- Volume 15 Issue 23
DOI QR Code
Induction of Apoptosis by IGFBP3 Overexpression in Hepatocellular Carcinoma Cells
- Han, Jian-Jun (Department of Cancer Intervention Treatment Center, Shandong Cancer Hospital and Institute) ;
- Xue, De-Wen (Department of Cancer Intervention Treatment Center, Shandong Cancer Hospital and Institute) ;
- Han, Qiu-Rong (Department of Obstetrics and Gynecology, Heze Municipal Hospital) ;
- Liang, Xiao-Hong (Department of Immunology Shandong University School of Medicine) ;
- Xie, Li (Department of Basic Research Center, Shandong Cancer Hospital and Institute) ;
- Li, Sheng (Department of Hepatobiliary Surgery, Shandong Cancer Hospital and Institute) ;
- Wu, Hui-Yong (Department of Cancer Intervention Treatment Center, Shandong Cancer Hospital and Institute) ;
- Song, Bao (Department of Basic Research Center, Shandong Cancer Hospital and Institute)
- Published : 2015.01.06
Background: The insulin-like growth factor (IGF) system comprises a group of proteins that play key roles in regulating cell growth, differentiation, and apoptosis in a variety of cellular systems. The aim of this study was to investigate the role of insulin-like growth factor binding protein 3 (IGFBP3) in hepatocellular carcinoma. Materials and Methods: Expression of IGF2, IGFBP3, and PTEN was analyzed by qRT-PCR. Lentivirus vectors were used to overexpress IGFBP3 in hepatocellular carcinoma cell (HCC) lines. The effect of IGFBP3 on proliferation was investigated by MTT and colony formation assays. Results: Expression of IGF2, IGFBP3, and PTEN in several HCC cell lines was lower than in normal cell lines. After 5-aza-2'-deoxycytidine/trichostatin A treatment, significant demethylation of the promoter region of IGFBP3 was observed in HCC cells. Overexpression of IGFBP3 induced apoptosis and reduced colony formation in HUH7 cells. Conclusions: Expression of IGF2, IGFBP3, and PTEN in several HCC cell lines was lower than in normal cell lines. After 5-aza-2'-deoxycytidine/trichostatin A treatment, significant demethylation of the promoter region of IGFBP3 was observed in HCC cells. Overexpression of IGFBP3 induced apoptosis and reduced colony formation in HUH7 cells.
Hepatocellular carcinoma;IGF signaling pathway;IGFBP3;proliferation
- Ailin A, Valiollah D, Dabidi R, et al (2013). Pretreatment effects of regular aerobic training on the IGF system and hepatotoxicity induced by doxorubicin in rats. Asian Pac J Cancer Prev, 14, 7427-31. https://doi.org/10.7314/APJCP.2013.14.12.7427
- Albrecht S, Schweinitz D, Waha A, et al (1994). Loss of maternal alleles on chromosome arm 11p in hepatoblastoma. Cancer Res, 54, 5041-4.
- Buendia MA (2002). Genetic alterations in hepatoblastoma and hepatocellular carcinoma: common and distinctive aspects. Med Pediatr Oncol, 39, 530-5. https://doi.org/10.1002/mpo.10180
- Rainier S, Dobry Cj and Feinberg AP (1995). Loss of imprinting in hepatoblastoma. Cancer Res, 55, 1836-8.
- Breuhahn K, Longerich T and Schirmacher P (2006). Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene, 25, 3787-800. https://doi.org/10.1038/sj.onc.1209556
- Chang YS, Wang L, Suh YA, et al (2004). Mechanisms underlying lack of insulin-like growth factor-binding protein-3 expression in non-small-cell lung cancer. Oncogene, 23, 6569-80. https://doi.org/10.1038/sj.onc.1207882
- Foulstone E, Prince S, Zaccheo O, et al (2005). Insulin-like growth factor ligands, receptors, and binding proteins in cancer. J Pathol, 205, 145-53. https://doi.org/10.1002/path.1712
- Grimberg A and Cohen P (2000). Role of insulin-like growth factors and their binding proteins in growth control and carcinogenesis. J Cell Physiol, 183, 1-9. https://doi.org/10.1002/(SICI)1097-4652(200004)183:1<1::AID-JCP1>3.0.CO;2-J
- Hanafusa T, Yumoto Y, Nouso K, et al (2002). Reduced expression of insulin-like growth factor binding protein-3 and its promoter hypermethylation in human hepatocellular carcinoma. Cancer Lett, 176, 149-58. https://doi.org/10.1016/S0304-3835(01)00736-4
