Basic fibroblast growth factor upregulates survivin expression in hepatocellular carcinoma cells via a protein kinase B-dependent pathway

Sun,Bo; Xu,Haiyan; Zhang,Gang; Zhu,Yongbao; Sun,Hukui; Hou,Guihua

doi:10.3892/or.2013.2479

Basic fibroblast growth factor upregulates survivin expression in hepatocellular carcinoma cells via a protein kinase B-dependent pathway

Authors:
- Bo Sun
- Haiyan Xu
- Gang Zhang
- Yongbao Zhu
- Hukui Sun
- Guihua Hou
View Affiliations

Affiliations: Institute of Experimental Nuclear Medicine, School of Medicine, Shandong University, Jinan, Shandong, P.R. China, Affiliated Hospital of Tianjin Academy of Traditional Chinese Medicine, Tianjin, P.R. China, The First People's Hospital of Zibo City, Shandong, P.R. China, The Blood Center of Shandong Province, Jinan, Shandong, P.R. China
Published online on: May 15, 2013 https://doi.org/10.3892/or.2013.2479
Pages: 385-390

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Basic fibroblast growth factor (bFGF) plays an important role in tumor angiogenesis. Several studies have reported that bFGF may influence cell apoptosis through different signaling pathways. The aim of the present investigation was to study the effect of bFGF on the activities of protein kinase B (PKB)/survivin and cell apoptosis in hepatocellular carcinoma cells (Bel-7402). We treated Bel-7402 cells with bFGF and wortmannin [phosphatidylinositol 3-kinase (PI3K)-specific inhibitor] separately to observe the expression of PKB and survivin detected with RT-PCR and western blotting. The cell cycle and apoptosis were assayed with flow cytometry. We found a significant increase in PKB expression in the group treated with 25 ng/ml bFGF for 10 min (P<0.05), and this effect was significantly inhibited by pretreatment with wortmannin (200 nM) for 1 h. After treatment with 10 ng/ml bFGF, the expression of survivin mRNA in Bel-7402 cells increased significantly, and reached the peak at 16 h (P<0.05); however, this effect could be significantly inhibited by pretreatment with wortmannin (200 mM) in a time-dependent manner. Following incubation with 25 ng/ml bFGF for 10 min, the apoptosis rate and M phase were significantly decreased and S phase cells increased compared with the wortmannin (200 nM)-treated group. When this group was pretreated with wortmannin (200 nM) for 1 h, the apoptosis rate and S phase were significantly increased, M phase cells decreased. The results revealed that wortmannin could induce high apoptosis rates in hepatocellular carcinoma cells, and bFGF could inhibit the cell apoptosis induced by wortmannin. These findings indicate that bFGF could rapidly activate the PKB activities, enhance the expression of survivin and the proliferation of hepatocellular carcinoma cells via the PI3K pathway, thus it may serve as a novel molecule for early targeting therapy of hepatocellular carcinoma.

