Skip to main content

Advertisement

SpringerLink
Log in

Over-expression of FRZB in gastric cancer cell suppresses proliferation and induces differentiation

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Frizzled motif associated with bone development (FRZB) was a member of secreted frizzled related proteins (sFRPs) family. Previous evidences showed that FRZB played role in embryogenesis and diseases such as osteoarthritis and prostate cancer. The purpose of our study is to clarify the role of FRZB in gastric cancer cell proliferation and differentiation.

Methods

The expression of FRZB in gastric cancer tissues were detected by immunohistochemistry. The expression of FRZB in eight gastric cancer cell lines and one immortal gastric epithelial cell GES-1 were detected by western blotting and real-time quantitative PCR. To investigate the role of over-expressed FRZB in gastric cancer cells, FRZB/pcDNA3.1 plasmid was constructed and transfected into gastric cancer cell line SGC7901. The changes of biological features in these stable transfectants were examined.

Results

FRZB was highly expressed in gastric cancer (90%), intestinal metaplasia (100%) and gastric dysplasia (90%), but no or just weakly (3/40) expressed in normal gastric mucosa. FRZB staining was stronger in intestinal-type gastric cancer tissues than that in diffuse-type ones and was positive correlated with differentiation grade. The expression of FRZB in eight gastric cancer cell lines was higher than in GES-1. Over-expressed FRZB inhibited cell proliferation in vitro and in vivo which was first caused by prolonged cell division progression in G2/M phase, and second by higher sensitivity to apoptotic inducing factors and spontaneous apoptosis. Our findings gave evidences that FRZB suppressed gastric cancer cell proliferation and modulated the balance between proliferation and differentiation in gastric cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Alberts SR, Cervantes A, van de Velde CJ (2003) Gastric cancer: epidemiology, pathology and treatment. Ann Oncol 14(Suppl 2):ii31–ii36

    PubMed  Google Scholar 

  • Borello U, Coletta M, Tajbakhsh S, Leyns L, De Robertis EM, Buckingham M, Cossu G (1999) Transplacental delivery of the Wnt antagonist Frzb1 inhibits development of caudal paraxial mesoderm and skeletal myogenesis in mouse embryos. Development 126:4247–4255

    PubMed  CAS  Google Scholar 

  • Banyai L, Patthy L (1999) The NTR module. Domains of netrins, secreted frizzled related proteins, and type I procollagen C-proteinase enhancer protein are homologous with tissue inhibitors of metalloproteases. Protein Sci 8:1636–1642

    Article  PubMed  CAS  Google Scholar 

  • Byun T, Karimi M, Marsh JL, Milovanovic T, Lin F, Holcombe RF (2005) Expression of secreted Wnt antagonists in gastrointestinal tissues: potential role in stem cell homeostasis. J Clin Pathol 58:515–519

    Article  PubMed  CAS  Google Scholar 

  • Cheng XX, Wang ZC, Chen XY, Sun Y, Kong QY, Liu J, Li H (2005) Correlation of Wnt-2 expression and beta-catenin intracellular accumulation in Chinese gastric cancers: relevance with tumour dissemination. Cancer Lett 223:339–347

    Article  PubMed  CAS  Google Scholar 

  • Correa P (1992) Human gastric carcinogenesis: a multistep and multifactorial process—First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 52:6735–6740

    PubMed  CAS  Google Scholar 

  • Correa P, Chen VW (1994) Gastric cancer. Cancer Surv 19–20:55–76

    PubMed  Google Scholar 

  • Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–776

    Article  PubMed  CAS  Google Scholar 

  • Hoang B, Moos M Jr, Vukicevic S, Luyten FP (1996) Primary structure and tissue distribution of FRZB, a novel protein related to Drosophila frizzled, suggest a role in skeletal morphogenesis. J Biol Chem 271:26131–26137

    Article  PubMed  CAS  Google Scholar 

  • Jiang Y, Wang L, Gong W, Wei D, Le X, Yao J, Ajani J, Abbruzzese JL, Huang S, Xie K (2004) A high expression level of insulin-like growth factor I receptor is associated with increased expression of transcription factor Sp1 and regional lymph node metastasis of human gastric cancer. Clin Exp Metastasis 21:755–764

    Article  PubMed  CAS  Google Scholar 

  • Katoh M (2005) WNT/PCP signaling pathway and human cancer (review). Oncol Rep 14:1583–1588

    PubMed  CAS  Google Scholar 

  • Kelleher FC, Fennelly D, Rafferty M (2006) Common critical pathways in embryogenesis and cancer. Acta Oncol 45:375–388

    Article  PubMed  CAS  Google Scholar 

  • Kim JH, Takahashi T, Chiba I, Park JG, Birrer MJ, Roh JK, De Lee H, Kim JP, Minna JD, Gazdar AF (1991) Occurrence of p53 gene abnormalities in gastric carcinoma tumors and cell lines. J Natl Cancer Inst 83:938–943

    Article  PubMed  CAS  Google Scholar 

  • Koppert LB, van der Velden AW, van de Wetering M, Abbou M, van den Ouweland AM, Tilanus HW, Wijnhoven BP, Dinjens WN (2004) Frequent loss of the AXIN1 locus but absence of AXIN1 gene mutations in adenocarcinomas of the gastro-oesophageal junction with nuclear beta-catenin expression. Br J Cancer 90:892–899

    Article  PubMed  CAS  Google Scholar 

  • Kuniyasu T, Nakamura T, Tabuchi Y, Kuroda Y (1998) Immunohistochemical evaluation of thymidylate synthase in gastric carcinoma using a new polyclonal antibody: the clinical role of thymidylate synthase as a prognostic indicator and its therapeutic usefulness. Cancer 83:1300–1306

    Article  PubMed  CAS  Google Scholar 

  • Lee JH, Abraham SC, Kim HS, Nam JH, Choi C, Lee MC, Park CS, Juhng SW, Rashid A, Hamilton SR, Wu TT (2002) Inverse relationship between APC gene mutation in gastric adenomas and development of adenocarcinoma. Am J Pathol 161:611–618

    PubMed  CAS  Google Scholar 

  • Lee AY, He B, You L, Dadfarmay S, Xu Z, Mazieres J, Mikami I, McCormick F, Jablons DM (2004) Expression of the secreted frizzled-related protein gene family is downregulated in human mesothelioma. Oncogene 23:6672–6676

    Article  PubMed  CAS  Google Scholar 

  • Leyns L, Wang S, Krinks M, Moos M Jr (1997) Frzb-1, an antagonist of Wnt-1 and Wnt-8, does not block signaling by Wnts -3A, -5A, or -11. Biochem Biophys Res Commun 236:502–504

    Article  Google Scholar 

  • Lickert H, Kispert A, Kutsch S, Kemler R (2001) Expression patterns of Wnt genes in mouse gut development. Mech Dev 105:181–184

    Article  PubMed  CAS  Google Scholar 

  • Lin K, Wang S, Julius MA, Kitajewski J, Moos M Jr, Luyten FP (1997) The cysteine-rich frizzled domain of Frzb-1 is required and sufficient for modulation of Wnt signaling. Proc Natl Acad Sci USA 94:11196–11200

    Article  PubMed  CAS  Google Scholar 

  • Loughlin J, Dowling B, Chapman K, Marcelline L, Mustafa Z, Southam L, Ferreira A, Ciesielski C, Carson DA, Corr M (2004) Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females. Proc Nat Acad Sci 101:9757–9762

    Article  PubMed  CAS  Google Scholar 

  • Marsit CJ, Karagas MR, Andrew A, Liu M, Danaee H, Schned AR, Nelson HH, Kelsey KT (2005) Epigenetic inactivation of SFRP genes and TP53 alteration act jointly as markers of invasive bladder cancer. Cancer Res 65:7081–7085

    Article  PubMed  CAS  Google Scholar 

  • McBride HJ, Fatke B, Fraser SE (2003) Wnt signaling components in the chicken intestinal tract. Dev Biol 256:18–33

    Article  PubMed  CAS  Google Scholar 

  • Person AD, Garriock RJ, Krieg PA, Runyan RB, Klewer SE (2005) Frzb modulates Wnt-9a-mediated beta-catenin signaling during avian atrioventricular cardiac cushion development. Dev Biol 278:35–48

    Article  PubMed  CAS  Google Scholar 

  • Philipson L (1998) Cell cycle exit: growth arrest, apoptosis, and tumor suppression revisited. Mol Med 4:205–213

    PubMed  CAS  Google Scholar 

  • Roder DM (2002) The epidemiology of gastric cancer. Gastric Cancer 5(Suppl 1):5–11

    Article  PubMed  Google Scholar 

  • Rohatgi PR, Yao JC, Hess K, Schnirer I, Rashid A, Mansfield PF (2006) Outcome of gastric cancer patients after successful gastrectomy: influence of the type of recurrence and histology on survival. Cancer 107:2576–2580

    Article  PubMed  Google Scholar 

  • Saitoh T, Katoh M (2002) Expression and regulation of WNT5A and WNT5B in human cancer: up-regulation of WNT5A by TNFalpha in MKN45 cells and up-regulation of WNT5B by beta-estradiol in MCF-7 cells. Int J Mol Med 10:345–349

    PubMed  CAS  Google Scholar 

  • Schneider VA, Mercola M (2001) Wnt antagonism initiates cardiogenesis in Xenopus laevis. Genes Dev 15:304–315

    Article  PubMed  CAS  Google Scholar 

  • Seidensticker MJ, (2000) Biochemical interactions in the wnt pathway. Biochim Biophys Acta 1495:168–182

    Article  PubMed  CAS  Google Scholar 

  • Shi Y, Zhai H, Wang X, Han Z, Liu C, Lan M, Du J, Guo C, Zhang Y, Wu K, Fan D (2004) Ribosomal proteins S13 and L23 promote multidrug resistance in gastric cancer cells by suppressing drug-induced apoptosis. Exp cell Res 296:337–346

    Article  PubMed  CAS  Google Scholar 

  • Sokol S (2000) A role for Wnts in morpho-genesis and tissue polarity. Nat Cell Biol 2:E124–E125

    Article  PubMed  CAS  Google Scholar 

  • Suh E, Traber PG (1996) An intestine-specific homeobox gene regulates proliferation and differentiation. Mol Cell Biol 16:619–625

    PubMed  CAS  Google Scholar 

  • Suzuki H, Itoh F, Toyota M, Kikuchi T, Kakiuchi H, Hinoda Y, Imai K (1999) Distinct methylation pattern and microsatellite instability in sporadic gastric cancer. Int J Cancer 83:309–313

    Article  PubMed  CAS  Google Scholar 

  • Suzuki H, Watkins DN, Jair KW, Schuebel KE, Markowitz SD, Chen WD, Pretlow TP, Yang B, Akiyama Y, Van Engeland M, Toyota M, Tokino T, Hinoda Y, Imai K, Herman JG, Baylin SB (2004) Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet 36:417–422

    Article  PubMed  CAS  Google Scholar 

  • Tamura G, Kihana T, Nomura K, Terada M, Sugimura T, Hirohashi S (1991) Detection of frequent p53 gene mutations in primary gastric cancer by cell sorting and polymerase chain reaction single-strand conformation polymorphism analysis. Cancer Res 51:3056–3058

    PubMed  CAS  Google Scholar 

  • The World Health Report (1997) Conquering suffering enriching humanity. World Health Organization, Geneva

    Google Scholar 

  • Tu SP, Jiang XH, Lin MC, Cui JT, Yang Y, Lum CT, Zou B, Zhu YB, Jiang SH, Wong WM, Chan AO, Yuen MF, Lam SK, Kung HF, Wong BC (2003) Suppression of survivin expression inhibits in vivo tumorigenicity and angiogenesis in gastric cancer. Cancer Res 63:7724–7732

    PubMed  CAS  Google Scholar 

  • Wada N, Kawakami Y, Ladher R, Francis-West PH, Nohno T (1999) Involvement of Frzb-1 in mesenchymal condensation and cartilage differentiation in the chick limb bud. Int J Dev Biol 43:495–500

    PubMed  CAS  Google Scholar 

  • Wang S, Krinks M, Lin K, Luyten FP, Moos M Jr (1997) Frzb, a secreted protein expressed in the Spemann organizer, binds and inhibits Wnt-8. Cell 88:757–766

    Article  PubMed  CAS  Google Scholar 

  • Wei D, Gong W, Kanai M, Schlunk C, Wang L, Yao JC, Wu TT, Huang S, Xie K (2005a) Drastic down-regulation of Kruppel-like factor 4 expression is critical in human gastric cancer development and progression. Cancer Res 65:2746–2754

    Article  PubMed  CAS  Google Scholar 

  • Wei D, Gong W, Oh SC, Li Q, Kim WD, Wang L, Le X, Yao J, Wu TT, Huang S, Xie K (2005b) Loss of RUNX3 expression significantly affects the clinical outcome of gastric cancer patients and its restoration causes drastic suppression of tumor growth and metastasis. Cancer Res 65:4809–4816

    Article  PubMed  CAS  Google Scholar 

  • Whitfield ML, Sherlock G, Saldanha AJ, Murray JI, Ball CA, Alexander KE, Matese JC, Perou CM, Hurt MM, Brown PO, Botstein D (2002) Identification of genes periodically expressed in the human cell cycle and their expression in tumors. Mol Biol Cell 13:1977–2000

    Article  PubMed  CAS  Google Scholar 

  • Wittekind Ch, Sobin LH (2002) TNM classification of malignant tumours, 6th edn. Wiley-Liss, New York

    Google Scholar 

  • Zi X, Guo Y, Simoneau AR, Hope C, Xie J, Holcombe RF, Hoang BH (2005) Expression of Frzb/secreted Frizzled-related protein 3, a secreted Wnt antagonist, in human androgen-independent prostate cancer PC-3 cells suppresses tumor growth and cellular invasiveness. Cancer Res 65:9762–9770

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by The National Key Fundamental Research (973 Project of China 2002CB713700) and The National High Technology Research and Development Program of China (863 Program 2002BA711A06).

Author information

Authors and Affiliations

  1. Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 197 Rui Jin er Road, Shanghai, 200025, China

    Ying Qu, Jian-fang Li, Qu Cai, Yun-wei Wang, Qin-long Gu, Zheng-gang Zhu & Bing-ya Liu

Authors
  1. Ying Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jian-fang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qu Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yun-wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qin-long Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zheng-gang Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bing-ya Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bing-ya Liu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Qu, Y., Li, Jf., Cai, Q. et al. Over-expression of FRZB in gastric cancer cell suppresses proliferation and induces differentiation. J Cancer Res Clin Oncol 134, 353–364 (2008). https://doi.org/10.1007/s00432-007-0291-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-007-0291-0

Keywords

Search

Navigation