Lentivirus-mediated RNAi knockdown of insulin-like growth factor-1 receptor inhibits the growth and invasion of hepatocellular carcinoma via down-regulating midkine expression.
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.
Department of Gastroenterology, The Affiliated Shenzhen Shajing Hospital, Guangzhou Medical University, Shenzhen, China.
Cai Qun
CQ
Bie
Department of Gastroenterology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Xu You
XY
Liu
Department of General Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China.
Ming Rong
MR
Cao
Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China.
Qiu Yan
QY
Huang
Department of Gastroenterology, The Affiliated Shenzhen Shajing Hospital, Guangzhou Medical University, Shenzhen, China.
Hui Jun
HJ
Tang
Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China.
Min
M
Wang
Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China.
Guo Li
GL
Cao
Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China.
Ting Zhuang
TZ
Yi
Department of Gastroenterology, The Affiliated Shenzhen Shajing Hospital, Guangzhou Medical University, Shenzhen, China.
Sheng Lan
SL
Wu
Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China.
Wei Jie
WJ
Xu
Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China.
Shao Hui
SH
Tang
D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D000078792:Midkine; D009414:Nerve Growth Factors / Q000235:genetics*; D034622:RNA Interference; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
C000597236:IGF1R protein, human; C066254:MDK protein, human; D009414:Nerve Growth Factors; D017451:Receptors, Somatomedin; D000078792:Midkine; D017526:Receptor, IGF Type 1
HCC; IGF-1R; RNA interference; gene therapy; lentiviral vector