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 mucosaassociated 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 ¼ 0.03), to achieve complete remission (75% vs 43%, P ¼ 0.001), and had a better 5-year disease-free survival rate (73% vs 29%, Po0.001) 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.

Status of Epstein-Barr Virus Coinfection withHelicobacter pyloriin Gastric Cancer

“…Also, dysregulation of FOXD3 promotes gastric carcinogenesis [222]. Many other genes found upregulated by H. pylori are associated with cell cycle progression and proliferation (p14, p16, p21, p27, RAB40C, COX 2, FOS, ERBB2, FGFR2, ABL1, ECOP, JAK2, MYC, MET, SIRT1, PDCD4, TRAF6, GMNN, and CCNE2) [213, 223–242], apoptosis (RECK, SMAD4, TRAIL, MCL1, BIM, XIAP, and PDK1) [243–250], and invasion and metastasis (PTEN, WNT 5a, EDNRA, ROR2, EPB41L3, MMP1, MMP10, HMGA2, ROBO1, TGF- β , EZH2, casein kinase 2, and ZEB) [251–262]. Several studies showed that the upregulation of inflammatory cytokines IL1- β , NOS 2, and TNF- α induced methylation [46–49, 51, 52, 263].…”

Low miR200b-5p levels in minor salivary glands: a novel molecular marker predicting lymphoma development in patients with Sjögren’s syndrome

“…Interestingly, miR200b miRNAs have been almost exclusively associated with solid tumours. A recent study suggests that the elevated miR200b expression and subsequent inhibition of zinc finger E-box-binding homeobox 1 transcription factor and increased BCL6 protein expression is associated with the better prognosis of the Helicobacter pylori -positive gastric diffuse large B cell lymphomas compared with H. pylori -negative ones 26. To this end, it would be interesting to investigate whether miR200b-5p levels are downregulated in other lymphomas that are not associated with SS.…”

Identification of microRNAs implicated in the late differentiation stages of normal B cells suggests a central role for miRNA targets ZEB1 and TP53

“…In humans, Zeb1 is almost absent in quiescent B cells of the mantle zone but it is expressed in proliferating GC B cells of tonsils (http://www.proteinatlas.org/ENSG00000148516-ZEB1/tissue/tonsil). High Zeb1 expression was also associated with adverse overall survival in diffuse large and mantle B cell lymphomas [45–47]. The higher Zeb1 expression levels in malignant lymphomas suggest its involvement during B cell differentiation either at early stages or after BCR activation.…”