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

Abstract

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