Skip to main content

Advertisement

Log in

Expression of PRL-3 regulates proliferation and invasion of breast cancer cells in vitro

  • Gynecologic Oncology
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

The protein tyrosine phosphatase PRL-3 plays an important role in cancer cell migration, invasion and metastasis. In breast cancer, PRL-3 is overexpressed in 70–75% of tumors and even more frequently in lymph node metastases. Moreover, PRL-3 overexpression in breast cancer is associated with an adverse disease outcome. Aim of this study was to determine the role of PRL-3 in breast cancer cell proliferation, migration and invasion in vitro.

Methods

PRL-3 mRNA expression was evaluated in 6 breast cancer cell lines by quantitative real-time PCR. To investigate the effect of PRL-3 expression in breast cancer cells in vitro we both up- and downregulated PRL-3 expression in breast cancer cells and performed in vitro wound repair cell motility assays and invasion assays. The influence of PRL-3 knockdown in MCF-7 cells on the expression of several gene products involved in cell invasion and cytoskeletal function was evaluated with real-time PCR.

Results

PRL-3 mRNA expression was demonstrated in all breast cancer cell lines evaluated. Knockdown of PRL-3 in MCF-7 cells resulted in decreased proliferation, wound healing and invasion. PRL-3 knockdown in MCF-7 cells resulted in a significant reduction of heparanase, MMP-9, actin gamma-2 and Myosin 9 expression, and significant elevation of E-cadherin.

Conclusions

We conclude that PRL-3 is an important regulatory factor for breast cancer cell proliferation and invasion. Loss of PRL-3 function induces an antimetastatic gene expression profile in breast cancer cells. Due to its role in tumor growth and metastasis, PRL-3 emerges as a new therapeutic target in breast cancer therapy.

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

Access this article

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. Diamond RH, Cressman DE, Laz TM, Abrams CS, Taub R (1994) PRL-1, a unique nuclear protein tyrosine phosphatase, affects cell growth. Mol Cell Biol 14:3752–3762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Zeng Q, Hong W, Tan YH (1998) Mouse PRL-2 and PRL-3, two potentially prenylated protein tyrosine phosphatases homologous to PRL-1. Biochem Biophys Res Commun 244:421–427

    Article  CAS  PubMed  Google Scholar 

  3. Cates CA, Michael RL, Stayrook KR, Harvey KA, Burke YD, Randall SK, Crowell PL, Crowell DN (1996) Prenylation of oncogenic human PTP (CAAX) protein tyrosine phosphatases. Cancer Lett 110:49–55

    Article  CAS  PubMed  Google Scholar 

  4. Wang Q, Holmes DI, Powell SM, Lu QL, Waxman J (2002) Analysis of stromal-epithelial interactions in prostate cancer identifies PTPCAAX2 as a potential oncogene. Cancer Lett 175:63–69

    Article  CAS  PubMed  Google Scholar 

  5. Bardelli A, Saha S, Sager JA, Romans KE, Xin B, Markowitz SD, Lengauer C, Velculescu VE, Kinzler KW, Vogelstein B (2003) PRL-3 expression in metastatic cancers. Clin Cancer Res 9:5607–5615

    CAS  PubMed  Google Scholar 

  6. Guo K, Li J, Tang JP, Koh V, Gan BQ, Zeng Q (2004) Catalytic domain of PRL-3 plays an essential role in tumor metastasis: formation of PRL-3 tumors inside the blood vessels. Cancer Biol Ther 3:945–951

    Article  CAS  PubMed  Google Scholar 

  7. Saha S, Bardelli A, Buckhaults P, Velculescu VE, Rago C, St Croix B, Romans KE, Choti MA, Lengauer C, Kinzler KW, Vogelstein B (2001) A phosphatase associated with metastasis of colorectal cancer. Science 294:1343–1346

    Article  CAS  PubMed  Google Scholar 

  8. Kato H, Semba S, Miskad UA, Seo Y, Kasuga M, Yokozaki H (2004) High expression of PRL-3 promotes cancer cell motility and liver metastasis in human colorectal cancer: a predictive molecular marker of metachronous liver and lung metastases. Clin Cancer Res 10:7318–7328

