A polymorphic minisatellite region of BORIS regulates gene expression and its rare variants correlate with lung cancer susceptibility

Aberrant expression of BORIS/CTCFL (Brother of the Regulator of Imprinted Sites/CTCF-like protein) is reported in different malignancies. In this study, we characterized the entire promoter region of BORIS/CTCFL, including the CpG islands, to assess the relationship between BORIS expression and lung cancer. To simplify the construction of luciferase reporter cassettes with various-sized portions of the upstream region, genomic copies of BORIS were isolated using TAR cloning technology. We analyzed three promoter blocks: the GATA/CCAAT box, the CpG islands and the minisatellite region BORIS-MS2. Polymorphic minisatellite sequences were isolated from genomic DNA prepared from the blood of controls and cases. Of the three promoter blocks, the GATA/CCAAT box was determined to be a critical element of the core promoter, while the CpG islands and the BORIS-MS2 minisatellite region were found to act as regulators. Interestingly, the polymorphic minisatellite region BORIS-MS2 was identified as a negative regulator that repressed the expression levels of luciferase reporter cassettes less effectively in cancer cells compared with normal cells. We also examined the association between the size of BORIS-MS2 and lung cancer in a case–control study with 590 controls and 206 lung cancer cases. Rare alleles of BORIS-MS2 were associated with a statistically significantly increased risk of lung cancer (odds ratio, 2.04; 95% confidence interval, 1.02–4.08; and P=0.039). To conclude, our data provide information on the organization of the BORIS promoter region and gene regulation in normal and cancer cells. In addition, we propose that specific alleles of the BORIS-MS2 region could be used to identify the risk for lung cancer.

Role of Gastric Stem Cells in Gastric Carcinogenesis by Chronic Helicobacter pylori Infection

Gastric cancer is a disease with the second cancer-related mortality in the world. Helicobacter pylori infection that is one of major causes of gastric carcinogenesis induces a chronic inflammation in stomach. The epithelial-mesenchymal transition and/or the accumulation of genetic mutation occur during regenerating the injured gastric epithelial cells due to chronic inflammation by the infection of H. pylori. Normal gastric cells can be transformed into cancer stem cells by the epithelial-mesenchymal transition and/or the accumulation of genetic mutation that initiate the development of gastric cancer. Gastric epithelial cells, bone marrow-derived cells and gastric stem cells in gastric tissue might be the source of gastric cancer stem cells as the target cells that might be susceptible for epithelial-mesenchymal transition and/or the accumulation of genetic mutation. Normal stem cells in gastric tissue regenerating the injured gastric tissue also have the potential to be cancer stem cells known as the origin of cancer development when their ability for regulating differentiation and/or proliferation of normal stem cells is damaged by epithelial-mesenchymal transition and/or the accumulation of genetic mutation. Therefore if the mechanism regulating the transformation of normal stem cells to cancer stem cells is discovered, it might suggest the fundamental therapeutic strategy for preventing the development of gastric cancer by the chronic infection of H. pylori.