Expression of EMT-related genes in lymph node metastasis in endometrial cancer: a TCGA-based study

Abstract

Background Endometrial cancer (EC) with metastasis in pelvic/para-aortic lymph nodes suggests an unsatisfactory prognosis. Nevertheless, there is still rare literature focusing on the role of epithelial-mesenchymal transition (EMT) in lymph node metastasis (LNM) in EC. Methods Transcriptional data were derived from the TCGA database. Patients with stage IA–IIIC2 EC were included, constituting the LN-positive and LN-negative groups. To evaluate the extent of EMT, an EMT signature composed of 315 genes was adopted. The EMT-related genes (ERGs) were obtained from the dbEMT2 database, and the differentially expressed ERGs (DEERGs) between these two groups were screened. On the basis of DEERGs, pathway analysis was carried out. We eventually adopted the logistic regression model to build an ERG-based gene signature with predictive value for LNM in EC. Results A total of 498 patients were included, with 75 in the LN-positive group. Median EMT score of tumor tissues from LN-negative group was − 0.369, while that from the LN-positive group was − 0.296 (P < 0.001), which clearly exhibited a more mesenchymal phenotype for LNM cases on the EMT continuum. By comparing expression profiles, 266 genes were identified as DEERGs, in which 184 were upregulated and 82 were downregulated. In pathway analysis, various EMT-related pathways were enriched. DEERGs shared between molecular subtypes were comparatively few. The ROC curve and logistic regression analysis screened 7 genes with the best performance to distinguish between the LN-positive and LN-negative group, i.e., CIRBP, DDR1, F2RL2, HOXA10, PPARGC1A, SEMA3E, and TGFB1. A logistic regression model including the 7-gene-based risk score, age, grade, myometrial invasion, and histological subtype was built, with an AUC of 0.850 and a favorite calibration (P = 0.074). In the validation dataset composed of 83 EC patients, the model exhibited a satisfactory predictive value and was well-calibrated (P = 0.42). Conclusion The EMT status and expression of ERGs varied in LNM and non-LNM EC tissues, involving multiple EMT-related signaling pathways. Aside from that, the distribution of DEERGs differed among molecular subtypes. An ERG-based gene signature including 7 DEERGs exhibited a desirable predictive value for LNM in EC, which required further validation based upon clinical specimens in the future.

Semaphorins and Their Roles in Breast Cancer: Implications for Therapy Resistance

“…Firstly, SEMA3E, through its receptor, PlexinD1, promotes the proliferation, migration and invasion of cancer cells through its ability to activate the oncogenic signalling of epidermal growth factor receptor (EGFR) and HER-2 [32]. Secondly, SEMA3E induces the nuclear translocation of the Snail2 transcription factor to induce EMT in tumour cells [33,34]. In a panel of 68 primary breast cancer biopsies, it appeared to be the overexpression of SEMA3E but not the PlexinD1 receptor that drove BC progression, since SEMA3E mRNA levels were significantly higher in patients with distant breast cancer metastasis at diagnosis compared to those patients whose tumours were localised to the breast, whereas PlexinD1 levels were similar in both.…”