Insulin-like Growth Factor I Receptor: A Novel Target for Hepatocellular Carcinoma Gene Therapy

Author(s): Li Wang, Min Yao, Wenjie Zheng, Miao Fang, Mengna Wu, Jianying Sun, Zhizhen Dong*, Dengfu Yao*.

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 19 , Issue 4 , 2019

Submit Manuscript
Submit Proposal

Graphical Abstract:


Abstract:

Human insulin-like growth factor (IGF) axis affects the molecular pathogenesis of hepatocellular carcinoma (HCC), especially in the abnormality of hepatic IGF-I receptor (IGF-IR) or IGF-II expression as a key molecule in hepatocarcinogenesis. However, the over-expression of hepatic IGFIR is associated with HCC progression with largely unknown mechanisms. The IGF-IR as one key molecule of the IGF signal pathway plays an important role in the hepatocyte malignant transformation. Attaching importance to IGF-IR might improve the prognostic or the therapeutic technique of HCC. This article reviews IGF-IR alteration during HCC development, and the effects of silencing IGF-IR gene by specific short hairpin RNA on the inhibition of cell proliferation in vitro or HCC xenograft growth in vivo to elucidate it as a novel molecular-targeted therapy for HCC.

Keywords: Hepatocellular carcinoma, insulin-like growth factor-I receptor, molecular targeted, gene therapy, gene amplification, xenograft tumor, cell proliferation.

