Abstract
To study the mechanisms of gastric tumorigenesis, we have established CSN cell line from human normal gastric mucosa, and CS12, a tumorigenic and invasive gastric cancer cell line from CSN passages. Many stem cell markers were expressed in both CSN and CS12 cells, but LGR5 and NANOG were expressed only in CS12 cells. Increased expression of homeobox A13 (HoxA13) and its downstream cascades was significant for the tumorigenic activity of CS12 cells, and was associated with recruitment of E2F-1 to HoxA13 promoter accompanied with increased trimethylation of histone H3 lysine 4 (H3K4me3) at the hypomethylated E2F motifs. Knockdown of HoxA13 caused the downregulation of long non-coding RNA HOTTIP and insulin growth factor-binding protein 3 (IGFBP-3) genes, indicating that both were targets of HoxA13. Concurrent regulation of HoxA13-HOTTIP was mediated by the mixed lineage leukemia-WD repeat domain 5 complex, which caused the trimethylation of H3K4 and then stimulated cell proliferation. HoxA13 transactivated the IGFBP-3 promoter through the HOX-binding site. Activation of IGFBP-3 stimulated the oncogenic potential and invasion activity. Increased expression of HoxA13 (63.2%) and IGFBP-3 (28.6%) was detected in human gastric cancer tissues and was found in the gastric cancer data of The Cancer Genome Atlas. Taken together, the HoxA13–HOTTIP–IGFBP-3 cascade is critical for the carcinogenic characteristics of CS12 cells.
Highlights
Homeobox genes are known as the transcriptional regulators of mammalian embryogenic development and are deregulated in tumorigenesis
Cellcycle analysis showed that 27%–32% of CS12 cells were in S-phase, whereas only 18%–22% of CSN cells were in S-phase (Figure 1C)
The results showed that MLL1 and WD repeat domain 5 (WDR5) densely occupied at the E1 site but not at the NS site, which was coincident with increased H3K4me3 and homeobox A13 (HoxA13) expression in CS12 but not in CSN cells (Figures 2 and 4E)
Summary
Homeobox genes are known as the transcriptional regulators of mammalian embryogenic development and are deregulated in tumorigenesis. There are few known direct targets of Hox proteins, and their mechanism of regulation is incompletely understood. The homeobox A13 (HoxA13) gene is the most posterior of the HOX clusters in 7p15.2. This gene is expressed in the genital tubercle during embryogenesis [1, 2] and plays an essential role in skeletogenesis, interdigital programmed cell death, and cell sorting of autopod formation. HoxA13 is essential for placental vascular patterning and labyrinth endothelial specification through direct regulation of tyrosine kinase with immunoglobulinlike and epidermal growth factor-like domain 1 and forkhead box F1 [11]
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