scholarly journals Mitochondrial Dysfunctions in Type I Endometrial Carcinoma: Exploring Their Role in Oncogenesis and Tumor Progression

2018 ◽  
Vol 19 (7) ◽  
pp. 2076 ◽  
Author(s):  
Clara Musicco ◽  
Gennaro Cormio ◽  
Vito Pesce ◽  
Vera Loizzi ◽  
Ettore Cicinelli ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Tumor Progression ◽  
Type I ◽  
Normal Endometrium ◽  
Dna Mutations ◽  
Mitochondrial Alterations ◽  
Slow Progression ◽  
Multistep Process ◽  
Respiratory Complex I

Type I endometrial cancer (EC) is the most common form of EC, displaying less aggressive behavior than type II. The development of type I endometrial cancer is considered a multistep process, with slow progression from normal endometrium to hyperplasia, the premalignant form, and endometrial cancer as a result of an unopposed estrogenic stimulation. The role of mitochondria in type I EC tumor progression and prognosis is currently emerging. This review aims to explore mitochondrial alterations in this cancer and in endometrial hyperplasia focusing on mitochondrial DNA mutations, respiratory complex I deficiency, and the activation of mitochondrial quality control systems. A deeper understanding of altered mitochondrial pathways in type I EC could provide novel opportunities to discover new diagnostic and prognostic markers as well as potential therapeutic targets.

scholarly journals Role of miRNAs in Normal Endometrium and in Endometrial Disorders: Comprehensive Review

2021 ◽  
Vol 10 (16) ◽  
pp. 3457
Author(s):  
Kamila Kolanska ◽  
Sofiane Bendifallah ◽  
Geoffroy Canlorbe ◽  
Arsène Mekinian ◽  
Cyril Touboul ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Mirna Expression ◽  
Expression Patterns ◽  
Mirna Regulation ◽  
Rigorous Analysis ◽  
Sexual Hormones ◽  
Physiological Mechanisms ◽  
Normal Endometrium ◽  
Gynecological Disorders

The molecular responses to hormonal stimuli in the endometrium are modulated at the transcriptional and post-transcriptional stages. Any imbalance in cellular and molecular endometrial homeostasis may lead to gynecological disorders. MicroRNAs (miRNAs) are involved in a wide variety of physiological mechanisms and their expression patterns in the endometrium are currently attracting a lot of interest. miRNA regulation could be hormone dependent. Conversely, miRNAs could regulate the action of sexual hormones. Modifications to miRNA expression in pathological situations could either be a cause or a result of the existing pathology. The complexity of miRNA actions and the diversity of signaling pathways controlled by numerous miRNAs require rigorous analysis and findings need to be interpreted with caution. Alteration of miRNA expression in women with endometriosis has been reported. Thus, a potential diagnostic test supported by a specific miRNA signature could contribute to early diagnosis and a change in the therapeutic paradigm. Similarly, specific miRNA profile signatures are expected for RIF and endometrial cancer, with direct implications for associated therapies for RIF and adjuvant therapies for endometrial cancer. Advances in targeted therapies based on the regulation of miRNA expression are under evaluation.

scholarly journals NLRC5 promotes cell migration and invasion by activating the PI3K/AKT signaling pathway in endometrial cancer

2020 ◽  
Vol 48 (5) ◽  
pp. 030006052092535
Author(s):  
Yijun Fan ◽  
Zhen Dong ◽  
Yuchuan Shi ◽  
Shiying Sun ◽  
Bing Wei ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cell Migration ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Migration And Invasion ◽  
Akt Signaling Pathway ◽  
Positive Role ◽  
Normal Endometrium ◽  
Cell Migration And Invasion

Objective NOD-like receptor family caspase recruitment domain family domain-containing 5 (NLRC5) is involved in the development of cancer. Our objective was to explore the role of NLRC5 in the progression of endometrial cancer (EC). Methods The roles of NLRC5 in migration and invasion of AN3CA EC cells were examined by cell wound-healing assay, Transwell migration, and invasion analysis. Overexpression of NLRC5 was achieved with NLRC5 plasmid, and knockdown of NLRC5 was achieved using small interfering (si)RNA-NLRC5 in AN3CA cells. The expression of NLRC5 was detected by immunohistochemical, western blot, and quantitative real-time PCR. LY294002 was used to inhibit the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway. Results NLRC5 was downregulated in EC tissue compared with normal endometrium. Overexpression of NLRC5 led to upregulation of cell migration and invasion in AN3CA cells and expression of matrix metallopeptidase (MMP)-9. Inhibition of NLRC5 restricted migration and invasion of AN3CA cells and expression of MMP9. Overexpression of NLRC5 promoted the activation of PI3K/AKT signaling pathway. Inhibiting PI3K/AKT signaling pathway by using LY294002 blocked the positive role of NLRC5 in migration and invasion of AN3CA cells and expression of MMP9. Conclusions These results demonstrate that NLRC5 promotes EC progression by activating the PI3K/AKT signaling pathway.