[1]
Shiraha, H.; Yamamoto, K.; Namba, M. Human hepatocyte carcinogenesis.(review) Int. J. Oncol., 2013, 42, 1133-1138.
[2]
Hui, K.M. Human hepatocellular carcinoma: Expression profiles-based molecular interpretations and clinical applications. Cancer Lett., 2009, 286, 96-102.
[3]
Raza, S.A.; Clifford, G.M.; Franceschi, S. Worldwide variation in the relative importance of hepatitis B and hepatitic C viruses in hepatocellular carcinoma: A systematic review. Br. J. Cancer, 2007, 96, 1127-1134.
[4]
Kew, M.C. Hepatitis B virus x protein in the pathogenesis of hepatitis B virus- induced hepatocellular carcinoma. J. Gastroenterol. Hepatol., 2011, 26, 144-152.
[5]
Fan, J.G.; Farrell, G.C. Epidemiology of non-alcoholic fatty liver disease in China. J. Hepatol., 2009, 50, 204-210.
[6]
Ding, J.; Wang, H. Multiple interactive factors in hepatocarcinogenesis. Cancer Lett., 2014, 346, 17-23.
[7]
Arzumanyan, A.; Reis, H.M.; Feitelson, M.A. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat. Rev. Cancer, 2012, 13, 123-135.
[8]
Wang, L.; Yao, M.; Dong, Z.; Zhang, Y.; Yao, D. Circulating specific biomarkers in diagnosis of hepatocellular carcinoma and its metastasis monitoring. Tumor Biol., 2014, 35, 9-20.
[9]
Yao, D.F.; Jiang, D.R.; Huang, Z.W.; Lu, J.X.; Tao, Q.Y.; Yu, Z.J.; Meng, X.Y. Abnormal expression of hepatoma specific gammaglutamyl transferase and alteration of gamma-glutamyl transferase gene methylation status in patients with hepatocellular carcinoma. Cancer, 2000, 88, 761-769.
[10]
Bruix, J.; Gores, G.J.; Mazzaferro, V. Hepatocellular carcinoma: Clinical frontiers and perspectives. Gut, 2014, 63, 844-885.
[11]
Yang, J.D.; Roberts, L.R. Hepatocellular carcinoma: A global view. Nat. Rev. Gastroenterol. Hepatol., 2010, 7, 449-458.
[12]
Jain, S.; Singhal, S.; Lee, P.; Xu, R. Molecular genetics of hepatocellular neoplasia. Am. J. Transl. Res., 2010, 2, 105-118.
[13]
Zhu, A.X.; Ancukiewicz, M.; Supko, J.G.; Sahani, D.V.; Blaszkowsky, L.S.; Meyerhardt, J.A.; Abrams, T.A.; McCleary, N.J.; Bhargava, P.; Muzikansky, A.; Sheehan, S.; Regan, E.; Vasudev, E.; Knowles, M.; Fuchs, C.S.; Ryan, D.P.; Jain, R.K.; Duda, D.G. Efficacy, safety, pharmacokinetics, and biomarkers of cediranib monotherapy in advanced hepatocellular carcinoma: A phase II study. Clin. Cancer Res., 2013, 19, 1557-1566.
[14]
Tang, Y.H.; Wen, T.F.; Chen, X. Resection margin in hepatectomy for hepato- cellular carcinoma: A systematic review. Hepatogastroenterology, 2012, 59, 1393-1397.
[15]
Nussbaum, T.; Samarin, J.; Ehemann, V.; Bissinger, M.; Ryschich, E.; Khamidjanov, A.; Yu, X.; Gretz, N.; Schirmacher, P.; Breuhahn, K. Autocrine insulin-like growth factor-II stimulation of tumor cell migration is a progression step in human hepatocarcinogenesis. Hepatology, 2008, 48, 146-156.
[16]
Tovar, V.; Alsinet, C.; Villanueva, A.; Hoshida, Y.; Chiang, D.Y.; Sole, M.; Moyano, S.; Toffanin, S.; Mínguez, B.; Cabellos, L.; Peix, J.; Schwartz, M.; Mazzaferro, V.; Bruix, J.; Llovet, J.M. IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage. J. Hepatol., 2010, 52, 550-559.
[17]
Alexia, C.; Bras, M.; Fallot, G.; Vadrot, N.; Daniel, F.; Lasfer, M.; Tamouza, H.; Groyer, A. Pleiotropic effects of PI-3′ kinase/Akt signaling in human hepatoma cell proliferation and drug-induced apoptosis. Ann. N. Y. Acad. Sci., 2006, 1090, 1-17.
[18]
