Endometrial cancer (EC) is one of the most frequent causes of cancer death among women in developed countries. Histopathological diagnosis and imaging techniques for EC are limited, thus new prognostic markers are needed to offer patients the best treatment and follow-up.In the present paper we showed that the level of mitochondrial ribosomal protein MRPS18-2 (S18-2) increased in EC compared with the normal endometrium and hyperplasia, based on a study of 42 patient biopsies. Importantly, high expression of free E2F1 in EC correlates well with high S18-2 expression. The EC cell line HEC-1-A, which overexpresses S18-2 constitutively, showed an increased proliferation capacity in vitro and in vivo (in SCID mice). Moreover, pan-keratin, beta-catenin and E-cadherin signals are diminished in these cells, compared to the parental HEC-1-A line, in contrast to vimentin signal that is increased. This may be associated with epithelial-mesenchymal cell transition (EMT).We conclude that high expression of S18-2 and free E2F1, and low pan-keratin, beta-catenin, and E-cadherin signals might be a good set of prognostic markers for EC.
Summary. Aim: To analyze copy number variations of HER-2/neu, c-MYC and CCNE1 oncogenes and their protein expression in endometrioid endometrial carcinomas in relation to the degree of tumor progression and presence of a family history of cancer in cancer patients. Materials and Methods: The study was conducted on endometrial cancer (EC) samples from 68 patients with I–II FIGO stages of disease. Copy number analysis of HER-2/neu, c-MYC and CCNE1 genes was performed by quantitative PCR. Protein expression was analyzed using immunohistochemistry. Results: Assessment of copy number variations of HER-2/neu, c-MYC and CCNE1 genes revealed their amplification in the tumors of 18.8, 25.0 and 14.3% of EC patients, respectively. High expression of corresponding proteins was detected in 14.6, 23.5 and 65.6% of patients, respectively. It was established that HER-2/neu gene amplification is more common in the group of tumors of low differentiation grade than in moderate grade EC (35.7 and 5.5% of cases, respectively, p < 0.05). Also, high expression of c-Myc protein was more frequently observed in low differentiated tumors compared to the moderately differentiated EC (36.6 and 13.2% of cases, respectively, p < 0.05). Expression of HER-2/neu and cyclin E proteins was found to be dependent on the depth of tumor invasion into the myometrium. High expression of HER-2/neu protein was observed in 25.0 and 4.1% of EC patients with tumor invasion > ½ and < ½ of the myometrium, respectively, and cyclin E — in 86.7 and 46.6% of cases, respectively, p < 0.05. It was shown that among patients with a family history of cancer, a larger proportion of cases with high expression of c-Myc protein was observed compared to the group of patients with sporadic tumors (43.8 and 17.3%, respectively; p < 0.05). Conclusions: Amplification of HER-2/neu gene, along with high expression of c-Myc, HER-2/neu and cyclin E proteins, are associated with such indices of tumor progression as a low differentiation grade and deep myometrial invasion, suggesting the potential possibility of including these markers in the panel for determining the molecular EC subtype associated with an aggressive course of the disease. In a certain category of EC patients, there is a relationship between a family history of cancer and high expression of c-Myc protein.
