MicroRNA-146a Downregulates NFκB Activity via Targeting TRAF6 and Functions as a Tumor Suppressor Having Strong Prognostic Implications in NK/T Cell Lymphoma

Purpose: We investigated prognostic implications of microRNAs in extranodal NK/T cell lymphoma (NKTL). Experimental Design: We measured miRNA expression in NKTL tissues and cell lines, using real-time PCR, and analyzed its role in NKTL, using cell lines. Results: Multivariate analysis showed low miR-146a expression (P < 0.001; HR = 13.110), primary non-upper aerodigestive tract lesion (non-UAT; P = 0.008; HR = 5.376) and high International Prognostic Index (IPI; >= 3; P = 0.013; HR = 3.584) to be independent poor prognostic factors. miR-146a expression could subdivide UAT-NKTL into 2 prognostic groups, resulting in the following prognostic groups: (i) UAT(Low-146a), (ii) UAT(High-146a), and (iii) non-UAT. Compared with UAT(High-146a), UAT(Low-146a) showed distinctively poor prognosis (P < 0.001; HR = 15.620), similar to the non-UAT group. In vitro, miR-146a overexpression in NKTL cell lines, SNK6 and YT, inhibited nuclear factor kappa B (NF kappa B) activity, suppressed cell proliferation, induced apoptosis, and enhanced chemosensitivity. TNF receptor-associated factor 6, a target of miR-146a and a known NF kappa B activator, was downregulated by miR-146a in SNK6 and YT cells. Promoter methylation of miR-146a gene was observed in SNK6 and YT cells, as well as in NKTL tissues with low miR-146a expression, and miR-146a expression was induced by the conversion of methylation status with a demethylating agent in SNK6 and YT cells. Conclusions: These results suggest that miR-146a might function as a potent tumor suppressor in NKTL and be useful for patient assessment and therapeutic targeting. Clin Cancer Res; 17(14); 4761-71. (C)2011 AACR.