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Mutated Genes and Abnormal Protein Expression (38)
Clicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.
|PTEN ||10q23.31 ||BZS, DEC, CWS1, GLM2, MHAM, TEP1, MMAC1, PTEN1, 10q23del || ||-PTEN mutations in Endometrial Cancer || 496|
|TP53 ||17p13.1 ||P53, BCC7, LFS1, TRP53 || ||-TP53 Mutations in Endometrial Cancer || 229|
|MSH6 ||2p16 ||GTBP, HSAP, p160, GTMBP, HNPCC5 || ||-MSH6 and Endometrial Cancer || 99|
|PIK3CA ||3q26.3 ||MCM, CWS5, MCAP, PI3K, CLOVE, MCMTC, p110-alpha || ||-PIK3CA and Endometrial Cancer || 79|
|JAZF1 ||7p15.2-p15.1 ||TIP27, ZNF802 || ||-JAZF1 and Endometrial Cancer || 32|
|ARID1A ||1p35.3 ||ELD, B120, OSA1, P270, hELD, BM029, MRD14, hOSA1, BAF250, C1orf4, BAF250a, SMARCF1 || ||-ARID1A and Endometrial Cancer || 27|
|CYP1B1 ||2p22.2 ||CP1B, GLC3A, CYPIB1, P4501B1 || ||-CYP1B1 and Endometrial Cancer || 25|
|ESR1 ||6q25.1 ||ER, ESR, Era, ESRA, ESTRR, NR3A1 || ||-ESR1 and Endometrial Cancer || 21|
|PPP2R1A ||19q13.41 ||MRD36, PR65A, PP2AAALPHA, PP2A-Aalpha || ||-PPP2R1A and Endometrial Cancer || 15|
|YWHAE ||17p13.3 ||MDS, HEL2, MDCR, KCIP-1, 14-3-3E || ||-YWHAE and Endometrial Cancer || 14|
|HSD17B2 ||16q24.1-q24.2 ||HSD17, SDR9C2, EDH17B2 || ||-HSD17B2 and Endometrial Cancer || 13|
|SUZ12 ||17q11.2 ||CHET9, JJAZ1 || ||-SUZ12 and Endometrial Cancer || 13|
|POLE ||12q24.3 ||FILS, POLE1, CRCS12 || ||-POLE and Endometrial Cancer || 13|
|GPER1 ||7p22.3 ||mER, CEPR, GPER, DRY12, FEG-1, GPR30, LERGU, LyGPR, CMKRL2, LERGU2, GPCR-Br || ||-GPER and Endometrial Cancer || 10|
|ETV5 ||3q28 ||ERM || ||-ETV5 and Endometrial Cancer || 6|
|PIK3R1 ||5q13.1 ||p85, AGM7, GRB1, IMD36, p85-ALPHA || ||-PIK3R1 and Endometrial Cancer || 6|
|RBL2 ||16q12.2 ||Rb2, P130 ||Prognostic ||-RBL2 and Endometrial Cancer || 6|
|PIK3CB ||3q22.3 ||PI3K, PIK3C1, P110BETA, PI3KBETA || ||-PIK3CB and Endometrial Cancer || 6|
|ESR2 ||14q23.2 ||Erb, ESRB, ESTRB, NR3A2, ER-BETA, ESR-BETA || ||-ESR2 and Endometrial Cancer || 5|
|HSD17B1 ||17q11-q21 ||HSD17, EDHB17, EDH17B2, SDR28C1 || ||-HSD17B1 and Endometrial Cancer || 5|
|SFRP4 ||7p14.1 ||FRP-4, FRPHE, sFRP-4 || ||-SFRP4 and Endometrial Cancer || 5|
|ADIPOR2 ||12p13.31 ||PAQR2, ACDCR2 || ||-ADIPOR2 and Endometrial Cancer || 4|
|BAG1 ||9p12 ||HAP, BAG-1, RAP46 ||Overexpression ||-BAG1 overexpression in Endometrial Cancer || 4|
|PAEP ||9q34 ||GD, GdA, GdF, GdS, PEP, PAEG, PP14 || ||-PAEP and Endometrial Cancer || 4|
|ADIPOR1 ||1q32.1 ||CGI45, PAQR1, ACDCR1, CGI-45, TESBP1A || ||-ADIPOR1 and Endometrial Cancer || 4|
|LEPR ||1p31 ||OBR, OB-R, CD295, LEP-R, LEPRD || ||-LEPR and Endometrial Cancer || 3|
|EBAG9 ||8q23 ||EB9, PDAF || ||-EBAG9 and Endometrial Cancer || 3|
|POLD1 ||19q13.3 ||CDC2, MDPL, POLD, CRCS10 || ||-POLD1 and Endometrial Cancer || 3|
|PAPPA ||9q33.2 ||PAPA, DIPLA1, PAPP-A, PAPPA1, ASBABP2, IGFBP-4ase || ||-PAPPA and Endometrial Cancer || 3|
|HTRA1 ||10q26.3 ||L56, HtrA, ARMD7, ORF480, PRSS11, CARASIL || ||-HTRA1 and Endometrial Cancer || 3|
|KLLN ||10q23 ||CWS4, KILLIN || ||-killin protein, human and Endometrial Cancer || 2|
|ERRFI1 ||1p36 ||MIG6, RALT, MIG-6, GENE-33 || ||-ERRFI1 and Endometrial Cancer || 2|
|TRIM27 ||6p22 ||RFP, RNF76 || ||-TRIM27 and Endometrial Cancer || 2|
|PIK3R2 ||19q13.2-q13.4 ||p85, MPPH, P85B, MPPH1, p85-BETA || ||-PIK3R2 and Endometrial Cancer || 2|
|ARID5B ||10q21.2 ||MRF2, DESRT, MRF-2 || ||-ARID5B mutations in Endometrial Carcinoma || 1|
|CTNND1 ||11q12.1 ||CAS, p120, CTNND, P120CAS, P120CTN, p120(CAS), p120(CTN) || ||-CTNND1 and Endometrial Cancer || 1|
|NUTM2A ||10q23.2 ||FAM22A || ||-NUTM2A and Endometrial Cancer || 1|
|ARHGEF5 ||7q35 ||P60, TIM, GEF5, TIM1 || ||-ARHGEF5 and Endometrial Cancer || 1|
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
Jiang H, Hu H, Lin F, et al.S100P is Overexpressed in Squamous Cell and Adenosquamous Carcinoma Subtypes of Endometrial Cancer and Promotes Cancer Cell Proliferation and Invasion.
