TNF‑α enhances the effect of TGF‑β on Gli2 expression in the KG‑1 leukemic cell line

Li,Zhe; Li,Bin; Pan,Jing; Jin,Jieping

doi:10.3892/etm.2014.1743

TNF‑α enhances the effect of TGF‑β on Gli2 expression in the KG‑1 leukemic cell line

Authors:
- Zhe Li
- Bin Li
- Jing Pan
- Jieping Jin
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Affiliations: Department of Hematology, First Affiliated Hospital of Liaoning Medical College, Jinzhou, Liaoning 121001, P.R.China
Published online on: May 28, 2014 https://doi.org/10.3892/etm.2014.1743
Pages: 676-680

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Abstract

The Hedgehog (Hh) signaling pathway regulates a variety of tumor‑related diseases, including leukemia. The present study aimed to determine whether there was an interaction between the Hh signaling pathway and transforming growth factor (TGF)‑β in the KG‑1 cell line. KG‑1 cells were treated with TGF‑β, tumor necrosis factor (TNF)‑α and specific inhibitor of smad3 (SIS3). The expression level of Gli family zinc finger 2 (Gli2) was detected by quantitative polymerase chain reaction (qPCR) and western blot analyses. The results revealed that TGF‑β significantly decreased the expression level of Gli2 in KG‑1 cells, and that TNF‑α and TGF‑β together further reduced Gli2 expression in KG‑1 cells. SIS3 inhibited the effect of TGF‑β. These results suggest that Gli2 expression in KG‑1 cells is suppressed by TGF‑β in a Smad3‑dependent manner, TNF‑α can enhance the effect of TGF‑β on Gli2 expression and that this occurs independently of Hh receptor signaling.

