TLR family gene expression in relation to the HIF1α and the VEGFR pathway activation in endometrial cancer.

INTRODUCTION: Malignant neoplasm of the endometrium is the most common malignant neoplasm of the female reproductive system. Toll Like Receptors (TLR) play a significant role in innate and late-immunity against infections or damaged tissues. TLRs are also involved in the development of tumors in their natural microenvironment. TLRs play an important role in angiogenesis, necessary for survival and growth of the tumor. Hypoxia playing a critical role in angiogenesis, carcinogenesis, tumor progression and distant metastasis is primarily mediated through hypoxia inducible factors (HIFs). Vascular endothelial growth factor family proteins (VEGF) are also strongly involved in tumor angiogenesis and their action is strongly associated with TLR receptors. OBJECTIVES: The aim of the study was to correlate the expression of selected TLRs and VEGFR's as well as HIF1α with clinicopathological data of endometrial cancer patients. MATERIAL AND METHODS: 123 neoplastic endometrial samples were included in the study. 51 samples of healthy endometrium served as control. The expression of TLR1, TLR2, TLR3, TLR4, VEGFR1 and VEGFR2, VEGF-A and HIF1α was examined after RNA isolation at the mRNA level by Real Time-PCR. RESULTS: We have noted a significant correlation between the expression of selected TLR and VEGFR's and clinical stage as well as pathological grading of endometrial cancer. CONCLUSIONS: Received correlations confirm a significant contribution of some TLR expression and the receptor for VEGF in the pathogenesis of epithelial endometrial cancer.

Betaglycan Gene (TGFBR3) Polymorphism Is Associated with Increased Risk of Endometrial Cancer.

We investigated single nucleotide polymorphism (SNP) of the betaglycan gene (TGFBR3) encoding the TGFß co-receptor in endometrial cancer (EC) and its association with betaglycan expression. The study group included 153 women diagnosed with EC and 248 cancer-free controls. SNP genotyping and gene expression were analyzed using TaqMan probes. Three out of the eight SNPs tested, i.e., rs12566180 (CT; OR = 2.22; 95% CI = 1.15-4.30; p = 0.0177), rs6680463 (GC; OR = 2.34; 95% CI = 1.20-4.53; p = 0.0120) and rs2296621 (TT; OR = 6.40; 95% CI = 1.18-34.84; p = 0.0317) were found to be significantly associated with increased risk of EC (adjusted to age, body mass index, menarche and parity). Among the analyzed SNPs, only rs2296621 demonstrated the impact on the increased cancer aggressiveness evaluated by the WHO grading system (G3 vs. G1/2, GT-OR = 4.04; 95% CI = 1.56-10.51; p = 0.0026; T-OR = 2.38; 95% CI = 1.16-4.85; p = 0.0151). Linkage disequilibrium (LD) analysis revealed high LD (r2 ≥ 0.8) in two haploblocks, constructed by rs2770186/rs12141128 and rs12566180/rs6680463, respectively. In the case of C/C haplotype (OR = 4.82; 95% CI = 1.54-15.07; p = 0.0116-Bonferroni corrected) and T/G haplotype (OR = 3.25; 95% CI = 1.29-8.15; p = 0.0328-Bonferroni corrected) in haploblock rs12566180/rs6680463, significantly higher frequency was observed in patients with EC as compared to the control group. The genotype-phenotype studies showed that SNPs of the TGFBR3 gene associated with an increased risk of EC, i.e., rs12566180 and rs2296621 may affect betaglycan expression at the transcriptomic level (rs12566180-CC vs. TT, p < 0.01; rs2296621-GG vs. TT, p < 0.001, GT vs. TT, p < 0.05). Functional consequences of evaluated TGFBR3 gene SNPs were supported by RegulomeDB search. In conclusion, polymorphism of the TGFBR3 gene may be associated with an increased EC occurrence, as well as may be the molecular mechanism responsible for observed betaglycan down-regulation in EC patients.

Expression of voltage-dependent anion channels in endometrial cancer and its potential prognostic significance.

