Läubli Heinz, Alisson-Silva Frederico, Stanczak Michal A, Siddiqui Shoib S, Deng Liwen, Verhagen Andrea, Varki Nissi, Varki Ajit
From the Departments of Medicine and Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093
From the Departments of Medicine and Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093.
J Biol Chem. 2014 Nov 28;289(48):33481-91. doi: 10.1074/jbc.M114.593129. Epub 2014 Oct 15.
Lectin galactoside-binding soluble 3 binding protein (LGALS3BP, also called Mac-2 binding protein) is a heavily glycosylated secreted molecule that has been shown previously to be up-regulated in many cancers and has been implicated in tumor metastatic processes, as well as in other cell adhesion and immune functions. The CD33-related subset of sialic acid-binding immunoglobulin-like lectins (Siglecs) consists of immunomodulatory molecules that have recently been associated with the modulation of immune responses to cancer. Because up-regulation of Siglec ligands in cancer tissue has been observed, the characterization of these cancer-associated ligands that bind to inhibitory CD33-related Siglecs could provide novel targets for cancer immunomodulatory therapy. Here we used affinity chromatography of tumor cell extracts to identify LGALS3BP as a novel sialic acid-dependent ligand for human Siglec-9 and for other immunomodulatory Siglecs, such as Siglec-5 and Siglec-10. In contrast, the mouse homolog Siglec-E binds to murine LGALS3BP with lower affinity. LGALS3BP has been observed to be up-regulated in human colorectal and prostate cancer specimens, particularly in the extracellular matrix. Finally, LGALS3BP was able to inhibit neutrophil activation in a sialic acid- and Siglec-dependent manner. These findings suggest a novel immunoinhibitory function for LGALS3BP that might be important for immune evasion of tumor cells during cancer progression.
凝集素半乳糖苷结合可溶性3结合蛋白（LGALS3BP，也称为Mac-2结合蛋白）是一种高度糖基化的分泌分子，此前已证实在多种癌症中上调，并与肿瘤转移过程以及其他细胞黏附与免疫功能有关。唾液酸结合免疫球蛋白样凝集素（Siglecs）的CD33相关亚群由免疫调节分子组成，这些分子最近与癌症免疫反应的调节相关。由于已观察到癌症组织中Siglec配体上调，因此鉴定这些与抑制性CD33相关Siglec结合的癌症相关配体可为癌症免疫调节治疗提供新靶点。在此，我们利用肿瘤细胞提取物的亲和层析法鉴定出LGALS3BP是人类Siglec-9以及其他免疫调节性Siglec（如Siglec-5和Siglec-10）的一种新型唾液酸依赖性配体。相比之下，小鼠同源物Siglec-E与小鼠LGALS3BP的结合亲和力较低。已观察到LGALS3BP在人类结直肠癌和前列腺癌标本中上调，尤其是在细胞外基质中。最后，LGALS3BP能够以唾液酸和Siglec依赖性方式抑制中性粒细胞活化。这些发现提示LGALS3BP具有一种新型免疫抑制功能，这可能在癌症进展过程中对肿瘤细胞的免疫逃逸很重要。
