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Suppressed expression of LDHB promotes pancreatic cancer progression via inducing glycolytic phenotype

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Abstract

Lactate dehydrogenase B (LDHB) is widely expressed in adult somatic tissue and is one of the two subunits of lactate dehydrogenase, which is the key glycolytic enzyme and catalyzes the interconversion of pyruvate and lactate. However, the roles of LDHB in glycolysis and tumor progression were obscure in different types of cancer. Here, we determined the roles of LDHB in pancreatic cancer development and progression. We found suppressed expression of LDHB in pancreatic cancer which was due to promoter hypermethylation and deceased expression of LDHB led to glycolytic transition. Functional analysis revealed that suppressed expression of LDHB promoted pancreatic cancer cells proliferation, invasion, and migration in hypoxia. Thus, LDHB might function as a suppressor of glycolysis and suppressed pancreatic cancer progression.

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References

  1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  2. Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, Locasale JW, Son J, Zhang H, Coloff JL, et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell. 2012;149:656–70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Osthus RC, Shim H, Kim S, Li Q, Reddy R, Mukherjee M, Xu Y, Wonsey D, Lee LA, Dang CV. Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem. 2000;275:21797–800.

    Article  CAS  PubMed  Google Scholar 

  4. Dang CV, Semenza GL. Oncogenic alterations of metabolism. Trends Biochem Sci. 1999;24:68–72.

    Article  CAS  PubMed  Google Scholar 

  5. Drent M, Cobben NA, Henderson RF, Wouters EF, van Dieijen-Visser M. Usefulness of lactate dehydrogenase and its isoenzymes as indicators of lung damage or inflammation. Eur Respir J. 1996;9:1736–42.

    Article  CAS  PubMed  Google Scholar 

  6. Koukourakis MI, Kontomanolis E, Giatromanolaki A, Sivridis E, Liberis V. Serum and tissue LDH levels in patients with breast/gynaecological cancer and benign diseases. Gynecol Obstet Invest. 2009;67:162–8.

    Article  CAS  PubMed  Google Scholar 

  7. Koukourakis MI, Giatromanolaki A, Sivridis E, Bougioukas G, Didilis V, Gatter KC, Harris AL. Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis. Br J Cancer. 2003;89:877–85.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Koukourakis MI, Giatromanolaki A, Simopoulos C, Polychronidis A, Sivridis E. Lactate dehydrogenase 5 (LDH5) relates to up-regulated hypoxia inducible factor pathway and metastasis in colorectal cancer. Clin Exp Metastas. 2005;22:25–30.

    Article  CAS  Google Scholar 

  9. Shim H, Dolde C, Lewis BC, Wu CS, Dang G, Jungmann RA, Dalla-Favera R, Dang CV. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc Natl Acad Sci USA. 1997;94:6658–63.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Lin Q, Cong X, Yun Z. Differential hypoxic regulation of hypoxia-inducible factors 1alpha and 2alpha. Mol Cancer Res. 2011;9:757–65.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Leiblich A, Cross SS, Catto JW, Phillips JT, Leung HY, Hamdy FC, Rehman I. Lactate dehydrogenase-B is silenced by promoter hypermethylation in human prostate cancer. Oncogene. 2006;25:2953–60.

    Article  CAS  PubMed  Google Scholar 

  12. Maekawa M, Taniguchi T, Ishikawa J, Sugimura H, Sugano K, Kanno T. Promoter hypermethylation in cancer silences LDHB, eliminating lactate dehydrogenase isoenzymes 1-4. Clin Chem. 2003;49:1518–20.

    Article  CAS  PubMed  Google Scholar 

  13. Dennison JB, Molina JR, Mitra S, Gonzalez-Angulo AM, Balko JM, Kuba MG, Sanders ME, Pinto JA, Gomez HL, Arteaga CL, et al. Lactate dehydrogenase B: a metabolic marker of response to neoadjuvant chemotherapy in breast cancer. Clin Cancer Res. 2013;19:3703–13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. McCleland ML, Adler AS, Shang Y, Hunsaker T, Truong T, Peterson D, Torres E, Li L, Haley B, Stephan JP, et al. An integrated genomic screen identifies LDHB as an essential gene for triple-negative breast cancer. Cancer Res. 2012;72:5812–23.

