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.
Graphical Abstract
[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.
[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.
[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.
Related Books
Science of Spices and Culinary Herbs - Latest Laboratory, Pre-clinical, and Clinical Studies
Frontiers in Natural Product Chemistry
Therapeutic Use of Plant Secondary Metabolites
Therapeutic Implications of Natural Bioactive Compounds
Frontiers in Bioactive Compounds
Frontiers in Natural Product Chemistry
Frontiers in Natural Product Chemistry
Science of Spices and Culinary Herbs - Latest Laboratory, Pre-clinical, and Clinical Studies
Frontiers in Natural Product Chemistry
Frontiers in Natural Product Chemistry
Article Metrics
38
4
1
1