    Article  CAS  PubMed  Google Scholar 

  9. Peng L, Ning J, Meng L, Shou C (2004) The association of the expression level of protein tyrosine phosphatase PRL-3 protein with liver metastasis and prognosis of patients with colorectal cancer. J Cancer Res Clin Oncol 130:521–526

    Article  CAS  PubMed  Google Scholar 

  10. Wang Y, Li ZF, He J, Li YL, Zhu GB, Zhang LH, Li YL (2007) Expression of the human phosphatases of regenerating liver (PRLs) in colonic adenocarcinoma and its correlation with lymph node metastasis. Int J Colorectal Dis 22:1179–1184

    Article  PubMed  Google Scholar 

  11. Miskad UA, Semba S, Kato H, Yokozaki H (2004) Expression of PRL-3 phosphatase in human gastric carcinomas: close correlation with invasion and metastasis. Pathobiology 71:176–184

    Article  CAS  PubMed  Google Scholar 

  12. Li ZR, Wang Z, Zhu BH, He YL, Peng JS, Cai SR, Ma JP, Zhan WH (2007) Association of tyrosine PRL-3 phosphatase protein expression with peritoneal metastasis of gastric carcinoma and prognosis. Surg Today 37:646–651

    Article  CAS  PubMed  Google Scholar 

  13. Polato F, Codegoni A, Fruscio R, Perego P, Mangioni C, Saha S, Bardelli A, Broggini M (2005) PRL-3 phosphatase is implicated in ovarian cancer growth. Clin Cancer Res 11:6835–6839

    Article  CAS  PubMed  Google Scholar 

  14. Wang Z, He YL, Cai SR, Zhan WH, Li ZR, Zhu BH, Chen CQ, Ma JP, Chen ZX, Li W, Zhang LJ (2008) Expression and prognostic impact of PRL-3 in lymph node metastasis of gastric cancer: its molecular mechanism was investigated using artificial microRNA interference. Int J Cancer 123:1439–1447

    Article  CAS  PubMed  Google Scholar 

  15. Dai N, Lu AP, Shou CC, Li JY (2009) Expression of phosphatase regenerating liver 3 is an independent prognostic indicator for gastric cancer. World J Gastroenterol 15:1499–1505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ren T, Jiang B, Xing X, Dong B, Peng L, Meng L, Xu H, Shou C (2009) Prognostic significance of phosphatase of regenerating liver-3 expression in ovarian cancer. Pathol Oncol Res. 15:555–560

    Article  CAS  PubMed  Google Scholar 

  17. Zeng Q, Dong JM, Guo K, Li J, Tan HX, Koh V, Pallen CJ, Manser E, Hong W (2003) PRL-3 and PRL-1 promote cell migration, invasion, and metastasis. Cancer Res 63:2716–2722

    CAS  PubMed  Google Scholar 

  18. Wu X, Zeng H, Zhang X, Zhao Y, Sha H, Ge X, Zhang M, Gao X, Xu Q (2004) Phosphatase of regenerating liver-3 promotes motility and metastasis of mouse melanoma cells. Am J Pathol 164:2039–2054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Radke I, Götte M, Kersting C, Mattsson B, Kiesel L, Wülfing P (2006) Expression and prognostic impact of the protein tyrosine phosphatases PRL-1, PRL-2, and PRL-3 in breast cancer. Br J Cancer 95:347–354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hao RT, Zhang XH, Pan YF, Liu HG, Xiang YQ, Wan L, Wu XL (2010) Prognostic and metastatic value of phosphatase of regenerating liver-3 in invasive breast cancer. J Cancer Res Clin Oncol 136:1349–1357

    Article  CAS  PubMed  Google Scholar 

  21. Wang L, Peng L, Dong B, Kong L, Meng L, Yan L, Xie Y, Shou C (2006) Overexpression of phosphatase of regenerating liver-3 in breast cancer: association with a poor clinical outcome. Ann Oncol 17:1517–1522

