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Endometrial Cancer Overview: Molecular Biology and Its Potential Clinical Application
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Endometrial Cancer Overview: Molecular Biology and Its Potential Clinical Application

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 26693

Special Issue Editors

Dr. Massimiliano Fambrini

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Guest Editor
Dipartimento di Scienze Biomediche, Sperimentali e Cliniche "Mario Serio", Largo Brambilla, 3, 50134 Firenze, Italy
Interests: gynecologic oncology; endometrial cancer; fertility sparing treatment; molecular biology and prognostic biomarker for gynecological malignancies
Dr. Flavia Sorbi

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Guest Editor
Dipartimento di Scienze Biomediche, Sperimentali e Cliniche "Mario Serio", Largo Brambilla, 3, 50134 Firenze, Italy
Interests: gynecologic oncology; ovarian cancer; genetic and molecular characterization in gynaecological cancer; bioelectrical properties of cancerous tissue
Prof. Dr. Felice Petraglia

E-Mail Website
Guest Editor
Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50121 Florence, Italy
Interests: gynecology and obstetrics; reproductive disorders; endometriosis; uterine fibroids; placental disorders

Special Issue Information

Endometrial cancer (EC), which arises in the lining of the uterus, is the most common gynecologic malignancy. Approximately 90% of cases of EC are sporadic, whereas the remaining 10% of cases are hereditary. Although most ECs are diagnosed early, mainly due to symptomatic postmenopausal metrorrhagia, up to 20% of the lesions progress to a high-stage tumor. Unfortunately, the five-year survival in these women drops to 15%, compared to 90% in women diagnosed with confined disease. In the past twenty years, there has been a shift in the EC paradigm to consider it as a multiplicity of disease types rather than a single disease. For EC, four molecular subgroups have undergone extensive studies in recent years: POLE ultramutated, mismatch repair-deficient, p53 mutant and EC lacking any of these alterations, referred to as NSMP. Nonetheless, patients with histologically similar ECs may have very different outcomes, notably in patients with high-grade EC. Improved understanding of the molecular basis for EC could reveal potential biomarkers of disease diagnosis and progression, as well as lead to the identification of molecular targets for novel therapeutic strategies of treatment. Numerous agents targeting different components have been developed and studied as single agents or in combination with traditional cytotoxic agents; additionally, molecular targeted therapies can be combined to deliver increased benefits to patients. Continued investigation into the molecular pathways of EC development and progression are needed to increase our knowledge of this disease process and will lead to the discovery of novel, superior treatment options for patients.

Prof. Massimiliano Fambrini
Dr. Flavia Sorbi
Prof. Felice Petraglia

Guest Editors

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Keywords

  • Endometrial cancer
  • Liquid biopsy
  • Molecular biology
  • Predictive and prognostic biomarker

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Published Papers (6 papers)

