TRAF3IP2, a novel therapeutic target in glioblastoma multiforme.
TRAF3IP2, a novel therapeutic target in glioblastoma multiforme.
复制标题
DOI：
10.18632/oncotarget.25710
复制
发表时间：
2018-07-03
期刊：
影响因子：
--
通讯作者：
Izadpanah R
中科院分区：
文献类型：
--
作者：
Alt EU;Barabadi Z;Pfnür A;Ochoa JE;Daneshimehr F;Lang LM;Lin D;Braun SE;Chandrasekar B;Izadpanah R
多形性胶质母细胞瘤（胶质母细胞瘤）仍然是最致命的癌症之一。存在于肿瘤微环境（TME）中的促炎和促肿瘤发生介质促进肿瘤细胞和相邻非恶性细胞之间的通信，导致胶质母细胞瘤生长。由于这些介质中的大多数是NF-κB和/或AP-1应答基因的产物，并且TRAF 3相互作用蛋白2（TRAF 3 IP 2）是这两种转录因子的上游调节因子，因此我们假设靶向TRAF 3 IP 2通过抑制NF-κB和促炎/促肿瘤发生介质来减弱肿瘤生长。我们的体外数据表明，类似于原发性胶质母细胞瘤肿瘤组织，恶性胶质母细胞瘤细胞系（U87和U118）表达高水平的TRAF 3 IP 2。TRAF 3 IP 2表达沉默可抑制基础和诱导型NF-κB活化、促炎介质诱导、参与细胞周期进程和血管生成的基因簇以及球状体形成。此外，沉默TRAF 3 IP 2显著增加细胞凋亡。体内研究表明TRAF 3 IP 2沉默的U87细胞形成更小的肿瘤。此外，用慢病毒TRAF 3 IP 2 shRNA治疗由野生型U87细胞形成的现有肿瘤显著地使其大小消退。残留肿瘤的分析显示促炎/促肿瘤发生/促血管生成介质和驱动蛋白的表达减少。相反，IL-10，一种抗炎细胞因子的表达增加。总之，这些新数据表明TRAF 3 IP 2是胶质母细胞瘤中恶性信号传导的主要调节因子，其靶向调节TME并通过抑制参与炎症、血管生成、生长和恶性转化的介质的表达来抑制肿瘤生长。我们的数据将TRAF 3 IP 2确定为胶质母细胞瘤生长和扩散的潜在治疗靶点。
Glioblastoma multiforme (glioblastoma) remains one of the deadliest cancers. Pro-inflammatory and pro-tumorigenic mediators present in tumor microenvironment (TME) facilitate communication between tumor cells and adjacent non-malignant cells, resulting in glioblastoma growth. Since a majority of these mediators are products of NF-κB- and/or AP-1-responsive genes, and as TRAF3 Interacting Protein 2 (TRAF3IP2) is an upstream regulator of both transcription factors, we hypothesized that targeting TRAF3IP2 blunts tumor growth by inhibiting NF-κB and pro-inflammatory/pro-tumorigenic mediators. Our in vitro data demonstrate that similar to primary glioblastoma tumor tissues, malignant glioblastoma cell lines (U87 and U118) express high levels of TRAF3IP2. Silencing TRAF3IP2 expression inhibits basal and inducible NF-κB activation, induction of pro-inflammatory mediators, clusters of genes involved in cell cycle progression and angiogenesis, and formation of spheroids. Additionally, silencing TRAF3IP2 significantly increases apoptosis. In vivo studies indicate TRAF3IP2-silenced U87 cells formed smaller tumors. Additionally, treating existing tumors formed by wild type U87 cells with lentiviral TRAF3IP2 shRNA markedly regresses their size. Analysis of residual tumors revealed reduced expression of pro-inflammatory/pro-tumorigenic/pro-angiogenic mediators and kinesins. In contrast, the expression of IL-10, an anti-inflammatory cytokine, was increased. Together, these novel data indicate that TRAF3IP2 is a master regulator of malignant signaling in glioblastoma, and its targeting modulates the TME and inhibits tumor growth by suppressing the expression of mediators involved in inflammation, angiogenesis, growth, and malignant transformation. Our data identify TRAF3IP2 as a potential therapeutic target in glioblastoma growth and dissemination.