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Molecular Landscape of the Epithelial-Mesenchymal Transition in Endometrioid Endometrial Cancer.

ABSTRACT: Modern diagnostics are based on molecular analysis and have been focused on searching for new molecular markers to use in diagnostics. Included in this has been the search for the correlation between gene expression in tissue samples and liquid biological materials. The aim of this study was to evaluate the differences in the expression profile of messenger RNA (mRNA) and micro-RNA (miRNA) related to the epithelial-mesenchymal transition (EMT) in different grades of endometrial cancer (G1-G3), in order to select the most promising molecular markers. The study material consisted of tissue samples and whole blood collected from 30 patients with endometrial cancer (study group; G1 = 15; G2 = 8; G3 = 7) and 30 without neoplastic changes (control group). The molecular analysis included the use of the microarray technique and RTqPCR. Microarray analysis indicated the following number of mRNA differentiating the endometrial cancer samples from the control (tissue/blood): G1 vs. C = 21/18 mRNAs, G2 vs. C = 19/14 mRNAs, and G3 vs. C = 10/9 mRNAs. The common genes for the tissue and blood samples (Fold Change; FC > 3.0) were G1 vs. C: TGFB1, WNT5A, TGFB2, and NOTCH1; G2 vs. C: BCL2L, SOX9, BAMBI, and SMAD4; G3 vs. C STAT1 and TGFB1. In addition, mRNA TGFB1, NOTCH1, and BCL2L are common for all grades of endometrial cancer. The analysis showed that miR-144, miR-106a, and miR-30d are most strongly associated with EMT, making them potential diagnostic markers.

SUBMITTER: Oplawski M

PROVIDER: S-EPMC8038735 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundEvery year approximately 74,000 women die of endometrial cancer, mainly due to recurrent or metastatic disease. The presence of tumor infiltrating lymphocytes (TILs) as well as progesterone receptor (PR) positivity has been correlated with improved prognosis. This study describes two mechanisms by which progesterone inhibits metastatic spread of endometrial cancer: by stimulating T-cell infiltration and by inhibiting epithelial-to-mesenchymal cell transition (EMT).Methodology and principal findingsParaffin sections from patients with (n = 9) or without (n = 9) progressive endometrial cancer (recurrent or metastatic disease) were assessed for the presence of CD4+ (helper), CD8+ (cytotoxic) and Foxp3+ (regulatory) T-lymphocytes and PR expression. Progressive disease was observed to be associated with significant loss of TILs and loss of PR expression. Frozen tumor samples, used for genome-wide expression analysis, showed significant regulation of pathways involved in immunesurveillance, EMT and metastasis. For a number of genes, such as CXCL14, DKK1, DKK4, PEG10 and WIF1, quantitive RT-PCR was performed to verify up- or downregulation in progressive disease. To corroborate the role of progesterone in regulating invasion, Ishikawa (IK) endometrial cancer cell lines stably transfected with PRA (IKPRA), PRB (IKPRB) and PRA+PRB (IKPRAB) were cultured in presence/absence of progesterone (MPA) and used for genome-wide expression analysis, Boyden- and wound healing migration assays, and IHC for known EMT markers. IKPRB and IKPRAB cell lines showed MPA induced inhibition of migration and loss of the mesenchymal marker vimentin at the invasive front of the wound healing assay. Furthermore, pathway analysis of significantly MPA regulated genes showed significant down regulation of important pathways involved in EMT, immunesuppression and metastasis: such as IL6-, TGF-β and Wnt/β-catenin signaling.ConclusionIntact progesterone signaling in non-progressive endometrial cancer seems to be an important factor stimulating immunosurveilance and inhibiting transition from an epithelial to a more mesenchymal, more invasive phenotype.

Project description:Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries. The aim of this study was to analyze the expression of SNAIL, SLUG, TWIST1, TWIST2, ZEB1, and ZEB 2 in primary tumor and the correlation with morphological and clinical characteristics of EC. The study included 158 patients with EC after surgical treatments: total hysterectomy and lymphadenectomy. The percentages of EC specimens testing positively for the EMT transcription factors were 84.5% for SNAIL, 92.2% for SLUG, 10.9% for TWIST1, 100% for TWIST2, 89% for ZEB1, and 98% for ZEB2. The expression of SLUG in patients with FIGO stage III or IV, type II EC, myometrial invasion ≥ 50% of the uterine wall thickness, and adnexal involvement and in patients with distant metastases was significantly higher. SLUG and ZEB2 expressions were identified as significant predictors of higher FIGO stages (III or IV) on univariate analysis. The overexpression of SLUG was a significant predictor of more aggressive type II EC, myometrial invasion ≥ 50% of the uterine wall thickness, and distant metastases on both univariate and multivariate analysis. Moreover, the overexpression of SLUG and ZEB2 was shown to be significant predictors of adnexal involvement on univariate analysis. ZEB 2 overexpression was identified in multivariate analysis as another independent predictor associated with a lesser likelihood of type II EC. Both univariate and multivariate analyses demonstrated that SLUG expression was the only predictor of 5-year survival in the study group. The overexpression of SLUG was associated with a significant increase in mortality hazard on univariate analysis and was shown to be a highly significant predictor of death on multivariate analysis. Conclusions. Selected proteins of the EMT pathway play a role in endometrial carcinogenesis; SLUG and ZEB2 expressions in the primary tumor might predict clinical outcomes in EC and drive therapeutic decisions regarding adjuvant treatment in patients with this malignancy.

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Molecular Landscape of the Epithelial-Mesenchymal Transition in Endometrioid Endometrial Cancer.

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