Extracellular matrix protein CCN1 limits oncolytic efficacy in glioma.
Extracellular matrix protein CCN1 limits oncolytic efficacy in glioma.
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DOI：
10.1158/0008-5472.can-11-2526
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发表时间：
2012-03-15
期刊：
影响因子：
11.2
通讯作者：
Kaur B
中科院分区：
文献类型：
--
作者：
Haseley A;Boone S;Wojton J;Yu L;Yoo JY;Yu J;Kurozumi K;Glorioso JC;Caligiuri MA;Kaur B
溶瘤病毒疗法作为治疗胶质瘤的一种选择已经被广泛探索，但其有效性仍然有限。CCN1是一种在癌细胞中升高的细胞外基质(ECM)蛋白，通过结合细胞表面受体来调节其黏附和迁移。在这项研究中，我们基于CCN1诱导的证据，检验了CCN1在限制溶瘤病毒治疗脑胶质瘤疗效中的假设作用。值得注意的是，我们发现胶质瘤ECM中的外源性CCN1协调了一种细胞抗病毒反应，减少了病毒复制，限制了细胞溶解效果。基因表达谱分析和实时聚合酶链式反应分析显示，CCN1暴露可显著诱导I型干扰素反应基因。这种诱导伴随着JAK/STAT信号通路的激活，与先天抗病毒细胞反应的诱导一致。这两种作用都是通过CCN1与细胞表面整合素α6β1结合，激活其信号并导致干扰素-α的快速分泌而实现的，而这是天然抗病毒作用所必需的。总之，我们的发现揭示了整合素信号通路如何介导I型抗病毒干扰素反应的激活，从而限制溶瘤病毒治疗的疗效。此外，他们建议进行治疗干预，以抑制CCN1-整合素α6的相互作用，从而使胶质瘤对病毒溶瘤敏感。
Oncolytic viral therapy has been explored widely as an option for glioma treatment but its effectiveness has remained limited. CCN1 is an extracellular matrix (ECM) protein elevated in cancer cells that modulates their adhesion and migration by binding cell surface receptors. In this study, we examined an hypothesized role for CCN1 in limiting the efficacy of oncolytic viral therapy for glioma, based on evidence of CCN1 induction that occurs in this setting. Strikingly, we found that exogenous CCN1 in glioma ECM orchestrated a cellular antiviral response that reduced viral replication and limited cytolytic efficacy. Gene expression profiling and real time PCR analysis revealed a significant induction of type-I interferon responsive genes in response to CCN1 exposure. This induction was accompanied by activation of the Jak/Stat signaling pathway, consistent with induction of an innate antiviral cellular response. Both effects were mediated by the binding of CCN1 to the cell surface integrin α6β1, activating its signaling and leading to rapid secretion of interferon-α, which was essential for the innate antiviral effect. Together, our findings reveal how an integrin signaling pathway mediates activation of a type-I antiviral interferon response that can limit the efficacy of oncolytic viral therapy. Further, they suggest therapeutic interventions to inhibit CCN1-integrin α6 interactions to sensitize gliomas to viral oncolysis.