mTOR and Toll-like receptor 5 in gastric diffuse large B-cell lymphoma as markers for resistance and sensitivity to H. pylori eradication therapy

Background: Gastric diffuse large B-cell lymphoma (DLBCL) is often associated with Helicobacter pylori (H. pylori) infection. Early-stage gastric DLBCLs could be treated with H. pylori eradication therapy (HPET), and are classified into a sensitive group and a resistant group. Methods: Genome-wide miRNA and mRNA profiles were performed on gastric DLBCLs that had been treated with HPET. MicroRNAs and mRNAs preferentially associated with resistance or sensitivity to HPET were identified. Pathway enrichment and a miR-centered bioinformatic approach were also used. The candidate markers were further evaluated with a luciferase assay and Western blotting in BJAB or U2932 lymphoma cell lines of B-cell origin. These markers were verified in an independent series, and clinical and pathological correlations were established. Results: Genome-wide miRNA and mRNA profiles showed that the resistant group had higher levels of miR-155 and lower levels of DEPTOR (an inhibitor of mTOR) than the sensitive group. BJAB cells transfected with miR-155 also had lower DEPTOR and higher mTOR levels. Therefore, miR-155-mediated inhibition of DEPTOR with secondary activation of mTOR was a potential marker for resistance HPET. In contrast, pathway enrichment analysis showed that Toll-like receptor 5 (TLR5), the receptor for bacterial flagellin, was a potential marker for sensitivity to HPET. In an independent series, stronger expression of pS6K1 (a direct target of mTOR) was associated with the resistant group, and morphologic evidence of active gastritis was associated with the sensitive group. Conclusions: These findings showed that miR-155 and TLR5 were markers for resistance and sensitivity to HPET. Furthermore, histological evaluation of active gastritis might be used as a surrogate marker to predict responsiveness to HPET in gastric DLBCL. These data also suggested the possibility that mTOR inhibitors might be used in gastric DLBCLs resistant to HPET. Gastric diffuse large B-cell lymphoma (DLBCL) is often associated with H. pylori infection, and can be treated with H. pylori eradicatin therapy (HPET). Genome-wide mRNA profiling was performed in 8 gastric DLBCLs sensitive to HPET, and 8 gastric DLBCL resistant to HPET. Tissue blocks of 16 cases of gastric DLBCLs were retireved from the archives f the Department of Pathology at National Taiwan University Hospital. Total RNA was extracted from formalin-fixed paraffin-embedded tissue blocks, and mRNA profiling was performed. Differential expressed mRNAs between the sensitive and the resistant groups were compared.