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Overexpression of stathmin is resistant to paclitaxel treatment in patients with non-small cell lung cancer

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Tumor Biology

Abstract

Paclitaxel can exert therapeutic effects by interacting with microtubules. Stathmin and β-III-tubulin, which have impact on microtubule activity, are believed to be involved in the chemotherapy. The purpose of the present study was to evaluate the associations between stathmin and β-III-tubulin expression and treatment response and survivals in patients with non-small cell lung cancer (NSCLC). Two hundred thirty-eight patients who were treated by platinum-based chemotherapy were enrolled in this study, among them, 111 patients also received paclitaxel treatment. Formalin-fixed and paraffin-embedded tumor tissues were collected for messenger RNA (mRNA) and protein detection. We assessed the associations of the two molecules with treatment response and survival outcome. High level of stathmin exhibited poor response to chemotherapy (for mRNA, P = 0.041; for protein, P = 0.017). Overexpression of stathmin was associated with shorter overall survival (for mRNA, P = 0.012; for protein, P = 0.014) and progression-free survival (for mRNA, P = 0.039; for protein, P = 0.022). Of note, this association was only observed in patients who were treated by both platinum and paclitaxel. Similar effects were not observed for β-III-tubulin. The findings demonstrated that paclitaxel effect may be interfered with stathmin; overexpression of stathmin is a predictive marker for a worse prognosis in patients with NSCLC who were treated by both platinum and paclitaxel chemotherapy.

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References

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.

    Article  PubMed  Google Scholar 

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  3. Williams CD, Gajra A, Ganti AK, Kelley MJ. Use and impact of adjuvant chemotherapy in patients with resected non-small cell lung cancer. Cancer. 2014;120:1939–47.

    Article  CAS  PubMed  Google Scholar 

  4. Liu L, Zhao E, Li C, Huang L, Xiao L, Cheng L, et al. Trim28, a new molecular marker predicting metastasis and survival in early-stage non-small cell lung cancer. Cancer Epidemiol. 2013;37:71–8.

    Article  CAS  PubMed  Google Scholar 

  5. Inomata M, Hayashi R, Tokui K, Taka C, Okazawa S, Kambara K, et al. Usefulness of the palliative prognostic index in patients with lung cancer. Med Oncol. 2014;31:154.

    Article  PubMed  Google Scholar 

  6. Banna GL, Lipari H, Nicolosi M, Basile A, Fraggetta F, Vaglica M, et al. A three-drug induction chemotherapy with gemcitabine, carboplatin, and paclitaxel for stage III non-small cell lung cancer. Med Oncol. 2013;30:533.

    Article  PubMed  Google Scholar 

  7. Jouveshomme S, Canoui-Poitrine F, Le Thuaut A, Bastuji-Garin S. Results of platinum-based chemotherapy in unselected performance status (PS) 2 patients with advanced non-small cell lung cancer: a cohort study. Med Oncol. 2013;30:544.

    Article  PubMed  Google Scholar 

  8. Buonato JM, Lazzara MJ. ERK1/2 blockade prevents epithelial-mesenchymal transition in lung cancer cells and promotes their sensitivity to EGFR inhibition. Cancer Res. 2014;74:309–19.

    Article  CAS  PubMed  Google Scholar 

  9. Douillard JY, Ostoros G, Cobo M, Ciuleanu T, McCormack R, Webster A, et al. First-line gefitinib in caucasian EGFR mutation-positive nsclc patients: a phase-IV, open-label, single-arm study. Br J Cancer. 2014;110:55–62.

    Article  CAS  PubMed  Google Scholar 

  10. Janke C. The tubulin code: molecular components, readout mechanisms, and functions. J Cell Biol. 2014;206:461–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kingston DG, Snyder JP. The quest for a simple bioactive analog of paclitaxel as a potential anticancer agent. Acc Chem Res. 2014;47:2682–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Laurie SA, Solomon BJ, Seymour L, Ellis PM, Goss GD, Shepherd FA, et al. Randomised, double-blind trial of carboplatin and paclitaxel with daily oral cediranib or placebo in patients with advanced non-small cell lung cancer: NCIC clinical trials group study BR29. Eur J Cancer. 2014;50:706–12.

