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

Abstract

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.

Construction and Validation of a Ferroptosis-Related Prognostic Model for Endometrial Cancer

“…Ferroptosis releases damage-related molecular patterns that can be sensed by immune cells to amplify the inflammatory response. With the advent of immunotherapy, people are increasingly aware of the impact of the immune microenvironment on cancer behavior and clinical outcomes ( López-Janeiro et al, 2021 ). Furthermore, we found that activated CD8 T cells, eosinophils, CD56dim natural killer cells, and activated B cells are good prognostic factors for EC, which is basically consistent with the research results of the previous research ( López-Janeiro et al, 2021 ).…”

“…With the advent of immunotherapy, people are increasingly aware of the impact of the immune microenvironment on cancer behavior and clinical outcomes ( López-Janeiro et al, 2021 ). Furthermore, we found that activated CD8 T cells, eosinophils, CD56dim natural killer cells, and activated B cells are good prognostic factors for EC, which is basically consistent with the research results of the previous research ( López-Janeiro et al, 2021 ). Activated CD8 T cells and eosinophils have been widely verified to have significant antitumor effects ( Sakkal et al, 2016 ; Loo Yau et al, 2021 ; Pauken et al, 2021 ).…”

Spatial Proteomic Analysis of Isogenic Metastatic Colorectal Cancer Cells Reveals Key Dysregulated Proteins Associated with Lymph Node, Liver, and Lung Metastasis

“…To avoid differences in the amount of protein labeled by each TMT reagent, the total sum of signals of each channel were corrected by computing normalization factors to equal these sums. Sample loading (SL) normalization was carried out with R Studio (version 4.1.1) according to established protocol (https://github.com/pwilmart, accessed on 15 May 2020), using "tidyverse", "psych", "gridExtra" and "scales" packages (Figure S1) [26,27]. Data were then exported to Microsoft Excel 2019 and Perseus (Version 1.6.6) for the subsequent analysis.…”

Identification of the Prognostic Signature Associated With Tumor Immune Microenvironment of Uterine Corpus Endometrial Carcinoma Based on Ferroptosis-Related Genes

“…In addition, other genes such as retinoblastoma (Rb), nuclear factor erythroid 2-related factor 2 (NRF2), and metallothionein (MT)-1G are reported to be associated with ferroptosis and protect liver cancer from induction of sorafenib (Louandre et al, 2015;Sun et al, 2016a,b). In 2021, researchers have revealed that ferroptosis process was aberrantly regulated in UCEC and an activator of ferroptosis can induce cell death in UCEC cells (Lopez-Janeiro et al, 2021;Zhang et al, 2021). However, the prognosis value of ferroptosis in the endometrial carcinoma still remains blank.…”