Epigenetic induction of tumor stemness via the Lipopolysaccharide-TET3-HOXB2 signaling axis in esophageal squamous cell carcinoma

Abstract

Background: Esophageal squamous cell cancer (ESCC) is one kind of frequent digestive tumor. The inflammatory environment plays an important role in the tumorigenesis and development of ESCC. Cancer stem cells are a small group of tumor cells with stem cell characteristics, which become the potential causes of failure to tumor treatment. Methods: ELISA was performed to detect the lipopolysaccharide concentration in cancer tissues. qPCR, Western blot, FACS, Immunohistochemistry, Immunofluorescence and Dot blot were applied to detect target genes expression. CCK-8, Colony-formation, Transwell, Sphere and Xenograft were performed to investigate the function of cells, influenced by risk factors. The survival curve was drawn with the Kaplan-Meier product limit estimator. Nano-hmC-Seal-seq was applied to detect the downstream target of TET3. ChIP-qPCR was performed to demonstrate the transcriptional regulation of stem cell-associated genes by HOXB2. Results: Lipopolysaccharide concentration was significantly up-regulated in ESCC. High concentration of lipopolysaccharide stimulation induced the stemness of ESCC cells. TET3 expression was elevated with lipopolysaccharide stimulation via p38/ERK-MAPK pathway in ESCC and negatively correlated with patients’ survival. TET3 induced the stemness of ESCC cells. Nano-hmC-Seal-seq showed that TET3 overexpression led to a significant increase in 5hmC levels of HOXB2 gene region, which was thus identified as the downstream target of TET3. The binding of HOXB2 to NANOG and cMYC was verified by ChIP-qPCR. Conclusions: Lipopolysaccharide served as a tumor promotor in ESCC by inducing cancer cell stemness through the activation of a LPS-TET3-HOXB2 signaling axis, which might provide a novel therapeutic strategy for ESCC.

Ten-eleven translocation proteins (TETs): tumor suppressors or tumor enhancers?

“…It could also stimulate cell cycle arrest and senescence in TNBC cells. Thus, the EZH2-H3K27me3-TET1 axis could become a potentially promising therapeutic target via modulation of the epigenetic landscape [112].…”