    Article  CAS  PubMed  Google Scholar 

  13. Zhang HL, Ruan L, Zheng LM, Whyte D, Tzeng CM, Zhou XW. Association between class III beta-tubulin expression and response to paclitaxel/vinorebine-based chemotherapy for non-small cell lung cancer: a meta-analysis. Lung Cancer. 2012;77:9–15.

    Article  PubMed  Google Scholar 

  14. Xi W, Rui W, Fang L, Ke D, Ping G, Hui-Zhong Z. Expression of stathmin/op18 as a significant prognostic factor for cervical carcinoma patients. J Cancer Res Clin Oncol. 2009;135:837–46.

    Article  PubMed  Google Scholar 

  15. Akhtar J, Wang Z, Yu C, Zhang ZP, Bi MM. Stmn-1 gene: a predictor of survival in stage IIA esophageal squamous cell carcinoma after Ivor-Lewis esophagectomy? Ann Surg Oncol. 2014;21:315–21.

    Article  PubMed  Google Scholar 

  16. Belletti B, Baldassarre G. Stathmin: a protein with many tasks. New biomarker and potential target in cancer. Expert Opin Ther Targets. 2011;15:1249–66.

    Article  CAS  PubMed  Google Scholar 

  17. Werner HM, Trovik J, Halle MK, Wik E, Akslen LA, Birkeland E, et al. Stathmin protein level, a potential predictive marker for taxane treatment response in endometrial cancer. PLoS One. 2014;9:e90141.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Phadke AP, Jay CM, Wang Z, Chen S, Liu S, Haddock C, et al. In vivo safety and antitumor efficacy of bifunctional small hairpin RNAs specific for the human stathmin 1 oncoprotein. DNA Cell Biol. 2011;30:715–26.

    Article  CAS  PubMed  Google Scholar 

  19. Rana S, Maples PB, Senzer N, Nemunaitis J. Stathmin 1: a novel therapeutic target for anticancer activity. Expert Rev Anticancer Ther. 2008;8:1461–70.

    Article  CAS  PubMed  Google Scholar 

  20. 20 Nie W, Xu MD, Gan L, Huang H, Xiu Q, Li B: Overexpression of stathmin 1 is a poor prognostic biomarker in non-small cell lung cancer. Lab Invest 2014.

  21. Su D, Smith SM, Preti M, Schwartz P, Rutherford TJ, Menato G, et al. Stathmin and tubulin expression and survival of ovarian cancer patients receiving platinum treatment with and without paclitaxel. Cancer. 2009;115:2453–63.

    Article  CAS  PubMed  Google Scholar 

  22. Chen G, Wang H, Gharib TG, Huang CC, Thomas DG, Shedden KA, et al. Overexpression of oncoprotein 18 correlates with poor differentiation in lung adenocarcinomas. Mol Cell Proteomics. 2003;2:107–16.

    Article  CAS  PubMed  Google Scholar 

  23. Seve P, Isaac S, Tredan O, Souquet PJ, Pacheco Y, Perol M, et al. Expression of class III {beta}-tubulin is predictive of patient outcome in patients with non-small cell lung cancer receiving vinorelbine-based chemotherapy. Clin Cancer Res. 2005;11:5481–6.

    Article  CAS  PubMed  Google Scholar 

  24. Rolfo C, Giovannetti E, Hong DS, Bivona T, Raez LE, Bronte G, et al. Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors. Cancer Treat Rev. 2014;40:990–1004.

    Article  CAS  PubMed  Google Scholar 

  25. Tsai CM, Chiu CH, Chang KT, Chen JT, Lai CL, Chen YM, et al. Gefitinib enhances cytotoxicities of antimicrotubule agents in non-small-cell lung cancer cells exhibiting no sensitizing epidermal growth factor receptor mutation. J Thorac Oncol. 2012;7:1218–27.

