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Elevated cytokeratin-19 expression associated with apoptotic resistance and malignant progression of human cervical carcinoma

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Abstract

Cytokeratin-19 is an intermediate filament protein associated with the integrity of cell structure, and its elevated expression has been reported to correlate with the disease progression of oesophagus and lung cancers. In this study, we examined the level of cytokeratin-19 in five cervical cancer cell lines by immunobinding and Western blotting analyses. Compared with two control cell lines, FS-4 (foreskin cell line) and G9T (glioma cell line), all five cervical carcinoma cell lines (Caski, CC7T, ME180, HeLa and SIHA) showed higher cytokeratin-19 expression. By double-staining flow cytometry, expression of cytokeratin-19 in cervical cancer cells was suggested to be in a cell cycle-independent manner. Furthermore, we could specifically localize the SIHA cell-derived tumours in nude mice by injecting with cytokeratin-19-recognized radiolabelled MAb Cx-99 antibody, suggesting the possibility of using cytokeratin-19 as a marker of cervical carcinoma. A clinical investigation was therefore performed on 19 patients (11 patients with cervical carcinoma and eight patients with benign neoplasia). In the 11 patients having cervical carcinoma, all eight patients with advanced stages and one out of three patients with early stage diseases showed higher cytokeratin-19 protein contents than the other 10 patients with benign neoplasia. This suggested that elevation of cytokeratin-19 level was associated with cervical cancer staging. In addition, we have studied the biological significance of elevated cytokeratin-19 level in malignant cervical cancer. The apoptotic rate of cervical carcinoma cells in response to cisplatin was increased if their cellular cytokeratin-19 level was reduced by specific antibody MAb Cx-99. These results indicated that elevation of cytokeratin-19 expression could associate with the apoptotic resistance and malignant progression of cervical carcinoma.

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References

  1. Chou P, Chen V. Mass screening for cervical cancer in Taiwan. Cancer 1989; 64: 962–968.

    Article  PubMed  CAS  Google Scholar 

  2. Ng HT, Yuan CC, Kan YY, Ho ESC, Yen MS, Chao KC. An evaluation of chemotherapy in patients with cancer of cervix and lymph node metastases. Arch General Obstet 1995; 256: 1–4.

    CAS  Google Scholar 

  3. Brodman M, Friedman F Jr, Dotting P, Janus C, Plaxe S, Cohen C. A comparative study of computerized tomography, magnetic resonance imaging, and staging for the detection of early cervix cancer. Gynecol Oncol 1990; 36: 409–412.

    Article  PubMed  CAS  Google Scholar 

  4. Lagasse LD, Ballon SC, Berman ML, Watring WG. Pretreatment lymphangiography and operative evaluation in carcinoma of the cervix. Am J Obstet Gynecol 1979; 134: 219–224.

    PubMed  CAS  Google Scholar 

  5. Rutanen EM, Lindgren J, Sipponen P, Stenman UH, Saksela E, Seppala M. Carcinoembryonic antigen in malignant and nonmalignant gynecologic tumors. Cancer 1978; 42: 581–590.

    Article  PubMed  CAS  Google Scholar 

  6. Kato H, Miyauchi F, Morioka H, Fujino T, Torigoe T. Tumor antigen of human cervical squamous cell carcinoma. Correlation of circulating levels with disease progress. Cancer 1979; 43: 585–590.

    Article  PubMed  CAS  Google Scholar 

  7. Bamford PN, Ormerod MG, Sloane JP, Warburton MJ. An immunohistochemical study of the distribution of epithelial antigens in the uterine cervix. Obstet Gynecol 1983; 61: 603–608.

    PubMed  CAS  Google Scholar 

  8. Lam CP, Yuan CC, Jeng FS, Tsai LC, Yeh SH, Ng HT. Evaluation of carcinoembryonic antigen, tissue polypeptide antigen, and squamous cell carcinoma antigen in the detection of cervical cancers. Chin Med J (Taipei) 1992; 50: 7–13.

    CAS  Google Scholar 

  9. Yuan CC, Tsai LC, Hsu SC, et al. Production and characterization of a monoclonal antibody (Cx-99) against cervical carcinoma. Br J Cancer 1992; 65: 201–207.

