miR-155 inhibits DEPTOR in gastric diffuse large B-cell lymphoma resistant 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 eradication therapy (HPET). Both increased miR155 and decreased DEPTOR were associated with resistance to HPET. MiR-155 inhibits DEPTOR when transfected into BJAB cells, supporting that miR-155 inhibits DEPTOR in gastric DLBCL resistant to HPET. MiR-155 or an empty EGFP+ vector was transfected into BJAB cells. The EGFP+ cells were isolated with flow cytometry. Genome-wide mRNA profiling was performed.