    Article  CAS  PubMed  Google Scholar 

  26. Han ZX, Wang HM, Jiang G, Du XP, Gao XY, Pei DS. Overcoming paclitaxel resistance in lung cancer cells via dual inhibition of stathmin and Bcl-2. Cancer Biother Radiopharm. 2013;28:398–405.

    Article  CAS  PubMed  Google Scholar 

  27. Alli E, Bash-Babula J, Yang JM, Hait WN. Effect of stathmin on the sensitivity to antimicrotubule drugs in human breast cancer. Cancer Res. 2002;62:6864–9.

    CAS  PubMed  Google Scholar 

  28. Alli E, Yang JM, Hait WN. Silencing of stathmin induces tumor-suppressor function in breast cancer cell lines harboring mutant p53. Oncogene. 2007;26:1003–12.

    Article  CAS  PubMed  Google Scholar 

  29. Balachandran R, Welsh MJ, Day BW. Altered levels and regulation of stathmin in paclitaxel-resistant ovarian cancer cells. Oncogene. 2003;22:8924–30.

    Article  CAS  PubMed  Google Scholar 

  30. Mistry SJ, Bank A, Atweh GF. Synergistic antiangiogenic effects of stathmin inhibition and taxol exposure. Mol Cancer Res. 2007;5:773–82.

    Article  CAS  PubMed  Google Scholar 

  31. George SL. Response rate as an endpoint in clinical trials. J Natl Cancer Inst. 2007;99:98–9.

  32. Jakobsen JN, Santoni-Rugiu E, Sorensen JB. Longitudinal assessment of TUBB3 expression in non-small cell lung cancer patients. Cancer Chemother Pharmacol. 2014;73:43–51.

    Article  CAS  PubMed  Google Scholar 

  33. Saura C, Tseng LM, Chan S, Chacko RT, Campone M, Manikhas A, et al. Neoadjuvant doxorubicin/cyclophosphamide followed by ixabepilone or paclitaxel in early stage breast cancer and evaluation of betaIII-tubulin expression as a predictive marker. Oncologist. 2013;18:787–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Vilmar AC, Santoni-Rugiu E, Sorensen JB. Class III beta-tubulin in advanced NSCLC of adenocarcinoma subtype predicts superior outcome in a randomized trial. Clin Cancer Res. 2011;17:5205–14.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was partly supported by Postdoctoral Science Foundation of China (No. 2014M552461). We would like to thank all the participants and staff of Shaan’Xi Tumor Hospital for their valuable contributions on collecting specimens and sorting out clinical data.

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    Authors and Affiliations

    1. Department of Pathology, School of Medicine, Xi’an Jiaotong University, 76 Yanta West Road, Xi’an, 710061, Shaanxi, China

      Ruifang Sun & Changfu Xu

    2. Department of Thoracic Surgery, Tumor Hospital of Shaanxi Province, 309 Yanta West Road, Xi’an, Shaanxi, China

      Zhigang Liu, Weidong Lv, Jia Liu & Guangyan Lei

    3. Key Laboratory of Environment and Genes Related to Diseases, School of Medicine, Xi’an Jiaotong University, 76 Yanta West Road, Xi’an, Shaanxi, China

      Lumin Wang

    4. Department of Pathology, Tumor Hospital of Shaanxi Province, 309 Yanta West Road, Xi’an, Shaanxi, China

      Caixia Ding & Yong Yuan

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    1. Ruifang Sun
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    Correspondence to Ruifang Sun.

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    Ruifang Sun and Zhigang Liu contributed equally to this work.

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    Sun, R., Liu, Z., Wang, L. et al. Overexpression of stathmin is resistant to paclitaxel treatment in patients with non-small cell lung cancer. Tumor Biol. 36, 7195–7204 (2015). https://doi.org/10.1007/s13277-015-3361-y

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    • DOI: https://doi.org/10.1007/s13277-015-3361-y

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