- Ibanez de Caceres I, Dulaimi E, Hoffman AM, et al (2006). Identification of novel target genes by an epigenetic reactivation screen of renal cancer. Cancer Res, 66, 5021-8. https://doi.org/10.1158/0008-5472.CAN-05-3365
- Kaneda A and Feinberg AP (2005). Loss of imprinting of IGF2: a common epigenetic modifier of intestinal tumor risk. Cancer Res, 65, 11236-40. https://doi.org/10.1158/0008-5472.CAN-05-2959
- Kraus JA, Albrecht S, Wiestler OD, von Schweinitz D, Pietsch T (1996). Loss of heterozygosity on chromosome 1 in human hepatoblastoma. Int J Cancer, 67, 467-71. https://doi.org/10.1002/(SICI)1097-0215(19960807)67:4<467::AID-IJC1>3.0.CO;2-Q
- Ma DZ, Xu Z, Liang YL, et al (2005). Down-regulation of PTEN expression due to loss of promoter activity in human hepatocellular carcinoma cell lines. World J Gastroenterol, 11, 4472-7. https://doi.org/10.3748/wjg.v11.i29.4472
- Maehama T, Dixon JE (1998). The tumor suppressor, PTEN/ MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3, 4, 5-trisphosphate. J Biol Chem, 273, 13375-8. https://doi.org/10.1074/jbc.273.22.13375
- Mannhardt B, Weinzimer SA, Wagner M, et al (2000). Human papillomavirus type 16 E7 oncoprotein binds and inactivates growth-inhibitory insulin-like growth factor binding protein 3. Mol Cell Biol, 20, 6483-95. https://doi.org/10.1128/MCB.20.17.6483-6495.2000
- Natsuizaka M, Kinugasa H, Kagawa S, et al (2014). IGFBP3 promotes esophageal cancer growth by suppressing oxidative stress in hypoxic tumor microenvironment. Am J Cancer Res, 4, 29-41.
- Oda H, Imai Y, Nakatsuru Y, Hata J, Ishikawa T (1996). Somatic mutations of the APC gene in sporadic hepatoblastomas. Cancer Res, 56, 3320-3.
- Rehem RN and El-Shikh WM (2011). Serum IGF-1, IGF-2 and IGFBP-3 as parameters in the assessment of liver dysfunction in patients with hepatic cirrhosis and in the diagnosis of hepatocellular carcinoma. Hepatogastroenterology, 58, 949-54.
- Shin KH, Kim JM, Rho KS, et al (2002). Inactivation of the PTEN gene by mutation, exonic deletion, and loss of transcript in human oral squamous cell carcinomas. Int J Oncol, 21, 997-1001.
- Steenman M, Westerveld A and Mannens M (2000). Genetics of beckwith-wiedemann syndrome-associated tumors: common genetic pathways. Genes Chromosomes Cancer, 28, 1-13. https://doi.org/10.1002/(SICI)1098-2264(200005)28:1<1::AID-GCC1>3.0.CO;2-#
- Tang SH, Yang DH, Huang W, et al (2006). Hypomethylated P4 promoter induces expression of the insulin-like growth factor-II gene in hepatocellular carcinoma in a Chinese population. Clin Cancer Res, 12, 4171-7. https://doi.org/10.1158/1078-0432.CCR-05-2261
- Tomii K, Tsukuda K, Toyooka S, et al (2007). Aberrant promoter methylation of insulin-like growth factor binding protein-3 gene in human cancers. Int J Cancer, 120, 566-73. https://doi.org/10.1002/ijc.22341
- Voz ML, Agten NS, VandeVen WJ, Kas K (2000). PLAG1, the main translocation target in pleomorphic adenoma of the salivary glands, is a positive regulator of IGF-II. Cancer Res, 60, 106-13.
- Weber RG, Pietsch T, von Schweinitz D and Lichter P (2000). Characterization of genomic alterations in hepatoblastomas: a role for gains on chromosomes 8q and 20 as predictors of poor outcome. Am J Pathol, 157, 571-8. https://doi.org/10.1016/S0002-9440(10)64567-1
- Ye QM, Xin X, Yi WL, et al (2013). Prostate cancer risk in relation to a single nucleotide polymorphism in the insulinlike growth factor-binding protein-3 (IGFBP3) Gene: a meta-analysis. Asian Pac J Cancer Res, 13, 6299-303
- Long-term hypoxia exposure enhanced IGFBP-3 protein synthesis and secretion resulting in cell apoptosis in H9c2 myocardial cells vol.33, pp.4, 2015, https://doi.org/10.3109/08977194.2015.1077824
- Microarray gene expression analysis in ovine ductus arteriosus during fetal development and birth transition vol.80, pp.4, 2016, https://doi.org/10.1038/pr.2016.123
- Analysis of microarrays of miR-34a and its identification of prospective target gene signature in hepatocellular carcinoma vol.18, pp.1, 2018, https://doi.org/10.1186/s12885-017-3941-x