Bogorad Roman L, Yin Hao, Zeigerer Anja, Nonaka Hidenori, Ruda Vera M, Zerial Marino, Anderson Daniel G, Koteliansky Victor
1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2].
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
Nat Commun. 2014 May 21;5:3869. doi: 10.1038/ncomms4869.
Integrins play an important role during development, regulating cell differentiation, proliferation and survival. Here we show that knockdown of integrin subunits slows down the progression of hepatocellular carcinoma (HCC). Using nanoparticulate delivery of short interfering RNAs targeting β1 and αv integrin subunits, we downregulate all integrin receptors in hepatocytes. Short-term integrin knockdown (2 weeks) does not cause apparent structural or functional perturbations of normal liver tissue. Alterations in liver morphology accumulate on sustained integrin downregulation (7 weeks). The integrin knockdown leads to significant retardation of HCC progression, reducing proliferation and increasing tumour cell death. This tumour retardation is accompanied by reduced activation of the MET oncogene as well as expression of its mature form on the cell surface. Our data suggest that transformed proliferating cells from HCC are more sensitive to knockdown of integrins than normal quiescent hepatocytes, highlighting the potential of small interfering RNA-mediated inhibition of integrins as an anti-cancer therapeutic approach.
整合素在发育过程中发挥重要作用，调节细胞分化、增殖和存活。在此我们表明，整合素亚基的敲低会减缓肝细胞癌（HCC）的进展。通过纳米颗粒递送靶向β1和αv整合素亚基的短干扰RNA，我们下调了肝细胞中的所有整合素受体。短期整合素敲低（2周）不会引起正常肝组织明显的结构或功能扰动。持续整合素下调（7周）时肝脏形态的改变会累积。整合素敲低导致HCC进展显著延缓，减少增殖并增加肿瘤细胞死亡。这种肿瘤生长延缓伴随着MET癌基因激活的减少及其在细胞表面成熟形式表达的降低。我们的数据表明，HCC中转化的增殖细胞比正常静止肝细胞对整合素敲低更敏感，突出了小干扰RNA介导的整合素抑制作为一种抗癌治疗方法的潜力。
