Lentivirus-mediated RNAi knockdown of insulin-like growth factor-1 receptor inhibits the growth and invasion of hepatocellular carcinoma via down-regulating midkine expression

• Published in: Oncotarget Vol. 7; no. 48; pp. 79305 - 79318
• Main Authors: Bie, Cai Qun, Liu, Xu You, Cao, Ming Rong, Huang, Qiu Yan, Tang, Hui Jun, Wang, Min, Cao, Guo Li, Yi, Ting Zhuang, Wu, Sheng Lan, Xu, Wei Jie, Tang, Shao Hui
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 29.11.2016
• Subjects: Adult; Aged; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - therapy; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Genetic Therapy; Humans; Lentivirus - genetics; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Liver Neoplasms - therapy; Male; Middle Aged; Nerve Growth Factors - genetics; Receptors, Somatomedin - genetics; Research Paper; RNA Interference; Xenograft Model Antitumor Assays; HCC; gene therapy; RNA interference; IGF-1R; lentiviral vector
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.13027

The insulin-like growth factor-1 receptor (IGF-1R) overexpression contributes to the development of a variety of cancers. The present study explored the role of IGF-1R in the development and progression of hepatocellular carcinoma (HCC) and the possibility of IGF-1R silencing by lentivirus-mediated RNA interference (RNAi) as a therapeutic target for HCC. We showed that IGF-1R mRNA was up-regulated in Huh7 and Hep3B cells and human HCC tissues, and that IGF-1R knockdown by RNAi led to decreased proliferation, apoptosis induction, and decreased migration and invasion of Huh7 and Hep3B cells. Further, the in vivo study indicated that IGF-1R knockdown markedly diminished the tumorigenesis and metastasis of Huh7 xenograft. Moreover, the intratumoral administration of lentivirus-IGF-1R siRNA led to significant tumor growth inhibition in an established Huh7 xenograft model. Mechanistic investigations showed that midkine was found to be the most significantly down-regulated protein in Huh7 cells with IGF-1R knockdown, and ectopic overexpression of midkine significantly rescued inhibition of Huh7 cell proliferation, migration, and invasion caused by IGF-1R suppression. Collectively, these data suggest that IGF-1R inhibition by RNAi can significantly suppress HCC growth and invasion at least partially through down-regulating midkine expression, and IGF-1R is a potential target for HCC gene therapy.