    Article  CAS  PubMed  Google Scholar 

  22. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  23. Viola M, Brüggemann K, Karousou E, Caon I, Caravà E, Vigetti D, Greve B, Stock C, De Luca G, Passi A, Götte M (2017) MDA-MB-231 breast cancer cell viability, motility and matrix adhesion are regulated by a complex interplay of heparan sulfate, chondroitin-/dermatan sulfate and hyaluronan biosynthesis. Glycoconj J 34:411–420

    Article  CAS  PubMed  Google Scholar 

  24. Ustaalioglu BB, Bilici A, Barisik NO, Aliustaoglu M, Vardar FA, Yilmaz BE, Seker M, Gumus M (2012) Clinical importance of phosphatase of regenerating liver-3 expression in breast cancer. Clin Transl Oncol 14:911–922

    Article  CAS  PubMed  Google Scholar 

  25. Rouleau C, Roy A, St Martin T, Dufault MR, Boutin P, Liu D, Zhang M, Puorro-Radzwill K, Rulli L, Reczek D, Bagley R, Byrne A, Weber W, Roberts B, Klinger K, Brondyk W, Nacht M, Madden S, Burrier R, Shankara S, Teicher BA (2006) Protein tyrosine phosphatase PRL-3 in malignant cells and endothelial cells: expression and function. Mol Cancer Ther 5:219–229

    Article  CAS  PubMed  Google Scholar 

  26. Cailleau R, Young R, Olive M, Reeves WJJ (1974) Breast tumor cell lines from pleural effusions. J Natl Cancer Inst 53:661–674

    Article  CAS  PubMed  Google Scholar 

  27. Soule HD, Vazguez J, Long A, Albert S, Brennan M (1973) A human cell line from a pleural effusion derived from a breast carcinoma. J Natl Cancer Inst 51:1409–1416

    Article  CAS  PubMed  Google Scholar 

  28. Qian F, Li YP, Sheng X, Zhang ZC, Song R, Dong W, Cao SX, Hua ZC, Xu Q (2007) PRL-3 siRNA inhibits the metastasis of B16-BL6 mouse melanoma cells in vitro and in vivo. Mol Med 13:151–159

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Dong Q, Ding X, Chang B, Wang H, Wang A (2016) PRL-3 promotes migration and invasion and is associated with poor prognosis in salivary adenoid cystic carcinoma. J Oral Pathol Med 45:111–118

    Article  CAS  PubMed  Google Scholar 

  30. Li Z, Zhan W, Wang Z, Zhu B, He Y, Peng J, Cai S, Ma J (2006) Inhibition of PRL-3 gene expression in gastric cancer cell line SGC7901 via microRNA suppressed reduces peritoneal metastasis. Biochem Biophys Res Commun 348:229–237

    Article  CAS  PubMed  Google Scholar 

  31. Cohen I, Pappo O, Elkin M, San T, Bar-Shavit R, Hazan R, Peretz T, Vlodavsky I, Abramovitch R (2006) Heparanase promotes growth, angiogenesis and survival of primary breast tumors. Int J Cancer 118:1609–1617

    Article  CAS  PubMed  Google Scholar 

  32. Götte M, Yip GW (2006) Heparanase, hyaluronan, and CD44 in cancers: a breast carcinoma perspective. Cancer Res 66:10233–10237

    Article  PubMed  Google Scholar 

  33. Maxhimer JB, Quiros RM, Stewart R, Dowlatshahi K, Gattuso P, Fan M, Prinz RA, Xu X (2002) Heparanase-1 expression is associated with the metastatic potential of breast cancer. Surgery. 132:326–333