The exchange of metabolites between mitochondria and cytosol occurs through pores formed by voltage-dependent anion channel proteins. Voltage-dependent anion channels appear to be master regulators of mitochondrial bioenergetics and the intracellular flow of energy. Deregulation of voltage-dependent anion channels expression is thought to be related to mitochondrial dysfunction in cancer. The aim of this study was to investigate the mRNA and protein expression levels of VDAC1, VDAC2, and VDAC3 in relation to clinicopathological characteristics of endometrial cancer as well as the prognostic significance of voltage-dependent anion channels expression for overall survival. VDAC1 and VDAC3 expressions were significantly higher in cancer compared to normal tissues. Kaplan-Meier analysis indicated that high expression of all VDAC genes or high VDAC2 protein level predicted poor overall survival. Multivariate analysis identified the VDAC1 and VDAC2 mRNA levels as well as VDAC2 protein level as independent prognostic factors. Our results suggest that increased expression of voltage-dependent anion channels correlates with tumor progression and may serve as a potential prognostic biomarker in endometrial cancer.

Relationship between polycomb-group protein BMI-1 and phosphatases regulating AKT phosphorylation level in endometrial cancer.

The PI3K/AKT pathway is frequently activated in endometrial carcinoma. BMI-1 (B-lymphoma Mo-MLV insertion region 1) protein affects expression of PTEN (phosphatase and tensin homolog) in some cancers, but its significance for endometrial tumorigenesis is not known. The objective of this study was to determine the relationship between BMI-1 and expression of factors affecting AKT (protein kinase B) phosphorylation level in endometrial cancer. The expression of proteins and mRNAs was investigated in endometrial cancer specimens and samples of non-neoplastic endometrial tissue by Western blot and RT-PCR, respectively. The impact of BMI-1 down-regulation on AKT phosphorylation and expression of genes coding for several phosphatases were studied in HEC1A cells. The results showed that BMI-1 depletion caused increase in PHLPP1 and PHLPP2 (PH domain and leucine-rich repeat protein phosphatases 1/2) expression and decrease in phospho-AKT (pAKT) level. In more advanced tumours with higher metastatic potential, the expression of BMI-1 was lower compared to tumours less advanced and without lymph node metastasis. There were significant inverse correlations between BMI-1 and PHLPPs, especially PHLPP1 in normal endometrial samples. The inverse correlation between BMI-1 and PHLPP1/PHLPP2 expression was observed in PTEN positive but not PTEN negative cancers. Low PHLPP2 expression in tumours predicted poorer overall survival. BMI-1 impacts on AKT phosphorylation level in endometrial cells by regulation of PHLPP expression.

The role of the ßKlotho gene in uterine endometrial cancer.

OBJECTIVES: Endometrial cancer is the most common cancer of the female genital organs in developed countries, accounting for approximately 50% of all gynecological cancers. The Klotho gene was discovered in 1997 as an anti-aging gene that, when overexpressed, may extend the lifespan, but when disrupted, may be a factor responsible for premature aging syndrome. The aim of the study is to assess the relationship between the clinical and pathological features of endometrial cancer and ßKlotho gene expression. MATERIAL AND METHODS: The expression of ßKlotho gene was studied in 138 cases of endometrioid endometrial carcinoma specimens using Real Time PCR reaction in RNA isolated tissue samples by commercial tests. The expression profile was correlated with the clinicopathological characteristics of endometrial carcinoma. The chi-square independence test and Fisher's test for four-field tables were used to assess the statistical significance of the observed relationships. RESULTS: Significant relationships were found between ßKlotho gene expression and FIGO clinical stage, the degree of histological differentiation and the presence of metastases in the lymph nodes. Higher levels of gene expression correlate with lower degrees of clinical staging according to FIGO, the presence of highly-differentiated endometrial cancer (G1) and the absence of lymph node metastases. CONCLUSIONS: The ßKlotho gene expression might be involved in endometrioid endometrial cancer tumorgenesis. The ßKlotho may in future be used as an useful indicator for endometrial cancer, although further studies are needed.

Differential expression of ten-eleven translocation genes in endometrial cancers.

