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.

  • Article
  • Published:

PAX8 activates a p53-p21-dependent pro-proliferative effect in high grade serous ovarian carcinoma

Oncogene volume 37, pages 2213–2224 (2018)Cite this article

Subjects

Abstract

High grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer and it is now widely accepted that this disease often originates from the fallopian tube epithelium. PAX8 is a fallopian tube lineage marker with an essential role in embryonal female genital tract development. In the adult fallopian tube, PAX8 is expressed in the fallopian tube secretory epithelial cell (FTSEC) and its expression is maintained through the process of FTSEC transformation to HGSC. We now report that PAX8 has a pro-proliferative and anti-apoptotic role in HGSC. The tumor suppressor gene TP53 is mutated in close to 100% of HGSC; in the majority of cases, these are missense mutations that endow the mutant p53 protein with potential gain of function (GOF) oncogenic activities. We show that PAX8 positively regulates the expression of TP53 in HGSC and the pro-proliferative role of PAX8 is mediated by the GOF activity of mutant p53. Surprisingly, mutant p53 transcriptionally activates the expression of p21, which localizes to the cytoplasm of HGSC cells where it plays a non-canonical, pro-proliferative role. Together, our findings illustrate how TP53 mutations in HGSC subvert a normal regulatory pathway into a driver of tumor progression.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Piek JM, van Diest PJ, Zweemer RP, Jansen JW, Poort-Keesom RJ, Menko FH, et al. Dysplastic changes in prophylactically removed fallopian tubes of women predisposed to developing ovarian cancer. J Pathol. 2001;195:451–6.

    Article  CAS  Google Scholar 

  2. Medeiros F, Muto MG, Lee Y, Elvin JA, Callahan MJ, Feltmate C, et al. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol. 2006;30:230–6.

    Article  Google Scholar 

  3. Perets R, Drapkin R. It’s totally tubular….riding the new wave of ovarian cancer research. Cancer Res. 2015;76:10–7.

    Article  Google Scholar 

  4. Bowen NJ, Logani S, Dickerson EB, Kapa LB, Akhtar M, Benigno BB, et al. Emerging roles for PAX8 in ovarian cancer and endosalpingeal development. Gynecol Oncol. 2007;104:331–7.

    Article  CAS  Google Scholar 

  5. Chi N, Epstein JA. Getting your Pax straight: Pax proteins in development and disease. Trends Genet. 2002;18:41–7.

    Article  CAS  Google Scholar 

  6. Mansouri A, Chowdhury K, Gruss P. Follicular cells of the thyroid gland require Pax8 gene function. Nat Genet. 1998;19:87–90.

    Article  CAS  Google Scholar 

  7. Mittag J, Winterhager E, Bauer K, Grummer R, Congenital hypothyroid female pax8-deficient mice are infertile despite thyroid hormone replacement therapy. Endocrinology. 2007;148:719–25.

    Article  CAS  Google Scholar 

  8. Laury AR, Hornick JL, Perets R, Krane JF, Corson J, Drapkin R, et al. PAX8 reliably distinguishes ovarian serous tumors from malignant mesothelioma. Am J Surg Pathol. 2010;34:627–35.

    PubMed  Google Scholar 

  9. Laury AR, Perets R, Piao H, Krane JF, Barletta JA, French C, et al. A comprehensive analysis of PAX8 expression in human epithelial tumors. Am J Surg Pathol. 2011;35:816–26.

    Article  Google Scholar 

  10. Nonaka D, Chiriboga L, Soslow RA. Expression of pax8 as a useful marker in distinguishing ovarian carcinomas from mammary carcinomas. Am J Surg Pathol. 2008;32:1566–71.

    Article  Google Scholar 

  11. Li CG, Nyman JE, Braithwaite AW, Eccles MR, PAX8 promotes tumor cell growth by transcriptionally regulating E2F1 and stabilizing RB protein. Oncogene. 2011;30:4824–34.

    Article  CAS  Google Scholar 

  12. Rodgers LH, Ó hAinmhire E, Young AN, Burdette JE, Loss of PAX8 in high-grade serous ovarian cancer reduces cell survival despite unique modes of action in the fallopian tube and ovarian surface epithelium. Oncotarget. 2016;7:32785–95.

    Article  Google Scholar 

  13. Elias KM, Emori MM, Westerling T, Long H, Budina-Kolomets A, Li F, et al. Epigenetic remodeling regulates transcriptional changes between ovarian cancer and benign precursors. JCI insight. 2016;1:e87988.

  14. Kar SP, Adler E, Tyrer J, Hazelett D, Anton-Culver H, Bandera EV, et al. Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci. Br J Cancer. 2017;116:524–35. http://www.ncbi.nlm.nih.gov/pubmed/28103614. Accessed 14 Feb 2017.

