Skip to main content
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 2002 May;93(5):542–550. doi: 10.1111/j.1349-7006.2002.tb01289.x

Increased MCL–1 Expression Is Associated with Poor Prognosis in Ovarian Carcinomas

Kazushi Shigemasa 1,, Osamu Katoh 3, Yuko Shiroyama 1, Shoji Mihara 2, Keiji Mukai 1, Nobutaka Nagai 1, Koso Ohama 1
PMCID: PMC5927039  PMID: 12036450

Abstract

To investigate the potential role of the BCL–2 gene family (BAX, BCL–2, MCL–1, and BCL‐XL) in ovarian cancer development and progression, mRNA expression levels of these genes were measured using semi‐quantitative PCR in epithelial ovarian tumor tissues and normal ovaries. The immunohistochemical expression of MCL–1 in ovarian tumors was also examined. The expression levels of BAX and MCL–1 mRNA were significantly higher in ovarian cancers and in adenomas than in normal ovaries (P<0.05). In contrast, the BCL–2 mRNA expression level in ovarian cancers was significantly lower than in ovarian adenomas and in normal ovaries (P<0.05). Expression of BCL‐XL mRNA was no different between normal ovaries and ovarian tumors. Log‐rank testing showed that low BAX mRNA expression and high MCL–1 mRNA expression significantly correlate with poor survival for patients with stage III ovarian carcinomas (BAX, P=0.05; MCL–1, P=0.02). Immunohistochemical analysis showed that diffuse‐positive expression of MCL–1 protein in mucinous carcinomas was significantly higher than in mucinous low malignant potential (LMP) tumors (P=0.03). In ovarian cancer cases, diffuse‐positive expression of MCL–1 protein significantly correlates with advanced clinical stage, high histologic grade, and poor survival (stage, P<0.01; grade, P=0.01; survival, P=0.01). These results suggest that increased MCL–1 expression may play an important role in replacing the functions of increased BAX and decreased BCL–2 in ovarian carcinoma cells, thereby promoting cell survival, and resulting in a poor prognosis for patients with ovarian cancer.

Keywords: MCL–1, Semi‐quantitative PCR, Immunohistochemistry, Ovarian cancer, Prognosis

Full Text

The Full Text of this article is available as a PDF (13.1 MB).

