IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage.
IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage.
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DOI：
10.1016/j.jhep.2010.01.015
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发表时间：
2010-04
影响因子：
25.7
通讯作者：
Llovet JM
中科院分区：
文献类型：
--
作者：
Tovar V;Alsinet C;Villanueva A;Hoshida Y;Chiang DY;Solé M;Thung S;Moyano S;Toffanin S;Mínguez B;Cabellos L;Peix J;Schwartz M;Mazzaferro V;Bruix J;Llovet JM
IGF信号传导在多种人类恶性肿瘤中具有相关作用。我们分析了早期肝细胞癌（HCC; BCLC 0级或A级）中IGF信号激活的潜在分子机制，并评估了阻断该途径的新型靶向治疗。在104例HCC的队列中进行了轴的整合分子解剖，分析了基因和miRNA表达，结构畸变和蛋白质激活。在体外和HCC异种移植模型中评估了选择性IGF-1 R抑制剂（单克隆抗体A12）的治疗潜力。在21%的早期HCC中观察到IGF轴活化。鉴定了几种分子畸变，例如由胎儿启动子P3和P4-的再激活引起的IGF 2-的过表达、IGFBP 3下调和IGF 2 R的等位基因丢失（25%的病例）。开发了定义IGF-1 R激活的基因签名。总体而言，HCC中IGF信号传导的激活与mTOR信号传导显著相关（p=0.035），并且明显富集在HCC分子分类的增殖亚类中（p=0.001）。我们还发现IGF活化与miR-100/miR-216水平之间呈负相关（FDR<0.05）。体外研究表明，A12诱导的IGF-1 R活化和下游信号传导的消除显著降低了细胞活力和增殖。在体内A12延迟肿瘤生长和延长生存期，降低增殖率和诱导细胞凋亡综合基因组分析显示在HCC的增殖亚类中IGF信号传导的激活的富集。用A12有效阻断IGF信号传导为在临床试验中测试这种疗法提供了理论基础。
IGF signaling has a relevant role in a variety of human malignancies. We analyzed the underlying molecular mechanisms of IGF signaling activation in early hepatocellular carcinoma (HCC; BCLC class 0 or A) and assessed novel targeted therapies blocking this pathway An integrative molecular dissection of the axis was conducted in a cohort of 104 HCCs analyzing gene and miRNA expression, structural aberrations and protein activation. The therapeutic potential of a selective IGF-1R inhibitor, the monoclonal antibody A12, was assessed in vitro and in a xenograft model of HCC Activation of the IGF axis was observed in 21% of early HCCs. Several molecular aberrations were identified, such as overexpression of IGF2 –resulting from reactivation of fetal promoters P3 and P4-, IGFBP3 downregulation and allelic losses of IGF2R 25% of cases). A gene signature defining IGF-1R activation was developed. Overall, activation of IGF signaling in HCC was significantly associated with mTOR signaling (p=0.035) and was clearly enriched in the Proliferation subclass of the molecular classification of HCC (p=0.001). We also found an inverse correlation between IGF activation and miR-100/miR-216 levels (FDR<0.05). In vitro studies showed that A12-induced abrogation of IGF-1R activation and downstream signaling significantly decreased cell viability and proliferation. In vivoA12 delayed tumor growth and prolonged survival, reducing proliferation rates and inducing apoptosis Integrative genomic analysis showed enrichment of activation of IGF signaling in the Proliferation subclass of HCC. Effective blockage of IGF signaling with A12 provides the rationale for testing this therapy in clinical trials.