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,Min Wang,Shao Hui Tang,Ting Zhuang Yi,Wei Jie Xu,Qiu Yan Huang,Xu You Liu,Hui Jun Tang,Sheng Lan Wu,Guo Li Cao,Ming Rong Cao

doi:10.18632/oncotarget.13027

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.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most prevalent human cancer globally, and ranks third in the cause of cancer death [1]
The present study explored the role of insulin-like growth factor-1 receptor (IGF-1R) in the development and progression of hepatocellular carcinoma (HCC) and the possibility of insulin-like growth factor (IGF)-1R silencing by lentivirus-mediated RNA interference (RNAi) as a therapeutic target for HCC
To investigate the role of IGF-1R in HCC, we examined the level of IGF-1R mRNA in HCC cells, and in 29 human HCC tissues, 29 matched adjacent nontumorous tissues (MANT), and 12 normal adult liver tissues (NALT) by quantitative RT-PCR

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most prevalent human cancer globally, and ranks third in the cause of cancer death [1]. It has several malignant biological properties including aggressive growth, frequent metastases, and poor survival rates, and it demands in-depth studies on prevention and treatment of HCC to lighten the heavy disease burden [2]. IGF-1R expression and activation is associated with resistance to cancer therapy such as chemotherapy and radiotherapy [11]. It has been shown that R1507, a monoclonal antibody targeting the human IGF-1R, results in the inhibition of the proliferation of several cancers, such as lung, breast, prostate cancers, and postpones the growth of xenograft tumor in nude mice [12]. The application of small molecule inhibitors such as RNA interference (RNAi) targeting IGF-1R for gene therapy of HCC has not yet been explored thoroughly

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Results

Conclusion