    Article  CAS  Google Scholar 

  15. Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, Saleemuddin A, et al. A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol. 2007;211:26–35.

    Article  CAS  Google Scholar 

  16. Ahmed AA, Etemadmoghadam D, Temple J, Lynch AG, Riad M, Sharma R, et al. Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary. J Pathol. 2010;221:49–56.

    Article  CAS  Google Scholar 

  17. TCGA. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609–15..

  18. Perets R, Wyant G, Muto K, Bijron J, Poole B, Chin K, et al. Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in Brca;Tp53;Pten Models. Cancer Cell. 2013;24:751–65.

    Article  CAS  Google Scholar 

  19. Carcangiu ML, Radice P, Manoukian S, Spatti G, Gobbo M, Pensotti V, et al. Atypical epithelial proliferation in fallopian tubes in prophylactic salpingo-oophorectomy specimens from BRCA1 and BRCA2 germline mutation carriers. Int J Gynecol Pathol. 2004;23:35–40.

    Article  Google Scholar 

  20. Bijron JG, Seldenrijk CA, Zweemer RP, Lange JG, Verheijen RHM, van Diest PJ. Fallopian tube intraluminal tumor spread from noninvasive precursor lesions: a novel metastatic route in early pelvic carcinogenesis. Am J Surg Pathol. 2013;37:1123–30.

    Article  Google Scholar 

  21. Bieging KT, Attardi LD, Brady CA, Attardi LD, Vousden KH, Prives C, et al. Deconstructing p53 transcriptional networks in tumor suppression. Trends Cell Biol. 2012;22:97–106.

    Article  CAS  Google Scholar 

  22. Olive KP, Tuveson DA, Ruhe ZC, Yin B, Willis NA, Bronson RT, et al. Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell. 2004;119:847–60.

    Article  CAS  Google Scholar 

  23. Brachova P, Thiel KW, Leslie KK. The consequence of oncomorphic TP53 mutations in ovarian cancer. Int J Mol Sci. 2013;14:19257–75.

    Article  Google Scholar 

  24. Quartuccio SM, Karthikeyan S, Eddie SL, Lantvit DD, Ó hAinmhire E, Modi DA, et al. Mutant p53 expression in fallopian tube epithelium drives cell migration. Int J Cancer. 2015;137:1528–38.

    Article  CAS  Google Scholar 

  25. Iwanicki MP, Chen H-Y, Iavarone C, Zervantonakis IK, Muranen T, Novak M, et al. Mutant p53 regulates ovarian cancer transformed phenotypes through autocrine matrix deposition. JCI insight. 2016;1:e86829.

  26. Stuart ET, Haffner R, Oren M, Gruss P. Loss of p53 function through PAX-mediated transcriptional repression. EMBO J. 1995;14:5638–45.

    Article  CAS  Google Scholar 

  27. Li X, Cheung KF, Ma X, Tian L, Zhao J, Go MYY, et al. Epigenetic inactivation of paired box gene 5, a novel tumor suppressor gene, through direct upregulation of p53 is associated with prognosis in gastric cancer patients. Oncogene. 2012;31:3419–30.

    Article  CAS  Google Scholar 

  28. El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, et al. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993;75:817–25.

    Article  CAS  Google Scholar 

  29. Mhawech-Fauceglia P, Wang D, Samrao D, Godoy H, Ough F, Liu S, et al. Pair Box 8 (PAX8) protein expression in high grade, late stage (stages III and IV) ovarian serous carcinoma. Gynecol Oncol. 2012;127:198–201.

    Article  CAS  Google Scholar 

  30. Ordonez NG. Value of PAX 8 immunostaining in tumor diagnosis: a review and update. Adv Anat Pathol. 2012;19:140–51.

    Article  CAS  Google Scholar 

  31. Domcke S, Sinha R, Levine DA, Sander C, Schultz N. Evaluating cell lines as tumour models by comparison of genomic profiles. Nat Commun. 2013;4:2126.

    Article  Google Scholar 

  32. Cheung HW, Cowley GS, Weir BA, Boehm JS, Rusin S, Scott JA, et al. Systematic investigation of genetic vulnerabilities across cancer cell lines reveals lineage-specific dependencies in ovarian cancer. Proc Natl Acad Sci USA. 2011;108:12372–7.

    Article  CAS  Google Scholar 

  33. Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483:603–7.

    Article  CAS  Google Scholar 

  34. Yaginuma Y, Westphal H. Abnormal structure and expression of the p53 gene in human ovarian carcinoma cell lines. Cancer Res. 1992;52:4196–9.

