Nanoparticle-formulated siRNA targeting integrins inhibits hepatocellular carcinoma progression in mice.
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.
1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2].
Roman L
RL
Bogorad
1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2].
Hao
H
Yin
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
Anja
A
Zeigerer
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
Hidenori
H
Nonaka
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Vera M
VM
Ruda
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
Marino
M
Zerial
1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts 02139, USA [4] Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Daniel G
DG
Anderson
1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Skolkovo Institute of Science and Technology, ul. Novaya, d.100, Skolkovo 143025, Russian Federation.
Victor
V
Koteliansky
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D049109:Cell Proliferation; D018450:Disease Progression; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000378:metabolism*; D039001:Integrin alpha Chains / Q000235:genetics*; D039641:Integrin beta Chains / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000235:genetics*; D051379:Mice; D053758:Nanoparticles; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D034741:RNA, Small Interfering
D039001:Integrin alpha Chains; D039641:Integrin beta Chains; D034741:RNA, Small Interfering; D019859:Proto-Oncogene Proteins c-met