Insulin-like Growth Factor System in Hepatocarcinogenesis

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1 ISSN CN / Q http / / cjbmb bjmu edu cn Chinese Journal of Biochemistry and Molecular Biology ~ * IGF IGF1 IGF2 IGF1R IGF2R IGFBP Q1 Insulin-like Growth Factor System in Hepatocarcinogenesis 1 CAI Mi 2 1 HE Fu-Chu 2 ZHOU Gang-Qiao 2 * 1 College of Life Sciences and Biotechnology Beijing University of Technology Beijing China 2 State Key Laboratory of Proteomics Beijing Proteome Research Center Beijing Institute of Radiation Medicine Beijing China Abstract Hepatocellular carcinoma HCC is one of the most common cancers and ranks the fifth of the cancer mortality worldwide The complex interplay of multiple genetic and environmental factors is responsible for hepatocarcinogenesis among which the insulin-like growth factor IGF system composed of IGFs their receptors IGF1R and IGF2R and IGF binding proteins IGFBPs plays pivotal roles in the development of HCC as shown by accumulating evidences This review focuses on the recent studies about the IGF system members in hepatocarcinogenesis The development of anti-neoplasia drugs targeting the IGF system members for the treatment of HCC will be discussed Currently certain monoclonal antibodies small molecule inhibitors and antisense interference agents have been proven to be effective in inhibiting growth and promoting apoptosis of hepatic tumor cells Key words insulin-like growth factor system hepatocellular carcinoma problem and prospect hepatocellular carcinoma HCC 3 IGF IGF No 2008ZX * Tel / Fax zhougq114@ gmail com insulin-like growth factor IGF Received December Accepted March Supported by Chinese National Key Project for Infectious Diseases No IGFs ZX * Corresponding author Tel / Fax zhougq114@ gmail com insulin-like growth factor receptor IGFR

2 IGF1 IGF2 IGF1R IGF2R HpG2 insulin-like growth factor binding protein IGFBP IGF1 IGF1 2 IGF1 IGF2 1α hypoxia inducible factor 1-α HIF1α IGF1 IGF1R IGF2R IGFs IGF1 IGF1R 9 matrix IGF1R 2 Raf / metalloproteinase 9 MMP-9 Raf / MAPK 3 IGF1R / AKT PI3K / AKT MMP IGF2R Oliver-Marston 7 IGF1 IGF2 IGF2 IGF1 70% TGF-β1 4 IGFBP 6 IGF IGFBP1 ~ 6 IGF IGF1 5 Fig 1 Fig 1 IGF signaling pathway The biological activity of IGFs is mediated by the IGF1R mainly through two major downstream signal transduction pathways Raf / MAPK and PI3K / AKT pathway affecting cell proliferation differentiation and apoptosis The biological activity of IGFs is mainly regulated by IGFBPs The membrane protein IGF2R specifically inhibits the function of IGF2 in signal transduction activate inhibit 2 IGF1 2 1 IGF1 IGF1 8 Huynh 9 IGF1 mrna IGF1 10 IGF1 IGF1 Price 11 IGF1 IGF1 C6 IGF1 IGF1 IGF1 Kasprzak ~ 2005

3 IGF1 IGF2 Thorgeirsson ~ 9 80% IGF2 Tang 19 HBV IGF1 IGF2 P1 P3 P4 P3 P4 IGF2 2 2 IGF2 IGF2 IGF2 P4 P4 20 IGF2 30% IGF2 ~ 40% IGF2 IGF2 IGF2 13 IGF2 p53 HCC IGF TGF-α IGF AFP Sun 21 IGF HBx IGF1R Breuhahn 14 IGF1R GO 155 IGF2 47 Nussbaum AFP 15 sirna IGF2 4 IGF2 IGF1R IGF2 / IGF1R 3 IGF2 28% 3 1 IGF1R IGF1R IGF2 IGFs IGF1R HGF IGF2 IGF1R IGF2 / IGF1R 22 IGF1R IGF2 11p P1 ~ P4 IGF1R vascular endothial growth factor IGF2 VEGF epidermal growth factor 16 IGF2 EGFR HER2 / Neu P1 EGFR IGF1R EGFR EGFR P1 IGF2 IGF2 50% P3 extracellular regulated protein kinases ERK EGFR 70% IGF2 P3 ERK 23 P2 P4 17 IGF2 / IGF1R

4 IGF1R / IGF2R EGFR EGFR IGF2 IGF2 / M6PR IGF2 24 IGF1 IGF2 IGF1R IGF2 / M6PR 6q26-q27 Jones Lopez IGF1R IGF2R IGF1R M6P / IGF2 SV40LT c-myc IGF-2 IGF2 / M6PR Codoret 27c-myc IGF1R IGF2 / M6PR IGF2 / M6PR IGF1R IGF1R 4 IGF1R IGF1R IGF1R IGF IGFs IGF1R insulin IGF1R IGFs receptor IR IGFBP3 IGFBP IGF1R IR IGFBP3 IGFs 28 IGF1R IGFs IGF1R Huynh 9 Western IGFBP3 28 5% IGF1R IGFBP3 71 5% IGFR IMC-A12 IGFBP3 IGF1R IGFBP3 OSI-906 I IGFBP3 IGF1 3 2 IGF2 / M6PR IGF2 / M6PR IGF2 / M6PR M6P IGFBP IGFs IGF2 IGF1R 33 M6P Ricort 34 ~ 36 MCF-7 IGF2 IGF2 / M6PR IGF2 DNA % IGFBPs IGFs IGFs 32 IGFBP3 IGFBP3 IGFBP3-3 G Sedlaczek 30 IGFBP3 18 IGF2 IGF1R IGFBP3

5 5 395 References IGFBP3 IGFs IGFs IGFs IGFBP IGFBP IGFBP IGFBPs IGFs 29 IGFBP IGFs IGFBP IGF1R ~ 39 IGFBP3 RRR-α- E VSE D A 4- N- hydroxyphenyl retinamide 4-HPR fenretinide IGFBP3 Nat Rev Endocrinol IGFBP 7 Olivo-Marston S E Hursting S D Lavigne J et al 5 1 Sanyal A J Yoon S K Lencioni R The etiology of hepatocellular carcinoma and consequences for treatment J Oncologist S Weng C J Hsieh Y H Tsai CM et al Relationship of insulinlike growth factors system gene polymorphisms with the susceptibility and pathological development of hepatocellular IGFs J RNA IGF- 41 carcinoma J Ann Surg Oncol Annenkov A The insulin-like growth factor IGF receptor type 1 IGF1R as an essential component of the signalling network regulating neurogenesis J Mol Neurobiol Martin-Kleiner I Gall Troselj K Mannose-6-phosphate / insulinlike growth factor 2 receptor M6P / IGF2R in carcinogenesis J Cancer Lett Mohan S Baylink D J IGF-binding proteins are multifunctional and act via IGF-dependent and-independent mechanisms J J Endocrinol Clayton P E Banerjee I Murray P G et al Growth hormone the insulin-like growth factor axis insulin and cancer risk J Genetic reduction of circulating insulin-like growth factor-1 inhibits azoxymethane-induced colon tumorigenesis in mice J Mol Carcinog Elsammak M Y Amin G M Khalil G M et al Possible contribution of serum activin A and IGF-1 in the development of hepatocellular carcinoma in Egyptian patients suffering from combined hepatitis C virus infection and hepatic schistosomiasis Clin Biochem Huynh H Chow PK Ooi LL et al A possible role for insulinlike growth factor-binding protein-3 autocrine / paracrine loops in controlling hepatocellular carcinoma cell proliferation J Cell Growth Differ Scharf J G Braulke T The role of the IGF axis in hepatocarcinogenesis J Horm Metab Res IGF IGF 11 Price J A Kovach S J of hepatocellualr carcinoma J Johnson T et al Insulin-like growth factor I is a comitogen for hepatocyte growth factor in a rat model 13 Lund P Schubert D Niketeghad F et al Autocrine inhibition of chemotherapy response in human liver tumor cells by insulin- IGF IGF like growth factor-Ⅱ J 14 Breuhahn K hepatocarcinogenesis J Hepatology Kasprzak H A Trojan J Bierwagen M et al Usefulness of the antisense and triplex anti-igf-1 techniques for postoperative cellular gene therapy of malignant gliomas expressing IGF-1 J Neurol Neurochir Pol Cancer Lett Molecular mechanisms of progression in human Pathologe S Nussbaum T Samarin J Ehemann V et al Autocrine insulin-

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