Skip to main content

Advertisement

SpringerLink
Log in

Estrogen stimulates the proliferation of human endometrial cancer cells by stabilizing nucleophosmin/B23 (NPM/B23)

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Unopposed estrogen exposure is an important factor in the tumorigenesis of endometrial cancer. Nucleophosmin/B23 (NPM/B23), a phosphoprotein that has pleiotropic functions in cells, plays an important role in various cancers. However, the regulatory role of NPM/B23 in estrogen signaling in endometrial cancer has not been explored. Here, we report that NPM/B23 was required for estrogen-induced endometrial proliferation, and the increase in NPM/B23 was estrogen receptor α-dependent. Furthermore, estrogen increased NPM/B23 protein levels by repressing its ubiquitination and subsequently stabilizing the protein. The overexpression of the alternate reading frame (ARF) suppressed the estrogen-induced increase in the NPM/B23 protein levels, indicating that ARF inhibited the observed estrogen-mediated NPM/B23 stabilization. Our results suggest that one of the effects of estrogen on endometrial proliferation is the suppression of the NPM/B23–ARF interaction and the subsequent increase in NPM/B23 protein levels. This novel characterization of NPM/B23 in estrogen-mediated cell proliferation may extend our understanding of the tumorigenesis of steroid hormone-related cancers.

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
Fig. 6

Similar content being viewed by others

References

  1. Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108

    Article  PubMed  Google Scholar 

  2. Cancer Registry Annual Report, 2008 Taiwan. http://www.bhp.doh.gov.tw/BHPnet/Portal/StatisticsShow.aspx?No=200911300001

  3. Hacker NF, Friedlander M (2009) Uterine cancer. In: Berek JS, Hacker NF (ed) Berek and Hacker’s gynecologic oncology, 5th edn. Lippincott Williams & Wilkins, Philadelphia, pp 895

  4. Gross JM, Yee D (2002) How does the estrogen receptor work? Breast canc res 4:62–64

    Article  CAS  Google Scholar 

  5. Lim MJ, Wang XW (2006) Nucleophosmin and human cancer. Canc Detect Prev 30:481–490

    Article  CAS  Google Scholar 

  6. Okuwaki M (2008) The structure and functions of NPM1/nucleophosmin/B23, a multifunctional nucleolar acidic protein. J Biochem 143:441–448

    Article  PubMed  CAS  Google Scholar 

  7. Hsu CY, Yung BY (1998) Down-regulation of nucleophosmin/B23 during retinoic acid-induced differentiation of human promyelocytic leukemia HL-60 cells. Oncogene 16:915–923

    Article  PubMed  CAS  Google Scholar 

  8. Okuda M (2002) The role of nucleophosmin in centrosome duplication. Oncogene 21:6170–6174

    Article  PubMed  CAS  Google Scholar 

  9. Wu MH, Chang JH, Yung BY (2002) Resistance to UV-induced cell-killing in nucleophosmin/B23 over-expressed NIH 3T3 fibroblasts: enhancement of DNA repair and up-regulation of PCNA in association with nucleophosmin/B23 over-expression. Carcinogenesis 23:93–100

    Article  PubMed  Google Scholar 

  10. Li J, Zhang X, Sejas DP, Bagby GC, Pang Q (2004) Hypoxia-induced nucleophosmin protects cell death through inhibition of p53. J Biol Chem 279:41275–41279

    Article  PubMed  CAS  Google Scholar 

  11. Lin CY, Liang YC, Yung BY (2006) Nucleophosmin/B23 regulates transcriptional activation of E2F1 via modulating the promoter binding of NF-kappaB, E2F1 and pRB. Cell Signal 18:2041–2048

    Article  PubMed  CAS  Google Scholar 

  12. Shields LB, Gercel-Taylor C, Yashar CM, Wan TC, Katsanis WA, Spinnato JA, Taylor DD (1997) Induction of immune responses to ovarian tumor antigens by multiparity. J Soc Gynecol Investig 4:298–304

    Article  PubMed  CAS  Google Scholar 

  13. Pianta A, Puppin C, Franzoni A, Fabbro D, Di Loreto C, Bulotta S, Deganuto M, Paron I, Tell G, Puxeddu E et al (2010) Nucleophosmin is overexpressed in thyroid tumors. Biochem Biophys Res Commun 397:499–504

