1. Shengjing Hospital of China Medical University, Department of Obstetrics and Gynecology, Shenyang, China.
2. Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, China.
3. University Hospital, LMU Munich, Department of Obstetrics and Gynecology, Munich, Germany.
4. West China Second University Hospital, Sichuan University, Department of Obstetrics and Gynecology, Sichuan, China.
Background: Although tomoregulin-1 (TMEFF1) is involved in embryonic development and central nervous system regulation and is a cancer suppressor gene in brain cancers, its role in endometrial carcinoma remains unclear.
Methods: The expression and prognostic value of TMEFF1 were analyzed by bioinformatics methods and immunohistochemistry. An endometrial carcinoma cell line with low expression of TMEFF1 was constructed. Scratch and Transwell assays were used to determine the effect of TMEFF1 on cell invasion and migration. Changes in key proteins in the MAPK and PI3K/AKT signaling pathways and in epithelial-mesenchymal transition (EMT)-related proteins were analyzed using western blot. Chromatin immunoprecipitation assay (ChIP) was performed to identify whether the TMEFF1 promoter region binds to the transcription factor p53.
Results: TMEFF1 was significantly upregulated in endometrial carcinoma, was closely associated with FIGO stage (P=0.021) and lymph node metastasis (P=0.029), and was an independent risk factor for prognosis (P=0.044). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed that TMEFF1 and its related genes are involved in the cell cycle, regulation of mitosis, epigenetics, neural development, cell biological signal transduction and some key signal pathways. We also identified kinases, microRNAs and a transcription factor network related to TMEFF1 and the effect of TMEFF1 mutation on prognosis. In vitro knockdown of TMEFF1 significantly inhibited cell invasion and migration. Knockdown of TMEFF1 inhibited Epithelial-mesenchymal transition (EMT) and activation of the MAPK and PI3K/AKT pathways. However, the transcription factor p53 was not found to regulate the TMEFF1 gene.
Conclusion: TMEFF1 plays an important role in endometrial carcinoma and may thus be a potential anticancer therapeutic target for endometrial carcinoma.
Keywords: TMEFF1, endometrial carcinoma, EMT, MAPK, metastasis