Overexpression of TMEFF1 in Endometrial Carcinoma and the Mechanism Underlying its Promotion of Malignant Behavior in Cancer Cells

Abstract

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.

ST14 interacts with TMEFF1 and is a predictor of poor prognosis in ovarian cancer

“…High TMEFF1 expression has been detected in melanoma, liver cancer, and kidney cancer cell lines [ 9 ], but there have been no functional studies. We confirmed that TMEFF1 is an oncogene in ovarian cancer and endometrial carcinoma [ 10 , 49 ]. TMEFF1 promotes cell proliferation, migration and invasion, inhibits apoptosis through MAPK and PI3K/AKT signaling pathways [ 10 ], and interacts with the tumor marker protein AHNAK in ovarian cancer [ 20 ].…”

MIR503HG impeded ovarian cancer progression by interacting with SPI1 and preventing TMEFF1 transcription

“…TMEFF1 is highly expressed in endometrial cancer and is closely related to FIGO staging and lymph node metastasis. Interference with TMEFF1 inhibits the invasion, migration and EMT progress of endometrial cancer cells [ 27 ]. Butorphanol treatment suppressed the viability, migration, invasion and colony formation of ovarian cancer cells, and it was found that Butorphanol might play its role by decreasing TMEFF1 expression [ 28 ].…”

“…Mitogen-activated protein kinase (MAPK) pathway is a complex signal cascade that is often involved in tumorigenesis, tumor progression and drug resistance [ 30 ]. According to reports, TMEFF1 can promote the malignant behaviors of ovarian cancer and endometrial cancer cells by activating MAPK and PI3K/AKT signaling pathways [ 18 , 27 ]. Our data demonstrated that interference with MIR503HG activated the MAPK and PI3K/AKT signaling pathways, while TMEFF1 silence rescued the effect of MIR503HG siRNA on the two pathways, suggesting that MIR503HG might regulate the MAPK and PI3K/AKT pathways by affecting the expression of TMEFF1, thereby participating in the progression of ovarian cancer.…”

Opioids in cancer: The κ‑opioid receptor (Review)

“…Transmembrane protein with EGF-like and two follistatin like domains 1 (TMEFF1) serves a vital role in the development of various types of tumor, including brain ( 182 ), endometrial carcinoma ( 183 ) and ovarian cancer ( 184 ). Butorphanol significantly inhibits the malignant biological behavior of ES-2 and SKOV3 ovarian cancer cells and the expression of TMEFF1 is significantly downregulated in ovarian cancer cells ( 185 ).…”