    PubMed  CAS  Google Scholar 

  10. Traub P. Intermediate Filaments: A Review. Berlin, Germany: Springer, 1985.

    Google Scholar 

  11. Roberts RA, Cress AE, Dalton WS. Persistent intracellular binding of mitoxantrone in a human colon carcinoma cell line. Biochem Pharmacol 1989; 38: 4283–4290.

    Article  PubMed  CAS  Google Scholar 

  12. Bauman PA, Dalton WS, Anderson JM, Cress AE. Expression of cytokeratin confers multiple drug resistance. Proc Natl Acad Sci USA 1994; 91: 5311–5314.

    Article  PubMed  CAS  Google Scholar 

  13. Anderson JM, Heindl LM, Bauman PA, Ludi CW, Dalton WS, Cress AE. Cytokeratin expression results in a drug-resistant phenotype to six different chemotherapeutic agents. Clin Cancer Res 1996; 2: 97–105.

    PubMed  CAS  Google Scholar 

  14. Yuan CC, Huang HC, Tsai LC, Ng HT, Huang TS. Cytokeratin-19 associated with apoptosis and chemosensitivity in human cervical cancer cells. Apoptosis 1997; 2: 101–105.

    Article  PubMed  CAS  Google Scholar 

  15. Yamamoto K, Oka M, Hayashi H, Tangoku A, Gondo T, Suzuki T. CYFRA 21-1 is a useful marker for esophageal squamous cell carcinoma. Cancer 1997; 79: 1647–1655.

    Article  PubMed  CAS  Google Scholar 

  16. Stieber P, Bodenmuller H, Banauch D, et al. Cytokeratin 19 fragments: A new marker for non-small-cell lung cancer. Clin Biochem 1993; 26: 301–304.

    Article  PubMed  CAS  Google Scholar 

  17. Wieskopf B, Demangeat C, Purohit A, et al. Cyfra 21-1 as a biologic marker of non-small cell lung cancer. Evaluation of sensitivity, specificity, and prognostic role. Chest 1995; 108: 163–169.

    PubMed  CAS  Google Scholar 

  18. Szturmowicz M, Sakowicz A, Wiatr E, et al. Evaluation of the value of determining levels of cytokeratin-19 fragments for diagnosis of lung cancer. Pneumonol Alergol Pol1995; 63: 609–614.

    PubMed  CAS  Google Scholar 

  19. Cynowska B, Slominski JM, Wyrwinski J. Level of cytokeratin-19 in serum of patients with non small cell lung cancer. Pneumonol Alergol Pol 1995; 63: 615–620.

    PubMed  CAS  Google Scholar 

  20. Szturmowicz M, Sakowicz A, Rudzinski P, et al. The clinical value of Cyfra 21-1 estimation for lung cancer patients. Int J Biol Markers 1996; 11: 172–177.

    PubMed  CAS  Google Scholar 

  21. Tsai LC, Wang FM, Pan LC, Perng AC, Han SH. Immunological characteristics of monoclonal antibodies against human carcinoembryonic antigen (CEA). Proc Natl Sci Counc B ROC 1985; 9: 287–297.

    CAS  Google Scholar 

  22. Greenwood FC, Hunter WM, Glover JS. The preparation of 125I-labeled human growth hormone of high specific radioactivity. Biochem J 1963; 39: 114–123.

    Google Scholar 

  23. Huang TS, Shu CH, Shih YL, et al. Protein tyrosine phosphatase activities are involved in apoptotic cancer cell death induced by GL331, a new homolog of etoposide. Cancer Lett 1996; 110: 77–85.

    Article  PubMed  CAS  Google Scholar 

  24. Huang TS, Yang WK, Whang-Peng J. GL331-induced disruption of cyclin B1/CDC 2 complex and inhibition of CDC 2 kinase activity. Apoptosis 1996; 1: 213–217.

    Article  CAS  Google Scholar 

  25. Huang TS, Kuo ML, Shew JY, Chou YW, Yang WK. Distinct p53-mediated G1/S checkpoint responses in two NIH3T3 subclone cells following treatment with DNA-damaging agents. Oncogene 1996; 13: 625–632.

    PubMed  CAS  Google Scholar 

  26. Tsai LC, Cheng HM, Yeh SH, Yuan CC, Tsao D, Han SH. Localization of human colorectal antibody to carcinoembryonic antigen. Diagn Clin Immunol 1988; 5: 332–337.