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Research

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13 pages, 5755 KiB  
Article
In Silico Study to Predict the Structural and Functional Consequences of SNPs on Biomarkers of Ovarian Cancer (OC) and BPA Exposure-Associated OC
by Aeman Zahra, Marcia Hall, Jayanta Chatterjee, Cristina Sisu and Emmanouil Karteris
Int. J. Mol. Sci. 2022, 23(3), 1725; https://doi.org/10.3390/ijms23031725 - 2 Feb 2022
Cited by 5 | Viewed by 2619
Abstract
Background: Recently, we have shown that seven genes, namely GBP5, IRS2, KRT4, LINCOO707, MRPL55, RRS1 and SLC4A11, have prognostic power for the overall survival in ovarian cancer (OC). Methods: We present an analysis on the association of these [...] Read more.
Background: Recently, we have shown that seven genes, namely GBP5, IRS2, KRT4, LINCOO707, MRPL55, RRS1 and SLC4A11, have prognostic power for the overall survival in ovarian cancer (OC). Methods: We present an analysis on the association of these genes with any phenotypes and mutations indicative of involvement in female cancers and predict the structural and functional consequences of those SNPS using in silico tools. Results: These seven genes present with 976 SNPs/mutations that are associated with human cancers, out of which 284 related to female cancers. We have then analysed the mutation impact on amino acid polarity, charge and water affinity, leading to the identification of 30 mutations in gynaecological cancers where amino acid (aa) changes lead to opposite polarity, charges and water affinity. Out of these 30 mutations identified, only a missense mutation (i.e., R831C/R804C in uterine corpus endometrial carcinomas, UCEC) was suggestive of structural damage on the SLC4A11 protein. Conclusions: We demonstrate that the R831C/R804C mutation is deleterious and the predicted ΔΔG values suggest that the mutation reduces the stability of the protein. Future in vitro studies should provide further insight into the role of this transporter protein in UCEC. Full article
(This article belongs to the Special Issue Endometrial Cancer Overview: Molecular Biology and Its Potential Clinical Application)
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18 pages, 2687 KiB  
Article
miR-497-5p Decreased Expression Associated with High-Risk Endometrial Cancer
by Ivana Fridrichova, Lenka Kalinkova, Miloslav Karhanek, Bozena Smolkova, Katarina Machalekova, Lenka Wachsmannova, Nataliia Nikolaieva and Karol Kajo
Int. J. Mol. Sci. 2021, 22(1), 127; https://doi.org/10.3390/ijms22010127 - 24 Dec 2020
Cited by 24 | Viewed by 4534
Abstract
The current guidelines for diagnosis, prognosis, and treatment of endometrial cancer (EC), based on clinicopathological factors, are insufficient for numerous reasons; therefore, we investigated the relevance of miRNA expression profiles for the discrimination of different EC subtypes. Among the miRNAs previously predicted to [...] Read more.
The current guidelines for diagnosis, prognosis, and treatment of endometrial cancer (EC), based on clinicopathological factors, are insufficient for numerous reasons; therefore, we investigated the relevance of miRNA expression profiles for the discrimination of different EC subtypes. Among the miRNAs previously predicted to allow distinguishing of endometrioid ECs (EECs) according to different grades (G) and from serous subtypes (SECs), we verified the utility of miR-497-5p. In ECs, we observed downregulated miR-497-5p levels that were significantly decreased in SECs, clear cell carcinomas (CCCs), and carcinosarcomas (CaSas) compared to EECs, thereby distinguishing EEC from SEC and rare EC subtypes. Significantly reduced miR-497-5p expression was found in high-grade ECs (EEC G3, SEC, CaSa, and CCC) compared to low-grade carcinomas (EEC G1 and mucinous carcinoma) and ECs classified as being in advanced FIGO (International Federation of Gynecology and Obstetrics) stages, that is, with loco-regional and distant spread compared to cancers located only in the uterus. Based on immunohistochemical features, lower miR-497-5p levels were observed in hormone-receptor-negative, p53-positive, and highly Ki-67-expressing ECs. Using a machine learning method, we showed that consideration of miR-497-5p expression, in addition to the traditional clinical and histopathologic parameters, slightly improves the prediction accuracy of EC diagnosis. Our results demonstrate that changes in miR-497-5p expression influence endometrial tumorigenesis and its evaluation may contribute to more precise diagnoses. Full article
(This article belongs to the Special Issue Endometrial Cancer Overview: Molecular Biology and Its Potential Clinical Application)
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23 pages, 7224 KiB  
Article
The Effects of Cannabidiol and Prognostic Role of TRPV2 in Human Endometrial Cancer
by Oliviero Marinelli, Maria Beatrice Morelli, Daniela Annibali, Cristina Aguzzi, Laura Zeppa, Sandra Tuyaerts, Consuelo Amantini, Frédéric Amant, Benedetta Ferretti, Federica Maggi, Giorgio Santoni and Massimo Nabissi
Int. J. Mol. Sci. 2020, 21(15), 5409; https://doi.org/10.3390/ijms21155409 - 29 Jul 2020
Cited by 31 | Viewed by 6040
Abstract
Several studies support, both in vitro and in vivo, the anti-cancer effects of cannabidiol (CBD), a transient receptor potential vanilloid 2 (TRPV2) ligand. TRPV2, often dysregulated in tumors, is associated with altered cell proliferation and aggressiveness. Endometrial cancer (EC) is historically divided in [...] Read more.
Several studies support, both in vitro and in vivo, the anti-cancer effects of cannabidiol (CBD), a transient receptor potential vanilloid 2 (TRPV2) ligand. TRPV2, often dysregulated in tumors, is associated with altered cell proliferation and aggressiveness. Endometrial cancer (EC) is historically divided in type I endometrioid EC and type II non-endometrioid EC, associated with poor prognosis. Treatment options with chemotherapy and combinations with radiation showed only limited efficacy. Since no data are reported concerning TRPV2 expression as well as CBD potential effects in EC, the aim of this study was to evaluate the expression of TRPV2 in biopsies and cell lines as well as the effects of CBD in in vitro models. Overall survival (OS), progression-free survival (PFS), cell viability, migration, and chemo-resistance have been evaluated. Results show that TRPV2 expression increased with the malignancy of the cancer tissue and correlated with shorter PFS (p = 0.0224). Moreover, in vitro TRPV2 over-expression in Ishikawa cell line increased migratory ability and response to cisplatin. CBD reduced cell viability, activating predominantly apoptosis in type I cells and autophagy in mixed type EC cells. The CBD improved chemotherapeutic drugs cytotoxic effects, enhanced by TRPV2 over-expression. Hence, TRPV2 could be considered as a marker for optimizing the therapy and CBD might be a useful therapeutic option as adjuvant therapy. Full article
(This article belongs to the Special Issue Endometrial Cancer Overview: Molecular Biology and Its Potential Clinical Application)
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13 pages, 8210 KiB  
Article
MSX1—A Potential Marker for Uterus-Preserving Therapy of Endometrial Carcinomas
by Simon Eppich, Christina Kuhn, Elisa Schmoeckel, Doris Mayr, Sven Mahner, Udo Jeschke, Julia Gallwas and Helene Hildegard Heidegger
Int. J. Mol. Sci. 2020, 21(12), 4529; https://doi.org/10.3390/ijms21124529 - 25 Jun 2020
Cited by 9 | Viewed by 2744
Abstract
Prognostic factors are of great interest in patients with endometrial cancer. One potential factor could be the protein MSX1, a transcription repressor, that has an inhibitory effect on the cell cycle. For this study, endometrioid endometrial carcinomas (n = 53), clear cell [...] Read more.
Prognostic factors are of great interest in patients with endometrial cancer. One potential factor could be the protein MSX1, a transcription repressor, that has an inhibitory effect on the cell cycle. For this study, endometrioid endometrial carcinomas (n = 53), clear cell endometrial carcinomas (n = 6), endometrioid ovarian carcinomas (n = 19), and clear cell ovarian carcinomas (n = 11) were immunochemically stained for the protein MSX1 and evaluated using the immunoreactive score (IRS). A significant stronger expression of MSX1 was found in endometrioid endometrial carcinomas (p < 0.001), in grading 2 (moderate differentiation) (p = 0.001), and in tumor material of patients with no involvement of lymph nodes (p = 0.031). Correlations were found between MSX1 expression and the expression of β-Catenin, p21, p53, and the steroid receptors ERα, ERβ, PRα, and PRβ. A significant (p = 0.023) better survival for patients with an MSX1 expression in more than 10% of the tumor cells was observed for endometrioid endometrial carcinomas (21.3 years median survival (MSX1-positive) versus 17.3 years (MSX1-negative)). Although there is evidence that MSX1 expression correlates with improved long-term survival, further studies are necessary to evaluate if MSX1 can be used as a prognostic marker. Full article
(This article belongs to the Special Issue Endometrial Cancer Overview: Molecular Biology and Its Potential Clinical Application)
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Review

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26 pages, 1347 KiB  
Review
Non-Coding RNAs as Prognostic Markers for Endometrial Cancer
by Roberto Piergentili, Simona Zaami, Anna Franca Cavaliere, Fabrizio Signore, Giovanni Scambia, Alberto Mattei, Enrico Marinelli, Caterina Gulia and Federica Perelli
Int. J. Mol. Sci. 2021, 22(6), 3151; https://doi.org/10.3390/ijms22063151 - 19 Mar 2021
Cited by 54 | Viewed by 4150
Abstract
Endometrial cancer (EC) has been classified over the years, for prognostic and therapeutic purposes. In recent years, classification systems have been emerging not only based on EC clinical and pathological characteristics but also on its genetic and epigenetic features. Noncoding RNAs (ncRNAs) are [...] Read more.
Endometrial cancer (EC) has been classified over the years, for prognostic and therapeutic purposes. In recent years, classification systems have been emerging not only based on EC clinical and pathological characteristics but also on its genetic and epigenetic features. Noncoding RNAs (ncRNAs) are emerging as promising markers in several cancer types, including EC, for which their prognostic value is currently under investigation and will likely integrate the present prognostic tools based on protein coding genes. This review aims to underline the importance of the genetic and epigenetic events in the EC tumorigenesis, by expounding upon the prognostic role of ncRNAs. Full article
(This article belongs to the Special Issue Endometrial Cancer Overview: Molecular Biology and Its Potential Clinical Application)
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18 pages, 1452 KiB  
Review
Targeting Epigenetic Regulators for Endometrial Cancer Therapy: Its Molecular Biology and Potential Clinical Applications
by Futaba Inoue, Kenbun Sone, Yusuke Toyohara, Yu Takahashi, Asako Kukita, Aki Hara, Ayumi Taguchi, Michihiro Tanikawa, Tetsushi Tsuruga and Yutaka Osuga
Int. J. Mol. Sci. 2021, 22(5), 2305; https://doi.org/10.3390/ijms22052305 - 25 Feb 2021
Cited by 20 | Viewed by 5397
Abstract
Endometrial cancer is one of the most frequently diagnosed gynecological malignancies worldwide. However, its prognosis in advanced stages is poor, and there are only few available treatment options when it recurs. Epigenetic changes in gene function, such as DNA methylation, histone modification, and [...] Read more.
Endometrial cancer is one of the most frequently diagnosed gynecological malignancies worldwide. However, its prognosis in advanced stages is poor, and there are only few available treatment options when it recurs. Epigenetic changes in gene function, such as DNA methylation, histone modification, and non-coding RNA, have been studied for the last two decades. Epigenetic dysregulation is often reported in the development and progression of various cancers. Recently, epigenetic changes in endometrial cancer have also been discussed. In this review, we give the main points of the role of DNA methylation and histone modification in endometrial cancer, the diagnostic tools to determine these modifications, and inhibitors targeting epigenetic regulators that are currently in preclinical studies and clinical trials. Full article
(This article belongs to the Special Issue Endometrial Cancer Overview: Molecular Biology and Its Potential Clinical Application)
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