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Down-regulation of succinate dehydrogenase subunit B and up-regulation of pyruvate dehydrogenase kinase 1 predicts poor prognosis in recurrent nasopharyngeal carcinoma

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Tumor Biology

Abstract

Succinate dehydrogenase subunit B (SDHB) and pyruvate dehydrogenase kinase 1 (PDK1) play key roles in the regulation of growth and survival of various cancers. This study aimed to investigate expression of SDHB and PDK1 in recurrent nasopharyngeal carcinoma (rNPC) tissues and analyzed the association of SDHB and PDK1 expression with the clinical significance and potential prognostic implication of rNPC. Immunohistochemistry was performed to determine the expression of SDHB and PDK1 in tissues in primary NPC (pNPC) and rNPC patients. Our results revealed that expression of SDHB in rNPC was significantly lower than that in pNPC, while the expression of PDK1 was higher compared to pNPC. The expression levels of SDHB and PDK1 were associated with T stage, N stage, clinical stage, and metastasis of rNPC. Survival analysis showed that patients with low SDHB expression had a significantly shorter overall survival time than those with high SDHB expression. Patients with high PDK1 expression had a shorter survival time than patients with low PDK1 expression. Multivariate analysis showed that the expression of SDHB and PDK1 was an independent predictor for the survival of patients with rNPC. Our results demonstrated that down-regulation of SDHB and up-regulation of PDK1 may be novel biomarkers for predicting advanced tumor progression and unfavorable prognosis in rNPC patients.

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References

  1. 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 

  2. Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. Mach-nc collaborative group. Meta-analysis of chemotherapy on head and neck cancer. Lancet. 2000;355:949–55.

    Article  CAS  PubMed  Google Scholar 

  3. Chan AT, Teo PM, Ngan RK, Leung TW, Lau WH, Zee B, et al. Concurrent chemotherapy-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: progression-free survival analysis of a phase III randomized trial. J Clin Oncol. 2002;20:2038–44.

    Article  CAS  PubMed  Google Scholar 

  4. Lin JC, Jan JS, Hsu CY, Liang WM, Jiang RS, Wang WY. Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: positive effect on overall and progression-free survival. J Clin Oncol. 2003;21:631–7.

    Article  PubMed  Google Scholar 

  5. Erkal HS, Serin M, Cakmak A. Nasopharyngeal carcinomas: analysis of patient, tumor and treatment characteristics determining outcome. Radiother Oncol. 2001;61:247–56.

    Article  CAS  PubMed  Google Scholar 

  6. Ho FC, Tham IW, Earnest A, Lee KM, Lu JJ. Patterns of regional lymph node metastasis of nasopharyngeal carcinoma: a meta-analysis of clinical evidence. BMC Cancer. 2012;12:98.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Pawlu C, Bausch B, Neumann HP. Mutations of the SDHB and SDHD genes. Familial Cancer. 2005;4:49–54.

    Article  PubMed  Google Scholar 

  8. Blank A, Schmitt AM, Korpershoek E, van Nederveen F, Rudolph T, Weber N, et al. SDHB loss predicts malignancy in pheochromocytomas/sympathetic paragangliomas, but not through hypoxia signalling. Endocr Relat Cancer. 2010;17:919–28.

    Article  PubMed  Google Scholar 

  9. Shimizu T, Inoue K, Hachiya H, Shibuya N, Shimoda M, Kubota K. Frequent alteration of the protein synthesis of enzymes for glucose metabolism in hepatocellular carcinomas. J Gastroenterol. 2014;49:1324–32.

    Article  CAS  PubMed  Google Scholar 

  10. Cao Z, Song JH, Kang YW, Yoon JH, Nam SW, Lee JY, et al. Analysis of succinate dehydrogenase subunit B gene alterations in gastric cancers. Pathol Int. 2010;60:559–65.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang D, Wang W, Xiang B, Li N, Huang S, Zhou W, et al. Reduced succinate dehydrogenase B expression is associated with growth and de-differentiation of colorectal cancer cells. Tumour Biol. 2013;34:2337–47.

    Article  PubMed  Google Scholar 

  12. Gill AJ, Pachter NS, Chou A, Young B, Clarkson A, Tucker KM, et al. Renal tumors associated with germline SDHB mutation show distinctive morphology. Am J Surg Pathol. 2011;35:1578–85.

    Article  PubMed  Google Scholar 

  13. Fleming S, Mayer NJ, Vlatkovic LJ, McLean J, McConachie M, Baty D. Signalling pathways in succinate dehydrogenase B-associated renal carcinoma. Histopathology. 2014;64:477–83.

    Article  PubMed  Google Scholar 

  14. Montani M, Schmitt AM, Schmid S, Locher T, Saremaslani P, Heitz PU, et al. No mutations but an increased frequency of SDHx polymorphisms in patients with sporadic and familial medullary thyroid carcinoma. Endocr Relat Cancer. 2005;12:1011–6.

    Article  CAS  PubMed  Google Scholar 

  15. Miettinen M, Sarlomo-Rikala M, McCue P, Czapiewski P, Langfort R, Waloszczyk P, et al. Mapping of succinate dehydrogenase losses in 2258 epithelial neoplasms. Appl Immunohistochem Mol Morphol. 2014;22:31–6.

    Article  CAS  PubMed  Google Scholar 

  16. Ahmed N, Riley C, Quinn MA. An immunohistochemical perspective of PPAR beta and one of its putative targets PDK1 in normal ovaries, benign and malignant ovarian tumours. Br J Cancer. 2008;98:1415–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yu J, Chen KS, Li YN, Yang J, Zhao L. Silencing of PDK1 gene expression by RNA interference suppresses growth of esophageal cancer. Asian Pac J Cancer Prev. 2012;13:4147–51.

    Article  PubMed  Google Scholar 

  18. Liu Y, Wang J, Wu M, Wan W, Sun R, Yang D, et al. Down-regulation of 3-phosphoinositide-dependent protein kinase-1 levels inhibits migration and experimental metastasis of human breast cancer cells. Mol Cancer Res. 2009;7:944–54.

    Article  CAS  PubMed  Google Scholar 

  19. Galgano MT, Conaway M, Spencer AM, Paschal BM, Frierson Jr HF. PRK1 distribution in normal tissues and carcinomas: overexpression and activation in ovarian serous carcinoma. Human Pathol. 2009;40:1434–40.

    Article  CAS  Google Scholar 

  20. Han L, Zhang G, Zhang N, Li H, Liu Y, Fu A, et al. Prognostic potential of microRNA-138 and its target mRNA PDK1 in sera for patients with non-small cell lung cancer. Med Oncol. 2014;31:129.

    Article  PubMed  Google Scholar 

  21. Tsukamoto Y, Nakada C, Noguchi T, Tanigawa M, Nguyen LT, Uchida T, et al. MicroRNA-375 is downregulated in gastric carcinomas and regulates cell survival by targeting PDK1 and 14-3-3zeta. Cancer Res. 2010;70:2339–49.

    Article  CAS  PubMed  Google Scholar 

  22. Hur H, Xuan Y, Kim YB, Lee G, Shim W, Yun J, et al. Expression of pyruvate dehydrogenase kinase-1 in gastric cancer as a potential therapeutic target. Int J Oncol. 2013;42:44–54.

    CAS  PubMed  Google Scholar 

  23. Cen L, Hsieh FC, Lin HJ, Chen CS, Qualman SJ, Lin J. PDK-1/AKT pathway as a novel therapeutic target in rhabdomyosarcoma cells using OSU-03012 compound. Br J Cancer. 2007;97:785–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lin S, Huang ZX, Li WF, Zhang CH, Fang XB, Liao ZS. Function and chromosome location of differentially expressed genes in primary nasopharyngeal carcinoma. Chinese Archives of Otolaryngology-Head and Neck Surgery. 2010;17:455–7.

    Google Scholar 

  25. Huang ZX, Li WF, Lin S, Huang Y, Du JM, Tan YX, et al. Identification of differentially expressed genes in recurrent nasopharyngeal carcinoma and analysis of their chromosomal location. Chinese Journal of Otorhinolaryngology Head and Neck Surgery. 2010;45:47–51.

    PubMed  Google Scholar 

  26. Guzy RD, Sharma B, Bell E, Chandel NS, Schumacker PT. Loss of the SdhB, but not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis. Mol Cell Biol. 2008;28:718–31.

    Article  CAS  PubMed  Google Scholar 

  27. Lendvai N, Pawlosky R, Bullova P, Eisenhofer G, Patocs A, Veech RL, et al. Succinate-to-fumarate ratio as a new metabolic marker to detect the presence of SDHB/D-related paraganglioma: initial experimental and ex vivo findings. Endocrinology. 2014;155:27–32.

    Article  PubMed  Google Scholar 

  28. Doyle LA, Nelson D, Heinrich MC, Corless CL, Hornick JL. Loss of succinate dehydrogenase subunit B (SDHB) expression is limited to a distinctive subset of gastric wild-type gastrointestinal stromal tumours: a comprehensive genotype-phenotype correlation study. Histopathology. 2012;61:801–9.

    Article  PubMed  Google Scholar 

  29. Li Y, Yang KJ, Park J. Multiple implications of 3-phosphoinositide-dependent protein kinase 1 in human cancer. World J Biol Chem. 2010;1:239–47.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Bayascas JR, Leslie NR, Parsons R, Fleming S, Alessi DR. Hypomorphic mutation of PDK1 suppresses tumorigenesis in PTEN (+/−) mice. Curr Biol. 2005;15:1839–46.

    Article  CAS  PubMed  Google Scholar 

  31. Li X, Lin R, Li J. Epigenetic silencing of microRNA-375 regulates PDK1 expression in esophageal cancer. Dig Dis Sci. 2011;56:2849–56.

    Article  CAS  PubMed  Google Scholar 

  32. Tatsumi-Tamori A, Yoshizaki T, Miwa T, Furukawa M. Clinical evaluation of staging system for nasopharyngeal carcinoma: comparison of fourth and fifth editions of UICC TNM classification. Ann Otol Rhino Laryngol. 2000;109:1125–9.

    Article  CAS  Google Scholar 

  33. Patel SG, Shah JP. TNM staging of cancers of the head and neck: striving for uniformity among diversity. CA Cancer J Clin. 2005;55:242–58.

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Acknowledgments

This project was supported by a grant from the Wenzhou Science and Technology Bureau (No.Y20120022) and Ruian Science and Technology Bureau (No.201203081).

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    Authors and Affiliations

    1. Department of Otolaryngology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325200, China

      ZhiJian Dai, Congxi Chen, Longhe Cao, Xianhui Li, Xiaofeng Chen, Xiaoqing Su & Sen Lin

    2. Department of Pathology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

      Shenhua Pan

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    1. ZhiJian Dai
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    8. Sen Lin
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    Correspondence to Sen Lin.

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    ZhiJian Dai and Shenhua Pan contributed equally to this work.

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    Dai, Z., Pan, S., Chen, C. et al. Down-regulation of succinate dehydrogenase subunit B and up-regulation of pyruvate dehydrogenase kinase 1 predicts poor prognosis in recurrent nasopharyngeal carcinoma. Tumor Biol. 37, 5145–5152 (2016). https://doi.org/10.1007/s13277-015-4107-6

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    • DOI: https://doi.org/10.1007/s13277-015-4107-6

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