Inflammation-Induced microRNAs in B-cell lymphoma
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
Affiliations: 1: Rigshospitalet, Department of Hematology, Copenhagen, Denmark 2: Ohio State University (OSU), Columbia, OH, USA 3: University of California, San Diego (UCSD), La Jolla, CA, USA
Publication date: May 1, 2008