Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

ECM1 regulates tumor metastasis and CSC-like property through stabilization of β-catenin

Abstract

Extracellular Matrix Protein 1 (ECM1) is a marker for tumorigenesis and is correlated with invasiveness and poor prognosis in various types of cancer. However, the functional role of ECM1 in cancer metastasis is unclear. Here, we detected high ECM1 level in breast cancer patient sera that was associated with recurrence of tumor. The modulation of ECM1 expression affected not only cell migration and invasion, but also sphere-forming ability and drug resistance in breast cancer cell lines. In addition, ECM1 regulated the gene expression associated with the epithelial to mesenchymal transition (EMT) progression and cancer stem cell (CSC) maintenance. Interestingly, ECM1 increased β-catenin expression at the post-translational level through induction of MUC1, which was physically associated with β-catenin. Indeed, the association between β-catenin and the MUC1 cytoplasmic tail was increased by ECM1. Furthermore, forced expression of β-catenin altered the gene expression that potentiated EMT progression and CSC phenotype maintenance in the cells. These data provide evidence that ECM1 has an important role in cancer metastasis through β-catenin stabilization.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

References

  1. Mathieu E, Meheus L, Raymackers J, Merregaert J . Characterization of the osteogenic stromal cell line MN7: identification of secreted MN7 proteins using two-dimensional polyacrylamide gel electrophoresis, western blotting, and microsequencing. J Bone Miner Res 1994; 9: 903–913.

    Article  CAS  PubMed  Google Scholar 

  2. Wang L, Yu J, Ni J, Xu XM, Wang J, Ning H et al. Extracellular matrix protein 1 (ECM1) is over-expressed in malignant epithelial tumors. Cancer Lett 2003; 200: 57–67.

    Article  CAS  PubMed  Google Scholar 

  3. Kebebew E, Peng M, Reiff E, Duh QY, Clark OH, McMillan A . ECM1 and TMPRSS4 are diagnostic markers of malignant thyroid neoplasms and improve the accuracy of fine needle aspiration biopsy. Ann Surg 2005; 242: 353–361 discussion 361-353.

  4. Lal G, Hashimi S, Smith BJ, Lynch CF, Zhang L, Robinson RA et al. Extracellular matrix 1 (ECM1) expression is a novel prognostic marker for poor long-term survival in breast cancer: a Hospital-based Cohort Study in Iowa. Ann Surg Oncol 2009; 16: 2280–2287.

    Article  PubMed  Google Scholar 

  5. Han Z, Ni J, Smits P, Underhill CB, Xie B, Chen Y et al. Extracellular matrix protein 1 (ECM1) has angiogenic properties and is expressed by breast tumor cells. FASEB J 2001; 15: 988–994.

    Article  CAS  PubMed  Google Scholar 

  6. Wu QW, She HQ, Liang J, Huang YF, Yang QM, Yang QL et al. Expression and clinical significance of extracellular matrix protein 1 and vascular endothelial growth factor-C in lymphatic metastasis of human breast cancer. BMC Cancer 2012; 12: 47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wu Q, Li X, Yang H, Lu C, You J, Zhang Z . Extracellular matrix protein 1 is correlated to carcinogenesis and lymphatic metastasis of human gastric cancer. World J Surg Oncol 2014; 12: 132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Xiong GP, Zhang JX, Gu SP, Wu YB, Liu JF . Overexpression of ECM1 contributes to migration and invasion in cholangiocarcinoma cell. Neoplasma 2012; 59: 409–415.

    Article  CAS  PubMed  Google Scholar 

  9. Gu M, Guan J, Zhao L, Ni K, Li X, Han Z . Correlation of ECM1 expression level with the pathogenesis and metastasis of laryngeal carcinoma. Int J Clin Exp Pathol 2013; 6: 1132–1137.

    PubMed  PubMed Central  Google Scholar 

  10. Gilles C, Polette M, Birembaut P, Brunner N, Thompson EW . Expression of c-ets-1 mRNA is associated with an invasive, EMT-derived phenotype in breast carcinoma cell lines. Clin Exp Metastasis 1997; 15: 519–526.

