MicroRNAs Are Independent Predictors of Outcome in Diffuse Large B-Cell Lymphoma Patients Treated with R-CHOP

Alencar, Alvaro J.; Malumbres, Raquel; Kozloski, Goldi A.; Advani, Ranjana H.; Talreja, Neha; Chinichian, Shideh; Briones, Javier; Natkunam, Yasodha; Sehn, Laurie H.; Gascoyne, Randy D.; Tibshirani, Rob; Lossos, Izidore S.

doi:10.1158/1078-0432.ccr-11-0224

Cited by 123 publications

(104 citation statements)

References 46 publications

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“…17 We previously demonstrated that miR-181a has a prognostic value in DLBCL, by establishing a positive correlation between high endogenous miR-181a expression in tumor biopsies and longer survival in patients undergoing rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone therapy. 18 Beyond this prognostic value, we asked whether distinct miR-181a expression contributes to different DLBCL patient survival. Indeed, several studies demonstrated that miR-181a regulates key cell-survival proteins and oncogenic signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

miR-181a negatively regulates NF-κB signaling and affects activated B-cell–like diffuse large B-cell lymphoma pathogenesis

Kozloski¹,

Jiang²,

Bhatt

et al. 2016

Blood

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• miR-181a regulates the NF-kB signaling pathway by targeting CARD11, NFKBIA, NFKB1, RELA/P65, and REL.• miR-181a represses NF-kB signaling and decreases cell proliferation and survival most potently in the NF-kB dependent ABC-DLBCL subgroup.Distinct subgroups of diffuse large B-cell lymphoma (DLBCL) genetically resemble specific mature B-cell populations that are blocked at different stages of the immune response in germinal centers (GCs). The activated B-cell (ABC)-like subgroup resembles post-GC plasmablasts undergoing constitutive survival signaling, yet knowledge of the mechanisms that negatively regulate this oncogenic signaling remains incomplete. In this study, we report that microRNA (miR)-181a is a negative regulator of nuclear factor k-light-chain enhancer of activated B-cells (NF-kB) signaling. miR-181a overexpression significantly decreases the expression and activity of key NF-kB signaling components. Moreover, miR181a decreases DLBCL tumor cell proliferation and survival, and anti-miR-181a abrogates these effects. Remarkably, these effects are augmented in the NF-kB dependent ABC-like subgroup compared with the GC B-cell (GCB)-like DLBCL subgroup. Concordantly, in vivo analyses of miR-181a induction in xenografts results in slower tumor growth rate and prolonged survival in the ABC-like DLBCL xenografts compared with the GCB-like DLBCL. We link these outcomes to relatively lower endogenous miR-181a expression and to NF-kB signaling dependency in the ABC-like DLBCL subgroup. Our findings indicate that miR-181a inhibits NF-kB activity, and that manipulation of miR-181a expression in the ABC-like DLBCL genetic background may result in a significant change in the proliferation and survival phenotype of this malignancy. (Blood. 2016;127(23):2856-2866

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Section: Introductionmentioning

confidence: 99%

miR-181a negatively regulates NF-κB signaling and affects activated B-cell–like diffuse large B-cell lymphoma pathogenesis

Kozloski¹,

Jiang²,

Bhatt

et al. 2016

Blood

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“…Therefore, we selected miR-18a as a candidate for this plasma assay. MiR-18a also has been reported to show altered expression in various malignant diseases [30,31]. In breast cancer, the relationship with ERalpha, identified as a direct target of miR18a, has been elucidated.…”

Section: Introductionmentioning

confidence: 99%

Circulating miR-18a in plasma contributes to cancer detection and monitoring in patients with gastric cancer

et al. 2014

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Background Recently, circulating microRNAs have been reported to be stably detectable in plasma/serum and to function as potent non-invasive biomarkers in various cancers. We hypothesized that miR-18a could contribute to a novel plasma biomarker in patients with gastric cancer (GC). Methods We focused on miR-18a, which is a component of miR-17-92 cluster and has been reported as highly expressed in GC tissues. The study involved three steps: (1) confirmation of the higher miR-18a expression in primary GC tissues and GC cell lines than in normal gastric tissues and a fibroblast cell line; (2) evaluation of the plasma miR18a assay using quantitative RT-PCR by comparing 104 GC patients and 65 healthy volunteers; (3) evaluation of monitoring tumor dynamics by the plasma miR-18a assay. Results (1) The miR-18a expressions were significantly higher in GC tissues than in normal gastric tissues (P = 0.0286) and higher in all examined GC cell lines than in the fibroblast cell line. (2) The plasma miR-18a concentrations were significantly higher in GC patients than in healthy controls (P \ 0.0001). The value of the area under the receiver-operating characteristic curve was 0.8059. (3) The plasma miR-18a levels were significantly reduced in postoperative samples compared to in preoperative samples (P = 0.0002). In an miR-18a overexpressing cell line, the miR-18a concentration of cultured medium increased in both cell number and time-course dependent manners, suggesting microRNA might be released from cancer cells into the surrounding environment. Conclusions Circulating miR-18a could be a useful biomarker for screening GC and monitoring tumor dynamics.

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“…That said, these mice, or indeed mice that over-express AICDA, do not develop overt lymphoma (Muto et al, 2006). Interestingly, AICDA is also targeted by MIR181 (de Yebenes et al, 2008), an independent prognostic indicator of survival in R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) treated DLBCL patients (Alencar et al, 2011).…”

Section: Mir155mentioning

confidence: 99%

MicroRNAs and lymphomagenesis: a functional review

Lawrie

2012

Br J Haematol

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SummaryThe relatively recent discovery of microRNAs (miRNAs) has exposed an extra layer of gene expression regulation that affects many physiological and pathological processes of biology. Dysregulation of miRNAs is a ubiquitous feature of cancer in general, including lymphomas. The identity of these aberrantly-expressed miRNAs has been thoroughly investigated in all but a few types of lymphomas, however their functional role in lymphomagenesis much less so. This review focuses on those miRNAs that have an experimentally confirmed functional role in the pathogenesis of the most frequent forms of lymphoma. In particular, the MIR15A/16-1 cluster, MIR21, MIR155, MIR17HG (MIR17-92 cluster), MIR34A and MIR125B, which have in vivo animal model evidence for their involvement in lymphomagenesis, are highlighted.

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MicroRNAs Are Independent Predictors of Outcome in Diffuse Large B-Cell Lymphoma Patients Treated with R-CHOP

Cited by 123 publications

References 46 publications

miR-181a negatively regulates NF-κB signaling and affects activated B-cell–like diffuse large B-cell lymphoma pathogenesis

miR-181a negatively regulates NF-κB signaling and affects activated B-cell–like diffuse large B-cell lymphoma pathogenesis

Circulating miR-18a in plasma contributes to cancer detection and monitoring in patients with gastric cancer

MicroRNAs and lymphomagenesis: a functional review

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