Nussbaum Tanja, Samarin Jana, Ehemann Volker, Bissinger Michaela, Ryschich Eduard, Khamidjanov Akmal, Yu Xiaolei, Gretz Norbert, Schirmacher Peter, Breuhahn Kai
Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
Hepatology. 2008 Jul;48(1):146-56. doi: 10.1002/hep.22297.
The protumorigenic insulin-like growth factor (IGF)-II is highly expressed in a significant fraction of human hepatocellular carcinomas (HCC). However, a functional dissection that clarifies the contribution of IGF-II-binding receptors in tumor progression and a respective molecular characterization of IGF-II signaling has not been performed. Therefore, expression of IGF-II and its receptors IGF-receptor type I (IGF-IR) and insulin receptor (IR) was efficiently blocked using small interfering RNA (siRNA) in HCC cells. Despite functional IR-signaling, oncogenic IGF-II effects such as tumor cell viability, proliferation, and anti-apoptosis were solely transmitted by IGF-IR. Although IGF-II signaling was previously not described in the context of HCC cell migration, the IGF-II-dependent expression profile displayed a high percentage of genes involved in cell motility and adhesion. Indeed, IGF-II overexpression promoted HCC cell migration, especially in synergy with hepatocyte growth factor (HGF). The therapeutic relevance of IGF-II/IGF-IR signaling was tested in vitro and in a murine xenograft transplantation model using the IGF-IR inhibitor picropodophyllin (PPP). IGF-IR inhibition by small molecule treatment efficiently reduced IGF-II-dependent signaling and all protumorigenic properties of the IGF-II/IGF-IR pathway.
In human HCC cells, IGF-IR but not IR is involved in oncogenic IGF-II signaling. Autocrine stimulation of IGF-II induces HCC motility by integration of paracrine signals for full malignant competence. Thus, activation of IGF-II/IGF-IR signaling is likely a progression switch selected by function that promotes tumor cell dissemination and aggressive tumor behavior.
促肿瘤的胰岛素样生长因子（IGF）-II在相当一部分人类肝细胞癌（HCC）中高表达。然而，尚未进行功能剖析以阐明IGF-II结合受体在肿瘤进展中的作用以及IGF-II信号传导的相应分子特征。因此，在肝癌细胞中使用小干扰RNA（siRNA）有效阻断了IGF-II及其受体I型IGF受体（IGF-IR）和胰岛素受体（IR）的表达。尽管存在功能性IR信号传导，但致癌性IGF-II的作用，如肿瘤细胞活力、增殖和抗凋亡，仅由IGF-IR传递。尽管以前未在HCC细胞迁移的背景下描述IGF-II信号传导，但IGF-II依赖性表达谱显示出高比例的参与细胞运动和粘附的基因。事实上，IGF-II过表达促进了HCC细胞迁移，特别是与肝细胞生长因子（HGF）协同作用时。使用IGF-IR抑制剂鬼臼苦素（PPP）在体外和小鼠异种移植模型中测试了IGF-II/IGF-IR信号传导的治疗相关性。小分子治疗抑制IGF-IR有效降低了IGF-II依赖性信号传导以及IGF-II/IGF-IR途径的所有促肿瘤特性。
在人类HCC细胞中，致癌性IGF-II信号传导涉及IGF-IR而非IR。IGF-II的自分泌刺激通过整合旁分泌信号诱导HCC运动，以实现完全的恶性能力。因此，IGF-II/IGF-IR信号传导的激活可能是一种由功能选择的进展开关，可促进肿瘤细胞扩散和侵袭性肿瘤行为。