    Article  PubMed  CAS  Google Scholar 

  14. Tanaka M, Sasaki H, Kino I, Sugimura T, Terada M (1992) Genes preferentially expressed in embryo stomach are predominantly expressed in gastric cancer. Cancer Res 52:3372–3377

    PubMed  CAS  Google Scholar 

  15. Nozawa Y, Van Belzen N, Van der Made AC, Dinjens WN, Bosman FT (1996) Expression of nucleophosmin/B23 in normal and neoplastic colorectal mucosa. J Pathol 178:48–52

    Article  PubMed  CAS  Google Scholar 

  16. Subong EN, Shue MJ, Epstein JI, Briggman JV, Chan PK, Partin AW (1999) Monoclonal antibody to prostate cancer nuclear matrix protein (PRO:4-216) recognizes nucleophosmin/B23. Prostate 39:298–304

    Article  PubMed  CAS  Google Scholar 

  17. Tsui KH, Cheng AJ, Chang PL, Pan TL, Yung BY (2004) Association of nucleophosmin/B23 mRNA expression with clinical outcome in patients with bladder carcinoma. Urology 64:839–844

    Article  PubMed  Google Scholar 

  18. Itahana K, Bhat KP, Jin A, Itahana Y, Hawke D, Kobayashi R, Zhang Y (2003) Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation. Mol Cell 12:1151–1164

    Article  PubMed  CAS  Google Scholar 

  19. Colombo E, Bonetti P, Lazzerini Denchi E, Martinelli P, Zamponi R, Marine JC, Helin K, Falini B, Pelicci PG (2005) Nucleophosmin is required for DNA integrity and p19Arf protein stability. Mol Cell Biol 25:8874–8886

    Article  PubMed  CAS  Google Scholar 

  20. Lin CY, Tan BC, Liu H, Shih CJ, Chien KY, Lin CL, Yung BY (2010) Dephosphorylation of nucleophosmin by PP1beta facilitates pRB binding and consequent E2F1-dependent DNA repair. Mol Biol Cell 21:4409–4417

    Article  PubMed  CAS  Google Scholar 

  21. Skaar TC, Prasad SC, Sharareh S, Lippman ME, Brunner N, Clarke R (1998) Two-dimensional gel electrophoresis analyses identify nucleophosmin as an estrogen regulated protein associated with acquired estrogen-independence in human breast cancer cells. J Steroid Biochem Mol Biol 67:391–402

    Article  PubMed  CAS  Google Scholar 

  22. Zhu Y, Singh B, Hewitt S, Liu A, Gomez B, Wang A, Clarke R (2006) Expression patterns among interferon regulatory factor-1, human X-box binding protein-1, nuclear factor kappa B, nucleophosmin, estrogen receptor-alpha and progesterone receptor proteins in breast cancer tissue microarrays. Int J Oncol 28:67–76

    PubMed  CAS  Google Scholar 

  23. Chao A, Tsai CL, Wei PC, Hsueh S, Chao AS, Wang CJ, Tsai CN, Lee YS, Wang TH, Lai CH (2010) Decreased expression of microRNA-199b increases protein levels of SET (protein phosphatase 2A inhibitor) in human choriocarcinoma. Cancer Lett 291:99–107

    Article  PubMed  CAS  Google Scholar 

  24. Chao A, Lin CY, Lee YS, Tsai CL, Wei PC, Hsueh S, Wu TI, Tsai CN, Wang CJ, Chao AS et al (2012) Regulation of ovarian cancer progression by microRNA-187 through targeting disabled homolog-2. Oncogene 31:764–775

    Article  PubMed  CAS  Google Scholar 

  25. Wang TH, Chao A, Tsai CL, Chang CL, Chen SH, Lee YS, Chen JK, Lin YJ, Chang PY, Wang CJ et al (2010) Stress-induced phosphoprotein 1 as a secreted biomarker for human ovarian cancer promotes cancer cell proliferation. Mol Cell Proteomics 9:1873–1884

