title: Inhibition of ZEB1 by miR-200 characterizes Helicobacter pylori-positive gastric diffuse large B-cell lymphoma with a less aggressive behavior.
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.
authors.affiliation: Department of Pathology, National Taiwan University Hospital of Medicine, Taipei, Taiwan.
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Huang
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Sung-Hsin
authors.initials: SH
authors.lastname: Kuo
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
authors.affiliation: Department of Pathology, National Taiwan University Hospital of Medicine, Taipei, Taiwan.
authors.forename: Chung-Wu
authors.initials: CW
authors.lastname: Lin
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D016481:Helicobacter Infections / Q000175:diagnosis / Q000382:microbiology*; D016480:Helicobacter pylori / Q000302:isolation & purification*; D018398:Homeodomain Proteins / Q000032:analysis / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D016403:Lymphoma, Large B-Cell, Diffuse / Q000737:chemistry / Q000188:drug therapy / Q000235:genetics / Q000382:microbiology / Q000401:mortality / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000032:analysis / Q000235:genetics; D008875:Middle Aged; D009367:Neoplasm Staging; D010641:Phenotype; D051560:Proto-Oncogene Proteins c-bcl-6; D060888:Real-Time Polymerase Chain Reaction; D012074:Remission Induction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000235:genetics / Q000382:microbiology / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics; D016896:Treatment Outcome; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: C084103:BCL6 protein, human; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1