    PubMed  CAS  Google Scholar 

  27. Shu CH, Yang WK, Huang TS. Increased cyclin B1/CDC 2 kinase activity and phosphorylation of Bcl-2 associated with paclitaxel-induced apoptosis in human nasopharyngeal carcinoma cells. Apoptosis 1996; 1: 141–146.

    Article  CAS  Google Scholar 

  28. Huang TS, Shu CH, Yang WK, Whang-Peng J. Activation of CDC 25 phosphatase and CDC 2 kinase involved in GL331-induced apoptosis. Cancer Res 1997; 57: 2974–2978.

    PubMed  CAS  Google Scholar 

  29. Quinlan RA, Schiller DL, Hatzfeld M, et al. Patterns of expression and organization of cytokeratin intermediate filaments. Ann NY Acad Sci 1985; 455: 282–306.

    PubMed  CAS  Google Scholar 

  30. Farghaly SA. Tumor markers in gynecologic cancer. Gynecol Obstet Invest 1992; 34: 65–72.

    Article  PubMed  CAS  Google Scholar 

  31. Ferdeghini M, Gadducci A, Annicchiarico C, et al. Serum CYFRA 21-1 assay in squamous cell carcinoma of the cervix. Anticancer Res 1993; 13: 1841–1844.

    PubMed  CAS  Google Scholar 

  32. Holloway RW, To A, Moradi M, Boots L, Watson N, Shingleton HM. Monitoring the course of cervical carcinoma with the squamous cell carcinoma serum radio-immuoassay. Obstet Gynecol 1989; 74: 944–949.

    PubMed  CAS  Google Scholar 

  33. Hontag TW. Tumor markers in gynecologic oncology. Obstet Gynecol Surv 1990; 45: 94–105.

    Article  Google Scholar 

  34. Wahlstrom T, Lingren J, Korhonen M, Seppapa M. Distribution between endo-cervical and endometrial adenocarcinoma with immunoperoxidase staining of carcinoembryonic antigen in routine histological tissue specimens. Lancet 1979; 2: 1159–1161.

    Article  PubMed  CAS  Google Scholar 

  35. Fray RE, Husain OA, To AC, et al. The value of immunohistochemical markers in the diagnosis of cervical neoplasia. Br J Obstet Gynecol 1984; 91: 1034–1041.

    Google Scholar 

  36. Kruger WH, Stockschlader M, Hennings S, et al. Detection of cancer cells in peripheral blood stem cells of women with breast cancer by RT-PCR and cell culture. Bone Marrow Transplant 1996; 18 (Suppl 1): S18–20.

    PubMed  Google Scholar 

  37. Kruger WH, Krzizanowski C, Holweg M, et al. Reverse transcriptase/polymerase chain reaction detection of cytokeratin-19 mRNA in bone marrow and blood of breast cancer patients. J Cancer Res Clin Oncol 1996; 122: 679–686.

    Article  PubMed  CAS  Google Scholar 

  38. Hildebrandt M, Mapara MY, Korner IJ, Bargou RC, Moldenhauer G, Dorken B. Reverse transcriptasepolymerase chain reaction (RT-PCR)-controlled immunomagnetic purging of breast cancer cells using the magnetic cell separation (MACS) system: A sensitive method for monitoring purging efficiency. Exp Hematol 1997; 25: 57–65.

    PubMed  CAS  Google Scholar 

  39. Martin SJ, Green DR, Cotter TG. Dicing with death: dissecting the components of the apoptosis machinery. Trends Biochem Sci 1994; 19: 26–30.

    Article  PubMed  CAS  Google Scholar 

  40. Knapp LW, O'Guin WM, Sawyer RH. Drug-induced alterations of cytokeratin organization in cultured epithelial cells. Science 1983; 219: 501–503.

    PubMed  CAS  Google Scholar 

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Authors
  1. C-C. Yuan
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  2. T-S. Huang
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  3. H-T Ng
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  4. R-S. Liu
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  5. M-W. Hung
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  6. L-C. Tsai
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Yuan, CC., Huang, TS., Ng, HT. et al. Elevated cytokeratin-19 expression associated with apoptotic resistance and malignant progression of human cervical carcinoma. Apoptosis 3, 161–169 (1998). https://doi.org/10.1023/A:1009646705467

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