REFERENCES

  • 1. ) Parker , S. L. , Tong , T. , Bolden , S. and Wingo , P. A.Cancer statistics . CA Cancer J. Clin. , 46 , 5 – 27 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Kroemer , G.The proto‐oncogene Bcl–2 and its role in regulating apoptosis . Nat. Med. , 3 , 614 – 620 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Korsmeyer , S. J.BCL–2 gene family and the regulation of programmed cell death . Cancer Res. , 59 ( Suppl. ), 1693s – 1700s ( 1999. ). [PubMed] [Google Scholar]
  • 4. ) McDonnell , T. J. , Troncoso , P. , Brisbay , S. M. , Logothetis , C. , Chung , L. W. K. , Hsieh , J.‐T. , Tu , S.‐M. and Campbell , M. L.Expression of the protooncogene bcl–2 in the prostate and its association with emergence of androgen‐independent prostate cancer . Cancer Res. , 52 , 6940 – 6944 ( 1992. ). [PubMed] [Google Scholar]
  • 5. ) Campos , L. , Rouault , J.‐P. , Sabido , O. , Oriol , P. , Roubi , N. , Vasselon , C. , Archimbaud , E. , Magaud , J.‐P. and Guyotat , D.High expression of bcl–2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy . Blood , 81 , 3091 – 3096 ( 1993. ). [PubMed] [Google Scholar]
  • 6. ) Yunis , J. J. , Mayer , M. G. , Arnesen , M. A. , Aeppli , D. P. , Oken , M. M. and Frizzera , G.bcl–2 and other genomic alterations in the prognosis of large‐cell lymphoma . N. Engl. J. Med. , 320 , 1047 – 1054 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Pezzella , F. , Turley , H. , Kuzu , I. , Tungekar , M. F. , Dunnill , M. S. , Pierce , C. B. , Harris , A. , Gatter , K. C. and Mason , D. Y.bcl–2 protein in non‐small‐cell lung carcinoma . N. Engl. J. Med. , 329 , 690 – 694 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Leek , R. D. , Kaklamanis , L. , Pezzella , F. , Gatter , K. C. and Harris , A. L.bcl–2 in normal human breast and carcinoma, association with oestrogen receptor‐positive, epidermal growth factor receptor‐negative tumours and in situ cancer . Br. J. Cancer , 69 , 135 – 139 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. ) Henriksen , R. , Wilander , E. and Oberg , K.Expression and prognostic significance of Bcl–2 in ovarian tumours . Br. J. Cancer , 72 , 1324 – 1329 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. ) Herod , J. J. O. , Eliopoulos , A. G. , Warwick , J. , Niedobitek , G. , Young , L. S. and Kerr , D. J.The prognostic significance of Bcl–2 and p53 expression in ovarian carcinoma . Cancer Res. , 56 , 2178 – 2184 ( 1996. ). [PubMed] [Google Scholar]
  • 11. ) Shigemasa , K. , Hu , C. , West , C. M. , Clarke , J. , Parham , G. P. , Parmley , T. H. , Korourian , S. , Baker , V. V. and O'Brien , T. J.p16 overexpression: a potential early indicator of transformation in ovarian carcinoma . J. Soc. Gynecol. Invest. , 4 , 95 – 102 ( 1997. ). [PubMed] [Google Scholar]
  • 12. ) Shigemasa , K. , Hu , C. , West , C. M. , Moon , S. H. , Parham , G. P. , Parmley , T. H. , Korourian , S. , Baker , V. V. and O'Brien , T. J.p21: a monitor of p53 dysfunction in ovarian neoplasia . Int. J. Gynecol. Cancer , 7 , 296 – 303 ( 1997. ). [Google Scholar]
  • 13. ) Shigemasa , K. , Tanimoto , H. , Parham , G. P. , Parmley , T. H. , Ohama , K. and O'Brien , T. J.Cyclin D1 overexpression and p53 mutation status in epithelial ovarian cancer . J. Soc. Gynecol. Invest. , 6 , 102 – 108 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Shigemasa , K. , Underwood , L. J. , Beard , J. , Tanimoto , H. , Ohama , K. , Parmley , T. H. and O'Brien , T. J.Overexpression of testisin, a serine protease expressed by testicular germ cells, in epithelial ovarian tumor cells . J. Soc. Gynecol. Invest. , 7 , 11 – 18 ( 2000. ). [PubMed] [Google Scholar]
  • 15. ) Shigemasa , K. , Shiroyama , Y. , Sawasaki , T. , Fujii , T. , Nagai , N. , Parmley , T. H. , O'Brien , T. J. and Ohama , K.Underexpression of cyclin‐dependent kinase inhibitor p27 is associated with poor prognosis in serous ovarian carcinomas . Int. J. Oncol. , 18 , 953 – 958 ( 2001. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Krajewski , S. , Bodrug , S. , Krajewska , M. , Shabaik , A. , Gascoyne , R. , Berean , K. and Reed , J. C.Immunohistochemical analysis of Mel–1 protein in human tissues. Differential regulation of Mcl–1 and Bcl–2 protein production suggests a unique role for Mcl–1 in control of programmed cell death in vivo Am. J. Pathol. , 146 , 1309 – 1319 ( 1995. ). [PMC free article] [PubMed] [Google Scholar]
  • 17. ) Lomo , J. , Smeland , E. B. , Krajewski , S. , Reed , J. C. and Blomhoff , K.Expression of the Bcl–2 homologue Mcl–1 correlates with survival of peripheral blood B lymphocytes . Cancer Res. , 56 , 40 – 43 ( 1996. ). [PubMed] [Google Scholar]
