Department of Hematology, Provincial Hospital Affiliated to Shandong University, Jinan, People's Republic of China.
PLoS One. 2012;7(6):e39449. doi: 10.1371/journal.pone.0039449. Epub 2012 Jun 29.
Metadherin (MTDH) has been demonstrated as a potentially crucial mediator of various types of human malignancies. However, the expression and role of MTDH in diffuse large-B-cell lymphoma (DLBCL) have not been reported yet. This study aimed to illuminate the role of MTDH in the pathogenesis of DLBCL.
METHODOLOGY/PRINCIPAL FINDINGS: A remarkable elevation of MTDH on mRNA level was detected in DLBCL tissues by quantitative polymerase chain reaction (PCR). Using Western-blot analysis we found that the expression of MTDH protein was significantly upregulated in DLBCL cell lines and DLBCL tissues compared with peripheral blood mononuclear cells (PBMCs) from healthy samples and tissues from patients of reactive hyperplasia of lymph node. The results showed high expression of MTDH in 23 of 30 (76.67%) DLBCL tissues by using immunohistochemical analysis and the over expression of MTDH was strongly correlated to the clinical staging of patients with DLBCL (P<0.05). Furthermore, the finding suggested that the increase of MTDH in DLBCL cells could distinctly enhance cell proliferation and inhibit cell apoptosis; meanwhile, inhibition of MTDH expression by specific siRNA clearly enhanced LY8 cell apoptosis. Upregulation of MTDH elevated the protein level of total β-catenin and translocation of β-catenin to the nucleus directly or indirectly. Knockdown of MTDH decreased the level of total, cytoplasmic β-catenin and reduced nuclear accumulation of β-catenin protein. This indicated that the function of MTDH on the development of DLBCL was mediated through regulation of Wnt/β-catenin signaling pathway.
CONCLUSIONS/SIGNIFICANCE: Our results suggest that MTDH contributes to the pathogenesis of DLBCL mediated by activation of Wnt/β-catenin pathway. This novel study may contribute to further investigation on the useful biomarkers and potential therapeutic target in the DLBCL patients.
研究已经证实，MTDH（metadherin）是多种人类恶性肿瘤的潜在关键介质。然而，MTDH 在弥漫性大 B 细胞淋巴瘤（DLBCL）中的表达和作用尚未有报道。本研究旨在阐明 MTDH 在 DLBCL 发病机制中的作用。
方法/主要发现： 通过实时定量聚合酶链反应（PCR），在 DLBCL 组织中检测到 MTDH 的 mRNA 水平显著升高。通过 Western blot 分析，我们发现与健康样本的外周血单核细胞（PBMC）和反应性淋巴结增生组织相比，MTDH 蛋白在 DLBCL 细胞系和 DLBCL 组织中的表达显著上调。免疫组织化学分析显示，30 例 DLBCL 组织中有 23 例（76.67%）MTDH 高表达，MTDH 的过度表达与 DLBCL 患者的临床分期密切相关（P<0.05）。此外，研究发现，DLBCL 细胞中 MTDH 的增加可明显增强细胞增殖，抑制细胞凋亡；同时，特异性 siRNA 抑制 MTDH 表达可明显增强 LY8 细胞凋亡。MTDH 的上调直接或间接增加了总 β-连环蛋白的蛋白水平，并将 β-连环蛋白转位到细胞核。敲低 MTDH 降低了总、细胞质 β-连环蛋白的水平，并减少了 β-连环蛋白蛋白的核积累。这表明 MTDH 通过调节 Wnt/β-连环蛋白信号通路对 DLBCL 的发展起作用。
结论/意义：我们的结果表明，MTDH 通过激活 Wnt/β-连环蛋白通路促进 DLBCL 的发病机制。这项新的研究可能有助于进一步研究 DLBCL 患者有用的生物标志物和潜在的治疗靶点。
