Infection With a Hypervirulent Strain of Helicobacter Pylori Primes Gastric Cells Toward Intestinal Transdifferentiation Publisher Pubmed



Saberi S¹ ; Esmaeili M¹ ; Tashakoripour M² ; Eshagh Hosseini M² ; Baharvand H^{3, 4} ; Mohammadi M¹ Show Affiliations
Source: Microbial Pathogenesis Published:2022

Abstract

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. © 2021 Elsevier Ltd