  • 18. ) Rieger , L. , Weller , M. , Bornemann , A. , Schabet , M. , Dichgans , J. and Meyermann , R.BCL–2 family protein expression in human malignant glioma: a clinical‐pathological correlative study . J. Neurol. Sci. , 155 , 68 – 75 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Baekeland , M. , Holm , R. , Nesland , J. M. , Trope , C. G. and Kristensen , G. B.Expression of apoptosis‐related proteins is an independent determinant of patient prognosis in advanced ovarian cancer . J. Clin. Oncol. , 18 , 3775 – 3781 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Chao , J. R. , Wang , J. M. , Lee , S. F. , Peng , H. W. , Lin , Y. H. , Chou , C. H. , Li , J. C. , Huang , H. M. , Chou , C. K. , Kuo , M. L. , Yen , J. J. Y. and Yang‐Yen , H. F.mcl–1 is an immediate‐early gene activated by the granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) signaling pathway and is one component of the GM‐CSF viability response . Mol. Cell. Biol. , 18 , 4883 – 4898 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. ) Leu , C. M. , Chang , C. and Hu , C.Epidermal growth factor (EGF) suppresses staurosporine‐induced apoptosis by inducing mcl–1 via the mitogen‐activated protein kinase pathway . Oncogene , 19 , 1665 – 1675 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Puthier , D. , Bataille , R. and Amiot , M.IL–6 up‐regulates mcl–1 in human myeloma cells through JAK/STAT rather than ras/MAP kinase pathway . Eur. J. Immunol. , 29 , 3945 – 3950 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Wei , L. H. , Kuo , M. L. , Chen , C. A. , Chou , C. H. , Cheng , W. F. , Chang , M. C. , Su , J. L. and Hsieh , C. Y.The anti‐apoptotic role of interleukin–6 in human cervical cancer is mediated by up‐regulation of Mcl–1 through a PI3K/Akt pathway . Oncogene , 20 , 5799 – 5809 ( 2001. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Katoh , O. , Takahashi , T. , Oguri , T. , Kuramoto , K. , Mihara , K. , Kobayashi , M. , Hirata , S. and Watanabe , H.Vascular endothelial growth factor inhibits apoptotic death in hematopoietic cells after exposure to chemotherapeutic drugs by inducing MCL–1 acting as an antiapoptotic factor . Cancer Res. , 58 , 5565 – 5569 ( 1998. ). [PubMed] [Google Scholar]
  • 25. ) Marone , M. , Scambia , G. , Mozzetti , S. , Ferrandina , G. , Iacovella , S. , Pasqua , A. D. , Benedetti‐Panici , P. and Mancuso , S.bcl–2, bax, bcl‐xL, and bcl‐xS expression in normal and neoplastic ovarian tissues . Clin. Cancer Res. , 4 , 517 – 524 ( 1998. ). [PubMed] [Google Scholar]
  • 26. ) Witty , J. P. , Jensen , R. A. and Johnson , A. L.Expression and localization of BCL–2 related proteins in human ovarian cancers . Anticancer Res. , 18 , 1223 – 1230 ( 1998. ). [PubMed] [Google Scholar]
  • 27. ) Diebold , J. , Baretton , G. , Felchner , M. , Meier , W. , Dopfer , K. , Schmidt , M. and Lohrs , U.bcl–2 expression, p53 accumulation, and apoptosis in ovarian carcinomas . Anat. Pathol. , 105 , 341 – 349 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 28. ) Schuyer , M. , van der Burg , M. E. L. , Henzen‐Logmans , S. C. , Fieret , J. H. , Klijn , J. G. M. , Look , M. P. , Foekens , J. A. , Stoter , G. and Berns , E. M. J. J.Reduced expression of BAX is associated with poor prognosis in patients with epithelial ovarian cancer: a multifactorial analysis of TP53, p21, BAX and BCL–2 . Br. J. Cancer , 85 , 1359 – 1367 ( 2001. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. ) Miyashita , T. and Reed , J. C.Tumor suppressor p53 is a direct transcriptional activator of the human bax gene . Cell , 80 , 293 – 299 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Bosari , S. , Viale , G. , Radaelli , U. , Bossi , P. , Bonolidi , E. and Coggi , G.p53 accumulation in ovarian carcinomas and its prognostic implications . Hum. Pathol. , 24 , 1175 – 1179 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 31. ) Perego , P. , Giarola , M. , Righetti , S. C. , Supino , R. , Caserini , C. , Delia , D. , Pierotti , M. A. , Miyashita , T. , Reed , J. C. and Zunino , F.Association between cisplatin resistance and mutation of p53 gene and reduced BAX expression in ovarian carcinoma cell systems . Cancer Res. , 56 , 556 – 562 ( 1996. ). [PubMed] [Google Scholar]
  • 32. ) Tai , Y. T. , Lee , S. , Niloff , E. , Weisman , C. , Strobel , T. and Cannistra , S. A.BAX protein expression and clinical outcome in epithelial ovarian cancer . J. Clin. Oncol. , 16 , 2583 – 2590 ( 1998. ). [DOI] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES