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Overexpression of pyruvate kinase M2 predicts a poor prognosis for patients with osteosarcoma

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Tumor Biology

Abstract

It is stated that high expression of pyruvate kinase (PKM2) emerges as a significant player in the metabolism and progression of various human malignancies. However, the expression of PKM2 and its association with the prognosis of osteosarcoma had not yet been studied. In the present study, the expression and biological significance of PKM2 in osteosarcoma were investigated. We found that PKM2 expression was elevated in the cancerous tissues and it was more abundant than the adjacent normal tissues (60.2 vs 26.1 %, p < 0.001). Moreover, we showed that high PKM2 expression was positively correlated with Enneking stage (p = 0.006) and distant metastasis (p = 0.007) but not with the age, gender, tumor site, tumor size, histologic grade, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and local pain of the patients. Furthermore, Kaplan–Meier analysis revealed that the overall survival (OS) for patients with high PKM2 expression was significantly lower than those with low PKM2 expression (p < 0.001). Finally, multivariate analysis revealed that high PKM2 expression was an independent prognostic factor for osteosarcoma patients (p = 0.004). Collectively, these data indicated that elevated PKM2 might serve as a novel target for the treatment of osteosarcoma.

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References

  1. Ottaviani G, Jaffe N. The epidemiology of osteosarcoma. Pediatric and adolescent osteosarcoma. Springer; 2009. p. 3–13.

  2. Meyers PA, Schwartz CL, Krailo M, Kleinerman ES, Betcher D, Bernstein ML, Conrad E, Ferguson W, Gebhardt M, Goorin AM. Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol. 2005;23:2004–11.

    Article  CAS  PubMed  Google Scholar 

  3. Campanacci M. Bone and soft tissue tumors: clinical features, imaging, pathology and treatment. Springer Science & Business Media. 2013.

  4. Dass CR, Ek ET, Contreras KG, Choong PF. A novel orthotopic murine model provides insights into cellular and molecular characteristics contributing to human osteosarcoma. Clinical & experimental metastasis. 2006;23:367–80.

    Article  Google Scholar 

  5. Strauss SJ, Ng T, Mendoza-Naranjo A, Whelan J, Sorensen PH. Understanding micrometastatic disease and Anoikis resistance in ewing family of tumors and osteosarcoma. Oncologist. 2010;15:627–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Link MP, Goorin AM, Miser AW, Green AA, Pratt CB, Belasco JB, Pritchard J, Malpas JS, Baker AR, Kirkpatrick JA, et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med. 1986;314:1600–6.

    Article  CAS  PubMed  Google Scholar 

  7. Meyers PA, Heller G, Healey J, Huvos A, Lane J, Marcove R, Applewhite A, Vlamis V, Rosen G. Chemotherapy for nonmetastatic osteogenic sarcoma: the Memorial Sloan-Kettering experience. J Clin Oncol. 1992;10:5–15.

    CAS  PubMed  Google Scholar 

  8. Biteau K, Guiho R, Chatelais M, Taurelle J, Chesneau J, Corradini N, Heymann D, Redini F. L-MTP-PE and zoledronic acid combination in osteosarcoma: preclinical evidence of positive therapeutic combination for clinical transfer. American Journal of Cancer Res. 2016;6:677.

    Google Scholar 

  9. He H, Ni J, Huang J. Molecular mechanisms of chemoresistance in osteosarcoma (review. Oncol Lett. 2014;7:1352–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. The Journal of general physiology. 1927;8:519–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Macintyre AN, Rathmell JC. Pkm2 and the tricky balance of growth and energy in cancer. Mol Cell. 2011;42:713–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC. The m2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008;452:230–3.

