Inhibition of ZEB1 by miR-200 characterizes Helicobacter pylori-positive gastric diffuse large B-cell lymphoma with a less aggressive behavior

Mod Pathol. 2014 Aug;27(8):1116-25. doi: 10.1038/modpathol.2013.229. Epub 2014 Jan 3.

Abstract

Primary gastric diffuse large B-cell lymphomas may or may not have a concurrent component of mucosa-associated lymphoid tissue lymphoma. Diffuse large B-cell lymphoma/mucosa-associated lymphoid tissue lymphomas are often associated with Helicobacter pylori (H. pylori) infection, suggesting that the large cells are transformed from mucosa-associated lymphoid tissue lymphomas. In contrast, only limited data are available on the clinical and molecular features of pure gastric diffuse large B-cell lymphomas. In 102 pure gastric diffuse large B-cell lymphomas, we found H. pylori infection in 53% of the cases. H. pylori-positive gastric diffuse large B-cell lymphomas were more likely to present at an earlier stage (73% vs 52% at stage I/II, P=0.03), to achieve complete remission (75% vs 43%, P=0.001), and had a better 5-year disease-free survival rate (73% vs 29%, P<0.001) than H. pylori-negative gastric diffuse large B-cell lymphomas. Through genome-wide expression profiles of both miRNAs and mRNAs in nine H. pylori-positive and nine H. pylori-negative gastric diffuse large B-cell lymphomas, we identified inhibition of ZEB1 (zinc-finger E-box-binding homeobox 1) by miR-200 in H. pylori-positive gastric diffuse large B-cell lymphomas. ZEB1, a transcription factor for marginal zone B cells, can suppress BCL6, the master transcription factor for germinal center B cells. In 30 H. pylori-positive and 30 H. pylori-negative gastric diffuse large B-cell lymphomas, we confirmed that H. pylori-positive gastric diffuse large B-cell lymphomas had higher levels of miR-200 by qRT-PCR, and lower levels of ZEB1 and higher levels of BCL6 using immunohistochemistry. As BCL6 is a known predictor of a better prognosis in gastric diffuse large B-cell lymphomas, our data demonstrate that inhibition of ZEB1 by miR-200, with secondary increase in BCL6, is a molecular event that characterizes H. pylori-positive gastric diffuse large B-cell lymphomas with a less aggressive behavior.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Tumor* / analysis
  • Biomarkers, Tumor* / genetics
  • DNA-Binding Proteins / analysis
  • Disease-Free Survival
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genome-Wide Association Study
  • Helicobacter Infections / diagnosis
  • Helicobacter Infections / microbiology*
  • Helicobacter pylori / isolation & purification*
  • Homeodomain Proteins* / analysis
  • Homeodomain Proteins* / genetics
  • Humans
  • Immunohistochemistry
  • Lymphoma, Large B-Cell, Diffuse* / chemistry
  • Lymphoma, Large B-Cell, Diffuse* / drug therapy
  • Lymphoma, Large B-Cell, Diffuse* / genetics
  • Lymphoma, Large B-Cell, Diffuse* / microbiology
  • Lymphoma, Large B-Cell, Diffuse* / mortality
  • Lymphoma, Large B-Cell, Diffuse* / pathology
  • Male
  • MicroRNAs* / analysis
  • MicroRNAs* / genetics
  • Middle Aged
  • Neoplasm Staging
  • Phenotype
  • Proto-Oncogene Proteins c-bcl-6
  • Real-Time Polymerase Chain Reaction
  • Remission Induction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stomach Neoplasms* / chemistry
  • Stomach Neoplasms* / drug therapy
  • Stomach Neoplasms* / genetics
  • Stomach Neoplasms* / microbiology
  • Stomach Neoplasms* / mortality
  • Stomach Neoplasms* / pathology
  • Time Factors
  • Transcription Factors* / analysis
  • Transcription Factors* / genetics
  • Treatment Outcome
  • Zinc Finger E-box-Binding Homeobox 1

Substances

  • BCL6 protein, human
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Homeodomain Proteins
  • MIRN200 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins c-bcl-6
  • Transcription Factors
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1