Abstract
BackgroundIntestinal metaplasia, gastric-to-intestinal transdifferentiation, occurs as a result of the misexpression of certain regulatory factors, leading to genetic reprogramming. Here, we have evaluated the H. pylori-induced expression patterns of these candidate genes. MethodsThe expression levels of 1) tissue-specific transcription factors (RUNX3, KLF5, SOX2, SALL4, CDX1 and CDX2), 2) stemness factors (TNFRSF19, LGR5, VIL1) and 3) tissue-specific mucins (MUC5AC, MUC2) were evaluated by quantitative real-time PCR in gastric primary cells (GPCs), in parallel with two gastric cancer (MKN45 and AGS) cell lines, up to 96h following H. pylori infection. ResultsFollowing H. pylori infection of GPCs, RUNX3 declined at 24h post infection (−6.2 ± 0.3) and remained downregulated for up to 96h. Subsequently, overexpression of self-renewal and pluripotency transcription factors, KLF5 (3.6 ± 0.2), SOX2 (7.6 ± 0.5) and SALL4 (4.3 ± 0.2) occurred. The expression of TNFRSF19 and LGR5, demonstrated opposing trends, with an early rise of the former (4.5 ± 0.3) at 8h, and a simultaneous fall of the latter (-1.8 ± 0.5). This trend was reversed at 96h, with the decline in TNFRSF19 (−5.5 ± 0.2), and escalation of LGR5 (2.6 ± 0.2) and VIL1 (1.8 ± 0.3). Ultimately, CDX1 and CDX2 were upregulated by 1.9 and 4.7-fold, respectively. The above scenario was, variably observed in MKN45 and AGS cells. ConclusionOur data suggests an interdependent gene regulatory network, induced by H. pylori infection. This interaction begins with the downregulation of RUNX3, upregulation of self-renewal and pluripotency transcription factors, KLF5, SOX2 and SALL4, leading to the downregulation of TNFRSF19, upregulation of LGR5 and aberrant expression of intestine-specific transcription factors, potentially facilitating the process of gastric-to-intestinal transdifferentiation.
Highlights
Helicobacter pylori infects the majority of the population in the developing world 1
Intestinal type gastric cancer (GC) develops from a multi-step alteration process, which begins with superficial gastritis and can progress to chronic and atrophic gastritis, leading to intestinal metaplasia (IM) and intestinal type GC 7
The baseline mRNA levels and relative gene expression for the three groups of 1) tissue-specific transcription factors (RUNX3, KLF5, SOX2, SALL4, CDX1 and CDX2), 2) stemness factors (TNFRSF19, LGR5, VIL1) and 3) tissue-specific mucins (MUC5AC, MUC2) were found to be consistent over time (Fig. 1A). According to their comparative gene expression profiles, the three cell lines behaved as follows: Of the first category of genes, SOX2, SALL4, and CDX1 were expressed amongst the three cell lines
Summary
Helicobacter pylori infects the majority of the population in the developing world 1. This infection induces a number of complications, ranging from chronic active gastritis to peptic ulcers and gastric cancer (GC) 2,3. According to Lauren’s classification, intestinal type gastric cancer is one of the major subtypes of gastric adenocarcinoma with precancerous processes, clinical features and epidemiology, different from the diffuse subtype [5,6]. Intestinal type GC develops from a multi-step alteration process, which begins with superficial gastritis and can progress to chronic and atrophic gastritis, leading to intestinal metaplasia (IM) and intestinal type GC 7. Intestinal metaplasia, gastric-to-intestinal transdifferentiation, occurs as a result of the misexpression of certain regulatory factors, leading to genetic reprogramming. We have evaluated the H. pylori-induced expression patterns of these candidate genes
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