Skip to main content
Top
Published in: Journal of Cancer Research and Clinical Oncology 6/2013

01-06-2013 | Original Paper

KLF8 involves in TGF-beta-induced EMT and promotes invasion and migration in gastric cancer cells

Authors: Hui Zhang, Lili Liu, Yafang Wang, Guohong Zhao, Rougang Xie, Changhao Liu, Xiao Xiao, Kaichun Wu, Yongzhan Nie, Hongbo Zhang, Daiming Fan

Published in: Journal of Cancer Research and Clinical Oncology | Issue 6/2013

Login to get access

Abstract

Purpose

Krüppel-like factor 8 (KLF8), a downstream transcription factor of transforming growth factor-β1 (TGF-β1), has a role in tumorigenesis, tumor progress and epithelial-to-mesenchymal transition (EMT) induction. Recent studies mainly focused on its role in breast cancer and hepatocellular carcinoma; however, little is studied in gastric cancer. Here, we aim to explore whether KLF8 is involved in TGF-β1-induced EMT in gastric cancer cells.

Methods

Western blot and real-time PCR assays were used to detect the expression of KLF8, E-cadherin and vimentin in gastric cancer cell line SGC7901 treated with or without TGF-β1. The lentivirus-mediated RNA interference technique was used to knock down the expression of KLF8 in gastric cancer cell line SGC7901. In vitro, the ability of cell migration and invasion were measured by transwell and wound healing assays; the cell motility was detected by high content screening assay.

Results

TGF-β1 could induce EMT via down-regulating E-cadherin and up-regulating vimentin expression in gastric cancer cells. Further study found that TGF-β1 could induce KLF8 expression at the protein and mRNA levels in gastric cancer cells (P < 0.05). Western blot and real-time PCR assays found that small interference RNA (siRNA)-mediated KLF8 silence blocked TGF-β1-induced EMT-like transformation and subsequently reversed the loss of E-cadherin and gain of vimentin. In vitro, inhibition of KLF8 decreased TGF-β1-prompted cell migration, invasion and motility.

