miR-155 regulates HGAL expression and increases lymphoma cell motility

Abstract

IntroductionHGAL (Human Germinal-center Associated Lymphoma) is a germinal center (GC) specific gene involved in negative regulation of lymphocyte and lymphoma cell motility by at least 2 distinct molecular mechanisms. HGAL directly and independently binds to both actin and myosin II proteins, increasing binding between F-actin and myosin II and inhibiting the ability of myosin to translocate actin by reducing the maximal velocity of myosin head/actin movement. 1,2 In addition, HGAL inhibits lymphocyte motility by activating the RhoA signaling pathway by direct interaction with RhoA-specific guanine nucleotide exchange factors (RhoGEFs) PDZ-RhoGEF and LARG that stimulate the RhoA GDP-GTP exchange rate. 3 HGAL is also expressed in GC-derived lymphomas and distinguishes biologically distinct subgroups of diffuse large B-cell lymphomas (DLBCLs) 4,5 and classic Hodgkin lymphoma 6,7 characterized by longer survival. However, little is known about expression regulation of HGAL or its murine counterpart M17 protein. We have previously shown that IL-4 and IL-13 stimulation increases, whereas CD40 stimulation decreases, HGAL mRNA expression. 4 Recently, we also demonstrated that HGAL is directly regulated by the transcriptional repressor PRDM1/ Blimp-1, a master regulator of terminal B-cell differentiation. We showed that PRDM1 directly binds to the recognition sites within the upstream promoter of HGAL and transcriptionally suppresses its endogenous mRNA and protein levels. 8 However, additional factors most probably contribute to the restricted and tightly regulated expression of HGAL in GC lymphocytes and GC-derived lymphomas.microRNAs (miRNAs) are small noncoding RNAs that posttranscriptionally regulate expression of genes controlling multiple biologic processes. 9 The stage-specific expression of certain miRNAs in the immune system 10 suggests their participation in immune system regulation that may contribute to pathogenesis of lymphocyte-derived malignancies. 11,12 Therefore, we have searched for miRNAs implicated in immune responses and lymphomagenesis that might regulate HGAL expression. Herein we demonstrate that miR-155 directly down-regulates HGAL expression by binding to its 3Ј-untranslated region (3Ј-UTR), modulating its effects on RhoA activation and lymphocyte and lymphoma cell spontaneous and chemoattractant-induced motility. These findings disclose novel roles of miR-155 in the immune system and lymphoma biology. Methods Reagents and antibodiesMouse monoclonal anti-HGAL antibody was generated in our laboratory, as reported previously. 13,14 Mouse monoclonal anti-RhoA (26C4) and rabbit polyclonal anti-Rhotekin 2 (RTKN2; AA-18) antibodies were from Santa Cruz Biotechnology; rabbit polyclonal anti-myosin light chain kinase antibody (ab55475) was purchased from Abcam; ␤-actin antibody (A5316) and sodium lysophosphatidic acid (L7260) were purchased from Sigma-Aldrich; rhodamine labeled phalloidin was from Invitrogen; human fibronectin was purchased from BD Biosciences; SDF-1␣ was from MBL International. Sear...

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