THBS4 predicts poor outcomes and promotes proliferation and metastasis in gastric cancer

  • Xiangbo Chen
  • Yisen Huang
  • Yubin Wang
  • Qiuli Wu
  • Shunzhong Hong
  • Zicheng HuangEmail author
Original Article


Gastric cancer (GC), a common and lethal cancer in the world, has a high risk of metastasis. Our study was to explore the effects of THBS4 on GC progress and metastasis and the underlying mechanisms. The proliferations of MGC-803 and BGC-823 cells were analyzed via cell count, MTT, and soft agar colony formation assay. The migration and invasion of transfected GC cells was investigated via transwell migration and invasion assay. The mRNA abundance of THBS4 and KLF9 was detected by quantitative real-time PCR (qPCR). The analysis of Gene Expression Omnibus (GEO) dataset (GSE26253) suggested that THBS4 was up-regulated in recurrent GC patients and was positively correlated with the increase in pathological stage and poor prognosis in GC. THBS4 stimulated the proliferations of GC cells. Moreover, THBS4 overexpression fostered the migration and invasion of GC cells. Further, the bioinformatics analysis of the cancer genome atlas dataset suggested that there may be a positive correlation between THBS4 and KLF9 expression. QPCR analysis proved that transfected with THBS4 overexpression plasmid enhanced KLF9 expression in GC cells. THBS4 mRNA and protein expression were up-regulated in MGC-803 and BGC-823 cells compared to those in non-tumoral gastric cells. KLF9 overexpression significantly stimulated the proliferation and metastasis of MGC-803 and BGC-823 cells. Besides, KLF9 siRNA inhibited the enhanced viability, migration, and invasion of MGC-803 cells caused by the transfection with THBS4 overexpression plasmid. In conclusion, THBS4 had positive effects on GC proliferation and metastasis via targeting KLF9.


THBS4 Gastric cancer Proliferation Metastasis KLF9 



Gastric cancer


Gene Expression Omnibus


Quantitative real-time PCR


The cancer genome atlas




Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

13105_2019_665_MOESM1_ESM.docx (138 kb)
ESM 1 (DOCX 137 kb)


  1. 1.
    Bertucci F, Finetti P, Cervera N, Charafe-Jauffret E, Mamessier E, Adelaide J, Debono S, Houvenaeghel G, Maraninchi D, Viens P et al (2006) Gene expression profiling shows medullary breast cancer is a subgroup of basal breast cancers. Cancer Res 66:4636–4644CrossRefGoogle Scholar
  2. 2.
    Bieker JJ (2001) Kruppel-like factors: three fingers in many pies. J Biol Chem 276:34355–34358CrossRefGoogle Scholar
  3. 3.
    Chen C, Lei J, Zheng Q, Tan S, Ding K, Yu C (2018) Poly(rC) binding protein 2 (PCBP2) promotes the viability of human gastric cancer cells by regulating CDK2. FEBS Open Bio 8:764–773CrossRefGoogle Scholar
  4. 4.
    Chuang YC, Wu HY, Lin YL, Tzou SC, Chuang CH, Jian TY, Chen PR, Chang YC, Lin CH, Huang TH, Wang CC, Chan YL, Liao KW (2018) Blockade of ITGA2 induces apoptosis and inhibits cell migration in gastric cancer. Biol Proced Online 20:10CrossRefGoogle Scholar
  5. 5.
    Dakhova O, Ozen M, Creighton CJ, Li R, Ayala G, Rowley D, Ittmann M (2009) Global gene expression analysis of reactive stroma in prostate cancer. Clin Cancer Res 15:3979–3989CrossRefGoogle Scholar
  6. 6.
    Forster S, Gretschel S, Jons T, Yashiro M, Kemmner W (2011) THBS4, a novel stromal molecule of diffuse-type gastric adenocarcinomas, identified by transcriptome-wide expression profiling. Mod Pathol 24:1390–1403CrossRefGoogle Scholar
  7. 7.
    Greco SA, Chia J, Inglis KJ, Cozzi SJ, Ramsnes I, Buttenshaw RL, Spring KJ, Boyle GM, Worthley DL, Leggett BA, Whitehall VLJ (2010) Thrombospondin-4 is a putative tumour-suppressor gene in colorectal cancer that exhibits age-related methylation. BMC Cancer 10:494CrossRefGoogle Scholar
  8. 8.
    Huang S, Wang C, Yi Y, Sun X, Luo M, Zhou Z, Li J, Cai Y, Jiang X, Ke Y (2015) Kruppel-like factor 9 inhibits glioma cell proliferation and tumorigenicity via downregulation of miR-21. Cancer Lett 356:547–555CrossRefGoogle Scholar
  9. 9.
    Liu J, Cheng G, Yang H, Deng X, Qin C, Hua L, Yin C (2016) Reciprocal regulation of long noncoding RNAs THBS4003 and THBS4 control migration and invasion in prostate cancer cell lines. Mol Med Rep 14:1451–1458CrossRefGoogle Scholar
  10. 10.
    Mao Z, Fan X, Zhang J, Wang X, Ma X, Michalski CW, Zhang Y (2017) KLF9 is a prognostic Indicator in human pancreatic ductal adenocarcinoma. Anticancer Res 37:3795–3799Google Scholar
  11. 11.
    McCart Reed AE, Song S, Kutasovic JR, Reid LE, Valle JM, Vargas AC, Smart CE, Simpson PT (2013) Thrombospondin-4 expression is activated during the stromal response to invasive breast cancer. Virchows Arch 463:535–545CrossRefGoogle Scholar
  12. 12.
    McConnell BB, Yang VW (2010) Mammalian Kruppel-like factors in health and diseases. Physiol Rev 90:1337–1381CrossRefGoogle Scholar
  13. 13.
    Orditura M, Galizia G, Sforza V, Gambardella V, Fabozzi A, Laterza MM, Andreozzi F, Ventriglia J, Savastano B, Mabilia A, Lieto E, Ciardiello F, de Vita F (2014) Treatment of gastric cancer. World J Gastroenterol 20:1635–1649CrossRefGoogle Scholar
  14. 14.
    Pearson R, Fleetwood J, Eaton S, Crossley M, Bao S (2008) Kruppel-like transcription factors: a functional family. Int J Biochem Cell Biol 40:1996–2001CrossRefGoogle Scholar
  15. 15.
    Shen P, Sun J, Xu G, Zhang L, Yang Z, Xia S, Wang Y, Liu Y, Shi G (2014) KLF9, a transcription factor induced in flutamide-caused cell apoptosis, inhibits AKT activation and suppresses tumor growth of prostate cancer cells. Prostate 74:946–958CrossRefGoogle Scholar
  16. 16.
    Simmen FA, Su Y, Xiao R, Zeng Z, Simmen RC (2008) The Kruppel-like factor 9 (KLF9) network in HEC-1-A endometrial carcinoma cells suggests the carcinogenic potential of dys-regulated KLF9 expression. Reprod Biol Endocrinol 6:41CrossRefGoogle Scholar
  17. 17.
    Su F, Zhao J, Qin S, Wang R, Li Y, Wang Q, Tan Y, Jin H, Zhu F, Ou Y et al (2017) Over-expression of Thrombospondin 4 correlates with loss of miR-142 and contributes to migration and vascular invasion of advanced hepatocellular carcinoma. Oncotarget 8:23277–23288Google Scholar
  18. 18.
    Suske G, Bruford E, Philipsen S (2005) Mammalian SP/KLF transcription factors: bring in the family. Genomics 85:551–556CrossRefGoogle Scholar
  19. 19.
    Tong XD, Liu TQ, Wang GB, Zhang CL, Liu HX (2015) MicroRNA-570 promotes lung carcinoma proliferation through targeting tumor suppressor KLF9. Int J Clin Exp Pathol 8:2829–2834Google Scholar
  20. 20.
    Turner J, Crossley M (1999) Mammalian Kruppel-like transcription factors: more than just a pretty finger. Trends Biochem Sci 24:236–240CrossRefGoogle Scholar
  21. 21.
    Ying M, Sang Y, Li Y, Guerrero-Cazares H, Quinones-Hinojosa A, Vescovi AL, Eberhart CG, Xia S, Laterra J (2011) Kruppel-like family of transcription factor 9, a differentiation-associated transcription factor, suppresses Notch1 signaling and inhibits glioblastoma-initiating stem cells. Stem Cells 29:20–31CrossRefGoogle Scholar
  22. 22.
    Zhang QH, Dou HT, Tang YJ, Su S, Liu PS (2015) Lentivirus-mediated knockdown of Kruppel-like factor 9 inhibits the growth of ovarian cancer. Arch Gynecol Obstet 291:377–382CrossRefGoogle Scholar

Copyright information

© University of Navarra 2019

Authors and Affiliations

  • Xiangbo Chen
    • 1
  • Yisen Huang
    • 2
  • Yubin Wang
    • 2
  • Qiuli Wu
    • 1
  • Shunzhong Hong
    • 1
  • Zicheng Huang
    • 2
    Email author
  1. 1.Endoscopy CenterThe First Hospital of Quanzhou Affiliated to Fujian Medical UniversityQuanzhouChina
  2. 2.Department of GastroenterologyThe First Hospital of Quanzhou Affiliated to Fujian Medical UniversityQuanzhouChina

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