Conclusions

KLF8, a transcription factor, is involved in TGF-β1-induced EMT in gastric cancer cells and may be a novel therapeutic target for the treatment of gastric cancer.
Literature
go back to reference Chen G, Yang W, Jin W, Wang Y, Tao C, Yu Z (2012) Lentivirus-mediated gene silencing of KLF8 reduced the proliferation and invasion of gastric cancer cells. Mol Biol Rep 39(10):9809–9815 Chen G, Yang W, Jin W, Wang Y, Tao C, Yu Z (2012) Lentivirus-mediated gene silencing of KLF8 reduced the proliferation and invasion of gastric cancer cells. Mol Biol Rep 39(10):9809–9815
go back to reference Choi YH, Choi KC, Park YE (1997) Relationship of transforming growth factor beta 1 to angiogenesis in gastric carcinoma. J Korean Med Sci 12(5):427–432PubMed Choi YH, Choi KC, Park YE (1997) Relationship of transforming growth factor beta 1 to angiogenesis in gastric carcinoma. J Korean Med Sci 12(5):427–432PubMed
go back to reference Dang DT, Pevsner J, Yang VW (2000) The biology of the mammalian Kruppel-like family of transcription factors. Int J Biochem Cell Biol 32(11–12):1103–1121PubMedCrossRef Dang DT, Pevsner J, Yang VW (2000) The biology of the mammalian Kruppel-like family of transcription factors. Int J Biochem Cell Biol 32(11–12):1103–1121PubMedCrossRef
go back to reference Eaton SA, Funnell AP, Sue N, Nicholas H, Pearson RC, Crossley M (2008) A network of Kruppel-like Factors (Klfs). Klf8 is repressed by Klf3 and activated by Klf1 in vivo. J Biol Chem 283(40):26937–26947PubMedCrossRef Eaton SA, Funnell AP, Sue N, Nicholas H, Pearson RC, Crossley M (2008) A network of Kruppel-like Factors (Klfs). Klf8 is repressed by Klf3 and activated by Klf1 in vivo. J Biol Chem 283(40):26937–26947PubMedCrossRef
go back to reference Fu H, Hu Z, Wen J, Wang K, Liu Y (2009) TGF-beta promotes invasion and metastasis of gastric cancer cells by increasing fascin1 expression via ERK and JNK signal pathways. Acta Biochim Biophys Sin 41(8):648–656PubMedCrossRef Fu H, Hu Z, Wen J, Wang K, Liu Y (2009) TGF-beta promotes invasion and metastasis of gastric cancer cells by increasing fascin1 expression via ERK and JNK signal pathways. Acta Biochim Biophys Sin 41(8):648–656PubMedCrossRef
go back to reference Fu WJ, Li JC, Wu XY, Yang ZB, Mo ZN, Huang JW, Xia GW, Ding Q, Liu KD, Zhu HG (2010) Small interference RNA targeting Kruppel-like factor 8 inhibits the renal carcinoma 786–0 cells growth in vitro and in vivo. J Cancer Res Clin Oncol 136(8):1255–1265PubMedCrossRef Fu WJ, Li JC, Wu XY, Yang ZB, Mo ZN, Huang JW, Xia GW, Ding Q, Liu KD, Zhu HG (2010) Small interference RNA targeting Kruppel-like factor 8 inhibits the renal carcinoma 786–0 cells growth in vitro and in vivo. J Cancer Res Clin Oncol 136(8):1255–1265PubMedCrossRef
go back to reference Grandclement C, Pallandre JR, Valmary DS, Viel E, Bouard A, Balland J, Remy-Martin JP, Simon B, Rouleau A, Boireau W, Klagsbrun M, Ferrand C, Borg C (2011) Neuropilin-2 expression promotes TGF-beta1-mediated epithelial to mesenchymal transition in colorectal cancer cells. PLoS ONE 6(7):e20444PubMedCrossRef Grandclement C, Pallandre JR, Valmary DS, Viel E, Bouard A, Balland J, Remy-Martin JP, Simon B, Rouleau A, Boireau W, Klagsbrun M, Ferrand C, Borg C (2011) Neuropilin-2 expression promotes TGF-beta1-mediated epithelial to mesenchymal transition in colorectal cancer cells. PLoS ONE 6(7):e20444PubMedCrossRef
go back to reference Holian J, Qi W, Kelly DJ, Zhang Y, Mreich E, Pollock CA, Chen XM (2008) Role of Kruppel-like factor 6 in transforming growth factor-beta1-induced epithelial-mesenchymal transition of proximal tubule cells. Am J Physiol Renal Physiol 295(5):F1388–F1396PubMedCrossRef Holian J, Qi W, Kelly DJ, Zhang Y, Mreich E, Pollock CA, Chen XM (2008) Role of Kruppel-like factor 6 in transforming growth factor-beta1-induced epithelial-mesenchymal transition of proximal tubule cells. Am J Physiol Renal Physiol 295(5):F1388–F1396PubMedCrossRef