Cancer Invest. 2016; 34(10):477-488 [PubMed
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S100P is known to affect tumor development and metastasis of various cancers, but its role in endometrial cancer is unclear. We reported that S100P expression was dramatically elevated in both endometrial squamous cell carcinoma and adenosquamous carcinoma, but not in adenocarcinoma and normal endometrial samples. Moreover, we revealed an oncogenic role of S100P promoting cell proliferation, invasion, and migration while reducing apoptosis, possibly via its upregulation and/or activation of receptors of advanced glycation end products and consequently the oncogenic PI3K-AKT and MAPK pathways. Therefore, S100P might be a specific biomarker and a potential drug target for squamous cell and adenosquamous carcinoma subtypes of endometrial cancer.
Li Z, Wei D, Yang C, et al.Overexpression of long noncoding RNA, NEAT1 promotes cell proliferation, invasion and migration in endometrial endometrioid adenocarcinoma.
Biomed Pharmacother. 2016; 84:244-251 [PubMed
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Long noncoding RNAs (lncRNAs) are emerging as important modulators in the biological processes and tumorigenesis. However, whether lncRNAs are involved in endometrial endometrioid adenocarcinoma (EEC) remains unclear. In the present study, we explored the expression pattern, clinical significance and biological function of nuclear enriched abundant transcript 1 (NEAT1) in EEC. The expression levels of NEAT1 were elevated in EEC tissues and cell lines, and higher expression levels of NEAT1 were positively correlated with FIGO stage and lymph node metastasis. Overexpression of NEAT1 in HEC-59 cells transfected with pGCMV-NEAT1 promotes cell growth, colony formation ability as well as invasive and migratory ability; while knock-down of NEAT1 in HEC-59 cells by siNEAT1 transfection exhibited the opposite effects. Flow cytometry analysis showed that overexpression of NEAT1 led to an increase in S-phase cells and attenuated cell apoptosis, and knock-down of NEAT1 induced G0/G1 arrest and also induced cell apoptosis in HEC-59 cells. Tumor metastasis real-time PRC array showed that six metastasis-related genes (c-myc, insulin like growth factor 1(IGF1), matrix metallopeptidase 2 (MMP-2) and matrix metallopeptidase 7(MMP-7) were up-regulated, and Cadherin 1 and TIMP metallopeptidase inhibitor 2 were down-regulated) in NEAT1-overexpressing HEC-59 cells. Further qRT-PCR and western blot results confirmed that c-myc, IFG1, MMP-2 and MMP-7 were dys-regulated by NEAT1. Together, our data underscore the significance of NEAT1 in EEC development, and NEAT1 may a potential therapeutic target for EEC.
Caplakova V, Babusikova E, Blahovcova E, et al.DNA Methylation Machinery in the Endometrium and Endometrial Cancer.
Anticancer Res. 2016; 36(9):4407-20 [PubMed
] Related Publications
During the normal menstrual cycle, endometrial tissue undergoes many biochemical and morphological changes which are under the control of steroid hormone levels. DNA methylation plays a key role in gene expression regulation and influences functional changes in endometrial tissue. Eliminating senescent cells from the functional layer of the endometrium is mediated by apoptotic cell death, which helps maintain cellular homeostasis. Aberrant DNA methylation changes result in deregulation of important apoptotic proteins during endometrial carcinogenesis and thus apoptosis resistance development. Evading apoptosis is still a major problem in the successful treatment of endometrial cancer patients with advanced disease. Despite intensive study of the cancer epigenome, there is missing information about disrupted apoptotic gene regulation in DNA methylation levels. Therefore, it is necessary to spread our knowledge in the field of epigenetics to help us differentiate normal and cancer tissues and detect the early stages of cancer disease.
Lu L, Shen Y, Tseng KF, et al.Silencing of UCA1, a poor prognostic factor, inhibited the migration of endometrial cancer cell.
Cancer Biomark. 2016; 17(2):171-7 [PubMed
] Related Publications
BACKGROUND: Endometrial cancer (EC) is a common female malignancy. Most patients were diagnosed at an early stage with a favorable prognosis. But more than 30% patients were high risk at III/IV stage with invading deep into the myometrium and progressively lead to local or extra pelvic metastasis. Urothelial cancer-associated 1 (UCA1) had been reported as the oncogenic long non-coding RNA in many tumors, but the role of UCA1 in EC is still unclear.
METHOD: QRT-PCR was used to analysis the level of UCA1 in the proliferative endometrium, primary EC tissue and lymph node metastasis tissue of EC. According to the QRT-PCR results of primary EC tissue, survival curves were made using the Kaplan-Meier method, and the log rank test was used to analyze the differences of clinicopathological characteristics and survival between the low expression and high expression group of UCA1 in EC patients. Moreover we knocked down the expression of UCA1 in EC cell lines HTB-111 and Ishikawa, and detected the migration and invasion ability of them with wound healing assay and transwell assay.
RESULTS: The expression level of UCA1 using QRT-PCR method in lymph node metastasis tissue was the highest than that in the proliferative endometrium and primary EC tissues (1.15 ± 0.23, 3.23 ± 1.06 vs. 6.42 ± 1.46, P < 0.0001). For the primary EC tissue, the median fold change of UCA1 was used as a cutoff value. High UCA1 expression was observed to be closely correlated with lymph node metastasis (P = 0.008), distant metastasis (P = 0.003), grade (P = 0.009), advanced TNM stage (P = 0.031) and vessel invasive (P = 0.032). The 5-year overall survival rate in the high expression group was 41.7%, compared with 72.7% in the low expression group (P = 0.023). After silencing the UCA1, the migration and invasion ability of EC cell lines reduced significantly.
CONCLUSION: Our findings provide the convincing evidence that the UCA1 plays an important role in the metastasis of EC and may serve as a novel molecular marker to predict the aggressive tumor progression and unfavorable prognosis of EC patients.
Pokharel HP, Hacker NF, Andrews LChanging patterns of referrals and outcomes of genetic participation in gynaecological-oncology multidisciplinary care.
Aust N Z J Obstet Gynaecol. 2016; 56(6):633-638 [PubMed
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BACKGROUND: Genetic participation in gynaecological oncology multidisciplinary team meetings (MDT) may identify the sentinel cancer in women with hereditary breast-ovarian cancer syndrome or Lynch syndrome.
AIMS: To identify the changing patterns of genetic referral from 2010 to 2014 and the outcomes of referrals through clinical MDT case review.
MATERIALS AND METHODS: Medical records of cases of gynaecological cancer presented at the MDT meetings and genetics databases were reviewed to determine the frequency and outcomes of recommendations for genetic referral between 2010 and 2014.
