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IGF-I receptor as an emerging potential molecular-targeted for hepatocellular carcinoma in vitro and in vivo

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Tumor Biology

Abstract

Abnormal expression of insulin-like growth factor I receptor (IGF-IR) is associated with hepatocellular carcinoma (HCC) progression with largely unknown mechanisms. In this study, IGF-IR expression among different HCC cell lines and silencing its gene transcription on effects of HCC were investigated by short hairpin RNA (shRNA). Specific shRNA was successfully transfected into Bel-7404 or PLC/PRF/5 cells with 90 or 71 % efficiency. The inhibiting rate of IGF-IR at mRNA level were 54.9 % in Bel-7404 or 59.6 % in PLC/PRF/5 cells in accordance with its protein suppression, with the cell cycles at the G1 phase arrest and decreasing cyclinD1 via promoting apoptosis in vitro. With the xenograft models of PLC/PRF/5 cells inserted specific shRNA in vivo, the tumor-forming time (14.0 ± 1.1 days) or tumor volume (143 ± 24 mm3) in the shRNA group was significantly lengthened or smaller than those in the control group (7.2 ± 0.8 days or 372 ± 46 mm3, P < 0.001) or in the neg-shRNA group (7.5 ± 1.0 days or 350 ± 50 mm3, P < 0.001). Silencing the IGF-IR gene transcription inhibited cell proliferation or xenograft tumor growth of HCC, suggesting that IGF-IR might be a novel potential target for HCC gene therapy.

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Abbreviations

AFP:

Alpha-fetoprotein

FQ-RT-PCR:

Fluorescence quantitative reverse transcriptase-PCR

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

HCV:

Hepatitis C virus

IGF:

Insulin-like growth factor

IGF-II:

Insulin-like growth factor II

IGF-IR:

Insulin-like growth factor I receptor

miRNA:

MicroRNA

shRNA:

Short hairpin RNA

siRNA:

Small interfering RNA

PPP:

Picropodophyllin

References

  1. Shiraha H, Yamamoto K, Namba M. Human hepatocyte carcinogenesis (review). Int J Oncol. 2013;42(4):1133–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Chi M, Mikhitarian K, Shi C, Goff LW. Management of combined hepatocellular-cholangiocarcinoma: a case report and literature review. Gastrointest Cancer Res. 2012;5(6):199–202.

    PubMed  PubMed Central  Google Scholar 

  3. Cheng JW, Lv Y. New progress of non-surgical treatments for hepatocellular carcinoma. Med Oncol. 2013;30(1):381.

    Article  PubMed  Google Scholar 

  4. Hyodo T, Murakami T, Imai Y, Okada M, Hori M, Kagawa Y, et al. Hypovascular nodules in patients with chronic liver disease: risk factors for development of hypervascular hepatocellular carcinoma. Radiology. 2013;266(2):480–90.

    Article  PubMed  Google Scholar 

  5. Hu J, Gao DZ. Distinction immune genes of hepatitis-induced heptatocellular carcinoma. Bioinformatics. 2012;28(24):3191–4.

    Article  CAS  PubMed  Google Scholar 

  6. Arzumanyan A, Reis HM, Feitelson MA. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer. 2012;13(2):123–35.

    Article  Google Scholar 

  7. Kew MC. Hepatitis B virus x protein in the pathogenesis of hepatitis B virus-induced hepatocellular carcinoma. J Gastroenterol Hepatol. 2011;26(S1):144–52.

    Article  CAS  PubMed  Google Scholar 

  8. Wang L, Yao M, Dong Z, Zhang Y, Yao D. Circulating specific biomarkers in diagnosis of hepatocellular carcinoma and its metastasis monitoring. Tumour Biol. 2014;35(1):9–20.

    Article  PubMed  Google Scholar 

  9. Zhu AX, Ancukiewicz M, Supko JG, Sahani DV, Blaszkowsky LS, Meyerhardt JA, et al. Efficacy, safety, pharmacokinetics, and biomarkers of cediranib monotherapy in advanced hepatocellular carcinoma: a phase II study. Clin Cancer Res. 2013;19(6):1557–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hamed O, Kimchi ET, Sehmbey M, Gusani NJ, Kaifi JT, Staveley-O’Carroll K. Impact of genetic targets on cancer therapy: hepatocellular cancer. Adv Exp Med Biol. 2013;779(1):67–90.