Kurmasheva, R.T.; Dudkin, L.; Billups, C.; Debelenko, L.V.; Morton, C.L.; Houghton, P.J. The insulin-like growth factor-1 receptor-targeting antibody, CP-751, 871, suppresses tumor-derived VEGF and synergizes with rapamycin in models of childhood sarcoma. Cancer Res., 2009, 69, 7662-7671.
[19]
E,C. Li, J.; Shao, D.; Zhang, D.; Pan, Y.; Chen, L.; Zhang, X. The insulin-like growth factor-I receptor inhibitor picropodophyllin-induced selective apoptosis of hepatocellular carcinoma cell through a caspase-dependent mitochondrial pathway. Oncol. Res., 2014, 21, 103-110.
[20]
Hsu, H.H.; Cheng, L.H.; Ho, T.J.; Kuo, W.W.; Lin, Y.M.; Chen, M.C.; Lee, N.H.; Tsai, F.J.; Tsai, K.H.; Huang, C.Y. Apicidin-resistant HA22T hepatocellular carcinoma cells massively promote pro-survival capability via IGF-IR/PI3K/Akt signaling pathway activation. Tumor Biol., 2014, 35, 303-313.
[21]
Lee, J.S. The mutational landscape of hepatocellular carcinoma. Clin. Mol. Hepatol., 2015, 21, 220-229.
[22]
Forner, A.; Llovet, J.M.; Bruix, J. Hepatocellular carcinoma. Lancet, 2012, 379, 1245-1255.
[23]
Yan, X.D.; Yao, M.; Wang, L.; Zhang, H.J.; Yan, M.J.; Gu, X.; Shi, Y.; Chen, J.; Dong, Z.Z.; Yao, D.F. Overexpression of insulin-like growth factor-I receptor as a pertinent biomarker for hepatocytes malignant transformation. World J. Gastroenterol., 2013, 19, 6084-6092.
[24]
Qiu, L.W.; Yao, D.F.; Zong, L.; Lu, Y.Y.; Huang, H.; Wu, W.; Wu, X.H. Abnormal expression of insulin-like growth factor-II and its dynamic quantitative analysis at the early different stages of hepatocellular carcinoma development. Hepatobiliary Pancreat. Dis. Int., 2008, 7, 406-411.
[25]
Dong, Z.Z.; Yao, D.F.; Wu, W.; Yao, M.; Yu, H.B.; Shen, J.J.; Qiu, L.W.; Qian, Q.; Yao, N.H.; Sai, W.L.; Yang, J.L. Delated hepatocarcinogenesis through anti- angiogenic intervention in the nuclear factor-κappa B activation pathway in rats. Hepatobiliary Pancreat. Dis. Int., 2010, 9, 169-174.
[26]
Yao, D.F.; Huang, Z.W.; Chen, S.Z.; Huang, J.F.; Lu, J.X.; Xiao, M.B.; Meng, X.Y. Diagnosis of hepatocellular carcinoma by quantitative detection of hepatoma -specific bands of serum gamma-glutamyltransferase. Am. J. Clin. Pathol., 1998, 110, 743-749.
[27]
Yao, D.F.; Dong, Z.Z.; Yao, M. Specific molecular markers in hepatocellular carcinoma. Hepatobiliary Pancreat. Dis. Int., 2007, 6, 241-247.
[28]
Wang, L.; Yao, M.; Pan, L.H.; Qian, Q.; Yao, D.F. Glypican-3 as special biomarker or promising target molecule for primary liver cancer. Hepatobil Pancreat. Dis. Int., 2015, 14, 361-366.
[29]
Qian, J.; Yao, D.; Dong, Z.; Wu, W.; Qiu, L.; Yao, N.; Li, S.; Bian, Y.; Wang, Z.; Shi, G. Characteristics of hepatic igf-ii expression and monitored levels of circulating igf-ii mRNA in metastasis of hepatocellular carcinoma. Am. J. Clin. Pathol., 2010, 134, 799-806.
[30]
Dong, Z.Z.; Yao, D.F.; Yao, D.B.; Wu, X.H.; Wu, W.; Qiu, L.W.; Jiang, D.R.; Zhu, J.H.; Meng, X.Y. Expression and alteration of insulin-like growth factor II-messenger RNA in hepatoma tissues and peripheral blood of patients with hepatocellular carcinoma. World J. Gastroenterol., 2005, 11, 4655-4660.
[31]
Dong, Z.Z.; Yao, M.; Wang, L.; Yan, X.D.; Gu, X.; Shi, Y.; Yao, N.H.; Qiu, L.W.; Wu, W.; Yao, D.F. Abnormal expression of insulin-like growth factor-I receptor in hepatoma tissues and its inhibition promoting apoptosis of tumor cells. Tumor Biol., 2013, 34, 3397-3405.
