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New Insights into Endometrial Cancer 2022

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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 (25 December 2022) | Viewed by 33413

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Dr. Laura Paleari

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Research, Innovation and HTA Unit, (A.Li.Sa.) Liguria Health Authority, 16121 Genoa, Italy
Interests: cancer prevention; molecular biology; drug repurposing; health technology assessment; pharmacoeconomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Endometrial Cancer is a hormone dependent cancer with an increasing incidence that is estimated to growth in the next years. It is typically treated with surgery and/or chemo/radiation therapy. Recently, it has been demonstrated the clinical benefit of hormone therapies for advanced and recurrent Endometrial Cancers underlined the need to examine their characteristics (particularly steroid hormone receptors expression and functions) to assess their better use. Furthermore, a critical phase to drive the clinicians in the therapeutic choice is the histopathological and molecular classification. In fact, an even current challenge is to integrate IHC markers with molecular tests to identify prognostic groups. Moreover, the observations of the immunosuppressive nature of endometrial cancer environment are leading to promote studies to assess therapies aimed to boost immune response that might represent a significant potential in the disease treatment. For this reason, current and ongoing studies are trying to improve clinical responses through immunotherapies strategies combined or not with classic treatments.

This open-access Special Issue will bring together original research and review articles on molecular oncology with attention to endometrial cancer. It highlights new findings, methods, and technical advances in molecular cancer research. The main feature of this Special Issue is to provide an open-source sharing of significant works in the field of molecular oncology that can increase our understanding of endometrial cancer development, which may lead to the discovery of new molecular diagnostic technologies and targeted therapeutics.

Topics include but are not limited to: Molecular methods to personalize endometrial cancer screening and detection; Identification and new aspects of cellular signaling molecules and pathways for target discovery, drug design, personalized and gender medicine; DDI discovery in endometrial cancer management; Drug repurposing for endometrial cancer prevention/treatment; Molecular modeling studies.

Dr. Laura Paleari
Guest Editor

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 180 KiB

Open AccessEditorial

New Strategies for Endometrial Cancer Detection and Management

by Laura Paleari

Int. J. Mol. Sci. 2023, 24(7), 6462; https://doi.org/10.3390/ijms24076462 - 30 Mar 2023

Cited by 3 | Viewed by 1602

Abstract

With 400,000 new cases and over 80,000 deaths a year worldwide, endometrial cancer (EC) holds a rather unfortunate record, namely, that of the tumour with the highest increase in incidence, a unique trend among gynaecological cancers [...] Full article

(This article belongs to the Special Issue New Insights into Endometrial Cancer 2022)

Research

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13 pages, 3074 KiB

Open AccessArticle

Combination of EphA2- and Wee1-Targeted Therapies in Endometrial Cancer

by Santosh K. Dasari, Robiya Joseph, Sujanitha Umamaheswaran, Lingegowda S. Mangala, Emine Bayraktar, Cristian Rodriguez-Aguayo, Yutuan Wu, Nghi Nguyen, Reid T. Powell, Mary Sobieski, Yuan Liu, Mamur A. Chowdhury, Paola Amero, Clifford Stephan, Gabriel Lopez-Berestein, Shannon N. Westin and Anil K. Sood

Int. J. Mol. Sci. 2023, 24(4), 3915; https://doi.org/10.3390/ijms24043915 - 15 Feb 2023

Cited by 6 | Viewed by 2950

Abstract

EphA2 tyrosine kinase is upregulated in many cancers and correlated with poor survival of patients, including those with endometrial cancer. EphA2-targeted drugs have shown modest clinical benefit. To improve the therapeutic response to such drugs, we performed a high-throughput chemical screen to discover novel synergistic partners for EphA2-targeted therapeutics. Our screen identified the Wee1 kinase inhibitor, MK1775, as a synergistic partner to EphA2, and this finding was confirmed using both in vitro and in vivo experiments. We hypothesized that Wee1 inhibition would sensitize cells to EphA2-targeted therapy. Combination treatment decreased cell viability, induced apoptosis, and reduced clonogenic potential in endometrial cancer cell lines. In vivo Hec1A and Ishikawa-Luc orthotopic mouse models of endometrial cancer showed greater anti-tumor responses to combination treatment than to either monotherapy. RNASeq analysis highlighted reduced cell proliferation and defective DNA damage response pathways as potential mediators of the combination’s effects. In conclusion, our preclinical findings indicate that Wee1 inhibition can enhance the response to EphA2-targeted therapeutics in endometrial cancer; this strategy thus warrants further development. Full article