View Figures

View References

1	Hu M and Polyak K: Microenvironmental regulation of cancer development. Curr Opin Genet Dev. 18:27–34. 2008. View Article : Google Scholar
2	Bissell MJ and Radisky D: Putting tumours in context. Nat Rev Cancer. 1:46–54. 2001. View Article : Google Scholar : PubMed/NCBI
3	Radisky D, Hagios C and Bissell MJ: Tumors are unique organs defined by abnormal signaling and context. Semin Cancer Biol. 11:87–95. 2001. View Article : Google Scholar : PubMed/NCBI
4	Klagsbrun M and Soker S: VEGF/VPF: The angiogenesis factor found? Curr Biol. 3:699–702. 1993. View Article : Google Scholar : PubMed/NCBI
5	Neufeld G, Cohen T, Gengrinovitch S and Poltorak Z: Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 13:9–22. 1999.PubMed/NCBI
6	Tran J, Rak J, Sheehan C, et al: Marked induction of the IAP family antiapoptotic proteins survivin and XIAP by VEGF in vascular endothelial cells. Biochem Biophys Res Commun. 264:781–788. 1999. View Article : Google Scholar : PubMed/NCBI
7	Ouyang G, Liu M, Ruan K, et al: Upregulated expression of periostin by hypoxia in non-small-cell lung cancer cells promotes cell survival via the Akt/PKB pathway. Cancer Lett. 281:213–219. 2009. View Article : Google Scholar : PubMed/NCBI
8	Zhang L, Bhojani MS, Ross BD and Rehemtulla A: Molecular imaging of protein kinases. Cell Cycle. 7:314–317. 2008. View Article : Google Scholar : PubMed/NCBI
9	Zhang L, Lee KC, Bhojani MS, et al: Molecular imaging of Akt kinase activity. Nat Med. 13:1114–1119. 2007. View Article : Google Scholar : PubMed/NCBI
10	Kunkel MT, Ni Q, Tsien RY, Zhang J and Newton AC: Spatio-temporal dynamics of protein kinase B/Akt signaling revealed by a genetically encoded fluorescent reporter. J Biol Chem. 280:5581–5587. 2005. View Article : Google Scholar : PubMed/NCBI
11	Harvey RD and Lonial S: PI3 kinase/AKT pathway as a therapeutic target in multiple myeloma. Future Oncol. 3:639–647. 2007. View Article : Google Scholar : PubMed/NCBI
12	Yang L, Dan HC, Sun M, et al: Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. Cancer Res. 64:4394–4399. 2004. View Article : Google Scholar : PubMed/NCBI
13	Skrzypski M, Kaczmarek P and Le TT: Effects of orexin A on proliferation, survival, apoptosis and differentiation of 3T3-L1 preadipocytes into mature adipocytes. FEBS Lett. 586:4157–4164. 2012. View Article : Google Scholar : PubMed/NCBI
14	Jin P, Wang YH, Peng YG, Hu S, Lu Q and Yang LY: Effect of PI3K/AKT inhibitor on benign prostate hyperplasia and its mechanism: an experimental study. Zhonghua Nan Ke Xue. 16:1068–1075. 2010.(In Chinese).
15	Zhang HJ, Siu MK, Yeung MC, et al: Overexpressed PAK4 promotes proliferation, migration and invasion of choriocarcinoma. Carcinogenesis. 32:765–771. 2011. View Article : Google Scholar : PubMed/NCBI
16	Yang Q, Liu HY, Zhang YW, et al: Anandamide induces cell death through lipid rafts in hepatic stellate cells. J Gastroenterol Hepatol. 25:991–1001. 2010. View Article : Google Scholar : PubMed/NCBI
17	Altieri DC and Marchisio C: Survivin apoptosis: an interloper between cell death and cell proliferation in cancer. Lab Invest. 79:1327–1333. 1999.PubMed/NCBI
18	Yamamoto T and Tanigawa N: The role of survivin as a new target of diagnosis and treatment in human cancer. Med Electron Microsc. 34:207–212. 2001. View Article : Google Scholar : PubMed/NCBI
19	Tamm I, Want Y, Sausville E, et al: IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res. 58:5315–5320. 1998.PubMed/NCBI
20	Altieri DC: Survivin versatile modulation of cell division and apoptosis in cancer. Oncogene. 22:8581–8589. 2003. View Article : Google Scholar : PubMed/NCBI
21	Kajiwara Y, Yamasaki F, Hama S, et al: Exression of survivin in astrocytic tumors: correlation with malignant grade and prognosis. Cancer. 97:1077–1083. 2003. View Article : Google Scholar : PubMed/NCBI
22	Islam A, Kageyama H, Takada N, et al: High expression of survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma. Oncogene. 19:617–623. 2000. View Article : Google Scholar : PubMed/NCBI
