Abstract
Aberrant let-7c microRNA (miRNA) expression has been observed in Helicobacter pylori-related gastric cancer (GC) but fragmentary information is available on the let-7c dysregulation occurring with each phenotypic change involved in gastric carcinogenesis. Let-7c expression was assessed (qRT-PCR) in a series of 175 gastric biopsy samples representative of the whole spectrum of phenotypic changes involved in H. pylori-related gastric oncogenesis including: i) normal gastric mucosa, as obtained from dyspeptic controls (40 biopsy samples); ii) non-atrophic gastritis (40 samples); iii) atrophic-metaplastic gastritis (35 samples); iv) intra-epithelial neoplasia (30 samples); v) GC (30 samples). Let-7c expression was also tested in 20 biopsy samples obtained from 10 patients before and after H. pylori eradication therapy (median follow-up: 10 weeks; range: 7-14). The results obtained were further validated by in situ hybridization on multiple tissue specimens obtained from 5 surgically treated H. pylori-related GCs. The study also included 40 oxyntic biopsy samples obtained from serologically/histologically confirmed autoimmune gastritis (AIG: 20 corpus-restricted, non-atrophic; 20 corpus-restricted, atrophic-metaplastic). Let-7c expression dropped from non-atrophic gastritis to atrophic-metaplastic gastritis, intra-epithelial neoplasia, and invasive GC (p<0.001). It rose again significantly following H. pylori eradication (p=0.009). As in the H. pylori model, AIG also featured a significant let-7c down-regulation (p<0.001). The earliest phases of the two pathways to gastric oncogenesis (H. pylori-environmental and autoimmune host-related) are characterized by similar let-7c dysregulations. In H. pylori infection, let-7c down-regulation regresses after the bacterium's eradication, while it progresses significantly with the increasing severity of the histological lesions.
Highlights
Gastric cancer (GC) is a leading cause of cancerrelated death worldwide [1, 2], and about 90% of noncardia GCs are the ultimate consequence of longstandingHelicobacter pylori (H. pylori) infection [3,4,5,6,7]
For 10 patients enrolled as H. pylori-positive, paired biopsy samples were obtained after the bacterium’s eradication; in 8 of these 10 cases, let-7c expression was significantly higher after the eradication treatment (p=0.009; t-test; Figure 1B)
Let-7c expression was tested in 115 formalin-fixed paraffin-embedded (FFPE) samples representative of normal mucosa and each of the phenotypic lesions occurring in the oncogenic cascade
Summary
Gastric cancer (GC) is a leading cause of cancerrelated death worldwide [1, 2], and about 90% of noncardia GCs are the ultimate consequence of longstandingHelicobacter pylori (H. pylori) infection [3,4,5,6,7]. Gastric cancer (GC) is a leading cause of cancerrelated death worldwide [1, 2], and about 90% of noncardia GCs are the ultimate consequence of longstanding. The stepwise changes occurring in the gastric mucosa have been well characterized, starting from longstanding inflammation, which may result in atrophic www.impactjournals.com/oncotarget changes. Gastric mucosal atrophy is the “cancerization field” in which intra-epithelial neoplasia (IEN), and invasive cancer can develop [3, 9, 10]. In a minority of cases, the initiating cause of the mucosal inflammation is not environmental (H. pylori), but host-related (autoimmune gastritis [AIG]) [11, 12]. Autoimmune, corpus-restricted gastritis may result in mucosal atrophy too, and a higher risk of GC has been associated with AIG as well. The epidemiological and clinico-biological profiles of this “alternative” oncogenic pathway are less well defined than those of the H. pylorirelated model [9, 13]
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