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

// Cai Qun Bie 1, * , Xu You Liu 2, * , Ming Rong Cao 3, * , Qiu Yan Huang 4 , Hui Jun Tang 1 , Min Wang 4 , Guo Li Cao 4 , Ting Zhuang Yi 4 , Sheng Lan Wu 1 , Wei Jie Xu 4 , Shao Hui Tang 4 1 Department of Gastroenterology, The Affiliated Shenzhen Shajing Hospital, Guangzhou Medical University, Shenzhen, China 2 Department of Gastroenterology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China 3 Department of General Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China 4 Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China * These authors contributed equally to this work Correspondence to: Shao Hui Tang, email: tangshaohui206@163.com Keywords: IGF-1R, HCC, lentiviral vector, RNA interference, gene therapy Received: May 02, 2016 Accepted: October 26, 2016 Published: November 02, 2016 ABSTRACT 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.