    Article  CAS  PubMed  Google Scholar 

  11. Oft M, Peli J, Rudaz C, Schwarz H, Beug H, Reichmann E . TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev 1996; 10: 2462–2477.

    Article  CAS  PubMed  Google Scholar 

  12. Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2000; 2: 76–83.

    Article  CAS  PubMed  Google Scholar 

  13. Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J et al. Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 2002; 156: 299–313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133: 704–715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chaffer CL, Weinberg RA . A perspective on cancer cell metastasis. Science 2011; 331: 1559–1564.

    Article  CAS  PubMed  Google Scholar 

  16. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF . Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100: 3983–3988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C et al. Identification and expansion of human colon-cancer-initiating cells. Nature 2007; 445: 111–115.

    Article  CAS  PubMed  Google Scholar 

  18. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T et al. Identification of human brain tumour initiating cells. Nature 2004; 432: 396–401.

    Article  CAS  PubMed  Google Scholar 

  19. Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007; 1: 313–323.

    Article  CAS  PubMed  Google Scholar 

  20. Lee TK, Castilho A, Cheung VC, Tang KH, Ma S, Ng IO . CD24(+) liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell stem Cell 2011; 9: 50–63.

    Article  CAS  PubMed  Google Scholar 

  21. Dean M, Fojo T, Bates S . Tumour stem cells and drug resistance. Nat Rev Cancer 2005; 5: 275–284.

    Article  CAS  PubMed  Google Scholar 

  22. Clevers H . Wnt/beta-catenin signaling in development and disease. Cell 2006; 127: 469–480.

    Article  CAS  PubMed  Google Scholar 

  23. Neth P, Ries C, Karow M, Egea V, Ilmer M, Jochum M . The Wnt signal transduction pathway in stem cells and cancer cells: influence on cellular invasion. Stem Cell Rev 2007; 3: 18–29.

    Article  CAS  PubMed  Google Scholar 

  24. Takebe N, Harris PJ, Warren RQ, Ivy SP . Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat Rev Clin Oncol 2011; 8: 97–106.

    Article  CAS  PubMed  Google Scholar 

  25. Lee KM, Nam K, Oh S, Lim J, Kim YP, Lee JW et al. ECM1 regulates cell proliferation and trastuzumab resistance through activation of EGF-signaling. Breast Cancer Res 2014; 16: 479.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Reya T, Morrison SJ, Clarke MF, Weissman IL . Stem cells, cancer, and cancer stem cells. Nature 2001; 414: 105–111.

    Article  CAS  PubMed  Google Scholar 

  27. Huber MA, Azoitei N, Baumann B, Grunert S, Sommer A, Pehamberger H et al. NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 2004; 114: 569–581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Julien S, Puig I, Caretti E, Bonaventure J, Nelles L, van Roy F et al. Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. Oncogene 2007; 26: 7445–7456.

    Article  CAS  PubMed  Google Scholar 

  29. Maier HJ, Schmidt-Strassburger U, Huber MA, Wiedemann EM, Beug H, Wirth T . NF-kappaB promotes epithelial-mesenchymal transition, migration and invasion of pancreatic carcinoma cells. Cancer Lett 2010; 295: 214–228.

    Article  CAS  PubMed  Google Scholar 

  30. Matsuda A, Suzuki Y, Honda G, Muramatsu S, Matsuzaki O, Nagano Y et al. Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways. Oncogene 2003; 22: 3307–3318.

    Article  CAS  PubMed  Google Scholar 

  31. Yamamoto M, Bharti A, Li Y, Kufe D . Interaction of the DF3/MUC1 breast carcinoma-associated antigen and beta-catenin in cell adhesion. J Biol Chem 1997; 272: 12492–12494.

    Article  CAS  PubMed  Google Scholar 

  32. Huang L, Chen D, Liu D, Yin L, Kharbanda S, Kufe D . MUC1 oncoprotein blocks glycogen synthase kinase 3beta-mediated phosphorylation and degradation of beta-catenin. Cancer Res 2005; 65: 10413–10422.

    Article  CAS  PubMed  Google Scholar 

  33. Stein U, Arlt F, Walther W, Smith J, Waldman T, Harris ED et al. The metastasis-associated gene S100A4 is a novel target of beta-catenin/T-cell factor signaling in colon cancer. Gastroenterology 2006; 131: 1486–1500.

