Infection with a hypervirulent strain of Helicobacter pylori primes gastric cells toward intestinal transdifferentiation

Background: Intestinal 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.Methods: The 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.Results: Following 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. Conclusion: Our 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.

Automated summary

This study evaluated the expression patterns of candidate genes induced by H. pylori infection and found that it caused regulatory changes in genes related to gastric-to-intestinal transdifferentiation. These changes included upregulation of self-renewal and pluripotency factors and aberrant expression of intestine-specific transcription factors, further promoting the process of transdifferentiation. These findings may contribute to a better understanding of the mechanism of gastric-to-intestinal transdifferentiation.