Researchers at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine have discovered a potentially new therapeutic target to treat activated B-cell diffuse large B-cell lymphoma (DLBCL).
In the study, “MiR-181a negatively regulates NF-κB signaling and affects activated B-cell like diffuse large B-cell lymphoma pathogenesis,” published in the journal Blood, the team showed that a specific microRNA called miR-181a represses NF-κB signaling and decreases cell proliferation and tumor cell survival in DLBCL, the most common form of non-Hodgkin lymphoma (NHL), accounting for up to 30 percent of newly diagnosed cases in the United States.
Thanks to genomic advances, researchers and clinicians are now able to categorize DLBCLs into two subtypes, germinal center B-cell-like (GCB) and activated B-cell-like (ABC). ABC-like DLBCLs are known to be aggressive, deadly, and resistant to chemotherapy-induced cell death. The NFκB pathway, which plays a significant role in many cancers, is partly responsible for ABC-like lymphomas’ progression and survival, due to its permanent activity. While the NFκB pathway also exists in normal B-cells, it is turned on when necessary and subsequently turned off, but it is permanently turned on in ABC-like DLBCL, leading to the cancer’s continuous growth.
Research has also discovered that ABC-like DLBCLs have less miR-181a, a critical gene regulator that, like other microRNAs, shuts down gene expression post transcriptionally. Previous research from the same group has revealed that patients whose tumors contain miR-181a have better survival outcomes.
The team, led by Izidore S. Lossos, M.D., director of the Lymphoma Program at Sylvester, studied cell lines and tumor grafts in mice, observing that miR-181a levels were significantly lower in ABC-like tumors than in GCB-like tumors. Moreover, miR-181a is a negative regulator of NF-κB signalling, and miR-181a overexpression significantly decreased the expression and activity of key NF-κB signalling genes and transcription factors, such as CARD11, a known DLBCL oncogene (a gene that is involved in tumor progression/development).
Addition of miR-181a to ABC-like cell lines and tumor grafts reduced NFκB activity, diminished tumor growth, and significantly increased animal survival. Researchers believe that these findings explain why miR181a is biomarker for survival.
“We are trying to develop miR-181a as a potential therapy,” Lossos said in a news release, “but we are only at the beginning. Much more work needs to be done. It will not be a simple journey, but we are sure it can be done and tested in humans eventually to see that it indeed will improve patients’ outcomes.”
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