    CAS  PubMed  Google Scholar 

  35. Hua G, Lv X, He C, Remmenga SW, Rodabough KJ, Dong J, et al. YAP induces high-grade serous carcinoma in fallopian tube secretory epithelial cells. Oncogene. 2016;35:2247

    Article  CAS  Google Scholar 

  36. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993;75:805–16.

    Article  CAS  Google Scholar 

  37. Satyanarayana A, Hilton MB, Kaldis P. p21 inhibits Cdk1 in the absence of Cdk2 to maintain the G1/S phase DNA damage checkpoint. Mol Biol Cell. 2008;19:65–77.

    Article  CAS  Google Scholar 

  38. Cayrol C, Knibiehler M, Ducommun B. p21 binding to PCNA causes G1 and G2 cell cycle arrest in p53-deficient cells. Oncogene. 1998;16:311–20.

    Article  CAS  Google Scholar 

  39. Abbas T, Dutta A, p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 2009;9:400–14.

    Article  CAS  Google Scholar 

  40. Zhou BP, Liao Y, Xia W, Spohn B, Lee MH, Hung MC. Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol. 2001;3:245–52.

    Article  CAS  Google Scholar 

  41. Asada M, Yamada T, Ichijo H, Delia D, Miyazono K, Fukumuro K, et al. Apoptosis inhibitory activity of cytoplasmicp21(Cip1/WAF1) in monocytic differentiation. EMBO J. 1999;18:1223–34.

    Article  CAS  Google Scholar 

  42. Lee S, Helfman DM. Cytoplasmic p21Cip1 is involved in Ras-induced inhibition of the ROCK/LIMK/cofilin pathway. J Biol Chem. 2004;279:1885–91.

    Article  CAS  Google Scholar 

  43. Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2016;36:1461–73.

    Article  Google Scholar 

  44. Oren O, Smith BD. Eliminating cancer stem cells by targeting embryonic signaling pathways. Stem Cell Rev. 2016;13:17–23.

    Article  Google Scholar 

  45. Chan DW, Hui WWY, Wang JJ, Yung MMH, Hui LMN, Qin Y, et al. DLX1 acts as a crucial target of FOXM1 to promote ovarian cancer aggressiveness by enhancing TGF-β/SMAD4 signaling. Oncogene. 2016;36:1404–16.

    Article  Google Scholar 

  46. Blake JA, Ziman MR.Pax genes: regulators of lineage specification and progenitor cell maintenance. Development. 2014;141:737–51.

    Article  CAS  Google Scholar 

  47. Wistuba J, Mittag J, Luetjens CM, Cooper TG, Yeung C-H, Nieschlag E, et al. Male congenital hypothyroid Pax8-/- mice are infertile despite adequate treatment with thyroid hormone. J Endocrinol. 2007;192:99–109.

    Article  CAS  Google Scholar 

  48. Tung CS, Mok SC, Tsang YTM, Zu Z, Song H, Liu J, et al. PAX2 expression in low malignant potential ovarian tumors and low-grade ovarian serous carcinomas. Mod Pathol. 2009;22:1243–50.

    Article  CAS  Google Scholar 

  49. Al-Hujaily EM, Tang Y, Yao D-S, Carmona E, Garson K, Vanderhyden BC Divergent roles of PAX2 in the etiology and progression of ovarian cancer. Cancer Prev Res. 2015;8:1163–73.

    Article  CAS  Google Scholar 

  50. Shah S, Schrader KA, Waanders E, Timms AE, Vijai J, Miething C, et al. A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia. Nat Genet. 2013;45:1226–31.

    Article  CAS  Google Scholar 

  51. Liu W, Li X, Chu ESH, Go MYY, Xu L, Zhao G, et al. Paired box gene 5 is a novel tumor suppressor in hepatocellular carcinoma through interaction with p53 signaling pathway. Hepatology. 2011;53:843–53.

    Article  CAS  Google Scholar 

  52. Au AY, McBride C, Wilhelm KG,Jr, Koenig RJ, Speller B, Cheung L, et al. PAX8-peroxisome proliferator-activated receptor gamma (PPARgamma) disrupts normal PAX8 or PPARgamma transcriptional function and stimulates follicular thyroid cell growth. Endocrinology. 2006;147:367–76.

    Article  CAS  Google Scholar 

  53. Tong GX, Devaraj K, Hamele-Bena D, Yu WM, Turk A, Chen X. et al. Pax8: a marker of carcinoma of Müllerian origin in serous effusions. Diagn Cytopathol. 2011;39:567–74.

    Article  Google Scholar 

  54. Bass AJ, Thorsson V, Shmulevich I, Reynolds SM, Miller M, Bernard B, et al. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–9.

