High-mobility group box 2 is associated with prognosis of glioblastoma by promoting cell viability, invasion, and chemotherapeutic resistance

The expression profile of high-mobility group box 2 (HMGB2) in patients with glioblastoma multiforme (GBM) and its clinical signature with underlying mechanisms were not fully explored.HMGB2 protein levels were measured in 51 GBM patients by immunohistochemical studies. To clarify the precise role of HMGB2 on cell invasion and viability of 3 GBM cell lines, we did in vitro and in vivo analyses with lentivirus vectors and small interfering RNA. Transwell invasion assays and wound-healing assays were used to analyze the invasion of GBM cells. Expression of p53 and matrix metalloproteinase 2/tissue inhibitors of metalloproteinase 2 (MMP2/TIMP2) protein was analyzed by Western blot.HMGB2 protein expression was significantly higher in GBM than in controlled brain tissues (P .0001). HMGB2 overexpression was significantly correlated with shorter overall survival time, which was the only independent prognostic factor for overall survival in a multivariate analysis (P .017). HMGB2 knockdown by small interfering RNA decreased cell viability and invasion in vitro and significantly decreased tumor volume in vivo, which might be involved in the change of p53 expression and the balance of MMP2/TIMP2. Moreover, silencing of HMGB2 could significantly increase the sensitivity of GBM cells to temozolomide chemotherapy.Our present data suggest that HMGB2 expression is a significant prognostic factor and might play an important role in cell invasion and temozolomide-induced chemotherapeutic sensitivity of GBM. This study highlights the importance of HMGB2 as a novel prognostic marker and an attractive therapeutic target of GBM.

多形性胶质母细胞瘤（GBM）患者中高迁移率族蛋白B2（HMGB2）的表达谱及其临床特征和潜在机制尚未得到充分探究。通过免疫组化研究测量了51例GBM患者的HMGB2蛋白水平。为阐明HMGB2在3种GBM细胞系的细胞侵袭和活力方面的确切作用，我们利用慢病毒载体和小干扰RNA进行了体外和体内分析。采用Transwell侵袭实验和划痕愈合实验分析GBM细胞的侵袭情况。通过蛋白质印迹法分析p53以及基质金属蛋白酶2/金属蛋白酶组织抑制剂2（MMP2/TIMP2）蛋白的表达。GBM中的HMGB2蛋白表达显著高于对照脑组织（P＜0.0001）。HMGB2过表达与较短的总生存期显著相关，在多变量分析中，它是总生存期的唯一独立预后因素（P＜0.017）。小干扰RNA敲低HMGB2在体外降低了细胞活力和侵袭能力，在体内显著减小了肿瘤体积，这可能与p53表达的变化以及MMP2/TIMP2的平衡有关。此外，沉默HMGB2可显著提高GBM细胞对替莫唑胺化疗的敏感性。我们目前的数据表明，HMGB2表达是一个重要的预后因素，可能在GBM的细胞侵袭和替莫唑胺诱导的化疗敏感性中发挥重要作用。这项研究强调了HMGB2作为GBM一种新的预后标志物和有吸引力的治疗靶点的重要性。