Ten-eleven translocation proteins are α-ketoglutarate-dependent dioxygenases involved in the conversion of 5-methylcytosines (5-mC) to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine, and 5-carboxylcytosine that play a significant role in DNA demethylation. Deregulation of TET genes expression and changes in the level of 5-hmC are thought to be associated with the onset and progression of several types of cancer, but there are no such data related to endometrial cancer. The aim of the work was to investigate the messenger RNA expression levels of TET1, TET2, and TET3 in relation to clinicopathological characteristics of endometrial cancer as well as the correlation between expression of TET genes and the level of 5-hmC/5-mC. The prognostic significance of TETs expression for overall survival was established. We found that TET1 and TET2 messenger RNA expression was lower and TET3 was higher in cancers compared to normal tissues. Positive correlation between 5-hmC and the relative expression of TET1 and TET2 was found, but no correlation was observed in the case of TET3. Decreased expression of TET1 and TET2 was significantly associated with increased lymph node metastasis and International Federation of Gynecology and Obstetrics stage. Kaplan-Meier analysis indicated that low TET1 expression predicted poor overall survival (p = 0.038). Multivariate analysis identified the TET1 expression in endometrial cancer as an independent prognostic factor. Our results suggest that decreased expression of TET1 correlates with tumor progression and may serve as a potential prognostic biomarker in endometrial cancer.

[Histological grading of endometrial carcinoma. Clinical and patomorphological analysis]. / Dojrzalosc histologiczna raka blony sluzowej trzonu macicy. Analiza kliniczna i patomorfologiczna.

OBJECTIVE: Retrospective clinical and pathomorphological analysis of patients undergoing surgery due to endometrial carcinoma; analysis of the correlation between histological grading of endometrial cancer and selected pathomorphological results. MATERIAL AND METHODS: Statistical analysis was based on the pathomorphological results in a group of 353 patients operated because of endometrial carcinoma at the Clinical Department of Gynecologic Oncology Medical University of Lodz, between 2003 and 2013. A possible correlation between histological grading, clinical staging, myometrial infiltration, parametrial invasion and nodal metastases to ilio-obturator lymph nodes was investigated. RESULTS: Among poorly differentiated carcinomas G3, myometrial infiltration above half of its thickness was observed in 67.44% of the cases, whereas in the G2 and G1 groups it was detected in 60.82% and 39.33% of the affected individuals, respectively. Parametrial invasion was found in 24.39% of G3 cases, i.e. 4.23 times more often than in G2 (5.76%) and 10.65 times more often than in G1 (2.29%). Nodal metastases to ilio-obturator lymph nodes were present in 27.50% of poorly 10.86% of moderately and 8.11% of well-differentiated carcinomas. Uterine appendages were infiltrated in 23.25% of G3 cases--3.45 times more than in G2 (6.73%) and 6.82 times more than in G1 (3.4 1%). CONCLUSIONS: Histologic grading for carcinoma at the time of diagnosis is significantly related to clinical staging. No correlation between patient age and carcinoma grading or its clinical staging was observed. Risk of lymph node invasion for well-differentiated carcinomas is similar to the risk for moderately differentiated carcinomas, and should also be an indication for lymphadenectomy in that group of patients.

The role of WWOX tumor suppressor gene in the regulation of EMT process via regulation of CDH1-ZEB1-VIM expression in endometrial cancer.

This study defines the role of WWOX in the regulation of epithelial to mesenchymal transition. A group of 164 endometrial adenocarcinoma patients was studied as well as an ECC1 well-differentiated steroid-responsive endometrial cell line, which was transducted with WWOX cDNA by a retroviral system. The relationship between WWOX gene and EMT marker (CDH1, VIM, ZEB1, SNAI1) expression on mRNA (RT-qPCR) and protein levels (western blotting) was evaluated. The EMT processes were also analysed in vitro by adhesion of cells to extracellular matrix proteins, migration through a basement membrane, anchorage-independent growth and MMP activity assay. DNA microarrays (HumanOneArray™) were used to determine WWOX-dependent pathways in an ECC1 cell line. A positive correlation was observed between WWOX and ZEB1, and a negative correlation between CDH1 and VIM. WWOX expression was found to inversely correlate with the risk of recurrence of tumors in patients. However, in the WWOX-expressing ECC1 cell line, WWOX expression was found to be inversely related with VIM and positively with CDH1. The ECC1/WWOX cell line variant demonstrated increased migratory capacity, with increased expression of metalloproteinases MMP2/MMP9. However, these cells were not able to form colonies in suspension and revealed decreased adhesion to fibronectin and fibrinogen. Microarray analysis demonstrated that WWOX has an impact on the variety of cellular pathways including the cadherin and integrin signalling pathways. Our results suggest that the WWOX gene plays a role in the regulation of EMT processes in endometrial cancer by controlling the expression of proteins associated with cell motility, thus influencing tissue remodeling, with the suppression of mesenchymal markers.