RESULTS: Four hundred and sixty-two women of 2523 cases reviewed were recommended for referral, increasing from 8% in 2010 to 25% in 2014. However, 167 of 462 patients (36%) had not registered with a Hereditary Cancer Clinic in NSW/ACT, including 11 women with high-grade serous ovarian cancer and seven women with abnormal MMR immunohistochemistry. Mutations were identified in 40 of 165 women (24%) undergoing breast cancer BRCA1/2 testing and in ten of 25 women (40%) who underwent MMR genetic testing. Eighty-one first- or second-degree relatives of these women have undergone predictive testing, identifying 48 mutation carriers and 33 non-carriers.
CONCLUSION: Changing indications and increased participation by a genetic consultant in the weekly MDT meeting has led to increasing genetic referrals over the last five years. Follow up of referrals needs to be addressed. With decreasing costs of genetic testing and use of readily transportable DNA collected through saliva or mouth swabs, we propose that distance should not be a barrier to this model being extended to all centres providing care to gynaecological cancer patients.
Guo Q, Qian Z, Yan D, et al.LncRNA-MEG3 inhibits cell proliferation of endometrial carcinoma by repressing Notch signaling.
Biomed Pharmacother. 2016; 82:589-94 [PubMed
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BACKGROUND: The long non-coding RNA MEG3 has shown functional role as a tumor suppressor in many cancer types, excluding endometrial carcinoma (EC). Thus, this study tried to reveal the MEG3 dysregulation in EC samples and potential functional mechanism due to its regulation on Notch signaling pathway.
METHODS: The expression profiles of MEG3 and two Notch signaling molecules, Notch1 and Hes1, were detected in both EC tissues and cell lines through real time PCR and western blot analysis. Lentiviral vector carrying whole MEG3 transcript or shRNA targeting MEG3 (shMEG3) was transfected for MEG3 dysfunction studies, and cell proliferation was analyzed through MTT and colony-formation assays. Xenograft models were also established by subcutaneous implantation and tumor growth was compared under MEG3 dysregulation.
RESULTS: Significant downregulation of MEG3 was observed in EC samples compared to control, while the protein levels of Notch1 and Hes1 were both upregulated. Cell proliferation was obviously inhibited by MEG3 overexpression, while opposite improved result was obtained in MEG3 knockout cells. Interestingly, MEG3-induced changes could be reversed by Notch1 regulators. Moreover, MEG3 overexpressing tumors showed strongly repressed growth in vivo, along with Notch signaling inhibition.
CONCLUSION: Downregulated MEG3 exhibited an anti-proliferative role in EC by repressing Notch signaling pathway.
Chen H, Fan Y, Xu W, et al.miR-10b Inhibits Apoptosis and Promotes Proliferation and Invasion of Endometrial Cancer Cells via Targeting HOXB3.
Cancer Biother Radiopharm. 2016; 31(6):225-31 [PubMed
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MicroRNAs are small RNA that are tightly interrelated with the initiation, development, and metastasis of cancers. Studies have shown that miR-10b is increased in various cancers. However, the underlying mechanisms of miR-10b in the occurrence and metastasis of endometrial cancer are poorly understood. To investigate its roles and correlations with Homeobox box 3 (HOXB3) in endometrial cancer, cancer tissues and adjacent normal endometrium tissues from 20 patients with endometrial cancer were studied. miR-10b expression was significantly up-regulated (p < 0.01) in endometrial cancer tissue, whereas HOXB3 was lowly expressed. The silence of miR-10b resulted in significantly enhanced cell apoptosis, and remarkably reduced cell proliferation, migration, and invasion (p < 0.05). Moreover, the protein levels of HOXB3 were increased in KLE cells with silenced miR-10b, and dual-luciferase reporter assay suggested that miR-10b could directly target HOXB3. Furthermore, overexpression of HOXB3 promoted cell apoptosis but inhibited cell proliferation, migration, and invasion (p < 0.01). To conclude, miR-10b might control cell apoptosis, proliferation, migration, and invasion in endometrial cancer via regulation of HOXB3 expression.
Rubio I, Ibáñez-Feijoo E, Andrés L, et al.Analysis of Lynch Syndrome Mismatch Repair Genes in Women with Endometrial Cancer.
Oncology. 2016; 91(3):171-6 [PubMed
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OBJECTIVE: Endometrial cancer is the second most frequent neoplasm in women with Lynch syndrome (LS). We sought to assess whether analyzing women with endometrial cancer would identify families with LS not identified with current clinical criteria.
METHODS: We included women diagnosed with endometrial cancer younger than 50 years and also older if they had a family cancer history associated with LS. In blood samples obtained, we analyzed mutations in mismatch repair (MMR) genes, as well as protein expression by immunohistochemistry and microsatellite instability (MSI) in tumour tissue.
RESULTS: A total of 103 patients were enrolled. We detected 14 pathogenic mutations and 4 genetic variants of unknown clinical significance in MMR genes. We found MSI in 41.66% of the women with a pathogenic mutation. In this group, 76.92% showed loss of at least one MMR protein. Women with mutations were younger at diagnosis, but all of them had a family history compatible with LS.
CONCLUSIONS: Analysis of the MMR genes, in particular MSH6, seems to be appropriate in women with endometrial cancer and a family history of tumours associated with LS.
Holzmann C, Löning T, Bullerdiek JHyperhaploid uterine mesenchymal tumors-a novel genetic subgroup?
Cancer Genet. 2016; 209(6):278-81 [PubMed
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Hyperhaploid karyotypes have been described to occur in subsets of various solid tumors and leukemias. In these cases, monosomy is noted for most of the chromosomes while a few chromosomes still remain disomic. Evidence has emerged that at least in some tumor entities these remaining chromosomes are non-randomly selected. In addition, structural alterations can accompany the reduced chromosome number and secondary duplication of the chromosome complement is also a frequent finding. In this report, we describe hyperhaploidy in a case of an endometrial stromal nodule of a 50 year old woman who underwent hysterectomy because of symptomatic uterine fibroids. In addition, we review two other recently described cases of uterine mesenchymal tumors with that type of genetic alteration. Despite some histologic differences, striking similarities between these three cases exist with respect to the chromosomes were retained as disomic. Thus, the question arises if hyperhaploidy defines a novel genetic subgroup of uterine mesenchymal tumors.
Bian Y, Chang X, Liao Y, et al.Promotion of epithelial-mesenchymal transition by Frizzled2 is involved in the metastasis of endometrial cancer.
Oncol Rep. 2016; 36(2):803-10 [PubMed
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The Wnt signaling pathway is essential for embryonic development, and genetic alteration in this network is closely correlated with tumorigenesis and progression. Previous research has shown that Wnt receptor Frizzled2 (Fzd2) is elevated in many metastatic cancer cell lines and high grade tumors. Yet, little is known about the Fzd2 expression and activity in human endometrial cancer (EC). In this study, we present evidence of a direct role of Fzd2 in human EC. We found that Fzd2 expression was higher in EC than that in adjacent normal tissues, and was correlated with epithelial‑mesenchymal transition markers. Next, it was determined that the stable overexpression of Fzd2 in HEC-1B and Ishikawa cells promoted cell migration and induced an EMT phenotype. Conversely, RNA interference-mediated depletion of Fzd2 inhibited EC cell migration. Additionally, mechanistic investigation revealed that elevated Fzd2 expression activated canonical Wnt signaling and was blocked by canonical Wnt signaling inhibitor XAV939. However, Fzd2 did not influence the proliferation of EC cells. Thus, Fzd2 may be a potential marker for EC metastasis and a target for future therapies for this disease.
Nowakowska M, Matysiak-Burzyńska Z, Kowalska K, et al.Angiotensin II promotes endometrial cancer cell survival.
Oncol Rep. 2016; 36(2):1101-10 [PubMed
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Endometrial cancer (EC) is one of the most common female cancers. One of the key processes involved in EC development is uncontrolled proliferation stimulated by local factors such as angiotensin. The aim of the present study was to evaluate the influence of angiotensin II (Ang II) on human EC cells. Biological assays and gene expression analysis were performed on three cell lines: ISH, MFE-296 and MFE-280. Our results indicated that at the beginning of cancerogenesis Ang II induced abnormal proliferation at lower doses. We also showed that dose-dependent induction of proliferation was connected with changes in the expression of MKI67, CCND1 and CCNE1 genes in well- and poorly differentiated cancer cells. After Ang II treatment, poorly differentiated endometrial cancer cell line acquired a mesenchymal phenotype, which was characterized by induced expression of EMT-related genes (VIM, CD44, SNAI1, ZEB1 and ZEB2). Our study revealed that Ang II influences EC cells in terms of cancer-related processes, and is responsible for increased proliferation, reduction in apoptosis, increased mobility and modulation of adhesion potential. Its effect and effectiveness appear to be highly connected with the differentiation status of the cancerous cells, as Ang II appears to play a crucial role in the early and late stages of malignant transformation.
Wang J, Bian Y, Liao Y, et al.Forkhead-box A1 induces cell senescence in endometrial cancer by regulating p16INK4a.
Oncol Rep. 2016; 36(2):795-802 [PubMed
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We previously identified FOXA1 as a tumor-suppressor in EC cells. In the present study, we sought to delineate the different roles of FOXA1 associated with cell senescence and further investigated the correlation between FOXA1 and p16INK4a in the progression of EC. Using reverse transcription-quantitative PCR (RT-qPCR), we found that FOXA1 expression was significantly downregulated in EC cells compared to that in normal endometrial cells. Functionally, senescence‑associated β-galactosidase staining, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), clonogenic and Transwell assays showed that in addition to acting as a pioneer factor, FOXA1 was significantly upregulated in senescent EC cells. Furthermore, restoration of FOXA1 expression triggered multiple steps of cellular senescence in EC cells and activated p16INK4a expression. All of these findings indicate that FOXA1 promotes cell senescence in EC by interaction with p16INK4a, possibly via the AKT pathway. Notably, a selective PI3K inhibitor raised the possibility that FOXA1‑induced senescence is associated with the AKT pathway in EC cells. Collectively, the present study provides a conceivable molecular mechanism by which cell senescence acts as the barrier to EC, and is regulated by FOXA1-induced p16INK4a expression. This may be a newly identified regulatory mechanism of cell senescence in EC.
Endometrioid carcinoma (EC) is one of the most common malignancies of the female genital system. Although the behavior of EC ranges from an excellent prognosis to aggressive disease with a poor outcome, the factors that determine its diversity have not been determined. Here, we show that S100A4, a calcium-binding protein of the EF-hand type, is correlated with the proliferation and invasion ability of EC. We demonstrated previously that EC cells with high aldehyde dehydrogenase (ALDH) activity were more tumorigenic than ALDH-lo cells. Screening by shotgun proteomics demonstrated that the expression level of S100A4 in ALDH-hi EC cells was significantly higher than that in ALDH-lo cells. S100A4-knockout cells generated by the CRISPR/Cas9 system showed reduced proliferation and invasion. These cells showed impaired AKT phosphorylation and matrix metalloproteinase-2 activation, accounting for their impaired proliferation and invasion, respectively. Furthermore, in clinical EC samples, elevated expression of S100A4 was highly related to myometrial and lymphatic invasion in well to moderately differentiated EC. Notably, strong and diffuse expression of S100A4 was observed in tumor tissues with a microcystic, elongated and fragmented ("MELF") pattern, which is associated with a highly invasive EC phenotype. Collectively, our results demonstrate not only that high expression of S100A4 contributes to an aggressive phenotype of EC, but also that its elevated expression is closely related to the MELF histopathological pattern.
Stampoliou A, Arapantoni-Dadioti P, Pavlakis KEpigenetic mechanisms in endometrial cancer.
J BUON. 2016 Mar-Apr; 21(2):301-6 [PubMed
] Related Publications
Purpose: Endometrial cancer is a very common type of cancer in females worldwide. Advances in diagnosis and treatment have not decreased the incidence of endometrial cancer. Lately, research has been focused on revealing the molecular and genetic characteristics of endometrial cancer in order to provide new insights in the biology of this entity, leading hopefully to innovating therapies. Research has revealed that epigenetic modifications govern endometrial carcinogenesis. In this review, the epigenetic mechanisms that are involved in endometrial cancer as well as the differences between the different types of endometrial cancer are discussed. The review also refers to the putative therapeutic benefits that hopefully can arise.
Bolton KA, Holliday EG, Attia J, et al.A novel polymorphic repeat in the upstream regulatory region of the estrogen-induced gene EIG121 is not associated with the risk of developing breast or endometrial cancer.
BMC Res Notes. 2016; 9:287 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: The estrogen-induced gene 121 (EIG121) has been associated with breast and endometrial cancers, but its mechanism of action remains unknown. In a genome-wide search for tandem repeats, we found that EIG121 contains a short tandem repeat (STR) in its upstream regulatory region which has the potential to alter gene expression. The presence of this STR has not previously been analysed in relation to breast or endometrial cancer risk.
RESULTS: In this study, the lengths of this STR were determined by PCR, fragment analysis and sequencing using DNA from 223 breast cancer patients, 204 endometrial cancer patients and 220 healthy controls to determine if they were associated with the risk of developing breast or endometrial cancer. We found this repeat to be highly variable with the number of copies of the AG motif ranging from 27 to 72 and having a bimodal distribution. No statistically significant association was identified between the length of this STR and the risk of developing breast or endometrial cancer or age at diagnosis.
CONCLUSIONS: The STR in the upstream regulatory region of EIG121 is highly polymorphic, but is not associated with the risk of developing breast or endometrial cancer in the cohorts analysed here. While this polymorphic STR in the regulatory region of EIG121 appears to have no impact on the risk of developing breast or endometrial cancer, its association with disease recurrence or overall survival remains to be determined.
Witek Ł, Janikowski T, Bodzek P, et al.Expression of tumor suppressor genes related to the cell cycle in endometrial cancer patients.
Adv Med Sci. 2016; 61(2):317-324 [PubMed
] Related Publications
PURPOSE: Endometrial cancer is the most common gynecological malignancy in developed countries. The role of tumor suppressor genes (TSG) in endometrioid endometrial adenocarcinoma (EEC) has an important impact on patient survival prognosis. Thus, it is important to identify TSG transcripts that differentiate endometrial adenocarcinoma into various pathomorphological grades. The aim of this study was to analyze the expression profile of tumor suppressor genes related to the cell cycle in patients with endometrial adenocarcinoma across histological differentiation and to identify transcripts which differentiate endometrium into various pathomorphological grades.
MATERIAL AND METHODS: Gene expression analysis was completed for 19 endometrial endometrioid adenocarcinomas and 5 normal specimens (obtained from women with diagnosed uterine fibroids, benign ovarian tumors and a prolapsed uterus with histopathologically confirmed endometrium in the proliferative phase) using Affymetrix HG-U133A oligonucleotide microarrays. The statistical analysis was performed using the GeneSpring13.0 software and PANTHER classification system.
RESULTS: Significant changes in gene expression were observed across histological differentiation. The WT-1, CYR 61, TSPYL5 genes were statistically and biologically significant in all cancer grades, and were considered to be primary for the G1 grade in endometrial cancer. The G2 cancer specific genes were BCL2L2 and HNRNPA0, whereas in G3 there was only BAK.
CONCLUSION: In conclusion, the WT-1, CYR61 and TSPYL5 gene expressions are potentially correlated with patient survival in all endometrial cancer grades. The TSGs identified are considered to be important in EEC pathogenesis and further research is needed to confirm this.
BACKGROUND The purpose of our study was to investigate the functional role of microRNA-340 (miR-340) in endometrial carcinoma (EC). MATERIAL AND METHODS Human EC cell line RL 95-2 was transfected with miR-340 mimics, inhibitors, or controls. After 48 h of transfection, the cell viability was determined by 3-(4, 5-dimethyl-2- thiazolyl)-2, 5-diphenyl -2-H-tetrazolium bromide (MTT) assay. The BrdU assay and apoptosis assay were performed to determine the effects of miR-340 mimics or inhibitors on cell proliferation and apoptosis, respectively. The underlying mechanisms involved in cell proliferation and apoptosis were explored by measuring the protein levels of cell cycle regulators (p27 kinase inhibition protein (KIP) 1 and p21) and apoptosis-related factors (B-cell lymphoma-2 (Bcl-2), Bax, pro-Caspase 3, and active-Caspase-3). RESULTS Overexpression of miR-340 significantly inhibited the cell viability (P<0.05) and cell proliferation (P<0.01) of RL 95-2 cells compared with the control group, but increased the apoptosis (P<0.01). However, suppression of miR-340 had opposite results. Moreover, the protein levels of p27 KIP1, Bax, pro-Caspase 3, and active-Caspase-3 were significantly increased by overexpression of miR-340 but were statistically decreased by suppression of miR-340. Contrary results were found in the protein levels of Bcl-2. However, no significant differences were found in p21 expression. CONCLUSIONS MiRNA-340 acts as an anti-oncogene in EC cell line RL 95-2 by inhibition of tumor cell proliferation and induction of apoptosis.
Chang B, Lu LX, Tu XY, et al.[Endometrial stromal sarcoma: morphologic features and detection of JAZF1-SUZ12 and YWHAE FAM22 fusion genes].
Zhonghua Bing Li Xue Za Zhi. 2016; 45(5):308-13 [PubMed
] Related Publications
OBJECTIVE: To study the morphologic features, immunophenotype and significance of expression of JAZF1-SUZ12 and YWHAE-FAM22 fusion genes in endometrial stromal sarcoma (ESS).
METHODS: Fifty-three cases of ESS were retrieved and the pathologic features were reviewed. Immunohistochemical study for estrogen receptor, progesterone receptor, CD10, cyclin D1, smooth muscle actin, desmin and H-caldesmon were carried out using tissue microarray technology. Reverse transcription-polymerase chain reaction (RT-PCR) was applied for detection of expression of JAZF1-SUZ12 and YWHAE-FAM22 fusion genes in 47 cases of ESS and 12 cases of other spindle cell neoplasia in uterus (including 2 cases of undifferentiated sarcoma, 3 cases of leiomyosarcoma, 3 cases of leiomyoma, 4 cases of adenosarcoma and 2 cases of uterine tumor resembling ovarian sex cord tumor).
RESULTS: The 53 cases of ESS studied included 43 cases of low-grade ESS and 10 cases of high-grade ESS. As for low-grade ESS, in addition to the classic morphologic features, smooth muscle differentiation was present in 7 cases (16.3%), sex cord-like differentiation in 2 cases (4.7%), rhabdoid differentiation in 1 case (2.3%), clear cell changes in 1 case (2.3%) and schwannoma-like palisading pattern in 1 case (2.3%). As for high-grade ESS, sex cord-like differentiation (1 case), mucinous microcystic changes (1 case) and focal clear cell changes (1 case) were also observed. The expression rate of estrogen receptor, progesterone receptor, CD10, cyclin D1, smooth muscle actin, desmin and H-caldesmon was 86.0%, 81.4%, 74.4%, 2.3%, 23.3%, 23.3% and 4.7% in low-grade ESS, respectively, and was 1/10, 6/10, 6/10, 7/10, 1/10, 1/10 and 0 in high-grade ESS, respectively. RNA extraction was successful in 47 cases of ESS, including 39 cases of low-grade ESS and 8 cases of high-grade ESS. The positive rate of JAZF1-SUZ12 fusion gene was 30.8% (12/39) in low-grade ESS. The positive rate of YWHAE-FAM22 fusion gene was 12.5% (1/8) in high-grade ESS. The 14 control cases were all negative for JAZF1-SUZ12 and YWHAE-FAM22 fusion genes.
CONCLUSIONS: As uncommon pathologic pattern may occur in both low-grade ESS and high-grade ESS, detection of JAZF1-SUZ1 and YWHAE-FAM22 fusion genes by RT-PCR would be helpful in diagnosis and differential diagnosis of ESS, especially for those tumors which lack typical morphologic features.
PURPOSE: Experimental and observational data link insulin, insulin-like growth factor (IGF), and estrogens to endometrial tumorigenesis. However, there are limited data regarding insulin/IGF and sex hormone axes protein and gene expression in normal endometrial tissues, and very few studies have examined the impact of endometrial cancer risk factors on endometrial tissue biology.
METHODS: We evaluated endometrial tissues from 77 premenopausal and 30 postmenopausal women who underwent hysterectomy for benign indications and had provided epidemiological data. Endometrial tissue mRNA and protein levels were measured using quantitative real-time PCR and immunohistochemistry, respectively.
RESULTS: In postmenopausal women, we observed higher levels of phosphorylated IGF-I/insulin receptor (pIGF1R/pIR) in diabetic versus non-diabetic women (p value =0.02), while women who reported regular nonsteroidal anti-inflammatory drug use versus no use had higher levels of insulin and progesterone receptors (both p values ≤0.03). We also noted differences in pIGF1R/pIR staining with OC use (postmenopausal women only), and the proportion of estrogen receptor-positive tissues varied by the number of live births and PTEN status (premenopausal only) (p values ≤0.04). Compared to premenopausal proliferative phase women, postmenopausal women exhibited lower mRNA levels of IGF1, but higher IGFBP1 and IGFBP3 expression (all p values ≤0.004), and higher protein levels of the receptors for estrogen, insulin, and IGF-I (all p values ≤0.02). Conversely, pIGF1R/pIR levels were higher in premenopausal proliferative phase versus postmenopausal endometrium (p value =0.01).
CONCLUSIONS: These results highlight links between endometrial cancer risk factors and mechanistic factors that may contribute to early events in the multistage process of endometrial carcinogenesis.
Next-generation sequencing studies have revealed genome-wide structural variation patterns in cancer, such as chromothripsis and chromoplexy, that do not engage a single discernable driver mutation, and whose clinical relevance is unclear. We devised a robust genomic metric able to identify cancers with a chromotype called tandem duplicator phenotype (TDP) characterized by frequent and distributed tandem duplications (TDs). Enriched only in triple-negative breast cancer (TNBC) and in ovarian, endometrial, and liver cancers, TDP tumors conjointly exhibit tumor protein p53 (TP53) mutations, disruption of breast cancer 1 (BRCA1), and increased expression of DNA replication genes pointing at rereplication in a defective checkpoint environment as a plausible causal mechanism. The resultant TDs in TDP augment global oncogene expression and disrupt tumor suppressor genes. Importantly, the TDP strongly correlates with cisplatin sensitivity in both TNBC cell lines and primary patient-derived xenografts. We conclude that the TDP is a common cancer chromotype that coordinately alters oncogene/tumor suppressor expression with potential as a marker for chemotherapeutic response.
Jurcevic S, Klinga-Levan K, Olsson B, Ejeskär KVerification of microRNA expression in human endometrial adenocarcinoma.
BMC Cancer. 2016; 16:261 [PubMed
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BACKGROUND: MicroRNAs are small non-coding RNAs that have been implicated in tumor initiation and progression. In a previous study we identified 138 miRNAs as differentially expressed in endometrial adenocarcinoma compared to normal tissues. One of these miRNAs was miRNA-34a, which regulates several genes involved in the Notch pathway, which is frequently altered in endometrial cancer. The aims of this study were to verify the differential expression of a subset of miRNAs and to scrutinize the regulatory role of mir-34a on the target genes NOTCH1 and DLL1.
METHODS: Twenty-five miRNAs that were previously identified as differentially expressed were subjected to further analysis using qPCR. To investigate the regulation of NOTCH1 and DLL1 by mir-34a, we designed gain- and loss-of-function experiments in Ishikawa and HEK293 cell lines by transfection with a synthetic mir-34a mimic and a mir-34a inhibitor.
RESULTS: Of the 25 validated miRNAs, seven were down-regulated and 18 were up-regulated compared to normal endometrium, which was fully consistent with our previous findings. In addition, the up-regulation of mir-34a led to a significant decrease in mRNA levels of NOTCH1 and DLL1, while down-regulation led to a significant increase in mRNA levels of these two genes.
CONCLUSIONS: We verified both up-regulated and down-regulated miRNAs in the tumor samples, indicating various roles of microRNAs during tumor development. Mir-34a functions as a regulator by decreasing the expression of NOTCH1 and DLL1. Our study is the first to identify a correlation between mir-34a and its target genes NOTCH1 and DLL1 in endometrial adenocarcinoma.
Winterhoff B, Hamidi H, Wang C, et al.Molecular classification of high grade endometrioid and clear cell ovarian cancer using TCGA gene expression signatures.
Gynecol Oncol. 2016; 141(1):95-100 [PubMed
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BACKGROUND: It is unclear whether the transcriptional subtypes of high grade serous ovarian cancer (HGSOC) apply to high grade clear cell (HGCCOC) or high grade endometrioid ovarian cancer (HGEOC). We aim to delineate transcriptional profiles of HGCCOCs and HGEOCs.
METHODS: We used Agilent microarrays to determine gene expression profiles of 276 well annotated ovarian cancers (OCs) including 37 HGCCOCs and 66 HGEOCs. We excluded low grade OCs as these are known to be distinct molecular entities. We applied the prespecified TCGA and CLOVAR gene signatures using consensus non-negative matrix factorization (NMF).
RESULTS: We confirm the presence of four TCGA transcriptional subtypes and their significant prognostic relevance (p<0.001) across all three histological subtypes (HGSOC, HGCCOC and HGEOCs). However, we also demonstrate that 22/37 (59%) HGCCOCs and 30/67 (45%) HGEOCs form 2 additional separate clusters with distinct gene signatures. Importantly, of the HGCCOC and HGEOCs that clustered separately 62% and 65% were early stage (FIGO I/II), respectively. These finding were confirmed using the reduced CLOVAR gene set for classification where most early stage HGCCOCs and HGEOCs formed a distinct cluster of their own. When restricting the analysis to the four TCGA signatures (ssGSEA or NMF with CLOVAR genes) most early stage HGCCOCs and HGEOC were assigned to the differentiated subtype.
CONCLUSIONS: Using transcriptional profiling the current study suggests that HGCCOCs and HGEOCs of advanced stage group together with HGSOCs. However, HGCCOCs and HGEOCs of early disease stages may have distinct transcriptional signatures similar to those seen in their low grade counterparts.
Myers AP, Filiaci VL, Zhang Y, et al.Tumor mutational analysis of GOG248, a phase II study of temsirolimus or temsirolimus and alternating megestrol acetate and tamoxifen for advanced endometrial cancer (EC): An NRG Oncology/Gynecologic Oncology Group study.
Gynecol Oncol. 2016; 141(1):43-8 [PubMed
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OBJECTIVE: Rapamycin analogs have reproducible but modest efficacy in endometrial cancer (EC). Identification of molecular biomarkers that predict benefit could guide clinical development.
METHODS: Fixed primary tissue and whole blood were collected prospectively from patients enrolled on GOG 248. DNA was isolated from macro-dissected tumors and blood; next-generation sequence analysis was performed on a panel of cancer related genes. Associations between clinical outcomes [response rate (RR) 20%; progression-free survival (PFS) median 4.9months] and mutations (PTEN, PIK3CA, PIK3R1, KRAS, CTNNB1, AKT1, TSC1, TSC2, NF1, FBXW7) were explored.
RESULTS: Sequencing data was obtained from tumors of 55 of the 73 enrolled pts. Mutation rates were consistent with published reports: mutations in PTEN (45%), PIK3CA (29%), PIK3R1 (24%), K-RAS (16%), CTNNB1 (18%) were common and mutations in AKT1 (4%), TSC1 (2%), TSC2 (2%), NF1 (9%) and FBXW7 (4%) were less common. Increased PFS (HR 0.16; 95% CI 0.01-0.78) and RR (response difference 0.83; 95% CI 0.03-0.99) were noted for AKT1 mutation. An increase in PFS (HR 0.46; 95% CI 0.20-0.97) but not RR (response difference 0.00, 95% CI -0.34-0.34) was identified for CTNNB1 mutation. Both patients with TSC mutations had an objective response. There were no statistically significant associations between mutations in PIK3CA, PTEN, PIK3R1, or KRAS and PFS or RR.
CONCLUSIONS: Mutations in AKT1, TSC1 and TSC2 are rare, but may predict clinical benefit from temsirolimus. CTNNB1 mutations were associated with longer PFS on temsirolimus.
Yang Y, Jiang Y, Jiang M, et al.Protocadherin 10 inhibits cell proliferation and induces apoptosis via regulation of DEP domain containing 1 in endometrial endometrioid carcinoma.
Exp Mol Pathol. 2016; 100(2):344-52 [PubMed
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Endometrial cancer is the most common gynecologic malignancy and about 80% of these cancers are endometrial endometrioid carcinoma (EEC). Previously, we have demonstrated that protocadherin 10 (PCDH10) is a tumor suppressor gene in EEC, and in this study we further explored the molecular mechanisms of PCDH10 in EEC. We first detect the PCDH10 expression in EEC tissues and then investigate the mechanism in two EEC cell lines. The mRNA and protein expression levels were measured by quantitative real time PCR (qRT-PCR) and western blot, respectively; Cell growth was determined by MTS, CCK-8 and colony formation assays; Cell cycle was determined by flow cytometry, and cell apoptosis was examined by flow cytometry and TUNEL assay. The downstream mediator of PCHD10 was confirmed by Topflash luciferase reporter assay. QRT-PCR and western blot results showed that PCDH10 was down-regulated in EEC clinical tissues. Restoration of PCDH10 suppressed cell growth and induced apoptosis in EEC cells. Dishevelled, EGL-10 and Pleckstrin domain containing 1 (DEPDC1) was a potential downstream mediator of PCDH10 as revealed by RNA-sequencing, and mechanistic studies suggested that DEPDC1 is a downstream mediator and promotes cell growth and induces apoptosis in EEC cells. Western blot further showed that PCDH10 restoration activate apoptotic signaling pathway via caspase signaling in both EEC cell lines and EEC clinical tissues. Collectively, our results suggest that PCDH10-DEPDC1-caspase signaling may be a novel regulatory axis in EEC development and it will be of great interest to explore the clinical significance of PCDH10 and DEPDC1 in the future.
Rodriguez-Freixinos V, Karakasis K, Oza AMNew Targeted Agents in Endometrial Cancer: Are We Really Making Progress?
Curr Oncol Rep. 2016; 18(4):23 [PubMed
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Endometrial cancer is the most common gynecological malignancy in Europe and North America. Metastatic and recurrent disease is generally incurable with poor prognosis. Recent advances in molecular profiling of endometrial cancer have elucidated four distinct molecular subtypes with different biology and prognosis which should facilitate the development of treatments tailored to disease-specific subgroups. To date, some molecular-targeted agents have shown interesting clinical activity in the recurrent setting, but no targeted therapies are approved for endometrial cancer. Novel pan-PI3K, AKT, and dual PI3K-mTOR inhibitors are being investigated with early signs of activity, but there are concerns about tolerability and toxicity in this often elderly patient population with comorbidities. The development of anti-angiogenic therapies, PARP inhibitors, and immunotherapies, alone or in combinations, appear to be promising strategies. This paper will describe the current evidence supporting the efficacy of molecular-targeted agents already tested in the treatment of metastatic and recurrent EC, and provide some insights on emerging data related to novel-targeted therapies.
McCampbell AS, Mittelstadt ML, Dere R, et al.Loss of p27 Associated with Risk for Endometrial Carcinoma Arising in the Setting of Obesity.
Curr Mol Med. 2016; 16(3):252-65 [PubMed
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Endometrial carcinoma (EC) exhibits the strongest association with obesity of all cancers. Growth of these tumors is driven by PI3K/AKT activation, and opposed by tumor suppressors, including the tuberous sclerosis complex 2 (TSC-2) and p27, with inactivation of TSC2 and loss or cytoplasmic mislocalization of p27 both being linked to PI3K/AKT activation. However, little is known about the involvement of p27 in the development of EC arising in the setting of obesity, especially its role early in disease progression. Using a panel of EC cell lines, in vitro studies using PI3K inhibitors provided evidence that p27 rescue contributes to the efficacy of interventions that inhibit endometrial cell growth. In "at risk" obese patients, and in an animal model of obesity-associated EC (Tsc2-deficient Eker rats), p27 was moderately-to-severely reduced in both "normal" endometrial glands as well as in endometrial complex atypical hyperplasia (obese women), and endometrial hyperplasia (obese rats). In obese Eker rats, an energy balance intervention; caloric restriction from 2-4 months of age, reduced weight, increased adiponectin and lowered leptin to produce a favorable leptin:adiponectin ratio, and reduced circulating insulin levels. Caloric restriction also increased p27 levels, relocalized this tumor suppressor to the nucleus, and significantly decreased hyperplasia incidence. Thus, dietary and pharmacologic interventions that inhibit growth and decrease risk for development of endometrial lesions are associated with increased expression and nuclear (re)localization of p27. These data suggest that p27 levels and localization may be useful as a biomarker, and possible determinant, of risk for EC arising in the setting of obesity.
Chen Z, Wang SH, Zhou J, et al.Contribution of PGR genetic polymorphisms to the pathogenesis of endometrial cancer: A meta-analysis.
J Cancer Res Ther. 2015 Oct-Dec; 11(4):810-7 [PubMed
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OBJECTIVE: The aim of this meta-analysis is to identify whether two common genetic polymorphisms (rs1042838 G > T and rs10895068 C > T) in the PGR gene may contribute to the pathogenesis of endometrial cancer.
MATERIALS AND METHODS: The MEDLINE (1966 ~ 2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), Web of Science (1945 ~ 2013) and the Chinese Biomedical Database (CBM) (1982 ~ 2013) were searched without language restrictions. Meta-analyses were conducted using the STATA software (Version 12.0, Stata Corporation, College Station, Texas, USA). We calculated odds ratio (OR) and its 95% confidence interval (95% CI) to estimate the relationships between PGR genetic polymorphisms and the pathogenesis of endometrial cancer.
RESULTS: Six studies with a total of 6,285 patients with endometrial cancer and 12,120 control subjects met the inclusion criteria for the meta-analysis. Our findings suggested that PGR rs1042838 polymorphism was significantly correlated with an increased risk of endometrial cancer (T allele vs. G allele: OR = 1.23, 95% CI: 1.07 ~ 1.42, P = 0.005; GT + TT vs. GG: OR = 1.21, 95% CI: 1.06 ~ 1.40, P = 0.006; TT vs. GG + GT: OR = 1.65, 95% CI: 1.09 ~ 2.49, P = 0.017; TT vs. GG: OR = 1.72, 95% CI: 1.12 ~ 2.65, P = 0.013; TT vs. GT: OR = 1.42, 95% CI: 1.01 ~ 2.00, P = 0.044, respectively). We also observed positive associations between PGR rs10895068 polymorphism and the pathogenesis of endometrial cancer (T allele vs. C allele: OR = 1.15, 95% CI: 1.02 ~ 1.29, P = 0.027; CT + TT vs. CC: OR = 1.14, 95% CI: 1.00 ~ 1.29, P = 0.045, respectively).
CONCLUSION: Ethnicity-stratified analysis indicated that rs1042838 and rs10895068 polymorphisms in the PGR gene might be strongly related to the pathogenesis of endometrial cancer among Caucasians and mixed populations (all P < 0.05). In conclusion, our findings provide empirical evidence that PGR rs1042838 and rs10895068 polymorphisms may be involved in the pathogenesis of endometrial cancer.
Endometrial stromal sarcomas (ESSs) belong to the rarest uterine malignancies (prevalence category <1-9/1,000,000). According to the new 2014 World Health Organisation (WHO) classification, they are separated into four categories; benign endometrial stromal nodules (ESNs), low grade endometrial stromal sarcomas (LG-ESSs), high-grade endometrial stromal sarcomas (HG-ESSs) and undifferentiated uterine sarcomas (UUSs). Due to heterogeneous histopathologic appearance these tumors still represent diagnostic challenge, even for experienced pathologists. ESSs are genetically very heterogeneous and several chromosomal translocations and gene fusions have so far been identified in these malignancies. To date the JAZF1/SUZ12 gene fusion is by far the most frequent and seems to be the cytogenetic hallmark of ESN and LG-ESS. Based on present literature data this gene fusion is present in approximately 75% of ESN, 50% of LG-ESS and 15% of HG-ESS cases. The frequency of JAZF1/SUZ12 appearance varies between classic ESS and different morphologic variants. This gene fusion is suggested to become a specific diagnostic tool, especially in difficult borderline cases. In combination with the recently described YWHAE/FAM22 gene fusion the JAZF1/SUZ12 fusion could be used to differentiate between LG-ESS and HG-ESS. The purpose of this review is to summarize literature data published in last two and a half decades about this gene fusion, as a contribution to our understanding of ESS genetics and pathogenesis.
BACKGROUND: The receptor for advanced glycation endproducts (RAGE) and microvascular status both play a critical role in cancer progression. However, the crosstalk between RAGE and microvascular formation in endometrial cancer remains largely unknown.
METHODS: RAGE expression and microvessel density were examined in 20 cases of normal endometrial tissue, 37 cases of well-differentiated endometrial cancer tissue, and 35 cases of poorly-differentiated endometrial cancer tissue. Regression analysis was used to examine the relationship between RAGE and microvessel density. The knockdown of RAGE was achieved using a small interfering RNA in HEC-1A endometrial cancer cells. A xenografted tumour model was used to evaluate RAGE-mediated microvascular formation and proliferation of endometrial cancer cells.
RESULTS: It was shown that (i) RAGE expression gradually increased in normal endometrium, well-differentiated endometrial cancer, and poorly-differentiated endometrial cancer, respectively; (ii) a positive correlation existed between RAGE and microvessel density in human endometrial cancer samples; (iii) RAGE knockdown was effective in decreasing microvessel formation in xenografted tumour models; and (iv) RAGE knockdown can significantly inhibit the proliferation of endometrial cancer cells in vivo.
CONCLUSIONS: These results indicate that RAGE may be a potential trigger in microvascular formation and proliferation in the development of endometrial cancer.
Estrogen signaling influences the development and progression of ovarian tumors, but the underlying mechanisms are not well understood. In a previous study we demonstrated that impairment of estrogen receptor alpha (ERα)-mediated olfactomedin 4 (OLFM4) expression promotes the malignant progression of endometrioid adenocarcinoma, and we identified OLFM4 as a potential target of miR-486-5p. In this study we investigated the role of OLFM4 in ovarian serous adenocarcinoma. Ovarian serous adenocarcinoma tissues had reduced OLFM4 expression. Expression of OLFM4 was positively correlated with ERα expression, and estrogen (E2) treatment in ovarian cancer cells induced OLFM4 expression in an ERα-dependent manner. In contrast to ERα, miR-486-5p levels were inversely correlated with OLFM4 expression in ovarian serous adenocarcinoma. Ovarian cancer cells transfected with miR-486-5p mimics showed decreased OLFM4 mRNA expression, and ovarian cancer cells treated with E2 showed reduced cellular miR-486-5p levels. OLFM4 knockdown enhanced proliferation, migration, and invasion by ovarian cancer cells. Low expression of OLFM4 was also associated with high tumor FIGO stage and poor tumor differentiation. These results suggest OLFM4 is downregulated by miR-486-5p, which contributes to ovarian cancer tumorigenesis. Conversely, estrogen receptor signaling downregulates miR-486-5p and upregulates OLFM4 expression, slowing the development and progression of ovarian cancer.