go back to reference Li X, Zhang YY, Wang Q, Fu SB (2005) Association between endogenous gene expression and growth regulation induced by TGF-beta1 in human gastric cancer cells. World J Gastroenterol 11(1):61–68PubMed Li X, Zhang YY, Wang Q, Fu SB (2005) Association between endogenous gene expression and growth regulation induced by TGF-beta1 in human gastric cancer cells. World J Gastroenterol 11(1):61–68PubMed
go back to reference Li JC, Yang XR, Sun HX, Xu Y, Zhou J, Qiu SJ, Ke AW, Cui YH, Wang ZJ, Wang WM, Liu KD, Fan J (2010) Up-regulation of Kruppel-like factor 8 promotes tumor invasion and indicates poor prognosis for hepatocellular carcinoma. Gastroenterology 139(6):2146–2157PubMedCrossRef Li JC, Yang XR, Sun HX, Xu Y, Zhou J, Qiu SJ, Ke AW, Cui YH, Wang ZJ, Wang WM, Liu KD, Fan J (2010) Up-regulation of Kruppel-like factor 8 promotes tumor invasion and indicates poor prognosis for hepatocellular carcinoma. Gastroenterology 139(6):2146–2157PubMedCrossRef
go back to reference Liu L, Liu N, Xu M, Liu Y, Min J, Pang H, Zhang N, Zhang H, Zhang H (2012) Lentivirus-delivered Kruppel-like factor 8 small interfering RNA inhibits gastric cancer cell growth in vitro and in vivo. Tumour Biol 33(1):53–61PubMedCrossRef Liu L, Liu N, Xu M, Liu Y, Min J, Pang H, Zhang N, Zhang H, Zhang H (2012) Lentivirus-delivered Kruppel-like factor 8 small interfering RNA inhibits gastric cancer cell growth in vitro and in vivo. Tumour Biol 33(1):53–61PubMedCrossRef
go back to reference Lv ZD, Na D, Liu FN, Du ZM, Sun Z, Li Z, Ma XY, Wang ZN, Xu HM (2010) Induction of gastric cancer cell adhesion through transforming growth factor-beta1-mediated peritoneal fibrosis. J Exp Clin Cancer Res 29:139PubMedCrossRef Lv ZD, Na D, Liu FN, Du ZM, Sun Z, Li Z, Ma XY, Wang ZN, Xu HM (2010) Induction of gastric cancer cell adhesion through transforming growth factor-beta1-mediated peritoneal fibrosis. J Exp Clin Cancer Res 29:139PubMedCrossRef
go back to reference Mehta TS, Monzur F, Zhao J (2010) Determination of nuclear localization signal sequences for Kruppel-like factor 8. Methods Mol Biol 647:171–186PubMedCrossRef Mehta TS, Monzur F, Zhao J (2010) Determination of nuclear localization signal sequences for Kruppel-like factor 8. Methods Mol Biol 647:171–186PubMedCrossRef
go back to reference Meng X, Ezzati P, Wilkins JA (2011) Requirement of podocalyxin in TGF-beta induced epithelial mesenchymal transition. PLoS ONE 6(4):e18715PubMedCrossRef Meng X, Ezzati P, Wilkins JA (2011) Requirement of podocalyxin in TGF-beta induced epithelial mesenchymal transition. PLoS ONE 6(4):e18715PubMedCrossRef
go back to reference Miyazono K (2009) Transforming growth factor-beta signaling in epithelial-mesenchymal transition and progression of cancer. Proc Jpn Acad Ser B Phys Biol Sci 85(8):314–323PubMedCrossRef Miyazono K (2009) Transforming growth factor-beta signaling in epithelial-mesenchymal transition and progression of cancer. Proc Jpn Acad Ser B Phys Biol Sci 85(8):314–323PubMedCrossRef
go back to reference Schnell O, Romagna A, Jaehnert I, Albrecht V, Eigenbrod S, Juerchott K, Kretzschmar H, Tonn JC, Schichor C (2012) Kruppel-like factor 8 (KLF8) is expressed in gliomas of different WHO grades and is essential for tumor cell proliferation. PLoS ONE 7(1):e30429PubMedCrossRef Schnell O, Romagna A, Jaehnert I, Albrecht V, Eigenbrod S, Juerchott K, Kretzschmar H, Tonn JC, Schichor C (2012) Kruppel-like factor 8 (KLF8) is expressed in gliomas of different WHO grades and is essential for tumor cell proliferation. PLoS ONE 7(1):e30429PubMedCrossRef
go back to reference Szkaradkiewicz A, Karpinski TM, Drews M, Borejsza-Wysocki M, Majewski P, Andrzejewska E (2010) Natural killer cell cytotoxicity and immunosuppressive cytokines (IL-10, TGF-beta1) in patients with gastric cancer. J Biomed Biotechnol 2010:901564PubMedCrossRef Szkaradkiewicz A, Karpinski TM, Drews M, Borejsza-Wysocki M, Majewski P, Andrzejewska E (2010) Natural killer cell cytotoxicity and immunosuppressive cytokines (IL-10, TGF-beta1) in patients with gastric cancer. J Biomed Biotechnol 2010:901564PubMedCrossRef