To date, genome instability is considered to be a common feature not only of tumor cells, but also of non-malignant cells of cancer patients, including peripheral blood lymphocytes (PBLs). The issue of the association between genome instability in tumor cells and PBLs, as well as of its relationship with tumor progression remains poorly understood. Aim: To evaluate the level DNA damage in tumor cells and PBLs of endometrial cancer (EC) patients with regard to clinical and morphological characteristics of the patients. Materials and Methods: DNA damage was assessed in 106 PBLs samples and 42 samples of tumor cell suspension from EC patients by comet assay. PBLs from 30 healthy women were used as control. The level of DNA damage was expressed as the percentage of DNA in the comet tails (% tail DNA). Results: It was revealed that the amount of DNA damage in PBLs of EC patients was 2.2 times higher in comparison with that of healthy donors (8.3 ± 0.7 and 3.7 ± 0.4% tail DNA, respectively) (p < 0.05). In this study, no association between the levels of DNA damage in endometrial tumor cells and PBLs was observed (r = 0.11; p > 0.05). The amounts of DNA damage both in tumor cells and PBLs were not related to the degree of tumor differentiation as well as the depth of myometrial invasion, but depended on the body mass index (BMI) of EC patients: high level of lesions was observed in patients with elevated BMI values. Furthermore, the level of DNA damage in tumor cells was associated to familial aggregation of cancer and was significantly higher in endometrial cells from patients with family history of cancer vs that from EC patients with sporadic tumors (32.3 ± 2.9 and 22.8 ± 1.8% tail DNA, respectively) (p < 0.05). It was also found that for women who had high level of DNA damage in PBLs, the risk of EC was greater (odds ratio value of 3.5) compared to those with low level of such lesions. Conclusion: Genome instability that appears as an increased level of DNA damage in tumor cells and PBLs of EC patients is associated with BMI and family history of cancer and can reflect a predisposition to cancer.
Summary. Background: It is known that more than half of the genes encoding human proteins are regulated by various microRNAs (miRNAs, miR), the expression of which may be associated with various pathological conditions. At the same time, the question of assessing the relationship between the expression of particular miRNAs and the aggressive molecular subtype of endometrial cancer remains open. Aim of the study was to determine the relationship between the expression of miR-34a, miR-125b, miR-142 and miR-101 in endometrioid carcinomas of the endometrium (ECE) and the features of the disease course. Materials and Methods: The samples of surgical material of 51 patients with ECE (mean age 59.8 ± 7.1 years), I–III stage were investigated using morphological, immunohistochemical methods, real time polymerase chain reaction (PCR), cytofluorometry. Results: In endometrial tumors with high proliferation index (> Me), the expression of miR-34a, miR-142 and miR-125b significantly decreased (1.8, 2.7 and 1.5 times, respectively) compared with those in ECE with low proliferation index (< Me). The expression of all studied miRNAs was lower in G3 tumors and those that deeply invaded the myometrium compared to G2 carcinomas and tumors with an invasion of < 1/2 myometrium and significantly decreased in tumors of patients with low stage III compared with stage I–II. The high (> Me) microvessel density in ECE was associated with a significant decrease of miR-125b and miR-101 expression, and the presence of signs of epithelial-mesenchymal transition — with a decreased expression of miR-34a and miR-101. Conclusions: The study revealed a significant heterogeneity of expression of miR-34a, miR-125b, miR-142 and miR-101 in ECE, which is associated with changes in morphofunctional characteristics of endometrial carcinoma.
Aim: To study the expression of adhesion markers (E-cadherin, β-catenin and vimentin) associated with epithelial-mesenchymal transition (EMT) and their role in progression of endometrial carcinoma (EC). Materials and Methods: Expression of E-cadherin, β-catenin and vimentin was studied immunohistochemically in the samples of surgical material of 55 EC patients stage I–III. The proliferation index was determined by flow cytometry. Results: In the group of vimentin-negative EC, tumors of low differentiation grade and deep invasion in myometrium as well as high expression of E-cadherin and β-catenin prevailed compared with the cases with high expression of vimentin. In addition, in EC with high expression of vimentin, an increase in the number of cells with expression of E-cadherin in the cytoplasm (78.9 ± 3.6%) and β-catenin with cytoplasmic-nuclear localization (73.7 ± 3.2%) was observed compared with these indices in vimentin-negative tumors (45.4 ± 4.2%, p < 0.001 and 54.5 ± 2.6%, respectively, p < 0.005), which may indicate EMT-associated changes in EC with high expression of vimentin. Conclusions: The progression of the endometrioid carcinoma may occur in the setting of various molecular changes, in particular, with decreased expression of E-cadherin and β-catenin and high expression of vimentin, or in the absence of vimentin, utilizing other mechanisms of regulation of proliferative and metastatic potential.
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