scholarly journals No Association Between Statin Use and the Prognosis of Endometrial Cancer in Women With Type 2 Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Elina Urpilainen ◽  
Anne Ahtikoski ◽  
Reetta Arima ◽  
Ulla Puistola ◽  
Peeter Karihtala
Keyword(s):  
Type 2 Diabetes ◽  
Endometrial Cancer ◽  
Cancer Diagnosis ◽  
Progression Free Survival ◽  
Epidemiological Studies ◽  
University Hospital ◽  
Type I ◽  
Statin Use

Preclinical studies have suggested statins have antiproliferative and anti-metastatic effects on endometrial cancer cells. Similarly, most previous epidemiological studies have reported a better prognosis of endometrial cancer in patients who used statins. In this study, we explored the role of statins in the prognosis of endometrial cancer in women with type 2 diabetes in a hospital-based cohort. This retrospective cohort consisted of 119 women with type 2 diabetes who were diagnosed and treated for endometrial cancer at Oulu University Hospital, Finland, between 2007 and 2014. The patients were classified as statin users (n = 58) and nonusers (n = 61) based on the type of medication they were using at the time of endometrial cancer diagnosis. Statin use showed no association with progression-free survival or overall survival in the whole cohort nor the subgroups with type I or type II histology, in lower or higher body mass index groups, or at an early or advanced stage. The results remained similar in the multivariate analysis after adjusting for the patient’s age, cancer stage, and histology. Furthermore, statin use seemed not to have any association with most of the prognostic factors at the time of endometrial cancer diagnosis.

scholarly journals Metalloproteinases in Endometrial Cancer—Are They Worth Measuring?

2021 ◽  
Vol 22 (22) ◽  
pp. 12472
Author(s):  
Kaja Michalczyk ◽  
Aneta Cymbaluk-Płoska
Keyword(s):  
Extracellular Matrix ◽  
Endometrial Cancer ◽  
Molecular Mechanisms ◽  
Tumor Development ◽  
Cell Detachment ◽  
Metastasis Formation ◽  
Invasion And Metastasis ◽  
Normal Endometrium ◽  
Affected Tissue

Endometrial cancer is one of the most common gynecological malignancies, yet the molecular mechanisms that lead to tumor development and progression are still not fully established. Matrix metalloproteinases (MMPs) are a group of enzymes that play an important role in carcinogenesis. They are proteases involved in the degradation of the extracellular matrix (ECM) that surrounds the tumor and the affected tissue allows cell detachment from the primary tumor causing local invasion and metastasis formation. Recent investigations demonstrate significantly increased metalloproteinase and metalloproteinase inhibitor levels in patients with endometrial cancer compared to those with normal endometrium. In this review, we aim to show their clinical significance and possible use in the diagnosis and treatment of patients with endometrial cancer. We have critically summarized and reviewed the research on the role of MMPs in endometrial cancer.

scholarly journals NADPH oxidase 4 expression in the normal endometrium and in endometrial cancer

Tumor Biology ◽  
2019 ◽  
Vol 41 (2) ◽  
pp. 101042831983000 ◽  
Author(s):  
Christine Degasper ◽  
Andrea Brunner ◽  
Natalie Sampson ◽  
Irina Tsibulak ◽  
Verena Wieser ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Endometrial Cancer ◽  
Body Mass ◽  
Prognostic Significance ◽  
Clinicopathological Parameters ◽  
Diabetic Patients ◽  
Type I ◽  
Prognostic Impact ◽  
Normal Endometrium ◽  
Nadph Oxidase 4