go back to reference Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890PubMedCrossRef Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890PubMedCrossRef
go back to reference van Vliet J, Turner J, Crossley M (2000) Human Kruppel-like factor 8: a CACCC-box binding protein that associates with CtBP and represses transcription. Nucleic Acids Res 28(9):1955–1962PubMedCrossRef van Vliet J, Turner J, Crossley M (2000) Human Kruppel-like factor 8: a CACCC-box binding protein that associates with CtBP and represses transcription. Nucleic Acids Res 28(9):1955–1962PubMedCrossRef
go back to reference Wang X, Zhao J (2007) KLF8 transcription factor participates in oncogenic transformation. Oncogene 26(3):456–461PubMedCrossRef Wang X, Zhao J (2007) KLF8 transcription factor participates in oncogenic transformation. Oncogene 26(3):456–461PubMedCrossRef
go back to reference Wang X, Zheng M, Liu G, Xia W, McKeown-Longo PJ, Hung MC, Zhao J (2007) Kruppel-like factor 8 induces epithelial to mesenchymal transition and epithelial cell invasion. Cancer Res 67(15):7184–7193PubMedCrossRef Wang X, Zheng M, Liu G, Xia W, McKeown-Longo PJ, Hung MC, Zhao J (2007) Kruppel-like factor 8 induces epithelial to mesenchymal transition and epithelial cell invasion. Cancer Res 67(15):7184–7193PubMedCrossRef
go back to reference Wang X, Urvalek AM, Liu J, Zhao J (2008) Activation of KLF8 transcription by focal adhesion kinase in human ovarian epithelial and cancer cells. J Biol Chem 283(20):13934–13942PubMedCrossRef Wang X, Urvalek AM, Liu J, Zhao J (2008) Activation of KLF8 transcription by focal adhesion kinase in human ovarian epithelial and cancer cells. J Biol Chem 283(20):13934–13942PubMedCrossRef
go back to reference Wei H, Wang X, Gan B, Urvalek AM, Melkoumian ZK, Guan JL, Zhao J (2006) Sumoylation delimits KLF8 transcriptional activity associated with the cell cycle regulation. J Biol Chem 281(24):16664–16671PubMedCrossRef Wei H, Wang X, Gan B, Urvalek AM, Melkoumian ZK, Guan JL, Zhao J (2006) Sumoylation delimits KLF8 transcriptional activity associated with the cell cycle regulation. J Biol Chem 281(24):16664–16671PubMedCrossRef
go back to reference Wu K, Liu BH, Zhao DY, Zhao Y (2001) Effect of vitamin E succinate on expression of TGF-beta1, c-Jun and JNK1 in human gastric cancer SGC-7901 cells. World J Gastroenterol 7(1):83–87PubMed Wu K, Liu BH, Zhao DY, Zhao Y (2001) Effect of vitamin E succinate on expression of TGF-beta1, c-Jun and JNK1 in human gastric cancer SGC-7901 cells. World J Gastroenterol 7(1):83–87PubMed
go back to reference Xiangming C, Natsugoe S, Takao S, Hokita S, Ishigami S, Tanabe G, Baba M, Kuroshima K, Aikou T (2001) Preserved Smad4 expression in the transforming growth factor beta signaling pathway is a favorable prognostic factor in patients with advanced gastric cancer. Clin Cancer Res 7(2):277–282PubMed Xiangming C, Natsugoe S, Takao S, Hokita S, Ishigami S, Tanabe G, Baba M, Kuroshima K, Aikou T (2001) Preserved Smad4 expression in the transforming growth factor beta signaling pathway is a favorable prognostic factor in patients with advanced gastric cancer. Clin Cancer Res 7(2):277–282PubMed
Metadata
Title
KLF8 involves in TGF-beta-induced EMT and promotes invasion and migration in gastric cancer cells
Authors
Hui Zhang
Lili Liu
Yafang Wang
Guohong Zhao
Rougang Xie
Changhao Liu
Xiao Xiao
Kaichun Wu
Yongzhan Nie
Hongbo Zhang
Daiming Fan
Publication date
01-06-2013
Publisher
Springer-Verlag
Published in
Journal of Cancer Research and Clinical Oncology / Issue 6/2013
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-012-1363-3

Other articles of this Issue 6/2013

Journal of Cancer Research and Clinical Oncology 6/2013 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine