Skip to main content

Advertisement

SpringerLink
Log in

γ-Catenin acts as a tumor suppressor through context-dependent mechanisms in colorectal cancer

  • Original Article
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Purpose

γ-Catenin is a protein closely related to β-catenin. While the overexpression of β-catenin has been linked with impaired prognosis and survival in various malignancies, both oncogenic and tumor suppressor functions have been described for γ-catenin. Thus, its role in cancer remains controversial. In this study, we examined the impact of γ-catenin expression on the malignant potential of colorectal cancer cells.

Methods

γ-Catenin was knocked down by short interfering RNA in the γ-catenin-proficient DLD-1 cell line and stably overexpressed in the γ-catenin-deficient cell line RKO. The effects of these molecular manipulations on the malignant potential of the cell lines were tested in vitro and in vivo in a xenograft tumor model.

Results

γ-Catenin contributed to Wnt signaling independent of the cellular context. Unlike its sister molecule β-catenin, γ-catenin inhibited cellular invasion and anoikis in cells endogenously expressing γ-catenin. In line with this tumor suppressor function, its de novo expression in RKO cells inhibited proliferation via cell cycle arrest. In a xenograft tumor model, overexpression of γ-catenin starkly reduced tumor growth in vivo.

Conclusions

This is the first report demonstrating a tumor-suppressive effect of γ-catenin in colorectal cancer both in vitro and in vivo. Detailed in vitro analysis revealed that effects of γ-catenin differ in γ-catenin proficient and deficient cells, indicating that its function in colorectal cancer is dependent on the cellular context. This finding adds to our understanding of γ-catenin and may have implications for future studies of catenin/Wnt targeted cancer therapies.

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

Similar content being viewed by others

References

  1. Zhurinsky J, Shtutman M, Ben-Ze’ev A (2000) Plakoglobin and beta-catenin: protein interactions, regulation and biological roles. J Cell Sci 113(Pt 18):3127–3139

    CAS  PubMed  Google Scholar 

  2. Ben-Ze’ev A, Geiger B (1998) Differential molecular interactions of beta-catenin and plakoglobin in adhesion, signaling and cancer. Curr Opin Cell Biol 10(5):629–639

    Article  PubMed  Google Scholar 

  3. Kolligs FT, Bommer G, Goke B (2002) Wnt/beta-catenin/tcf signaling: a critical pathway in gastrointestinal tumorigenesis. Digestion, 66 (3):131–144. doi:10.1159/000066755

  4. Williams BO, Barish GD, Klymkowsky MW, Varmus HE (2000) A comparative evaluation of beta-catenin and plakoglobin signaling activity. Oncogene 19(50):5720–5728. doi:10.1038/sj.onc.1203921

    Article  CAS  PubMed  Google Scholar 

  5. Maeda O, Usami N, Kondo M, Takahashi M, Goto H, Shimokata K, Kusugami K, Sekido Y (2004) Plakoglobin (gamma-catenin) has TCF/LEF family-dependent transcriptional activity in beta-catenin-deficient cell line. Oncogene 23(4):964–972. doi:10.1038/sj.onc.1207254

    Article  CAS  PubMed  Google Scholar 

  6. Miravet S, Piedra J, Miro F, Itarte E, Garcia de Herreros A, Dunach M (2002) The transcriptional factor Tcf-4 contains different binding sites for beta-catenin and plakoglobin. J Biol Chem 277(3):1884–1891. doi:10.1074/jbc.M110248200

    Article  CAS  PubMed  Google Scholar 

  7. Simcha I, Shtutman M, Salomon D, Zhurinsky J, Sadot E, Geiger B, Ben-Ze’ev A (1998) Differential nuclear translocation and transactivation potential of beta-catenin and plakoglobin. J Cell Biol 141(6):1433–1448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kolligs FT, Hu G, Dang CV, Fearon ER (1999) Neoplastic transformation of RK3E by mutant beta-catenin requires deregulation of Tcf/Lef transcription but not activation of c-myc expression. Mol Cell Biol 19(8):5696–5706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kolligs FT, Kolligs B, Hajra KM, Hu G, Tani M, Cho KR, Fearon ER (2000) gamma-catenin is regulated by the APC tumor suppressor and its oncogenic activity is distinct from that of beta-catenin. Genes Dev 14(11):1319–1331

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Caca K, Kolligs FT, Ji X, Hayes M, Qian J, Yahanda A, Rimm DL, Costa J, Fearon ER (1999) Beta- and gamma-catenin mutations, but not E-cadherin inactivation, underlie T-cell factor/lymphoid enhancer factor transcriptional deregulation in gastric and pancreatic cancer. Cell Growth Differ 10(6):369–376

    CAS  PubMed  Google Scholar 

  11. Shiina H, Breault JE, Basset WW, Enokida H, Urakami S, Li LC, Okino ST, Deguchi M, Kaneuchi M, Terashima M, Yoneda T, Shigeno K, Carroll PR, Igawa M, Dahiya R (2005) Functional loss of the gamma-catenin gene through epigenetic and genetic pathways in human prostate cancer. Cancer Res 65(6):2130–2138. doi:10.1158/0008-5472.CAN-04-3398

    Article  CAS  PubMed  Google Scholar 

  12. Skotheim RI, Abeler VM, Nesland JM, Fossa SD, Holm R, Wagner U, Florenes VA, Aass N, Kallioniemi OP, Lothe RA (2003) Candidate genes for testicular cancer evaluated by in situ protein expression analyses on tissue microarrays. Neoplasia 5(5):397–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Varis A, Wolf M, Monni O, Vakkari ML, Kokkola A, Moskaluk C, Frierson H Jr, Powell SM, Knuutila S, Kallioniemi A, El-Rifai W (2002) Targets of gene amplification and overexpression at 17q in gastric cancer. Cancer Res 62(9):2625–2629

    CAS  PubMed  Google Scholar 

  14. Nagel JM, Kriegl L, Horst D, Engel J, Gautam S, Mantzoros CS, Kirchner T, Goke B, Kolligs FT (2010) gamma-Catenin is an independent prognostic marker in early stage colorectal cancer. Int J Color Dis 25(11):1301–1309. doi:10.1007/s00384-010-1046-y

    Article  Google Scholar 

  15. Parker HR, Li Z, Sheinin H, Lauzon G, Pasdar M (1998) Plakoglobin induces desmosome formation and epidermoid phenotype in N-cadherin-expressing squamous carcinoma cells deficient in plakoglobin and E-cadherin. Cell Motil Cytoskeleton 40(1):87–100. doi:10.1002/(SICI)1097-0169(1998)40:1<87::AID-CM8>3.0.CO;2-C

    Article  CAS  PubMed  Google Scholar 

  16. Shafiei F, Rahnama F, Pawella L, Mitchell MD, Gluckman PD, Lobie PE (2008) DNMT3A and DNMT3B mediate autocrine hGH repression of plakoglobin gene transcription and consequent phenotypic conversion of mammary carcinoma cells. Oncogene 27(18):2602–2612. doi:10.1038/sj.onc.1210917

    Article  CAS  PubMed  Google Scholar 

  17. Winn RA, Bremnes RM, Bemis L, Franklin WA, Miller YE, Cool C, Heasley LE (2002) gamma-Catenin expression is reduced or absent in a subset of human lung cancers and re-expression inhibits transformed cell growth. Oncogene 21(49):7497–7506. doi:10.1038/sj.onc.1205963

    Article  CAS  PubMed  Google Scholar 

  18. Rieger-Christ KM, Ng L, Hanley RS, Durrani O, Ma H, Yee AS, Libertino JA, Summerhayes IC (2005) Restoration of plakoglobin expression in bladder carcinoma cell lines suppresses cell migration and tumorigenic potential. Br J Cancer 92(12):2153–2159. doi:10.1038/sj.bjc.6602651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Weng Z, Xin M, Pablo L, Grueneberg D, Hagel M, Bain G, Muller T, Papkoff J (2002) Protection against anoikis and down-regulation of cadherin expression by a regulatable beta-catenin protein. J Biol Chem 277(21):18677–18686. doi:10.1074/jbc.M105331200