[32]
Breuhahn, K.; Schirmacher, P. Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma. World J. Gastroenterol., 2008, 14, 1690-1698.
[33]
Weng, C.J.; Hsieh, Y.H.; Tsai, C.M.; Chu, Y.H.; Ueng, K.C.; Liu, Y.F.; Yeh, Y.H.; Su, S.C.; Chen, Y.C.; Chen, M.K.; Yang, S.F. Relationship of insulin-like growth factors system gene polymorphisms with the susceptibility and pathological development of hepato- cellular carcinoma. Ann. Surg. Oncol., 2010, 17, 1808-1815.
[34]
Lang, S.A.; Hackl, C.; Moser, C.; Fichtner-Feigl, S.; Koehl, G.E.; Schlitt, H.J.; Geissler, E.K.; Stoeltzing, O. Implication of RICTOR in the mTOR inhibitor- mediated induction of insulin-like growth factor-I receptor (IGF-IR) and human epidermal growth factor receptor-2 (Her2) expression in gastrointestinal cancer cells. Biochim. Biophys. Acta, 2010, 1803, 435-442.
[35]
Alexia, C.; Lasfer, M.; Groyer, A. Role of constitutively activated and insulin-like growth factor-stimulated ERK1/2 signaling in human hepatoma cell proliferation and apoptosis: Evidence for heterogeneity of tumor cell lines. Ann. N. Y. Acad. Sci., 2004, 1030, 219-229.
[36]
Yao, N.; Yao, D.; Wang, L.; Dong, Z.; Wu, W.; Qiu, L.; Yan, X.; Yu, D.; Chen, J.; Sai, W.; Zhang, H.; Yang, J. Inhibition of autocrine IGF-II on effect of human HepG2 cell proliferation and angiogenesis factor expression. Tumour Biol., 2012, 33, 1767-1776.
[37]
Alexia, C.; Fallot, G.; Lasfer, M.; Schweizer-Groyer, G.; Groyer, A. An evaluation of the role of insulin-like growth factors (IGF) and of type-I IGF receptor signalling in hepatocarcinogenesis and in the resistance of hepato- carcinoma cells against drug-induced apoptosis. Biochem. Pharmacol., 2004, 68, 1003-1015.
[38]
Yao, M.; Wang, L.; Qiu, L.; Qian, Q.; Yao, D. Encouraging microRNA-based therapeutic strategies for hepatocellular carcinoma. Anticancer. Agents Med. Chem., 2015, 15, 453-460.
[39]
Broderick, J.A.; Zamore, P.D. MicroRNA therapeutics. Gene therapy., 2011, 18, 1104-1110.
[40]
Yao, N.H.; Yao, D.F.; Dong, Z.Z.; Yan, X.D.; Chen, J.; Yao, M.; Wang, L.; Yan, M.J. Effects of inhibited IGF-IR expression on proliferation and apoptosis of human hepatocellular carcinoma cell lines. Zhonghua Gan Zang Bing Zazhi, 2013, 21, 376-380.
[41]
Yue, L.; Wang, Y.; Wang, H.; Gao, H.; Liang, J.; Sui, A.; Xiang, J.; Zhou, F.; Xu, C.; Zhao, W.; Liang, W.; Yao, R. Inhibition of hepatocellular carcinoma cell growth by an anti-insulin-like growth factor-I receptor monoclonal antibody. Oncol. Rep., 2012, 28, 1453-1460.
[42]
Price, J.A.; Kovach, S.J.; Johnson, T.; Koniarim, L.G.; Cahill, P.A.; Sitzmann, J.V.; McKillop, I.H. Insulin-like growth factor I is a comitogen for hepatocyte growth factor in a rat model of hepatocellular carcinoma. Hepatology, 2002, 36, 1089-1097.
[43]
Tomizawa, M.; Yokosuka, O. Picropodophyllin suppresses the proliferation and invasion of hepatocellular carcinoma under serum starvation. Mol. Med. Rep., 2008, 1, 685-688.
[44]
Xu, C.; Lee, S.A.; Chen, X. RNA interference as therapeutics for hepatocellular carcinoma. Recent Pat Anticancer Drug Discov., 2011, 6, 106-115.
[45]
Lee, Y.I.; Han, Y.J.; Lee, S.Y.; Lee, Y.I.; Park, S.K.; Park, Y.J.; Moon, H.B.; Shin, J.H.; Lee, J.H. Activation of insulin-like growth factor II signaling by mutant type p53: Physiological implications for potentiation of IGF-II signaling by p53 mutant 249. Mol. Cell. Endocrinol., 2003, 203, 51-63.
[46]
EI, Tayebi H.M.; Salah, W.; EI Sayed, I.H.; Salam, E.M.; Zekri, A.R.; Zayed, N.; Salem, E.S.; Esmat, G.; Abdelaziz, A.I. Expression of insulin-like growth factor-II, matrix metalloproteinases, and their tissue inhibitors as predictive markers in the peripheral blood of HCC patients. Biomarkers, 2011, 16, 346-354.
[47]
Freise, C.; Ruehl, M.; Erben, U.; Neumann, U.; Seehofer, D.; Kim, K.Y.; Trowitzsch-Kienast, W.; Stroh, T.; Zeitz, M.; Somasundaram, R. A hepato- protective Lindera obtusiloba extract suppresses growth and attenuates insulin like growth factor-1 receptor signaling and NF-kappaB activity in human liver cancer cell lines. BMC Complement. Altern. Med., 2011, 11, 39-46.
[48]
Zhang, H.J.; Yao, D.F.; Yao, M.; Huang, H.; Wang, L.; Yan, M.J.; Yan, X.D.; Gu, X.; Wu, W.; Lu, S.L. Annexin A2 silencing inhibits invasion, migration, and tumorigenic potential of hepatoma cells. World J. Gastroenterol., 2013, 19, 3792-3801.
[49]
Cuevas, E.P.; Escribano, O.; Monserrat, J.; Martínez-Botas, J.; Sánchez, M.G.; Chiloeches, A.; Hernández-Breijo, B.; Sánchez-Alonso, V.; Román, I.D.; Fernández-Moreno, M.D.; Guijarro, L.G. RNAi-mediated silencing of insulin receptor substrate-4 enhances actinomycin D- and tumor necrosis factor-alpha- induced cell death in hepatocarcinoma cancer cell lines. J. Cell. Biochem., 2009, 108, 1292-1301.
[50]
Campbell, C.I.; Moorehead, R.A. Mammary tumors that become independent of the type I insulin-like growth factor receptor express elevated levels of platelet- derived growth factor receptors. BMC Cancer, 2011, 11, 480.
[51]
Lin, R.X.; Wang, Z.Y.; Zhang, N.; Tuo, C.W.; Liang, Q.D.; Sun, Y.N.; Wang, S.Q. Inhibition of hepatocellular carcinoma growth by antisense oligonucleotides to type I insulin-like growth factor receptor in vitro and in an orthotopic model. Hepatol. Res., 2007, 37, 366-375.
[52]
Gailhouste, L.; Ochiya, T. Cancer-related microRNAs and their role as tumor suppressors and oncogenes in hepatocellular carcinoma. Histol. Histopathol., 2013, 28, 437-451.
[53]
Zhao, H.; Desai, V.; Wang, J.; Epstein, D.M.; Miglarese, M.; Buck, E. Epithelial- mesenchymal transition predicts sensitivity to the dual IGF-1R/IR inhibitor OSI-906 in hepatocellular carcinoma cell lines. Mol. Cancer Ther., 2012, 11, 503-513.
[54]
Yao, W.F.; Liu, J.W.; Sheng, G.L.; Huang, D.S. Blockade of IGF-IR exerts anticancer effects in hepatocellular carcinoma. Mol. Med. Rep., 2011, 4, 719-722.
[55]
Aleem, E.; Nehrbass, D.; Klimek, F.; Mayer, D.; Bannasch, P. Upregulation of the insulin receptor and type I insulin-like growth factor receptor are early events in hepatocarcinogenesis. Toxicol. Pathol., 2011, 39, 524-543.
[56]
Cao, H.; Phan, H.; Yang, L.X. Improved chemotherapy for hepatocellular carcinoma. Anticancer Res., 2012, 32, 1379-1386.
[57]
Lee, J.Y.; Han, C.Y.; Yang, J.W.; Smith, C.; Kim, S.K.; Lee, E.Y.; Kim, S.G.; Kang, K.W. Induction of glutathione transferase in insulin-like growth factor type I receptor-overexpressed hepatoma cells. Mol. Pharmacol., 2007, 72, 1082-1093.


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 19
ISSUE: 4
Year: 2019
Page: [272 - 280]
Pages: 9
DOI: 10.2174/1389557518666181025151608
Price: $58

Article Metrics

PDF: 23
HTML: 1
EPUB: 1
PRC: 1