(This article belongs to the Special Issue New Insights into Endometrial Cancer 2022)

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24 pages, 4187 KiB

Open AccessArticle

A Hypoxia Molecular Signature-Based Prognostic Model for Endometrial Cancer Patients

by Yang Jiao, Rui Geng, Zihang Zhong, Senmiao Ni, Wen Liu, Zhiqiang He, Shilin Gan, Qinghao Huang, Jinhui Liu and Jianling Bai

Int. J. Mol. Sci. 2023, 24(2), 1675; https://doi.org/10.3390/ijms24021675 - 14 Jan 2023

Cited by 4 | Viewed by 3119

Abstract

Endometrial cancer has the highest incidence of uterine corpus cancer, the sixth most typical cancer in women until 2020. High recurrence rate and frequent adverse events were reported in either standard chemotherapy or combined therapy. Hence, developing precise diagnostic and prognostic approaches for endometrial cancer was on demand. Four hypoxia-related genes were screened for the EC prognostic model by the univariate, LASSO, and multivariate Cox regression analysis from the TCGA dataset. QT-PCR and functional annotation analysis were performed. Associations between predicted risk and immunotherapy and chemotherapy responses were investigated by evaluating expressions of immune checkpoint inhibitors, infiltrated immune cells, m6a regulators, and drug sensitivity. The ROC curve and calibration plot indicated a fair predictability of our prognostic nomogram model. NR3C1 amplification, along with IL-6 and SRPX suppressions, were detected in tumor. High stromal score and enriched infiltrated aDCs and B cells in the high-risk group supported the hypothesis of immune-deserted tumor. Hypoxia-related molecular subtypes of EC were then identified via the gene signature. Cluster 2 patients showed a significant sensitivity to Vinblastine. In summary, our hypoxia signature model accurately predicted the survival outcome of EC patients and assessed translational and transcriptional dysregulations to explore targets for precise medical treatment. Full article

(This article belongs to the Special Issue New Insights into Endometrial Cancer 2022)

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14 pages, 2266 KiB

Open AccessArticle

Identification of NRAS Diagnostic Biomarkers and Drug Targets for Endometrial Cancer—An Integrated in Silico Approach

by Larsen Alessandro, Kat-Jun Eric Low, Aisha Abushelaibi, Swee-Hua Erin Lim, Wan-Hee Cheng, Sook-keng Chang, Kok-Song Lai, Yap Wai Sum and Sathiya Maran

Int. J. Mol. Sci. 2022, 23(22), 14285; https://doi.org/10.3390/ijms232214285 - 18 Nov 2022

Cited by 5 | Viewed by 2449

Abstract

The diagnosis of endometrial cancer involves sequential, invasive tests to assess the thickness of the endometrium by a transvaginal ultrasound scan. In 6–33% of cases, endometrial biopsy results in inadequate tissue for a conclusive pathological diagnosis and 6% of postmenopausal women with non-diagnostic specimens are later discovered to have severe endometrial lesions. Thus, identifying diagnostic biomarkers could offer a non-invasive diagnosis for community or home-based triage of symptomatic or asymptomatic women. Herein, this study identified high-risk pathogenic nsSNPs in the NRAS gene. The nsSNPs of NRAS were retrieved from the NCBI database. PROVEAN, SIFT, PolyPhen-2, SNPs&GO, PhD-SNP and PANTHER were used to predict the pathogenicity of the nsSNPs. Eleven nsSNPs were identified as “damaging”, and further stability analysis using I-Mutant 2.0 and MutPred 2 indicated eight nsSNPs to cause decreased stability (DDG scores < −0.5). Post-translational modification and protein–protein interactions (PPI) analysis showed putative phosphorylation sites. The PPI network indicated a GFR-MAPK signalling pathway with higher node degrees that were further evaluated for drug targets. The P34L, G12C and Y64D showed significantly lower binding affinity towards GTP than wild-type. Furthermore, the Kaplan–Meier bioinformatics analyses indicated that the NRAS gene deregulation affected the overall survival rate of patients with endometrial cancer, leading to prognostic significance. Findings from this could be considered novel diagnostic and therapeutic markers. Full article

(This article belongs to the Special Issue New Insights into Endometrial Cancer 2022)

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15 pages, 2343 KiB

Open AccessArticle

Identification of Candidate Biomarker and Drug Targets for Improving Endometrial Cancer Racial Disparities

by Pouya Javadian, Chao Xu, Virginie Sjoelund, Lindsay E. Borden, Justin Garland and Doris Mangiaracina Benbrook

Int. J. Mol. Sci. 2022, 23(14), 7779; https://doi.org/10.3390/ijms23147779 - 14 Jul 2022

Cited by 6 | Viewed by 2002

Abstract

Racial disparities in incidence and survival exist for many human cancers. Racial disparities are undoubtedly multifactorial and due in part to differences in socioeconomic factors, access to care, and comorbidities. Within the U.S., fundamental causes of health inequalities, including socio-economic factors, insurance status, access to healthcare and screening and treatment biases, are issues that contribute to cancer disparities. Yet even these epidemiologic differences do not fully account for survival disparities, as for nearly every stage, grade and histologic subtype, survival among Black women is significantly lower than their White counterparts. To address this, we sought to investigate the proteomic profiling molecular features of endometrial cancer in order to detect modifiable and targetable elements of endometrial cancer in different racial groups, which could be essential for treatment planning. The majority of proteins identified to be significantly altered among the racial groups and that can be regulated by existing drugs or investigational agents are enzymes that regulate metabolism and protein synthesis. These drugs have the potential to improve the worse outcomes of endometrial cancer patients based on race. Full article

(This article belongs to the Special Issue New Insights into Endometrial Cancer 2022)

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16 pages, 2123 KiB

Open AccessArticle

Sera Protein Signatures of Endometrial Cancer Lymph Node Metastases

by Doris Mangiaracina Benbrook, James Randolph Sanders Hocker, Katherine Marie Moxley and Jay S. Hanas

Int. J. Mol. Sci. 2022, 23(6), 3277; https://doi.org/10.3390/ijms23063277 - 18 Mar 2022

Cited by 2 | Viewed by 2166

Abstract

The presence of lymph node metastases in endometrial cancer patients is a critical factor guiding treatment decisions; however, surgical and imaging methods for their detection are limited by morbidity and inaccuracy. To determine if sera can predict the presence of positive lymph nodes, sera collected from endometrial cancer patients with or without lymph node metastases, and benign gynecology surgical patients (N = 20 per group) were subjected to electron spray ionization mass spectrometry (ES-MS). Peaks that were significantly different among the groups were evaluated by leave one out cross validation (LOOCV) for their ability to differentiation between the groups. Proteins in the peaks were identified by MS/MS of five specimens in each group. Ingenuity Pathway Analysis was used to predict pathways regulated by the protein profiles. LOOCV of sera protein discriminated between each of the group comparisons and predicted positive lymph nodes. Pathways implicated in metastases included loss of PTEN activation and PI3K, AKT and PKA activation, leading to calcium signaling, oxidative phosphorylation and estrogen receptor-induced transcription, leading to platelet activation, epithelial-to-mesenchymal transition and senescence. Upstream activators implicated in these events included neurostimulation and inflammation, activation of G-Protein-Coupled Receptor Gβγ, loss of HER-2 activation and upregulation of the insulin receptor. Full article

(This article belongs to the Special Issue New Insights into Endometrial Cancer 2022)

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14 pages, 3442 KiB

Open AccessArticle

Gel-Based Proteomic Identification of Suprabasin as a Potential New Candidate Biomarker in Endometrial Cancer

by Fulvio Celsi, Lorenzo Monasta, Giorgio Arrigoni, Ilaria Battisti, Danilo Licastro, Michelangelo Aloisio, Giovanni Di Lorenzo, Federico Romano, Giuseppe Ricci and Blendi Ura

Int. J. Mol. Sci. 2022, 23(4), 2076; https://doi.org/10.3390/ijms23042076 - 14 Feb 2022

Cited by 11 | Viewed by 2722

Abstract

Endometrial cancer (EC) is the most frequent gynaecologic cancer in postmenopausal women. We used 2D-DIGE and mass spectrometry to identify candidate biomarkers in endometrial cancer, analysing the serum protein contents of 10 patients versus 10 control subjects. Using gel-based proteomics, we identified 24 candidate biomarkers, considering only spots with a fold change in volume percentage ≥ 1.5 or intensity change ≤ 0.6, which were significantly different between cases and controls (p < 0.05). We used Western blotting analysis both in the serum and tissue of 43 patients for data validation. Among the identified proteins, we selected Suprabasin (SBSN), an oncogene previously associated with poor prognosis in different cancers. SBSN principal isoforms were subjected to Western blotting analysis in serum and surgery-excised tissue: both isoforms were downregulated in the tissue. However, in serum, isoform 1 was upregulated, while isoform 2 was downregulated. Data-mining on the TCGA and GTEx projects, using the GEPIA2.0 interface, indicated a diminished SBSN expression in the Uterine Corpus Endometrial Cancer (UCEC) database compared to normal tissue, confirming proteomic results. These results suggest that SBSN, specifically isoform 2, in tissue or serum, could be a potential novel biomarker in endometrial cancer. Full article

(This article belongs to the Special Issue New Insights into Endometrial Cancer 2022)

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19 pages, 3811 KiB

Open AccessArticle

Palmitate Enhances the Efficacy of Cisplatin and Doxorubicin against Human Endometrial Carcinoma Cells

by Zih-Syuan Wu, Shih-Ming Huang and Yu-Chi Wang

Int. J. Mol. Sci. 2022, 23(1), 80; https://doi.org/10.3390/ijms23010080 - 22 Dec 2021

Cited by 8 | Viewed by 3006

Abstract

Endometrial cancer is the most common gynecological cancer worldwide. At present there is no effective screening test for its early detection and no curative treatment for women with advanced-stage or recurrent disease. Overexpression of fatty acid synthase is a common molecular feature of a subgroup of sex steroid-related cancers associated with poor prognoses, including endometrial cancers. Disruption of this fatty acid synthesis leads to cell apoptosis, making it a potential therapeutic target. The saturated fatty acid palmitate reportedly induces lipotoxicity and cell death by inducing oxidative stress in many cell types. Here, we explored the effects of palmitate combined with doxorubicin or cisplatin in the HEC-1-A and RL95-2 human endometrial cancer cell lines. The results showed that physiological concentrations of exogenous palmitate significantly increased cell cycle arrest, DNA damage, autophagy, and apoptosis in both RL95-2 and HEC-1-A cells. It also increased the chemosensitivity of both cell types. Notably, we did not observe that palmitate lipotoxicity reflected increased levels of reactive oxygen species, suggesting palmitate acts via a different mechanism in endometrial cancer. This study thus provides a potential therapeutic strategy in which palmitate is used as an adjuvant in the treatment of endometrial cancer. Full article

(This article belongs to the Special Issue New Insights into Endometrial Cancer 2022)

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14 pages, 2262 KiB

Open AccessArticle

TET3- and OGT-Dependent Expression of Genes Involved in Epithelial-Mesenchymal Transition in Endometrial Cancer

by Piotr Ciesielski, Paweł Jóźwiak, Ewa Forma and Anna Krześlak

Int. J. Mol. Sci. 2021, 22(24), 13239; https://doi.org/10.3390/ijms222413239 - 8 Dec 2021

Cited by 14 | Viewed by 3154

Abstract

TET3 is a member of the TET (ten-eleven translocation) proteins family that catalyzes the conversion of the 5-methylcytosine into 5-hydroxymethylcytosine. TET proteins can also affect chromatin modifications and gene expression independently of their enzymatic activity via interactions with other proteins. O-GlcNAc transferase (OGT), the enzyme responsible for modification of proteins via binding of N-acetylglucosamine residues, is one of the proteins whose action may be dependent on TET3. Here, we demonstrated that in endometrial cancer cells both TET3 and OGT affected the expression of genes involved in epithelial to mesenchymal transition (EMT), i.e., FOXC1, TWIST1, and ZEB1. OGT overexpression was caused by an increase in TWIST1 and ZEB1 levels in HEC-1A and Ishikawa cells, which was associated with increased O-GlcNAcylation of histone H2B and trimethylation of H3K4. The TET3 had the opposite effect on gene expressions and histone modifications. OGT and TET3 differently affected FOXC1 expression and the migratory potential of HEC-1A and Ishikawa cells. Analysis of gene expressions in cancer tissue samples from endometrial cancer patients confirmed the association between OGT or TET3 and EMT genes. Our results contribute to the knowledge of the role of the TET3/OGT relationship in the complex mechanism supporting endometrial cancer progression. Full article

(This article belongs to the Special Issue New Insights into Endometrial Cancer 2022)

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Review

Jump to: Editorial, Research

10 pages, 296 KiB

Open AccessReview

TCGA Molecular Prognostic Groups of Endometrial Carcinoma: Current Knowledge and Future Perspectives

by Damiano Arciuolo, Antonio Travaglino, Antonio Raffone, Diego Raimondo, Angela Santoro, Daniela Russo, Silvia Varricchio, Paolo Casadio, Frediano Inzani, Renato Seracchioli, Antonio Mollo, Massimo Mascolo and Gian Franco Zannoni

Int. J. Mol. Sci. 2022, 23(19), 11684; https://doi.org/10.3390/ijms231911684 - 2 Oct 2022

Cited by 45 | Viewed by 4671

Abstract

The four TCGA-based molecular prognostic groups of endometrial carcinoma (EC), i.e., POLE-mutant, mismatch repair (MMR)-deficient, p53-abnormal, and “no specific molecular profile” (NSMP), have recently been integrated into ESGO-ESTRO-ESP guidelines. The POLE-mutant and MMR-deficient groups are associated with high mutational load, morphological heterogeneity, and inflammatory infiltration. These groups are frequent in high-grade endometrioid, undifferentiated/dedifferentiated, and mixed histotypes. POLE-mutant ECs show good prognosis and do not require adjuvant treatment, although the management of cases at stage >II is still undefined. MMR-deficient ECs show intermediate prognosis and are currently substratified based on clinicopathological variables, some of which might not have prognostic value. These groups may benefit from immunotherapy. P53-mutant ECs are typically high-grade and often morphologically ambiguous, accounting for virtually all serous ECs, most carcinosarcomas and mixed ECs, and half of clear-cell ECs. They show poor prognosis and are treated with chemoradiotherapy; a subset may benefit from HER2 inhibitors or PARP inhibitors. The NSMP group is the most frequent TCGA group; its prognosis is highly variable and affected by clinicopathological/molecular factors, most of which are still under evaluation. In conclusion, the TCGA classification has improved diagnosis, risk stratification, and management of EC. Further studies are needed to resolve the points of uncertainty that still exist. Full article

(This article belongs to the Special Issue New Insights into Endometrial Cancer 2022)

22 pages, 388 KiB

Open AccessReview

Vibrational Biospectroscopy: An Alternative Approach to Endometrial Cancer Diagnosis and Screening

by Roberta Schiemer, David Furniss, Sendy Phang, Angela B. Seddon, William Atiomo and Ketankumar B. Gajjar

Int. J. Mol. Sci. 2022, 23(9), 4859; https://doi.org/10.3390/ijms23094859 - 27 Apr 2022

Cited by 9 | Viewed by 3465

Abstract

Endometrial cancer (EC) is the sixth most common cancer and the fourth leading cause of death among women worldwide. Early detection and treatment are associated with a favourable prognosis and reduction in mortality. Unlike other common cancers, however, screening strategies lack the required sensitivity, specificity and accuracy to be successfully implemented in clinical practice and current diagnostic approaches are invasive, costly and time consuming. Such limitations highlight the unmet need to develop diagnostic and screening alternatives for EC, which should be accurate, rapid, minimally invasive and cost-effective. Vibrational spectroscopic techniques, Mid-Infrared Absorption Spectroscopy and Raman, exploit the atomic vibrational absorption induced by interaction of light and a biological sample, to generate a unique spectral response: a “biochemical fingerprint”. These are non-destructive techniques and, combined with multivariate statistical analysis, have been shown over the last decade to provide discrimination between cancerous and healthy samples, demonstrating a promising role in both cancer screening and diagnosis. The aim of this review is to collate available evidence, in order to provide insight into the present status of the application of vibrational biospectroscopy in endometrial cancer diagnosis and screening, and to assess future prospects. Full article

(This article belongs to the Special Issue New Insights into Endometrial Cancer 2022)

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