    Article  PubMed  CAS  Google Scholar 

  26. Nishida M (2002) The Ishikawa cells from birth to the present. Hum Cell 15:104–117

    Article  PubMed  Google Scholar 

  27. El-Sahwi K, Bellone S, Cocco E, Cargnelutti M, Casagrande F, Bellone M, Abu-Khalaf M, Buza N, Tavassoli FA, Hui P et al (2010) In vitro activity of pertuzumab in combination with trastuzumab in uterine serous papillary adenocarcinoma. Br J Cancer 102:134–143

    Google Scholar 

  28. Chi XZ, Kim J, Lee YH, Lee JW, Lee KS, Wee H, Kim WJ, Park WY, Oh BC, Stein GS et al (2009) Runt-related transcription factor RUNX3 is a target of MDM2-mediated ubiquitination. Cancer Res 69:8111–8119

    Article  PubMed  CAS  Google Scholar 

  29. Grisendi S, Mecucci C, Falini B, Pandolfi PP (2006) Nucleophosmin and cancer. Nat Rev Cancer 6:493–505

    Article  PubMed  CAS  Google Scholar 

  30. Yeh CW, Huang SS, Lee RP, Yung BY (2006) Ras-dependent recruitment of c-Myc for transcriptional activation of nucleophosmin/B23 in highly malignant U1 bladder cancer cells. Mol Pharmacol 70:1443–1453

    Article  PubMed  CAS  Google Scholar 

  31. Tawfic S, Olson MO, Ahmed K (1995) Role of protein phosphorylation in post-translational regulation of protein B23 during programmed cell death in the prostate gland. J Biol Chem 270:21009–21015

    Article  PubMed  CAS  Google Scholar 

  32. Chan PK (1992) Characterization and cellular localization of nucleophosmin/B23 in HeLa cells treated with selected cytotoxic agents (studies of B23-translocation mechanism). Exp Cell Res 203:174–181

    Article  PubMed  CAS  Google Scholar 

  33. Enomoto T, Lindstrom MS, Jin A, Ke H, Zhang Y (2006) Essential role of the B23/NPM core domain in regulating ARF binding and B23 stability. J Biol Chem 281:18463–18472

    Article  PubMed  CAS  Google Scholar 

  34. Liu X, Liu Z, Jang SW, Ma Z, Shinmura K, Kang S, Dong S, Chen J, Fukasawa K, Ye K (2007) Sumoylation of nucleophosmin/B23 regulates its subcellular localization, mediating cell proliferation and survival. Proc Natl Acad Sci U S A 104:9679–9684

    Article  PubMed  CAS  Google Scholar 

  35. Tago K, Chiocca S, Sherr CJ (2005) Sumoylation induced by the Arf tumor suppressor: a p53-independent function. Proc Natl Acad Sci U S A 102:7689–7694

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the Chang Gung Medical Research Foundation (CMRPG390202) and the Department of Health (DOH99-TD-B-111-005; DOH99-TD-C-111-006).

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Linkou Medical Center, 5 Fushin Street, Guishan, Taoyuan, 333, Taiwan

    Angel Chao, Chiao-Yun Lin, Chia-Lung Tsai, Ying-Yu Lin, Cheng-Tao Lin, Hung-Hsueh Chou, Tzu-Hao Wang, Chyong-Huey Lai & Hsin-Shih Wang

  2. Department of Clinical Pathology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan

    Swei Hsueh

  3. Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Tzu-Hao Wang

Authors
  1. Angel Chao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chiao-Yun Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chia-Lung Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Swei Hsueh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ying-Yu Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cheng-Tao Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hung-Hsueh Chou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tzu-Hao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chyong-Huey Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hsin-Shih Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Angel Chao, Chyong-Huey Lai or Hsin-Shih Wang.

Additional information

Angel Chao and Chiao-Yun Lin contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 460 kb)

ESM 2

(PDF 34 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chao, A., Lin, CY., Tsai, CL. et al. Estrogen stimulates the proliferation of human endometrial cancer cells by stabilizing nucleophosmin/B23 (NPM/B23). J Mol Med 91, 249–259 (2013). https://doi.org/10.1007/s00109-012-0950-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-012-0950-8

Keywords

Search

Navigation