Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
Oncogene. 2010 Apr 29;29(17):2517-27. doi: 10.1038/onc.2010.17. Epub 2010 Feb 15.
Insulin receptor (IR) and the type I IGF receptor (IGF1R) are structurally and functionally related. The function of IGF1R in cancer has been well documented and anti-IGF1R strategies to treat cancer have shown initial positive results. However, the role of IR in tumor biology, independent of IGF1R, is less clear. To address this issue, short hairpin RNA (shRNA) was used to specifically downregulate IR in two cancer cell lines, LCC6 and T47D. Cells with reduced IR showed reduced insulin-stimulated Akt activation, without affecting IGF1R activation. Cells with reduced IR formed fewer colonies in anchorage-independent conditions. LCC6 IR shRNA xenograft tumors in mice had reduced growth, angiogenesis and lymphangiogensis when compared with LCC6 wild-type cells. Accordingly, LCC6 IR shRNA clones produced less hypoxia-inducible factor-1alpha, vascular endothelial growth factor (VEGF)-A and VEGF-D. Furthermore, LCC6 IR shRNA cells formed fewer pulmonary metastases when compared with LCC6 wild-type cells. Using in vivo luciferase imaging, we have shown that LCC6 IR shRNA cells have less seeding and colonization potential in the lung and liver of mice than LCC6 cells. In conclusion, downregulation of IR inhibited cancer cell proliferation, angiogenesis, lymphangiogenesis and metastasis. Our data argue that IR should also be targeted in cancer therapy.
胰岛素受体 (IR) 和 I 型 IGF 受体 (IGF1R) 在结构和功能上相关。IGF1R 在癌症中的功能已得到充分证实,针对 IGF1R 的治疗策略已显示出初步的积极结果。然而,IR 在肿瘤生物学中的作用,独立于 IGF1R,尚不清楚。为了解决这个问题,使用短发夹 RNA (shRNA) 特异性下调两种癌细胞系 LCC6 和 T47D 中的 IR。IR 减少的细胞显示胰岛素刺激的 Akt 激活减少,而不影响 IGF1R 的激活。IR 减少的细胞在非锚定条件下形成的菌落较少。与 LCC6 野生型细胞相比,LCC6 IR shRNA 异种移植肿瘤在小鼠中的生长、血管生成和淋巴管生成减少。相应地,LCC6 IR shRNA 克隆产生的低氧诱导因子-1alpha、血管内皮生长因子 (VEGF)-A 和 VEGF-D 减少。此外,与 LCC6 野生型细胞相比,LCC6 IR shRNA 细胞形成的肺转移瘤较少。通过体内荧光素酶成像,我们已经表明 LCC6 IR shRNA 细胞在小鼠的肺和肝脏中的定植和定植潜力低于 LCC6 细胞。总之,IR 的下调抑制了癌细胞的增殖、血管生成、淋巴管生成和转移。我们的数据表明,IR 也应该成为癌症治疗的靶点。