    Article  PubMed  Google Scholar 

  34. Gari HH, DeGala GD, Ray R, Lucia MS, Lambert JR (2016) PRL-3 engages the focal adhesion pathway in triple-negative breast cancer cells to alter actin structure and substrate adhesion properties critical for cell migration and invasion. Cancer Lett 380:505–512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Peng L, Xing X, Li W, Qu L, Meng L, Lian S, Jiang B, Wu J, Shou C (2009) PRL-3 promotes the motility, invasion, and metastasis of LoVo colon cancer cells through PRL-3-integrin beta1-ERK1/2 and-MMP2 signaling. Mol Cancer. 8:110

    Article  PubMed  PubMed Central  Google Scholar 

  36. Götte M, Kersting C, Radke I, Kiesel L, Wülfing P (2007) An expression signature of syndecan-1 (CD138), E-cadherin and c-met is associated with factors of angiogenesis and lymphangiogenesis in ductal breast carcinoma in situ. Breast Cancer Res 9:R8

    Article  PubMed  PubMed Central  Google Scholar 

  37. Liu Y, Zhou J, Chen J, Gao W, Le Y, Ding Y, Li J (2009) PRL-3 promotes epithelial mesenchymal transition by regulating cadherin directly. Cancer Biol Ther 8:1352–1359

    Article  CAS  PubMed  Google Scholar 

  38. Kim SH, Kim Y, Kim M, Kim DS, Lee SC, Chi SW, Lee DH, Park SG, Park BC, Bae KH, Kang S (2009) Comparative proteomic analysis of mouse melanoma cell line B16, a metastatic descendant B16F10, and B16 overexpressing the metastasis-associated tyrosine phosphatase PRL-3. Oncol Res 17:601–612

    Article  PubMed  Google Scholar 

  39. Basak S, Jacobs SB, Krieg AJ, Pathak N, Zeng Q, Kaldis P, Giaccia AJ, Attardi LD (2008) The metastasis-associated gene Prl-3 is a p53 target involved in cell-cycle regulation. Mol Cell 30:303–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fiordalisi JJ, Keller PJ, Cox AD (2006) PRL tyrosine phosphatases regulate rho family GTPases to promote invasion and motility. Cancer Res 66:3153–3161

    Article  CAS  PubMed  Google Scholar 

  41. Peng L, Jin G, Wang L, Guo J, Meng L, Shou C (2006) Identification of integrin alpha1 as an interacting protein of protein tyrosine phosphatase PRL-3. Biochem Biophys Res Commun 342:179–183

    Article  CAS  PubMed  Google Scholar 

  42. Wang H, Quah SY, Dong JM, Manser E, Tang JP, Zeng Q (2007) PRL-3 down-regulates PTEN expression and signals through PI3K to promote epithelial-mesenchymal transition. Cancer Res 67:2922–2926

    Article  CAS  PubMed  Google Scholar 

  43. Lv J, Liu C, Huang H, Meng L, Jiang B, Cao Y, Zhou Z, She T, Qu L, Wei Song S, Shou C (2013) Suppression of breast tumor growth by DNA vaccination against phosphatase of regenerating liver 3. Gene Ther 20:834–845

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Birgit Pers for excellent technical assistance. This work was supported by the fund “Innovative Medical Research” of the University of Muenster Medical School (WÜ 110527).

Author information

Authors and Affiliations

Authors

Contributions

IR: manuscript writing, data interpretation, project development and design; MG: data interpretation, project development and design, supervision, manuscript editing; MS: data collection and interpretation, supervision, manuscript editing; NS: data collection and interpretation; LK: supervision and manuscript editing; PW: project development and design; supervision; manuscript editing.

Corresponding author

Correspondence to Isabel Radke.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Funding

This work was supported by the fund “Innovative Medical Research” of the University of Muenster Medical School (WÜ 110527).

Ethical approval

For this type of study (in vitro study on established cell lines) formal consent is not required. This article does not contain any studies with animals or patient samples.

Informed consent

Not applicable.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Radke, I., Götte, M., Smollich, M. et al. Expression of PRL-3 regulates proliferation and invasion of breast cancer cells in vitro. Arch Gynecol Obstet 296, 1153–1160 (2017). https://doi.org/10.1007/s00404-017-4542-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00404-017-4542-2

Keywords

Navigation