The aim of this study was to explore the role of NOX4 in the biology of the normal endometrium and endometrial cancer. NOX4 plays a key role in other adenocarcinomas and has been implicated in the pathogenesis of diabetes and obesity, which are important risk factors for endometrial cancer. NOX4 expression was assessed in 239 endometrial cancer and 25 normal endometrium samples by quantitative real-time polymerase chain reaction, in situ hybridization, and immunohistochemistry. DNA methylation of the NOX4 promoter was determined by means of MethyLight PCR. Data were correlated with clinicopathological parameters and analyzed in the context of diabetes and body mass index. In the normal endometrium, NOX4 microRNA expression was significantly higher in the secretory transformed compared with proliferative endometrium ( p = 0.008). In endometrial cancer specimens, NOX4 expression did not differ between diabetic and non-diabetic patients, but was the highest in patients with a body mass index ≤ 26 ( p = 0.037). The lowest NOX4 expression was found in carcinosarcomas ( p = 0.007). High NOX4 expression predicted poorer clinical outcome with regard to overall survival, especially in non-diabetic patients and those with a body mass index > 20. Independent prognostic significance of NOX4 transcripts was retained in type I endometrial cancer and was the most meaningful in patients with a body mass index > 20. No prognostic impact was shown for NOX4 promoter methylation in endometrial cancer. For the first time, we demonstrate that NOX4 plays a considerable role in the cycle-dependent changes in the normal endometrium and in the biology of endometrial cancer.

scholarly journals The role of exosomal PD-L1 in tumor progression and immunotherapy

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Feiting Xie ◽  
Mengxue Xu ◽  
Jian Lu ◽  
Lingxiang Mao ◽  
Shengjun Wang
Keyword(s):  
T Cells ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Transmembrane Protein ◽  
Biologically Active ◽  
Type I ◽  
Mesenchymal Transition

Abstract Programmed death ligand 1 (PD-L1), a type I transmembrane protein, binds to its receptor PD-1 to suppress the activation of T cells, thereby maintaining immunological homeostasis. In contrast, tumor cells highly express PD-L1, which binds to receptor PD-1 expressed on activated T cells, leading to immune escape. Anti-PD-1/PD-L1 immune checkpoint therapy blocks the binding of PD-1/PD-L1 to reinvigorate the exhausted T cells, thereby inhibiting tumor growth. Exosomes are biologically active lipid-bilayer nanovesicles secreted by various cell types that mediate intercellular signal communication. Numerous studies have shown that tumor cells are able to promote tumor epithelial-mesenchymal transition, angiogenesis, and immune escape by releasing exosomes. Recent studies imply that tumor-derived exosomes could carry PD-L1 in the same membrane topology as the cell surface, thereby resisting immune checkpoint therapy. In this review, we mainly discuss the role of exosomes in the regulation of tumor progression and the potential resistance mechanism to immunotherapy via exosomal PD-L1. In addition, we propose that exosomal PD-L1 may have the potential to be a target to overcome resistance to anti-PD-1/PD-L1 antibody therapy.

scholarly journals Combined genetic mutations and DNA-methylated genes as biomarkers for endometrial cancer detection from cervical scrapings

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Phui-Ly Liew ◽  
Rui-Lan Huang ◽  
Tzu-I Wu ◽  
Chi-Chun Liao ◽  
Chien-Wen Chen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Endometrial Cancer ◽  
Cancer Detection ◽  
Type I ◽  
Type Ii ◽  
Normal Endometrium ◽  
Epigenetic Biomarkers ◽  
Pap Smear Screening ◽  
Endometrial Cancers ◽  
Endometrial Carcinomas

Abstract Background Endometrial cancer is a common gynecologic cancer. Noninvasive molecular biomarkers for triage of high-risk patients for invasive procedures are needed. Based on the success of cytological Pap smear screening, cervical scrapings are a good source of DNA for molecular testing. In addition to genetic lesions, DNA methylation is a promising biomarker. We assessed the usefulness of combining genetic and epigenetic biomarkers from cervical scrapings to detect endometrial carcinomas. Methods We performed a retrospective case–control study of 96 consecutive cervical scrapings from patients with abnormal uterine bleeding who underwent surgery for diagnostic evaluation. Thirty and 16 cases were diagnosed with type I and type II endometrial cancers, respectively. The remaining non-cancer cases included normal endometrium (n = 12), benign uterine lesions (n = 20), and endometrial hyperplasia (n = 18). Quantitative methylation-specific PCR and mass spectrometry were used for DNA methylation and genetic mutation analysis. Logistic regression was used to evaluate the clinical performance of these candidate biomarkers. Results We tested the effectiveness of the methylation status of four genes (BHLHE22, CDO1, TBX5, and HAND2) in endometrial cancer detection. The area under the receiver operating characteristic curves ranged from 0.703 to 0.878, and panels of hypermethylated BHLHE22/CDO1/HAND2 (87.0% sensitivity and 86.0% specificity) and BHLHE22/CDO1/TBX5 (89.1% sensitivity and 80.0% specificity) showed significant differences and could distinguish benign from malignant endometrial lesions. The sensitivity and specificity in endometrial cancer detection for BHLHE22/CDO1 were 84.8% and 88.0%, respectively. Both type I and II endometrial carcinomas could be detected using a BHLHE22/CDO1-based methylation profile, suggesting that they may have common epigenomes. Moreover, PTEN and TP53 mutations were found in 63.3% of type I and 93.6% of type II endometrial cancers. Unexpectedly, PTEN and TP53 mutations were commonly found in cervical scrapings of the normal endometrium (25% and 33.3%, respectively) and in cases with benign uterine lesions (10% and 50%, respectively). Finally, combinations of any one mutation of PTEN and TP53 mutations had a sensitivity of 91.3%, but a specificity of only 42.0%. Conclusions Adding PTEN/TP53 mutation testing to BHLHE22/CDO1-based methylation testing did not improve the detection of endometrial cancer.

