MicroRNA profiling of follicular lymphoma identifies microRNAs related to cell proliferation and tumor response

Abstract

MicroRNAs can play an important role in tumorigenesis through post-transcriptional regulation of gene expression, and are not well characterized in follicular lymphoma. MicroRNA profiles of enriched follicular lymphoma tumor cells from 16 patients were generated by assaying 851 human microRNAs. Tandem gene expression profiles were obtained for predicting microRNA targets. The expression of 133 microRNAs was significantly different (> 2-fold; P<0.05) between follicular lymphoma and follicular hyperplasia. Forty-four microRNAs in three groups generated a unique follicular lymphoma signature. Of these, ten microRNAs were increased (miR-193a-5p, -193b*, -345, -513b, -574-3p, -584, -663, -1287, -1295, and -1471), 11 microRNAs were decreased (miR-17*, -30a, -33a, -106a*, -141, -202, -205, -222, -301b, -431*, and -570), and 23 microRNAs formed a group that was increased in most cases of follicular lymphoma but showed lower expression in a subset of cases (let-7a, let-7f, miR-7-1*, -9, -9*, -20a, -20b, -30b, -96, -98, -194, -195, -221*, -374a, -374b, -451, -454, -502-3p, -532-3p, -664*, -1274a, -1274b, and -1260). Higher expression of this last group was associated with improved response to chemotherapy. Gene expression analysis revealed increased expression of MAPK1, AKT1, PRKCE, IL4R and DROSHA and decreased expression of CDKN1A/p21, SOCS2, CHEK1, RAD51, KLF4, BLIMP1 and IRF4 in follicular lymphoma. Functional studies indicated that CDKN1A/p21 and SOCS2 expression is directly regulated by miR-20a/-20b and miR-194, respectively. Follicular lymphoma is characterized by a unique microRNA signature, containing a subset of microRNAs whose expression correlate with response to chemotherapy. miR-20a/b and miR-194 target CDKN1A and SOCS2 in follicular lymphoma, potentially contributing to tumor cell proliferation and survival.