Inflammation-Induced microRNAs in B-cell lymphoma
Abstract:Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 40% of non-Hodgkin lymphomas, with overall 3-year relapse-free survival of 53%. A germinal center B-cell (GCB-like) subgroup and an activated B-cell (ABC-like) subgroup exist, associated with good versus poor prognosis. In addition to differential expression of coding genes, ABC-type lymphoma cells express high levels of the non-coding microRNA miR-155, an onco-miR whose ectopic expression in the mouse has been shown to give rise to B-cell malignancies. DLBCL feature a dysregulated PI3 kinase pathway, which can promote proliferation and survival. PI3K is regulated by phosphatases PTEN (phosphatase and tensin homolog deleted on chromosome ten) and SHIP (SH2 domain-containing inositol 5-phosphatase). PTEN is a known tumor suppressor and overall mutated in human cancer with a frequency approaching that of p53.
We have identified Ship as the first bona-fide target of miR-155. Interestingly, we have recently found that concomitant ablation of both SHIP and PTEN, in murine B cells (bPTEN/SHIP−/−) induces lethal B-cell lymphoma with 100% penetrance, revealing a novel role for Ship as a tumor-suppressor. cDNA array analyses of DLBCL patient specimens indicate that low mRNA expression level of SHIP can be used as a negative prognostic marker for survival. RT-PCR analysis of micro-dissected lymphoma samples confirmed high levels of miR-155 and low levels of Ship in poor-prognosis ABC-cells as compared to GCB-cells. We further demonstrate that elevated levels of miR-155, and consequent abrogation of SHIP expression, is not due to point mutations or promoter hypermethylation of SHIP in primary DLBCL cells, but rather the result of a TNFα-mediated autocrine loop, a pro-inflammatory cytokine whose serum levels are elevated in DLBCL patients. Consequently, anti-TNFα regimens are sufficient to reduce miR-155 levels and restore expression of Ship in DLBCL cell lines, thus suggesting a novel approach for restoring tumor suppressor activity and inducing growth inhibition of these aggressive tumors. Our findings offer the first direct evidence that specific miRs can function as the link between inflammation and cancer. Finally, the verification of our hypothesis, TNFα promotes survival of DLBCL via miR-155 and SHIP, opens up a novel and immediately accessible (co)treatment for poor prognosis DLBCL.
Document Type: Abstract
Publication date: May 1, 2008