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1	Lum L and Beachy PA: The Hedgehog response network: sensors, switches, and routers. Science. 304:1755–1759. 2004. View Article : Google Scholar : PubMed/NCBI
2	Hao K, Tian XD, Qin CF, Xie XH and Yang YM: Hedgehog signaling pathway regulates human pancreatic cancer cell proliferation and metastasis. Oncol Rep. 29:1124–1132. 2013.PubMed/NCBI
3	Lauth M and Toftgård R: Non-canonical activation of GLI transcription factors: implications for targeted anti-cancer therapy. Cell Cycle. 6:2458–2463. 2007. View Article : Google Scholar : PubMed/NCBI
4	Dennler S, André J, Alexaki I, et al: Induction of sonic hedgehog mediators by transforming growth factor-β: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer Res. 67:6981–6986. 2007.
5	Bhardwaj G, Murdoch B, Wu D, et al: Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat Immunol. 2:172–180. 2001. View Article : Google Scholar : PubMed/NCBI
6	Detmer K, Walker AN, Jenkins TM, Steele TA and Dannawi H: Erythroid differentiation in vitro is blocked by cyclopamine, an inhibitor of hedgehog signaling. Blood Cells Mol Dis. 26:360–372. 2000.
7	Bai LY, Chiu CF, Lin CW, Hsu NY, Lin CL, Lo WJ and Kao MC: Differential expression of sonic hedgehog and Gli1 in hematological malignancies. Leukemia. 22:226–228. 2008. View Article : Google Scholar : PubMed/NCBI
8	Kobune M, Takimoto R, Murase K, et al: Drug resistance is dramatically restored by hedgehog inhibitors in CD34+ leukemic cells. Cancer Sci. 100:948–955. 2009.PubMed/NCBI
9	Fortunel N, Hatzfeld J, Kisselev S, et al: Release from quiescence of primitive human hematopoietic stem/progenitor cells by blocking their cell-surface TGF-β type II receptor in a short-term in vitro assay. Stem Cells. 18:102–111. 2000.PubMed/NCBI
10	Fortunel NO, Hatzfeld A and Hatzfeld JA: Transforming growth factor-β: pleiotropic role in the regulation of hematopoiesis. Blood. 96:2022–2036. 2000.
11	Jinnin M, Ihn H and Tamaki K: Characterization of SIS3, a novel specific inhibitor of Smad3, and its effect on transforming growth factor-β1-induced extracellular matrix expression. Mol Pharmacol. 69:597–607. 2006.PubMed/NCBI
12	Bale AE: Hedgehog signaling and human disease. Annu Rev Genomics Hum Genet. 3:47–65. 2002. View Article : Google Scholar : PubMed/NCBI
13	Hui CC and Angers S: Gli proteins in development and disease. Annu Rev Cell Dev Biol. 27:513–537. 2011. View Article : Google Scholar : PubMed/NCBI
14	Duman-Scheel M, Weng L, Xin S and Du W: Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E. Nature. 417:299–304. 2002. View Article : Google Scholar : PubMed/NCBI
15	Lai K, Kaspar BK, Gage FH and Schaffer DV: Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci. 6:21–27. 2003. View Article : Google Scholar : PubMed/NCBI
16	Bigelow RL, Chari NS, Unden AB, et al: Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through gli-1. J Biol Chem. 279:1197–1205. 2004. View Article : Google Scholar : PubMed/NCBI
17	Watkins DN, Berman DM, Burkholder SG, Wang B, Beachy PA and Baylin SB: Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature. 422:313–317. 2003. View Article : Google Scholar : PubMed/NCBI
18	Spinella-Jaegle S, Rawadi G, Kawai S, et al: Sonic hedgehog increases the commitment of pluripotent mesenchymal cells into the osteoblastic lineage and abolishes adipocytic differentiation. J Cell Sci. 114:2085–2094. 2001.
19	O’Flaherty JD, Barr M, Fennell D, Richard D, Reynolds J, O’Leary J and O’Byrne K: The cancer stem-cell hypothesis: its emerging role in lung cancer biology and its relevance for future therapy. J Thorac Oncol. 7:1880–1890. 2012.PubMed/NCBI
20	Weiss GJ and Korn RL: Metastatic basal cell carcinoma in the era of hedgehog signaling pathway inhibitors. Cancer. 118:5310–5319. 2012. View Article : Google Scholar : PubMed/NCBI
21	Irvine DA and Copland M: Targeting hedgehog in hematologic malignancy. Blood. 119:2196–2204. 2012. View Article : Google Scholar : PubMed/NCBI
22	Kasper M, Regl G, Frischauf AM and Aberger F: GLI transcription factors: mediators of oncogenic hedgehog signalling. Eur J Cancer. 42:437–445. 2006. View Article : Google Scholar : PubMed/NCBI
23	Bai CB, Auerbach W, Lee JS, Stephen D and Joyner AL: Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development. 129:4753–4761. 2002.PubMed/NCBI
24	Ikram MS, Neill GW, Regl G, et al: GLI2 is expressed in normal human epidermis and BCC and induces GLI1 expression by binding to its promoter. J Invest Dermatol. 122:1503–1509. 2004. View Article : Google Scholar : PubMed/NCBI
25	Ruiz I and Altaba A: Gli proteins encode context-dependent positive and negative functions: implications for development and disease. Development. 126:3205–3216. 1999.PubMed/NCBI
26	Roberts AB and Sporn MB: Transforming growth factor-β. Adv Cancer Res. 51:107–145. 1988.
27	Massagué J: How cells read TGF-β signals. Nat Rev Mol Cell Biol. 1:169–178. 2000.
28	Attisano L and Wrana JL: Signal transduction by the TGF-β superfamily. Science. 296:1646–1647. 2002.
29	Piacibello W, Severino A, Stacchini A and Aglietta M: Differential effects of transforming growth factor beta 1 on the proliferation of human lymphoid and myeloid leukemia cells. Haematologica. 76:460–466. 1991.PubMed/NCBI
30	Chen Y, Lu L and Wang L: Study on gene expression of TGF β1 and its receptor in leukemia cells and the serum TGF β1 level in the patients with acute leukemia. Zhonghua Xue Ye Xue Za Zhi. 19:576–580. 1998.(In Chinese).
31	Testa U, Masciulli R, Tritarelli E, et al: Transforming growth factor-β potentiates vitamin D3-induced terminal monocytic differentiation of human leukemic cell lines. J Immunol. 150:2418–2430. 1993.
32	Gough PJ and Raines EW: Advances in retroviral transduction of hematopoietic stem cells for the gene therapy of atherosclerosis. Curr Opin Lipidol. 14:491–497. 2003. View Article : Google Scholar : PubMed/NCBI
33	Kasperczyk H, Baumann B, Debatin KM and Fulda S: Characterization of sonic hedgehog as a novel NF-κB target gene that promotes NF-κB-mediated apoptosis resistance and tumor growth in vivo. FASEB J. 23:21–33. 2009.PubMed/NCBI
34	De Benedetti F, Falk LA, Ellingsworth LR, Ruscetti FW and Faltynek CR: Synergy between transforming growth factor-β and tumor necrosis factor-α in the induction of monocytic differentiation of human leukemic cell lines. Blood. 75:626–632. 1990.
35	ten Dijke P and Hill CS: New insights into TGF-β-Smad signalling. Trends Biochem Sci. 29:265–273. 2004.
36	Massagué J, Seoane J and Wotton D: Smad transcription factors. Genes Dev. 19:2783–2810. 2005.PubMed/NCBI
37	Roberts AB, Anzano MA, Wakefield LM, Roche NS, Stern DF and Sporn MB: Type β transforming growth factor: a bifunctional regulator of cellular growth. Proc Natl Acad Sci USA. 82:119–123. 1985.