    Article  CAS  PubMed  Google Scholar 

  20. Hakimelahi S, Parker HR, Gilchrist AJ, Barry M, Li Z, Bleackley RC, Pasdar M (2000) Plakoglobin regulates the expression of the anti-apoptotic protein BCL-2. J Biol Chem 275(15):10905–10911

    Article  CAS  PubMed  Google Scholar 

  21. Nagashima H, Okada M, Hidai C, Hosoda S, Kasanuki H, Kawana M (1997) The role of cadherin-catenin-cytoskeleton complex in angiogenesis: antisense oligonucleotide of plakoglobin promotes angiogenesis in vitro, and protein kinase C (PKC) enhances angiogenesis through the plakoglobin signaling pathway. Heart Vessels Suppl 12:110–112

    Google Scholar 

  22. Mukhina S, Mertani HC, Guo K, Lee KO, Gluckman PD, Lobie PE (2004) Phenotypic conversion of human mammary carcinoma cells by autocrine human growth hormone. Proc Natl Acad Sci U S A 101(42):15166–15171. doi:10.1073/pnas.0405881101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Simcha I, Geiger B, Yehuda-Levenberg S, Salomon D, Ben-Ze’ev A (1996) Suppression of tumorigenicity by plakoglobin: an augmenting effect of N-cadherin. J Cell Biol 133(1):199–209

    Article  CAS  PubMed  Google Scholar 

  24. Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H, Brannigan BW, Kapur R, Stott SL, Shioda T, Ramaswamy S, Ting DT, Lin CP, Toner M, Haber DA, Maheswaran S (2014) Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158(5):1110–1122. doi:10.1016/j.cell.2014.07.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. Harald Lahm

    Present address: Department of Cardiovascular Surgery, Division of Experimental Surgery, German Heart Center Munich, Technical University (TU), Munich Heart Alliance, Lazarettstraße 36, 80636, Munich, Germany

  2. Burkhard Göke

    Present address: University Hospital Hamburg-Eppendorf (UKE), Martinistraße 52, 20246, Hamburg, Germany

  3. Frank Thomas Kolligs

    Present address: Department of Internal Medicine and Gastroenterology, HELIOS Klinikum Berlin-Buch, Schwanebecker Chaussee 50, 13125, Berlin, Germany

Authors and Affiliations

  1. Department of Medicine II, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany

    Jutta Maria Nagel, Andrea Ofner, Burkhard Göke & Frank Thomas Kolligs

  2. Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilian University of Munich (LMU), Feodor-Lynen-Strasse 25, 81377, Munich, Germany

    Harald Lahm

Authors
  1. Jutta Maria Nagel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Harald Lahm
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrea Ofner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Burkhard Göke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Frank Thomas Kolligs
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jutta Maria Nagel.

Ethics declarations

Animal handling and experimentation were performed in accordance with German Animal Protection Law and approved by the Animal Care and Use Committee of Bavaria (AZ 55.2-1-54-2531-49/06).

Electronic supplementary material

Supplementary Figure 1.

Efficient siRNA knock-down of ß-catenin in DLD-1 cells as shown by Western Blot and Immunofluorescence. a DLD-1 cells were transfected with siRNA against ß-catenin. 48h after transfection, cells were harvested and probed with antibodies against ß-catenin by Western Blotting. Expression of β-actin served as a control for equal loading. b Control and ß-catenin siRNA transfected DLD-1 cells were stained with ß-catenin antibodies by immunofluorescence. (PPTX 397 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nagel, J.M., Lahm, H., Ofner, A. et al. γ-Catenin acts as a tumor suppressor through context-dependent mechanisms in colorectal cancer. Int J Colorectal Dis 32, 1243–1251 (2017). https://doi.org/10.1007/s00384-017-2846-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-017-2846-0

Keywords

Search

Navigation