Penicillin‑binding protein 1A mutation‑positive Helicobacter�pylori promotes epithelial‑mesenchymal transition in gastric cancer via the suppression of microRNA‑134

Abstract

Evidence suggests that Helicobacter pylori (H. pylori) is not only the main cause of gastric cancer (GC), but is also closely associated with its metastasis. One of the major virulence factors in H. pylori is the cytotoxin-associated gene A (CagA). With the growing proportion of amoxicillin-resistant H. pylori strains, the present study aimed to explore the effects of CagA- and penicillin-binding protein 1A (PBP1A) mutation-positive H. pylori (H. pyloriCagA+/P+) on GC cells, and its clinical significance. The clinical significance of H. pyloriCagA+/P+ infection was analyzed in patients with GC. In vitro, GC cells were infected with H. pyloriCagA+/P+ to investigate whether it was involved in the epithelial-mesenchymal transition (EMT) of SGC-7901 cells using immunofluorescence and western blot analysis. The results of clinical analysis demonstrated that, although CagA-negative H. pylori infection had no significant association with the characteristics of patients with GC, H. pyloriCagA+/P+ infection was significantly associated with various clinicopathological parameters, including invasion depth, lymphatic metastasis and distant metastasis. In vitro, the results indicated that H. pyloriCagA+/P+ promoted proliferation, invasion and EMT of SGC-7901 cells. MicroRNA (miR)-134 was downregulated in H. pyloriCagA+/P+ infected tissues compared with in those with H. pyloriCagA+/P- infection. miR-134 overexpression significantly reversed H. pyloriCagA+/P+ infection-associated cell proliferation, invasion and EMT. Furthermore, the results revealed that Forkhead box protein M1 (FoxM1) was a direct target of miR-134, and FoxM1 knockdown impeded H. pyloriCagA+/P+-induced EMT. In conclusion, the present study demonstrated that miR-134 may suppress the proliferation, invasion and EMT of SGC-7901 cells by targeting FoxM1, and may serve a protective role in the process of H. pyloriCagA+/P+-induced GC. These findings may lead to an improved understanding of H. pyloriCagA+/P+-associated poor clinical characteristics in patients with GC.

Helicobacter pylori Virulence Factors—Mechanisms of Bacterial Pathogenicity in the Gastric Microenvironment

“…Moreover, CagA is highly associated with the induction and further progression of the EMT within the gastric mucosa, which is associated with greater invasiveness properties. The process is stimulated via several CagA-related mechanisms such as the downregulation of programmed cell death protein 4 (PDCD4), induction of cancer stem cell-like properties, reduction in glycogen synthase kinase 3 (GSK-3) activity, overactivation of fibroblasts, suppression of microRNA-134, altering the yes-associated protein (YAP) pathway, or Afadin protein downregulation [ 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ]. Particular cagA genotypes present different severity of enhanced IL-8 and cytotoxin production, inflammatory responses, or apoptosis in gastric epithelial cells.…”

FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

“…Interestingly, PVT1 is located on chromosome band 8q24.21 and is frequently co-amplified with MYC [ 30 , 194 ]. Additional miRNAs established to target FOXM1 in ovarian cancer are miR-134 [ 195 , 196 , 197 , 198 , 199 ] and miR-216b [ 200 , 201 , 202 , 203 ]. Interestingly, a recent report indicates that FOXM1 acts as a transcriptional regulator of several miRNA molecules in triple-negative breast cancer, which has a similar molecular profile to HGSC [ 204 ].…”

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

“…Penicillin-binding protein (PBP) is a specialized acyl serine transferase released by H. pylori with an affinity for penicillin binding; any modifications within PBP might induce resistance to β-lactam antibiotics (amoxicillin, penicillin G, ampicillin) [197]. These mainly include either mutations or mosaics (or both) of PBP2X, PBP2B, and PBP1A [198]. It was shown that H. pylori PBPs might present unique characteristics because of several putative genes encoding PBPs.…”