Proteomic analysis of malignant and benign endometrium according to obesity and insulin-resistance status using Reverse Phase Protein Array

Raglan, Olivia; Assi, Nada; Nautiyal, Jaya; Gabra, Hani; Gunter, Marc J.; Kyrgiou, Maria

doi:10.1016/j.trsl.2019.12.003

Cited by 7 publications

(9 citation statements)

References 55 publications

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“…Filling this gap could enable the development of specific therapies for different subsets of endometrial tumors. Little has been published about the specific proteomic profile of low-grade, early-stage ECs, with most studies focusing on isolated protein dysregulation [11][12][13] or the usefulness of proteomics in endometrial cancer diagnosis [14].…”

Section: Introductionmentioning

confidence: 99%

Proteomic Analysis of Low-Grade, Early-Stage Endometrial Carcinoma Reveals New Dysregulated Pathways Associated with Cell Death and Cell Signaling

López-Janeiro

Ruz-Caracuel

Ramon-Patino

et al. 2021

Cancers

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Low-grade, early-stage endometrial carcinoma (EC) is the most frequent malignant tumor of the uterine corpus. However, the molecular alterations that underlie these tumors are far from being fully understood. The purpose of this study is to describe dysregulated molecular pathways from EC patients. Sixteen samples of tumor tissue and paired healthy controls were collected and both were subjected to mass spectrometry (MS)/MS proteomic analysis. Gene ontology and pathway analysis was performed to discover dysregulated pathways and/or proteins using different databases and bioinformatic tools. Dysregulated pathways were cross-validated in an independent external cohort. Cell signaling, immune response, and cell death-associated pathways were robustly identified. The SLIT/ROBO signaling pathway demonstrated dysregulation at the proteomic and transcriptomic level. Necroptosis and ferroptosis were cell death-associated processes aberrantly regulated, in addition to apoptosis. Immune response-associated pathways showed a dominance of innate immune responses. Tumor immune infiltrates measured by immunofluorescence demonstrated diverse lymphoid and myeloid populations. Our results suggest a role of SLIT/ROBO, necroptosis, and ferroptosis, as well as a prominent role of innate immune response in low-grade, early-stage EC. These results could guide future research in this group of tumors.

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Section: Introductionmentioning

confidence: 99%

Proteomic Analysis of Low-Grade, Early-Stage Endometrial Carcinoma Reveals New Dysregulated Pathways Associated with Cell Death and Cell Signaling

López-Janeiro

Ruz-Caracuel

Ramon-Patino

et al. 2021

Cancers

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“…The role of FN1, which encodes fibronectin, and DUSP4, which encodes dual-specificity protein phosphatase 4, in endometrial cancer is not well understood. A recent study by Raglan et al evaluated the TCGA proteomic data of 560 endometrial cancers and demonstrated that obese patients without cancer had upregulation of several proteins, including DUSP4 (30). Another recent study evaluated the predictive model of lymph node involvement in endometrial cancer using a combined proteomic and transcriptomic approach.…”

Section: Discussionmentioning

confidence: 99%

A 4-Gene Signature Associated With Recurrence in Low- and Intermediate-Risk Endometrial Cancer

et al. 2021

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BackgroundThe molecular profile of endometrial cancer has become an important tool in determining patient prognosis and their optimal adjuvant treatment. In addition to The Cancer Genome Atlas (TCGA), simpler tools have been developed, such as the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE). We attempted to determine a genetic signature to build a recurrence risk score in patients diagnosed with low- and intermediate-risk endometrial cancer.MethodsA case-control study was conducted. The eligible patients were women diagnosed with recurrence low- and intermediate-risk endometrial cancer between January 2009 and December 2014 at a single institution; the recurrence patients were matched to two nonrecurrence patients with the same diagnosis by age and surgical staging. Following RNA isolation of 51 cases, 17 recurrence and 34 nonrecurrence patients, the expression profile was determined using the nCounter® PanCancer Pathways Panel, which contains 770 genes.ResultsThe expression profile was successfully characterized in 49/51 (96.1%) cases. We identified 12 genes differentially expressed between the recurrence and nonrecurrence groups. The ROC curve for each gene was generated, and all had AUCs higher than 0.7. After backward stepwise logistic regression, four genes were highlighted: FN1, DUSP4, LEF1, and SMAD9. The recurrence risk score was calculated, leading to a ROC curve of the 4-gene model with an AUC of 0.93, sensitivity of 100%, and specificity of 72.7%.ConclusionWe identified a four-gene signature that may be associated with recurrence in patients with low- and intermediate-risk endometrial cancer. This finding suggests a new prognostic factor in this poorly explored group of patients with endometrial cancer.

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“…In diabetes mellitus, excessive plasma glucose concentrations can upregulate intestinal SGK1 expression and thus SGK1dependent stimulation of SGLT1, contributing to the maintenance of obesity (Dieter et al, 2004). A number of studies have proposed that abnormal glucose metabolism in the endometrium contributes to the increased risk of adverse pregnancy outcomes (Salker et al, 2017;Flannery et al, 2018;Raglan et al, 2020). It has now been reported, that SGLT1 is indeed expressed in the endometrium and controls glycogen accumulation essential for histiotrophic nutrition in pregnancy (Salker et al, 2017).…”

Section: Sgk1 Obesity and Diabetesmentioning

confidence: 99%

The Enigmatic Role of Serum & Glucocorticoid Inducible Kinase 1 in the Endometrium

Läng

Rajaxavier

Singh

et al. 2020

Front. Cell Dev. Biol.

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The serum-and glucocorticoid-inducible kinase 1 (SGK1) is subject to genetic up-regulation by diverse stimulators including glucocorticoids, mineralocorticoids, dehydration, ischemia, radiation and hyperosmotic shock. To become active, the expressed kinase requires phosphorylation, which is accomplished by PI3K/PDK1 and mTOR dependent signaling. SGK1 enhances the expression/activity of various transport proteins including Na + /K +-ATPase as well as ion-, glucose-, and amino acid-carriers in the plasma membrane. SGK1 can further up-regulate diverse ion channels, such as Na +-, Ca 2+-, K +-and Cl − channels. SGK1 regulates expression/activity of a wide variety of transcription factors (such as FKHRL1/Foxo3a, β-catenin, NFκB and p53). SGK1 thus contributes to the regulation of transport, glycolysis, angiogenesis, cell survival, immune regulation, cell migration, tissue fibrosis and tissue calcification. In this review we summarized the current findings that SGK1 plays a crucial function in the regulation of endometrial function. Specifically, it plays a dual role in the regulation of endometrial receptivity necessary for implantation and, subsequently in pregnancy maintenance. Furthermore, fetal programming of blood pressure regulation requires maternal SGK1. Underlying mechanisms are, however, still ill-defined and there is a substantial need for additional information to fully understand the role of SGK1 in the orchestration of embryo implantation, embryo survival and fetal programming.

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Proteomic analysis of malignant and benign endometrium according to obesity and insulin-resistance status using Reverse Phase Protein Array

Cited by 7 publications

References 55 publications

Proteomic Analysis of Low-Grade, Early-Stage Endometrial Carcinoma Reveals New Dysregulated Pathways Associated with Cell Death and Cell Signaling

Proteomic Analysis of Low-Grade, Early-Stage Endometrial Carcinoma Reveals New Dysregulated Pathways Associated with Cell Death and Cell Signaling

A 4-Gene Signature Associated With Recurrence in Low- and Intermediate-Risk Endometrial Cancer

The Enigmatic Role of Serum & Glucocorticoid Inducible Kinase 1 in the Endometrium

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