23	Ambrosini G, Adida C and Altieri D: A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med. 3:917–921. 1997. View Article : Google Scholar : PubMed/NCBI
24	Ngan CY, Yamamoto H, Takagi A, et al: Oxaliplatin induces mitotic catastrophe and apoptosis in esophageal cancer cells. Cancer Sci. 99:129–139. 2008.PubMed/NCBI
25	Huang CK, Lee SO, Lai KP, et al: Targeting androgen receptor in bone marrow mesenchymal stem cells leads to better transplantation therapy efficacy in liver cirrhosis. Hepatology. 57:1550–1563. 2013. View Article : Google Scholar
26	Hanahan D and Weinberg RA: The hallmarks of cancer. Cell. 100:57–70. 2000. View Article : Google Scholar
27	Hahn WC and Weinberg RA: Modelling the molecular circuitry of cancer. Nat Rev Cancer. 2:331–341. 2002. View Article : Google Scholar : PubMed/NCBI
28	López-Maury L, Marguerat S and Bähler J: Tuning gene expression to changing environments: from rapid responses to evolutionary adaptation. Nat Rev Genet. 9:583–593. 2008.PubMed/NCBI
29	Tateishi M, Ishida T, Mitsudomi T, Kaneko S and Sugimachi K: Immunohistochemical evidence of autocrine growth factors in adenocarcinoma of the human lung. Cancer Res. 50:7077–7080. 1990.PubMed/NCBI
30	Brattstrom D, Bergqvist M, Hesselius P, Larsson A, Wagenius G and Brodin O: Serum VEGF and bFGF adds prognostic information in patients with normal platelet counts when sampled before, during and after treatment for locally advanced non-small cell lung cancer. Lung Cancer. 43:55–62. 2004. View Article : Google Scholar
31	Sufen G, Xianghong Y, Yongxia C and Qian P: bFGF and PDGF-BB have a synergistic effect on the proliferation, migration and VEGF release of endothelial progenitor cells. Cell Biol Int. 35:545–551. 2011. View Article : Google Scholar : PubMed/NCBI
32	Drevs J, Zirrgiebel U and Schmidt-Gersbach CI: Soluble markers for the assessment of biological activity with PTK787/ZK 222584 (PTK/ZK), a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor in patients with advanced colorectal cancer from two phase I trials. Ann Oncol. 16:558–565. 2005. View Article : Google Scholar
33	Feng X, Zhang B, Wang J, et al: Adenovirus-mediated transfer of siRNA against basic fibroblast growth factor mRNA enhances the sensitivity of glioblastoma cells to chemotherapy. Med Oncol. 28:24–30. 2011. View Article : Google Scholar : PubMed/NCBI
34	Wang H, Rubin M, Fenig E, et al: Basic fibroblast growth factor causes growth arrest in MCF-7 human breast cancer cells while inducing both mitogenic and inhibitory G1 events. Cancer Res. 57:1750–1757. 1997.PubMed/NCBI
35	Shankland SJ, Pippin J, Flanagan M, et al: Mesangial cell proliferation mediated by PDGF and bFGF is determined by levels of the cyclin kinase inhibitor p27Kip1. Kidney Int. 51:1088–1099. 1997. View Article : Google Scholar : PubMed/NCBI
36	Johnson MR, Valentine C, Basilio C and Mansukhani A: FGF signaling activates STAT1 and p21 and inhibits the estrogen response and proliferation of MCF-7 cells. Oncogene. 16:2647–2656. 1998. View Article : Google Scholar : PubMed/NCBI
37	Carmeliet P, Lampugnani MG, Moons L, et al: Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell. 98:147–157. 1999. View Article : Google Scholar : PubMed/NCBI
38	Kim JW, Ho WJ and Wu BM: The role of the 3D environment in hypoxia-induced drug and apoptosis resistance. Anticancer Res. 31:3237–3245. 2011.PubMed/NCBI
39	Gerber HP, Dixit V and Ferrara N: Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. J Biol Chem. 273:13313–13316. 1998. View Article : Google Scholar : PubMed/NCBI
40	Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V and Ferrara N: Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem. 273:30336–30343. 1998.
41	Li F, Ambrosini G, Chu EY, Plescia J, et al: Control of apoptosis and mitotic spindle checkpoint by survivin. Nature. 396:580–584. 1998. View Article : Google Scholar : PubMed/NCBI