    Article  PubMed  Google Scholar 

  11. Maakaron JE, Cappellini MD, Graziadei G, Ayache JB, Taher AT. Hepatocellular carcinoma in hepatitis-negative patients with thalassemia intermedia: a closer look at the role of siderosis. Ann Hepatol. 2013;12(1):142–6.

    PubMed  Google Scholar 

  12. Broderick JA, Zamore PD. MicroRNA therapeutics. Gene Ther. 2011;18(12):1104–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Xu C, Lee SA, Chen X. RNA interference as therapeutics for hepatocellular carcinoma. Recent Pat Anticancer Drug Discov. 2011;6(1):106–15.

    Article  CAS  PubMed  Google Scholar 

  14. Gailhouste L, Ochiya T. Cancer-related microRNAs and their role as tumor suppressors and oncogenes in hepatocellular carcinoma. Histol Histopathol. 2013;28(4):437–51.

    CAS  PubMed  Google Scholar 

  15. EC, Li J, Shao D, Zhang D, Pan Y, Chen L, et al. The insulin-like growth factor-I receptor inhibitor picropodophyllin-induced selective apoptosis of hepato-cellular carcinoma cell through a caspase-dependent mitochondrial pathway. Oncol Res. 2014;21(2):103–10.

    Article  Google Scholar 

  16. Hsu HH, Cheng LH, Ho TJ, Kuo WW, Lin YM, Chen MC, et al. Apicidin-resistant HA22T hepatocellular carcinoma cells massively promote pro-survival capability via IGF-IR/PI3K/Akt signaling pathway activation. Tumour Biol. 2014;35(1):303–13.

    Article  CAS  PubMed  Google Scholar 

  17. Dong ZZ, Yao M, Qian J, Yan XD, Chen J, Yan MJ, et al. Abnormal expression of insulin-like growth factor-II and intervening of its mRNA transcription in the promotion of HepG2 cell apoptosis. Zhonghua Yi Xue Za Zhi. 2013;93(12):892–6 .Chinese

    CAS  PubMed  Google Scholar 

  18. Qian J, Yao D, Dong Z, Wu W, Qiu L, Yao N, et al. 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(5):799–806.

    Article  CAS  PubMed  Google Scholar 

  19. Yao N, Yao D, Wang L, Dong Z, Wu W, Qiu L, et al. Inhibition of autocrine IGF-II on effect of human HepG2 cell proliferation and angiogenesis factor expression. Tumour Biol. 2012;33(5):1767–76.

    Article  CAS  PubMed  Google Scholar 

  20. Qiu LW, Yao DF, Zong L, Lu YY, Huang H, Wu W, et al. Abnormal expression of insulin-like growth factor-II and its dynamic quantitative analysis at different stages of hepatocellular carcinoma development. Hepatobiliary Pancreatol Dis Int. 2008;7(4):406–11.

    Google Scholar 

  21. Zhang HJ, Yao DF, Yao M, Huang H, Wang L, Yan MJ, et al. Annexin A2 silencing inhibits invasion, migration, and tumorigenic potential of hepatoma cells. World J Gastroenterol. 2013;19(24):3792–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379(9822):1245–55.

    Article  PubMed  Google Scholar 

  23. Yang JD, Roberts LR. Hepatocellular carcinoma: a global view. Nat Rev Gastroenterol Hepatol. 2010;7(8):449–58.

    Article  Google Scholar 

  24. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142(6):1264–73.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Yang YH, Wen TF, Chen X. Resection margin in hepatectomy for hepatocellular carcinoma: a systematic review. Hepato-Gastroenterol. 2012;59(117):1393–7.

    Google Scholar 

  26. Ubagai T, Kikuchi T, Fukusato T, Ono Y. Aflatoxin B1 modulates the insulin-like growth factor-2 dependent signaling axis. Toxicol in Vitro. 2010;24(3):783–9.

    Article  CAS  PubMed  Google Scholar 

  27. Chen YW, Boyartchuk V, Lewis BC. Differential roles of insulin-like growth factor receptor- and insulin receptor-mediated signaling in the phenotypes of hepatocellular carcinoma cells. Neoplasia. 2009;11(9):835–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nussbaum T, Samarin J, Ehemann V, Bissinger M, Ryschich E, Khamidjanov A, et al. Autocrine insulin-like growth factor-II stimulation of tumor cell migration is a progression step in human hepato-carcinogenesis. Hepatology. 2008;48(1):146–56.

