Steiner Normann, Borjan Bojana, Hajek Roman, Jöhrer Karin, Göbel Georg, Willenbacher Wolfgang, Kern Johann, Gunsilius Eberhard, Untergasser Gerold
Department of Internal Medicine V, Hematology and Medical Oncology, Innsbruck Medical University, Innsbruck, Austria.
Laboratory for Tumor Biology and Angiogenesis, Innsbruck Medical University, Innsbruck, Austria.
Oncotarget. 2017 Apr 21;8(34):56243-56254. doi: 10.18632/oncotarget.17353. eCollection 2017 Aug 22.
Multiple myeloma (MM) is a plasma cell neoplasm that is mostly incurable due to acquired resistance during the treatment course. Thus, we evaluated expression and release of glucose-regulated protein 78 kDa (GRP78/BiP), an endoplasmic reticulum (ER) based pro-survival chaperone involved in immunoglobulin folding and unfolded protein responses.
GRP78 protein expression in the ER and on the cell surface did not significantly differ between MGUS, NDMM and RRMM patients although there was a trend to higher surface expression in RRMM. In bone marrow plasma, the amount of released GRP78 protein was not significantly increased between MGUS-, NDMM- and RRMM patients. MM cells of the three cell lines release GRP78 as full-length protein under apoptotic, but not under acidotic or ER-stress conditions. In necrosis, only proteolytic fragments of GRP78 were detected in supernatants of MM cells.
GRP78 protein expression and plasma levels were quantified in bone marrow aspirates of patients with monoclonal gammopathy of undetermined significance (MGUS, = 29), newly diagnosed MM (NDMM, = 29) and with relapsed/refractory MM (RRMM, = 15) by immunohistochemistry and sandwich ELISA. The human MM cell lines U266, NCI-H929 and OPM-2 were used for functional GRP78 release- and processing studies after induction of acidosis, ER stress, apoptosis and necrosis.
Ectopic expression of GRP78 on cell membrane or its release in the microenvironment is not a suitable marker to distinguish MGUS from NDMM and RRMM.
多发性骨髓瘤（MM）是一种浆细胞瘤，由于在治疗过程中获得性耐药，大多无法治愈。因此，我们评估了葡萄糖调节蛋白78 kDa（GRP78/BiP）的表达和释放，它是一种基于内质网（ER）的促生存伴侣蛋白，参与免疫球蛋白折叠和未折叠蛋白反应。
MGUS、NDMM和RRMM患者内质网和细胞表面的GRP78蛋白表达无显著差异，尽管RRMM患者的表面表达有升高趋势。在骨髓浆中，MGUS、NDMM和RRMM患者之间释放的GRP78蛋白量没有显著增加。三种细胞系的MM细胞在凋亡条件下而非酸中毒或内质网应激条件下以全长蛋白形式释放GRP78。在坏死过程中，MM细胞上清液中仅检测到GRP78的蛋白水解片段。
通过免疫组织化学和夹心ELISA对意义未明的单克隆丙种球蛋白病（MGUS，n = 29）、新诊断的MM（NDMM，n = 29）和复发/难治性MM（RRMM，n = 15）患者的骨髓穿刺物中GRP78蛋白表达和血浆水平进行定量。在诱导酸中毒、内质网应激、凋亡和坏死之后，使用人MM细胞系U266、NCI-H929和OPM-2进行功能性GRP78释放和加工研究。
GRP78在细胞膜上的异位表达或其在微环境中的释放不是区分MGUS与NDMM和RRMM的合适标志物。