scholarly journals Validation of Hepatocellular Carcinoma Experimental Models for TGF-β Promoting Tumor Progression

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1510 ◽  
Author(s):  
Serena Mancarella ◽  
Silke Krol ◽  
Alberto Crovace ◽  
Stefano Leporatti ◽  
Francesco Dituri ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Progression ◽  
Cell Lines ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Tumor Stroma ◽  
Experimental Models ◽  
Tumor Promoter ◽  
Type I

Transforming growth factor beta (TGF-β) is a pleiotropic cytokine with dual role in hepatocellular carcinoma (HCC). It acts as tumor-suppressor and tumor-promoter in the early and late stage respectively. TGF-β influences the tumor-stroma cross-talk affecting the tumoral microenvironment. Therefore, inhibiting the TGF- β mediated pathway alone and/or in combination with chemotherapeutics represents an important therapeutic option. Experimental models to dissect the role of TGF-β in HCC tumor progression as well as the effectiveness of specific inhibitors are tricky. HCC cell lines respond to TGF-β according to their epithelial phenotype. However, the mesenchymal and more aggressive HCC cell lines in vitro, do not develop tumors when transplanted in vivo, thus hampering the understanding of molecular pathways that dictate outcome. In addition, in this model the native immune system is abolished, therefore the contribution of inflammation in hepatocarcinogenesis is unreliable. Different strategies have been set up to engineer HCC animal models, including genetically modified mice, chemically induced HCC, or hydrodynamic techniques. Patient-derived xenograft is currently probably the most fascinating model, keeping in mind that models cannot mirror all the reality. In this context, we discuss the different available HCC mouse models including our experimental model treated with inhibitor of TGF-β receptor Type I kinase (Galunisertib) and a potential role of exosomes in TGF-β moderated tumor progression of HCC. Unfortunately, no positive results were obtained in our treated orthotopic model because it does not reproduce the critical tumor-stroma interactions of the HCC.

Picropodophyllin inhibits type I endometrial cancer cell proliferation via disruption of the PI3K/Akt pathway

2019 ◽  
Vol 51 (7) ◽  
pp. 753-760
Author(s):  
Lin Dong ◽  
Meirong Du ◽  
Qianzhou Lv
Keyword(s):  
Cell Proliferation ◽  
Endometrial Cancer ◽  
Prognostic Factor ◽  
Tumor Progression ◽  
Cell Line ◽  
Cell Lines ◽  
Growth Factor Receptor ◽  
Type I ◽  
Proliferation Capacity ◽  
Important Prognostic Factor

Abstract The type-I insulin-like growth factor receptor (IGF-IR) is overexpressed in endometrial cancer. High IGF-IR expression was considered as an important prognostic factor for tumor progression. The purpose of this study was to investigate the role and molecular mechanism of IGF-IR inhibitor picropodophyllin (PPP) in the growth and development of endometrial cancer. High expression of IGF-IR was observed in endometrial cancer tissues, as well as in ECC-1 and KLE cell lines. PPP suppressed the number of clones of ECC-1 and KLE cell lines; however, it had no significant effect on HEC-1-A cell line, which expressed lower IGF-IR than ECC-1 and KLE cell lines. Furthermore, PPP reduced cell proliferation capacity, inhibited the IGF-IR mRNA expression, and suppressed protein phosphorylation of IGF-IR and Akt in the three cell lines. In addition, PPP inhibited the protein expression of survivin in KLE cell line after 1 h of exposure, though this effect did not last for prolonged time. In conclusion, IGF-IR was mostly overexpressed in type I endometrial cancer. High IGF-IR expression was an important prognostic factor of tumor progression. PPP mediated the down-regulation of IGF-IR phosphorylation and inhibited cell proliferation via the PI3K/Akt signal pathway. PPP may have the potential to become a clinical treatment target in endometrial carcinoma.

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