    Article  Google Scholar 

  55. Chang K, Creighton CJ, Davis C, Donehower L, Drummond J, Wheeler D, et al. The cancer genome atlas pan-cancer analysis project. Nat Genet. 2013;45:1113–20.

    Article  CAS  Google Scholar 

  56. Doberstein K, Wieland A, Lee SBB, Blaheta RAA, Wedel S, Moch H, et al. L1-CAM expression in ccRCC correlates with shorter patients survival times and confers chemoresistance in renal cell carcinoma cells. Carcinogenesis. 2011;32:262–70. http://www.ncbi.nlm.nih.gov/pubmed/21097529. Accessed 1 Mar 2011.

    Article  Google Scholar 

  57. Rowan S, Ludwig RL, Haupt Y, Bates S, Lu X, Oren M, et al. Specific loss of apoptotic but not cell-cycle arrest function in a human tumor derived p53 mutant. EMBO J. 1996;15:827–38.

    Article  CAS  Google Scholar 

  58. Xia X, Ji T, Liu R, Weng Y, Fang Y, Wang Z, et al. Cytoplasmic p21 is responsible for paclitaxel resistance in ovarian cancer A2780 cells. Eur J Gynaecol Oncol. 2015;36:662–6.

    CAS  PubMed  Google Scholar 

  59. Perets R, Kaplan T, Stein I, Hidas G, Tayeb S, Avraham E, et al. Genome-wide analysis of androgen receptor targets reveals COUP-TF1 as a novel player in human prostate cancer. PLoS ONE. 2012;7:e46467.

    Article  CAS  Google Scholar 

  60. Blecher-Gonen R, Barnett-Itzhaki Z, Jaitin D, Amann-Zalcenstein D, Lara-Astiaso D, Amit I. High-throughput chromatin immunoprecipitation for genome-wide mapping of in vivo protein-DNA interactions and epigenomic states. Nat Protoc. 2013;8:539–54.

    Article  Google Scholar 

Download references

Acknowledgements

The work presented here was funded by The Israel Science Foundation (1901/13), Israel Cancer Research Fund, The European Commission (PCIG13-GA-2013-618174), Israel Cancer Association (20150894, 20170117), The women’s health grant at Rambam (all to R.P.), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to M.O.), Israel Science Foundation (822/12) (to S.L.), The Hymen Milgrom Trust (to S.L.). We would like to thank Prof. Ronny Drapkin (University of Pennsylvania) for FT237 immortalized FTSEC line and Prof. Reuven Agami (AVL, Nederland Cancer Institute) for retroviral p21 shRNA construct.

Author information

Author notes

  1. Dima Ghannam-Shahbari and Eyal Jacob contributed equally to this work.

Authors and Affiliations

  1. Clinical Research Institute at Rambam, Division of Oncology, Rambam Health Care Campus, Technion—Israel Institute of Technology, Haifa, Israel

    Dima Ghannam-Shahbari, Eyal Jacob, Reli Rachel Kakun, Tanya Wasserman, Lina Korsensky, Ofir Sternfeld & Ruth Perets

  2. Cell Death Research Laboratory, Department of Biology, Faculty of Sciences, University of Haifa, Mount Carmel, Haifa, Israel

    Juliana Kagan & Sarit Larisch

  3. Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel

    Debora Rosa Bublik & Moshe Oren

  4. Department of Pathology, The Talpiot Medical Leadership Program, Sheba Medical Center, Ramat Gan, Israel

    Sarit Aviel-Ronen

  5. Sheba Cancer Research Center, The Talpiot Medical Leadership Program, Sheba Medical Center, Ramat Gan, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel

    Keren Levanon

  6. Department of Pathology, Rambam Health Care Campus, Technion—Israel Institute of Technology, Haifa, Israel

    Edmond Sabo

  7. Department of Pathology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel

    Dov Hershkovitz

Authors
  1. Dima Ghannam-Shahbari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eyal Jacob
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Reli Rachel Kakun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tanya Wasserman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lina Korsensky
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ofir Sternfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Juliana Kagan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Debora Rosa Bublik
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sarit Aviel-Ronen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Keren Levanon
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Edmond Sabo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Sarit Larisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Moshe Oren
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Dov Hershkovitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ruth Perets
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ruth Perets.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ghannam-Shahbari, D., Jacob, E., Kakun, R.R. et al. PAX8 activates a p53-p21-dependent pro-proliferative effect in high grade serous ovarian carcinoma. Oncogene 37, 2213–2224 (2018). https://doi.org/10.1038/s41388-017-0040-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-017-0040-z

This article is cited by

Search

Advanced search

Quick links