[Effects of metformin on the survival of the SKOV-3 ovarian cancer cell line and the expression of genes encoding enzymes involved in O-Glcnacylation]. / Wplyw metforminy na przezywalnosc komórek raka jajnika linii SKOV-3 oraz ekspresje genów kodujacych enzymy zwiazane z O-G1cNAcylacja.

OBJECTIVES: The aim of the study was to evaluate the cytotoxic effect of metformin on the ovarian cancer cells SKOV-3 and analyze the impact of this compound on the expression of genes coding for O-GlcNAc cycling enzymes, i.e. O-GlcNAc transferase (OGT) and -N-acetylglucosaminidase (OGA). MATERIALS AND METHODS: Viability and proliferation of control cells and cells treated with metformin were evaluated by MTT test and trypan blue staining. OGT and OGA mRNA expressions analysis was performed using real-time PCR method. RESULTS: A metformin concentration-dependent decrease of SKOV-3 cell viability was observed. The IC50 parameter for metformin cytotoxicity was 14 mM. The SKOV-3 cell doubling time was 45 hours. The cell population treated with 10 mM metformin did not double even after 72 hours. There was no significant difference in mRNA level of OGA between control cells and cells treated with metformin. The OGT mRNA level was significantly higher in cells treated with metforrhin for 24 hours as compared to the control cells. The increase of OGT mRNA was dependent on time of incubation. Cells treated with metformin for 48 hour showed higher expression of OGT than cells treated for 24 hours. CONCLUSION: Antiproliferative activity of metformin suggests that this compound may be considered as a candidate for potential chemotherapeutic agent. However taking into account its impact on the expression of O-GlcNAc transferase, further studies on the molecular mechanism of metformin action are necessary

Topoisomerase IIß binding protein 1 c.*229C>T (rs115160714) gene polymorphism and endometrial cancer risk.

TopBP1 (topoisomerase IIß binding protein 1) protein is involved in DNA replication, DNA damage checkpoint response and transcriptional regulation. In this study we investigated whether alterations in the TopBP1 gene can influence the risk of endometrial cancer. We examined the association between five single nucleotide polymorphisms (rs185903567, rs116645643, rs115160714, rs116195487, and rs112843513) located in the 3'UTR region of the TopBP1 gene and endometrial cancer risk as well as allele-specific gene expression. One hundred twenty-one endometrial cancer patients were genotyped for these SNPs. Allele-specific TopBP1 mRNA and protein expressions were determined by real time PCR and western blotting methods, respectively. Only one SNP (rs115160714) showed an association with endometrial cancer. Compared to homozygous common allele carriers, heterozygous for the T variant had significantly increased risk of endometrial cancer [adjusted odds ratio (OR) = 5.59, 95 % confidence interval (CI): 1.96-15.91, p = 0.0003]. Mean TopBP1 mRNA and protein expression were higher in the individuals with the CT genotype. There was a significant association between the rs115160714 and tumor grade and FIGO classification. Most carriers of minor allele had a high grade tumors (G3) classified as FIGO III/IV. The results of our study raise a possibility that a genetic variation of TopBP1 may be implicated in the etiology of endometrial cancer.

The WWOX tumor suppressor gene in endometrial adenocarcinoma.

