squamous epithelia. GLUT1 was expressed in nearly all cases of CIN and ISCC, however, CAIX was expressed only in CIN III and ISCC. HIF-1alpha and MET expression was confined to the basal cells in normal squamous epithelia and was detected in the dysplastic cells of CIN and ISCC.. The role of HIF-1alpha and MET changes from response to proliferation to tumor progression during cervical carcinogenesis. GLUT1 expression, a glycolytic phenotype adaptive to glycolysis, occurs early during cervical carcinogenesis and is a specific marker for dysplasia or carcinoma. MET and CAIX may contribute tumor progression in later stage. CAIX expression, an acid-resistant phenotype, may be a powerful adaptive advantage during carcinogenesis. Successful adaptation to the hypoxia-glycolysis-acidosis sequence in a microenvironment is crucial during carcinogenesis.

Topics: Blotting, Western; Carcinoma, Squamous Cell; Cell Hypoxia; Cell Line, Tumor; Cell Transformation, Neoplastic; Erythropoietin; Female; Gene Expression Regulation, Neoplastic; Glucose Transporter Type 1; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Middle Aged; Papillomaviridae; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Tissue hypoxia is a characteristic property of cervical cancers that makes tumors resistant to chemo- and radiation therapy. Erythropoietin (Epo) is a hypoxia-inducible stimulator of erythropoiesis. Acting via its receptor (EpoR), Epo up-regulates bcl-2 and inhibits apoptosis of erythroid cells and rescues neurons from hypoxic damage. In addition to human papillomavirus infection, increased bcl-2 expression and decreased apoptosis are thought to play a role in the progression of cervical neoplasia. Using reverse transcriptase-polymerase chain reaction and Western blotting we showed that HeLa and SiHa cervical carcinoma cells and human cervical carcinomas express EpoR, and that hypoxia enhances EpoR expression. Exogenous Epo stimulated tyrosine phosphorylation and inhibited the cytotoxic effect of cisplatin in HeLa cervical carcinoma cells. Using immunohistochemistry, we examined the expression of Epo, EpoR, p16, hypoxia-inducible factor (HIF)-1alpha, and bcl-2 in benign and dysplastic cervical squamous epithelia and invasive squamous cell carcinomas (ISCCs). EpoR expression in benign epithelia was confined to the basal cell layers, whereas in dysplasias it increasingly appeared in more superficial cell layers and showed a significant correlation with severity of dysplasia. Diffuse EpoR expression was found in all ISCCs. Expression of Epo and HIF-1alpha was increased in dysplasias compared to benign epithelia. Focal Epo and HIF-1alpha expression was seen near necrotic areas in ISCCs, and showed correlation in their spatial distribution. Significant correlation was found between expression of EpoR, and p16 and bcl-2 in benign and dysplastic squamous epithelia. Our results suggest that increased expression of Epo and EpoR may play a significant role in cervical carcinogenesis and tumor progression. Hypoxia-inducible Epo signaling may play a significant role in the aggressive behavior and treatment resistance of hypoxic cervical cancers.

Topics: Carcinoma, Squamous Cell; Cell Hypoxia; Cell Survival; Cyclin-Dependent Kinase Inhibitor p16; Disease Progression; Dose-Response Relationship, Drug; Erythropoietin; Female; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Neoplasm Staging; Proto-Oncogene Proteins c-bcl-2; Receptors, Erythropoietin; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Transcription Factors; Tumor Cells, Cultured; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms