López-Janeiro Álvaro, Ruz-Caracuel Ignacio, Ramón-Patino Jorge L, De Los Ríos Vivian, Villalba Esparza María, Berjón Alberto, Yébenes Laura, Hernández Alicia, Masetto Ivan, Kadioglu Ece, Goubert Virginie, Heredia-Soto Victoria, Barderas Rodrigo, Casal José Ignacio, de Andrea Carlos E, Redondo Andrés, Mendiola Marta, Peláez-García Alberto, Hardisson David
Department of Pathology, Hospital Universitario La Paz, IdiPAZ, 28046 Madrid, Spain.
Department of Medical Oncology, Hospital Universitario La Paz, IdiPAZ, 28046 Madrid, Spain.
Cancers (Basel). 2021 Feb 14;13(4):794. doi: 10.3390/cancers13040794.
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.
低级别早期子宫内膜癌（EC）是子宫体最常见的恶性肿瘤。然而，这些肿瘤潜在的分子改变远未被完全理解。本研究的目的是描述EC患者失调的分子通路。收集了16份肿瘤组织样本和配对的健康对照样本，并对两者进行了质谱（MS）/MS蛋白质组分析。使用不同的数据库和生物信息学工具进行基因本体论和通路分析，以发现失调的通路和/或蛋白质。在一个独立的外部队列中对失调的通路进行交叉验证。细胞信号传导、免疫反应和细胞死亡相关通路被明确识别。SLIT/ROBO信号通路在蛋白质组和转录组水平表现出失调。除凋亡外，坏死性凋亡和铁死亡是异常调节的细胞死亡相关过程。免疫反应相关通路显示出先天免疫反应占主导地位。通过免疫荧光测量的肿瘤免疫浸润显示出不同的淋巴细胞和髓细胞群体。我们的结果表明SLIT/ROBO、坏死性凋亡和铁死亡的作用，以及先天免疫反应在低级别早期EC中的突出作用。这些结果可为该组肿瘤的未来研究提供指导。