    Article  CAS  PubMed  Google Scholar 

  34. Sanchez-Tillo E, de Barrios O, Siles L, Cuatrecasas M, Castells A, Postigo A . beta-catenin/TCF4 complex induces the epithelial-to-mesenchymal transition (EMT)-activator ZEB1 to regulate tumor invasiveness. Proc Natl Acad Sci USA 2011; 108: 19204–19209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tanida S, Mori Y, Ishida A, Akita K, Nakada H . Galectin-3 binds to MUC1-N-terminal domain and triggers recruitment of beta-catenin in MUC1-expressing mouse 3T3 cells. Biochim Biophys Acta 2014; 1840: 1790–1797.

    Article  CAS  PubMed  Google Scholar 

  36. Wen Y, Caffrey TC, Wheelock MJ, Johnson KR, Hollingsworth MA . Nuclear association of the cytoplasmic tail of MUC1 and beta-catenin. J Biol chem 2003; 278: 38029–38039.

    Article  CAS  PubMed  Google Scholar 

  37. Howe LR, Watanabe O, Leonard J, Brown AM . Twist is up-regulated in response to Wnt1 and inhibits mouse mammary cell differentiation. Cancer Res 2003; 63: 1906–1913.

    CAS  PubMed  Google Scholar 

  38. Horvay K, Casagranda F, Gany A, Hime GR, Abud HE . Wnt signaling regulates Snai1 expression and cellular localization in the mouse intestinal epithelial stem cell niche. Stem Cells Dev 2011; 20: 737–745.

    Article  CAS  PubMed  Google Scholar 

  39. Sakai D, Tanaka Y, Endo Y, Osumi N, Okamoto H, Wakamatsu Y . Regulation of Slug transcription in embryonic ectoderm by beta-catenin-Lef/Tcf and BMP-Smad signaling. Dev Growth Differ 2005; 47: 471–482.

    Article  CAS  PubMed  Google Scholar 

  40. Kirstetter P, Anderson K, Porse BT, Jacobsen SE, Nerlov C . Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. Nat Immunol 2006; 7: 1048–1056.

    Article  CAS  PubMed  Google Scholar 

  41. Takao Y, Yokota T, Koide H . Beta-catenin up-regulates Nanog expression through interaction with Oct-3/4 in embryonic stem cells. Biochem Biophys Res Commun 2007; 353: 699–705.

    Article  CAS  PubMed  Google Scholar 

  42. Liu W, Hsu DK, Chen HY, Yang RY, Carraway KL 3rd, Isseroff RR et al. Galectin-3 regulates intracellular trafficking of EGFR through Alix and promotes keratinocyte migration. J Invest Dermatol 2012; 132: 2828–2837.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhao Q, Guo X, Nash GB, Stone PC, Hilkens J, Rhodes JM et al. Circulating galectin-3 promotes metastasis by modifying MUC1 localization on cancer cell surface. Cancer Res 2009; 69: 6799–6806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Roy LD, Sahraei M, Subramani DB, Besmer D, Nath S, Tinder TL et al. MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition. Oncogene 2011; 30: 1449–1459.

    Article  CAS  PubMed  Google Scholar 

  45. Raina D, Uchida Y, Kharbanda A, Rajabi H, Panchamoorthy G, Jin C et al. Targeting the MUC1-C oncoprotein downregulates HER2 activation and abrogates trastuzumab resistance in breast cancer cells. Oncogene 2013; 33: 3422–31.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Alam M, Rajabi H, Ahmad R, Jin C, Kufe D . Targeting the MUC1-C oncoprotein inhibits self-renewal capacity of breast cancer cells. Oncotarget 2014; 5: 2622–34.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by an NRF grant (2013-059143) from the Korea Research Foundation and Converging Research Center Program (2014048814).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to I Shin.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lee, Km., Nam, K., Oh, S. et al. ECM1 regulates tumor metastasis and CSC-like property through stabilization of β-catenin. Oncogene 34, 6055–6065 (2015). https://doi.org/10.1038/onc.2015.54

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2015.54

This article is cited by

Search

Quick links