    Article  CAS  PubMed  Google Scholar 

  29. Okushin K, Asaoka Y, Fukuda I, Fujiwara N, Minami T, Sato M, et al. IGF-II producing hepatocellular carcinoma treated with sorafenib: metabolic complications and a foresight to molecular targeting therapy to the IGF signal. Case Rep Gastroenterol. 2012;6(3):784–9.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Alexia C, Bras M, Fallot G, Vadrot N, Daniel F, Lasfer M, et al. 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):1–17.

    Article  CAS  PubMed  Google Scholar 

  31. El Tayebi HM, Salah W, El Sayed IH, Salam EM, Zekri AR, Zayed N, et al. 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(4):346–54.

    Article  CAS  PubMed  Google Scholar 

  32. Breuhahn K, Schirmacher P. Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma. World J Gastroenterol. 2008;14(11):1690–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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(3):524–43.

    Article  CAS  PubMed  Google Scholar 

  34. Weng CJ, Hsieh YH, Tsai CM, Chu YH, Ueng KC, Liu YF, et al. Relationship of insulin-like growth factors system gene polymorphisms with the susceptibility and pathological development of hepatocellular carcinoma. Ann Surg Oncol. 2010;17(7):1808–15.

    Article  PubMed  Google Scholar 

  35. Tomizawa M, Yokosuka O. Picropodophyllin suppresses the proliferation and invasion of hepatocellular carcinoma under serum starvation. Mol Med Rep. 2008;1(5):685–8.

    CAS  PubMed  Google Scholar 

  36. Campbell CI, Moorehead RA. Mammary tumors that become independent of the type I insulin-like growth factor receptor expressed elevated levels of platelet-derived growth factor receptors. BMC Cancer. 2011;11:480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lang SA, Hackl C, Moser C, Fichtner-Feigl S, Koehl GE, Schlitt HJ, et al. 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(4):435–42.

    Article  CAS  PubMed  Google Scholar 

  38. Cuevas EP, Escribano O, Monserrat J, Martínez-Botas J, Sánchez MG, Chiloeches A, et al. RNAi-mediated silencing of insulin receptor substrate-4 enhances actinomycin D- and tumor necrosis factor-alpha-induced cell death in hepato-carcinoma cancer cell lines. J Cell Biochem. 2009;108(6):1292–301.

    Article  CAS  PubMed  Google Scholar 

  39. Freise C, Ruehl M, Erben U, Neumann U, Seehofer D, Kim KY, et al. A hepatoprotective 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(1):39–46.

    Article  PubMed  PubMed Central  Google Scholar 

  40. 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 hepatocarcinoma cells against drug-induced apoptosis. Biochem Pharmacol. 2004;68(6):1003–15.

    Article  CAS  PubMed  Google Scholar 

  41. Tovar V, Alsinet C, Villanueva A, Hoshida Y, Chiang DY, Solé M, et al. IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage. J Hepatol. 2010;52(4):550–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhao H, Desai V, Wang J, Epstein DM, 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(2):503–13.

    Article  CAS  PubMed  Google Scholar 

  43. Cao H, Phan H, Yang LX. Improved chemotherapy for hepatocellular carcinoma. Anticancer Res. 2012;32(4):1379–86.

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants-in-aid from the Projects of Nantong Society Development (HS2014078), the Jiangsu Health Projects (2014-YY-028 and 2013-WSN-011), the Priority Academic Program Development of Jiangsu (PADA), and the International S. & T. Cooperation Program of China (2013DFA32150). And we thank T. FitzGibbon, M.D., for comments on earlier drafts of the manuscript.

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Authors and Affiliations

  1. Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 West Temple Road, Nantong, 226001, China

    Min Yao, Junling Yang, Xiaodi Yan & Dengfu Yao

  2. Medical School of Nantong University, Nantong, 226001, China

    Min Yao & Li Wang

  3. Department of Oncology, Affiliated Hospital of Nantong University, Nantong, 226001, China

    Yin Cai

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  1. Min Yao
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  2. Li Wang
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  4. Xiaodi Yan
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Correspondence to Dengfu Yao.

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Min Yao, Li Wang, and Junling Yang contributed equally to this work

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Yao, M., Wang, L., Yang, J. et al. IGF-I receptor as an emerging potential molecular-targeted for hepatocellular carcinoma in vitro and in vivo . Tumor Biol. 37, 14677–14686 (2016). https://doi.org/10.1007/s13277-016-5296-3

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  • DOI: https://doi.org/10.1007/s13277-016-5296-3

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