Abstract
Recently, it was shown that leucine-rich repeat-containing receptor 5 (LGR5)-expressing stem cells are the cellular origin of intestinal-type gastric cancer. The aim of our study was to uncover regulatory mechanisms of LGR5 expression in gastric mucosa and their implications for cancer development. Reporter assays identified an LGR5 promoter fragment, which is highly relevant for active LGR5 expression. Chromatin immunoprecipitation verified that SP1 is bound within this region, and reporter activity increased in SP1 transfected cells. Subsequently, the expression of R-spondins (RSPO1 and RSPO2), ligands of LGR5, was explored in neoplastic and nonneoplastic gastric tissue and gastric cancer cell lines. Using IHC, distinct spatial expression patterns of LGR5, RSPO1, and RSPO2 were found in nonneoplastic stomach mucosa and gastric cancer. RSPO expression was lower in gastric cancer compared with nonneoplastic mucosa on both the transcriptional (P = 0.003 for RSPO1 and P = 0.000 for RSPO2; n = 50) and the translational level. Methylation-specific PCR showed higher methylation levels of RSPO1/2 and reexpression of RSPOs in the gastric cancer cell lines MKN45 and MKN74 were induced by demethylating 5-aza-C treatment. Finally, expression patterns of LGR5 and RSPO were similar in gastric cancer.Implications: This report identifies a regulatory mechanism of LGR5 expression in gastric carcinogenesis, with SP1 as an important component of the transcriptional complex and LGR5 activity, which is modulated by its ligands RSPO1 and RSPO2, whose expression is modulated by methylation.Visual Overview: http://mcr.aacrjournals.org/content/15/6/776/F1.large.jpg. Mol Cancer Res; 15(6); 776-85. ©2017 AACR.
Highlights
Despite a declining incidence, gastric cancer still belongs to the leading causes of cancer mortalities worldwide due to its late diagnosis at advanced stages impeding curative treatments [1,2,3]
We describe a specificity protein 1 (SP1)-mediated elevation of leucin-rich G-protein– coupled receptor 5 (LGR5) expression and dysregulation of RSPO1 and RSPO2 expression partly mediated by hypermethylation in the neoplastic gastric mucosa as well as functional consequences in disease-representative cell lines
The importance of LGR5þ cells in regenerating gastrointestinal epithelia has been supported in many recent studies [35]
Summary
Gastric cancer still belongs to the leading causes of cancer mortalities worldwide due to its late diagnosis at advanced stages impeding curative treatments [1,2,3]. CSCs are supposed to benefit from a higher chemotherapeutic resistance and higher signaling network plasticity, tumor tissues still mirror many features of cell type differentiation as well as tissue composition hierarchies, but are equipped with outstanding possibilities for de- and transdifferentiation [5]. To regulate this plasticity, microenvironmental cues may preserve stem cell properties and direct lineages of differentiation to allow for tightly controlled homeostasis; in a similar.
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