    Article  CAS  PubMed  Google Scholar 

  13. Iqbal MA, Bamezai RN. Resveratrol inhibits cancer cell metabolism by down regulating pyruvate kinase m2 via inhibition of mammalian target of rapamycin. PLoS One. 2012;7:e36764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gao X, Wang H, Yang JJ, Liu X, Liu Z-R. Pyruvate kinase m2 regulates gene transcription by acting as a protein kinase. Mol Cell. 2012;45:598–609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liu Q, Liang M, Liu T, Vuitton L, Zheng S, Gao X, Lu M, Li X, Sheyhidin I, Lu X. M2 isoform of pyruvate kinase (PKM2) is upregulated in Kazakh’s ESCC and promotes proliferation and migration of ESCC cells. Tumor Biol. 2015:1–8.

  16. Fan F-T, Shen C-S, Tao L, Tian C, Liu Z-G, Zhu Z-J, Liu Y-P, Pei C-S, Wu H-Y, Zhang L. PKM2 regulates hepatocellular carcinoma cell epithelial-mesenchymal transition and migration upon EGFR activation. Asian Pacific journal of cancer prevention: APJCP. 2013;15:1961–70.

    Article  Google Scholar 

  17. Azoitei N, Becher A, Steinestel K, Rouhi A, Diepold K, Genze F, Simmet T, Seufferlein T. PKM2 promotes tumor angiogenesis by regulating HIF-1α through NF-κb activation. Mol Cancer. 2016;15:1.

    Article  Google Scholar 

  18. He Y, Wang Y, Liu H, Xu X, He S, Tang J, Huang Y, Miao X, Wu Y, Wang Q. Pyruvate kinase isoform M2 (PKM2) participates in multiple myeloma cell proliferation, adhesion and chemoresistance. Leuk Res. 2015;39:1428–36.

    Article  CAS  PubMed  Google Scholar 

  19. Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res. 1980;153:106–20.

    Google Scholar 

  20. Gorlick R. Current concepts on the molecular biology of osteosarcoma. Pediatric and adolescent osteosarcoma. Springer; 2009. p. 467–478.

  21. Luo W, Semenza GL. Emerging roles of PKM2 in cell metabolism and cancer progression. Trends in Endocrinology & Metabolism. 2012;23:560–6.

    Article  Google Scholar 

  22. Yang W, Xia Y, Ji H, Zheng Y, Liang J, Huang W, Gao X, Aldape K, Lu Z. Nuclear PKM2 regulates [b]-catenin transactivation upon EGFR activation. Nature. 2011;480:118–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ma T, Patel H, Babapoor-Farrokhran S, Franklin R, Semenza GL, Sodhi A, Montaner S. KSHV induces aerobic glycolysis and angiogenesis through HIF-1-dependent upregulation of pyruvate kinase 2 in Kaposi’s sarcoma. Angiogenesis. 2015;18:477–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yang W, Xia Y, Hawke D, Li X, Liang J, Xing D, Aldape K, Hunter T, Yung WA, Lu Z. PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell. 2012;150:685–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhao Z, Song Z, Liao Z, Liu Z, Sun H, Lei B, Chen W, Dang C. PKM2 promotes stemness of breast cancer cell by through Wnt/β-catenin pathway. Tumor Biology. 2015;1–12.

  26. Gao Y, Xu D, Yu G, Liang J. Overexpression of metabolic markers HK1 and PKM2 contributes to lymphatic metastasis and adverse prognosis in Chinese gastric cancer. International journal of clinical and experimental pathology. 2015;8:9264.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This research was supported by grants from the Special Foundation for Young Scientists of the Second Affiliated Hospital of Nanhua University (85521846).

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Correspondence to Xiao-xu Wang.

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Zheng-xuan Liu and Liang Hong contributed equally to this work.

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Liu, Zx., Hong, L., Fang, Sq. et al. Overexpression of pyruvate kinase M2 predicts a poor prognosis for patients with osteosarcoma. Tumor Biol. 37, 14923–14928 (2016). https://doi.org/10.1007/s13277-016-5401-7

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  • DOI: https://doi.org/10.1007/s13277-016-5401-7

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