Endometrial cancer is a lethal malignancy, the causes of which remain to be determined. The aim of the present study, carried out on tumor samples from 79 patients, was to evaluate the role of the WWOX tumor suppressor gene in endometrial adenocarcinoma. The expression levels of WWOX and its protein content were assessed in normal endometrium and cancer samples. Quantitative PCR was used to assess the correlation between the expression levels of WWOX and the genes involved in the proliferation (MKI67), apoptosis (BAX, BCL2), signal transduction (EGFR), cell cycle (CCNE1, CCND1), cell adhesion (CDH1) and transcription regulation (TP73, NCOR1). The relationship between loss of hetero-zygosity (LOH) and WWOX mRNA levels was also investigated using high resolution melting. Results of the present study demonstrated a positive correlation of WWOX expression with BCL2 and CCND1 and a negative correlation with BAX, CDH1, NCOR1 and BCL2/BAX ratio. The results also showed that loss of heterozygosity at two analyzed loci of the WWOX gene is frequent in patients with endometrial cancer and that WWOX expression levels are lower in tumor samples than in normal tissue. In conclusion, WWOX may be involved in endometrial cancer.

[Molecular basis of gynecological oncology - TopBP1 protein as the guardian of genome integrity]. / Molekularne podstawy ginekologii onkologicznej - bialko TopBP1 jako straznik integralnosci genomu.

Breast cancer is the most common malignancy in women. Its estimated annual incidence is about one million cases worldwide. A number of risk factor have been identified, among them early menarche, late menopause, nulliparity and positive family history Moreover a number of highly penetrant breast and ovarian cancer susceptibility genes, such as BRCA 1 and BRCA2, have been identified. Recent findings suggest TopBP1 to be a breast and ovarian cancer susceptibility gene. Moreover; TopBPI protein may be an important prognostic marker of breast cancer TopBP1 protein is involved in DNA replication, mitosis and meiosis, as well as DNA repair Deregulation of these processes may have pathological implications in cancer

Correlation between VEGFR-2 receptor kinase domain-containing receptor (KDR) mRNA and angiotensin II receptor type 1 (AT1-R) mRNA in endometrial cancer.

PURPOSE: Angiogenesis, a multistep process that results in new blood vessel formation from preexisting vasculature is essential for both the growth of solid tumour and for metastasis. Stimulation of vascular endothelial growth factor receptor (VEGFR), a transmembrane glycoprotein, results in mitogenesis. Within this family of receptors, VEGFR 2/kinase-insert-domain containing receptor appears to be principally upregulated during tumorigenesis. The aim of this study was to determine the expression of VEGFR-2/kinase-insert-domain containing receptor (KDR) and its correlation with angiotensin receptor type 1 (AT1-R) and clinical factors in endometrial carcinoma. METHODS: The expression of KDR and AT1-R was studied in endometrial carcinoma and normal endometrium by Real-time RT-PCR and Western blot analysis in 136 samples. The expression profile was correlated with the clinicopathological characteristics of endometrial adenocarcinoma. RESULTS: We noted a significant correlation between the expression of KDR and AT1-R in tumour grade G1, G2 and G3 (R(s)=0.50; p=0.002, R(s)=0.69; p=0.0001, R(s)=0.52; p=0.005, respectively). In stage I and stage II carcinoma, a significant correlation was also found between the expression of KDR and AT1-R (R(s)=0.70, p=0.0001, R(s)=0.67; p=0.001, respectively). Moreover significant correlation was observed between both KDR and AT1-R in tissue with different myometrial invasion (R(s)=0.54, p=0.0001, R(s)=0.68; p=0.0001; respectively for tumours with invasion into the inner half and invasion into the outer half). CONCLUSIONS: Basing on received correlation between AT1-R and KDR expression and previous results we speculate that angiotensin through AT1-R modulates KDR expression and thus have influence on local VEGF level. However, further studies are required to clarify the biological interaction between KDR, AT1-R and other hormonal regulators in endometrial carcinoma.

[Expression of E-cadherin and beta1-integrin mRNA in endometrial cancer]. / Ekspresja genów kodujacych E-kadheryne i beta1-integryne w nowotworach blony sluzowej trzonu macicy.

OBJECTIVES: The metastatic ability of tumors is characteristic for malignant neoplasms and constitutes the main cause of therapeutics failures. Metastasis formation involves the sequence of processes such as proteolytic degradation of the basement membrane, migration, intravasation, extravasation, proliferation and angiogenesis. Cadherins and integrins are groups of proteins directly involved in these processes. In the present study we analyzed the mRNA expression of CDH1 and ITGB1 genes by real-time polymerase chain reaction (RT-PCR). The study included 106 endometrial carcinomas. CDH1 and ITGB1 mRNA expression was found in all of the studied samples. Generally the CDH1 and ITGB1 mRNA expression was significantly higher in well-differentiated rather than poorly differentiated tumors. MATERIALS AND METHODS: The mRNA expression levels of CDH1 and ITGB1 in series of 83 samples of endometrial carcinoma were studied by real time RT-PCR method. Statistical analysis of the obtained results was performed. RESULTS: CDH1 and ITGB1 gene expression was observed in all examined tissues and was correlated with cancer malignancy (G). In high grade malignant tumors (G1), CDH1 and ITGB1 gene expression was the highest, in G2 and G3 tumors the expression of both genes was gradually lowering. Moreover the statistically significant correlation between CDH1 and ITGB1 gene expression was observed. (Spearman test, r=0.29, p

[Molecular basis of gynecological oncology--TopBP1 protein and its participation in the transcription process]. / Molekularne podstawy ginekologii onkologicznej--bialko TopBP1 i jego udzial w procesie transkrypcji.

Breast and ovarian cancer are among the most common malignancies of women in the world. About 5 - 10% of the cases are considered familial. Germline mutations in the BRCA1 and BRCA2 genes are strong predictors of breast and/or ovarian cancer development. However currently known susceptibility genes including BRCA1, BRCA2, ATM, Chk2, PALB2, and BRIP1 explain less than 25% of familial breast and/ovarian cancers. Other genes, such as TopBP1 are also likely to be involved in hereditary predisposition to breast and/or ovarian cancer TopBP1 protein displays structural and functional similarities with BRCA1, and these two proteins have been suggested to function partially in the same cellular processes. TopBP1 protein is involved in DNA repair and cell cycle checkpoint control. Moreover TopBP1 interacts with transcription factors, such as E2F1, p53, Miz-1, HPV16 E2, and regulates their activity.

Expression of genes encoding for enzymes associated with O-GlcNAcylation in endometrial carcinomas: clinicopathologic correlations.

OBJECTIVES: O-GlcNAcylation is an abundant modification of cellular proteins which consist of single N-acetylglucosamine residues attached by O-linkage to serine or threonine residues. Abnormal O-GlcNAcylation seems to be a feature of malignant cancer cells. The aim of the present study was to determine the relationship between the expression of genes encoding O-GlcNAc cycling enzymes (OGT and MGEAS) and clinicopathological parameters of endometrial carcinomas. MATERIALS AND METHODS: The mRNA expression levels of O-GlcNAc cycling enzymes in series of 76 samples of endometrial carcinoma were studied by real time RT-PCR method. RESULTS: The OGT and MGEA5 mRNA expression was significantly higher in tumors of higher histological grade than in well-differentiated tumors. Statistically significant association was found between OGT and MGEA5 mRNA expression and depth of myometrial invasion. Both OGT and MGEA5 expression profiles showed no significant association with the clinical stage of endometrial cancer. CONCLUSION: O-GlcNAcylation may be an important regulatory modification involved in endometrial cancer pathogenesis but the actual significance of this modification for endometrial cancer progression needs to be investigated further.

Expression of GLUT1 and GLUT3 glucose transporters in endometrial and breast cancers.

Cancer cells have accelerated metabolism and high glucose requirements. The up-regulation of specific glucose transporters may represent a key mechanism by which malignant cells may achieve increased glucose uptake to support the high rate of glycolysis. In present study we analyzed the mRNA and protein expression of GLUT1 and GLUT3 glucose transporters by quantitative real-time polymerase chain reaction (Q-PCR) and Western blotting technique in 76 cases of endometrial carcinoma and 70 cases of breast carcinoma. SLC2A1 and SLCA2A3 mRNAs expression was found, respectively in 100% and 97.4% samples of endometrial cancers and only in 50% and 40% samples of breast cancers. In endometrial cancers GLUT1 and GLUT3 protein expression was identified in 67.1% and 30.3% of cases. Analogously, in breast cancers in 48.7% and 21% of samples, respectively. The results showed that both endometrial and breast poorly differentiated tumors (grade 2 and 3) had significantly higher GLUT1 and GLUT3 expression than well-differentiated tumors (grade 1). Statistically significant association was found between SLCA2A3 mRNA expression and estrogen and progesterone receptors status in breast cancers. GLUT1 has been reported to be involved in the uptake of glucose by endometrial and breast carcinoma cells earlier and the present study determined that GLUT3 expression is also involved. GLUT1 and GLUT3 seem to be important markers in endometrial and breast tumors differentiation.

Analysis of the expression of angiotensin II type 1 receptor and VEGF in endometrial adenocarcinoma with different clinicopathological characteristics.

In Poland, endometrial carcinoma takes second place after breast cancer among all cancers in women and is considered the most common genital cancer. It has been repeatedly reported that angiotensin is involved in the development and invasion of some cancers including breast, ovarian, and pancreatic ones. It is suggested that angiotensin two and its receptors are actively involved in tumour biology in endometrial adenocarcinoma. In the present study, we identify a possible relationship between the expression of AT1-R, AT2-R, ERα, and VEGF and clinicopathological characteristics of primary endometrial adenocarcinoma. We determined the above components both at the mRNA (real-time RT-PCR) and protein levels (Western Blot assay). Our results indicate that in patients with grade G3 adenocarcinoma, the expression of AT1-R significantly decreased in comparison with G1 patients (p = 0.034), but the level of ERα was the highest in G2 and the lowest in G3. Moreover, the level of VEGF mRNA significantly increased between G2 and G3 (p = 0.034). We also noted a significant correlation between the expression of AT1-R and AT2-R in FIGO stage 1 (R (s) = 0.9636; p = 0.0001) and that of AT2-R and VEGF (R (s) = 0.5377; p = 0.005). In grade G1 and G2 carcinoma, a significant correlation was also found between the expression of AT1-R and AT2-R (R (s) = 0.9924; p = 0.0001; R (s) = 0.8717, p = 0.0005, respectively), but in grade G1, a negative correlation was observed between AT1-R and VEGF (R (s) = -0.8945, p = 0.0005). Further studies are required to clarify the biological function of the angiotensin receptor in regulating VEGF expression in endometrial carcinoma.

The cytosol activity of thymidine phosphorylase in endometrial cancer.

BACKGROUND: Thymidine phosphorylase (TP) is identical with platelet-derived endothelial cell growth factor (PD-ECGF) which promotes angiogenesis. The aim of this study was to evaluate the cytosol activity of TP in tumor samples from patients with endometrial cancer. METHODS: The activity of TP was measured by the spectrophotometric method in the cytosol of endometrial tumor samples from 43 patients. Moreover, the expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) protein and microvessel density (MD) were examined in the same endometrial tumor samples by immunohistochemical staining. Normal endometrium from 16 women, treated surgically due to nononcological reasons served as a control.A relationship between the cytosol TP activity, PD-ECGF/TP protein expression, MD and clinicopathologic features was investigated. RESULTS: A significantly higher the cytosol TP activity, PD-ECGF/TP protein expression and MD was stated in malignant tumor samples when compared to the control (samples of normal endometrium). A positive statistically significant correlation between the cytosol enzyme activity and PD-ECGF/TP protein expression and MD was found, but weaker from the remaining ones between PD-ECGF/TP protein expression and MD was observed.Besides no correlation between the cytosol TP activity, PD-ECGF/TP protein expression as well as MD and grading or histopatological type of endometrial cancer was stated. CONCLUSION: The cytosol TP activity in endometrial cancer is significantly higher than in normal endometrium, with no relation as to the stage and grade of tumors, but correlates with the PD-ECGF/TP protein expression and MD may therefore be associated with favorable prognosis in patients treated with chemo- or radiotherapy after surgery.