    Article  CAS  PubMed  Google Scholar 

  15. Kim JH, Kim EL, Lee YK, Park CB, Kim BW, Wang HJ, Yoon CH, Lee SJ, Yoon G. Decreased lactate dehydrogenase B expression enhances claudin 1-mediated hepatoma cell invasiveness via mitochondrial defects. Exp Cell Res. 2011;317:1108–18.

    Article  CAS  PubMed  Google Scholar 

  16. 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 

  17. Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605–17.

    Article  CAS  PubMed  Google Scholar 

  18. Cui J, Shi M, Xie D, Wei D, Jia Z, Zheng S, Gao Y, Huang S, Xie K. FOXM1 promotes the warburg effect and pancreatic cancer progression via transactivation of LDHA expression. Clin Cancer Res. 2014;20:2595–606.

    Article  CAS  PubMed  Google Scholar 

  19. Shi M, Cui J, Du J, Wei D, Jia Z, Zhang J, Zhu Z, Gao Y, Xie K. A novel KLF4/LDHA signaling pathway regulates aerobic glycolysis in and progression of pancreatic cancer. Clin Cancer Res. 2014;20:4370–80.

    Article  CAS  PubMed  Google Scholar 

  20. Wang L, Wei D, Huang S, Peng Z, Le X, Wu TT, Yao J, Ajani J, Xie K. Transcription factor Sp1 expression is a significant predictor of survival in human gastric cancer. Clin Cancer Res. 2003;9:6371–80.

    CAS  PubMed  Google Scholar 

  21. Ginjala V, Nacerddine K, Kulkarni A, Oza J, Hill SJ, Yao M, Citterio E, van Lohuizen M, Ganesan S. BMI1 is recruited to DNA breaks and contributes to DNA damage-induced H2A ubiquitination and repair. Mol Cell Biol. 2011;31:1972–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Chen S, Sheng C, Liu D, Yao C, Gao S, Song L, Jiang W, Li J, Huang W. Enhancer of zeste homolog 2 is a negative regulator of mitochondria-mediated innate immune responses. J Immunol. 2013;191:2614–23.

    Article  CAS  PubMed  Google Scholar 

  23. Xue J, Lin X, Chiu WT, Chen YH, Yu G, Liu M, Feng XH, Sawaya R, Medema RH, Hung MC, et al. Sustained activation of SMAD3/SMAD4 by FOXM1 promotes TGF-beta-dependent cancer metastasis. J Clin Invest. 2014;124:564–79.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Khoo CP, Micklem K, Watt SM. A comparison of methods for quantifying angiogenesis in the Matrigel assay in vitro. Tissue Eng Part C Methods. 2011;17:895–906.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Draoui N, Feron O. Lactate shuttles at a glance: from physiological paradigms to anti-cancer treatments. Dis Model Mech. 2011;4:727–32.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006;439:871–4.

    Article  CAS  PubMed  Google Scholar 

  27. Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M, Zimmerman J, Eden E, Yakhini Z, Ben-Shushan E, Reubinoff BE, et al. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet. 2007;39:232–6.

    Article  CAS  PubMed  Google Scholar 

  28. Raaphorst FM. Deregulated expression of Polycomb-group oncogenes in human malignant lymphomas and epithelial tumors. Hum Mol Genet. 2005;14:R93–100.

    Article  CAS  PubMed  Google Scholar 

  29. Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, Harris AL. Pyruvate dehydrogenase and pyruvate dehydrogenase kinase expression in non small cell lung cancer and tumor-associated stroma. Neoplasia. 2005;7:1–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundfor K, Rofstad EK, Mueller-Klieser W. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res. 2000;60:916–21.

    CAS  PubMed  Google Scholar 

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Acknowledgments

Supported by Shanghai Jiao Tong University Oversea Training Scholarship (to J. Cui and M. Quan); Grants 81171887 and 91229117 from the National Natural Science Foundation of China (to L. Wang).

Conflict of interest

No potential conflicts of interest were disclosed.

Ethical standard

The use of the tissue microarray was approved by the medical ethics committee.

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    Authors and Affiliations

    1. Department of Oncology, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200080, People’s Republic of China

      Jiujie Cui, Weihua Jiang, Hai Hu, Feng Jiao, Ning Li, Ziliang Jin, Lei Wang, Yu Wang & Liwei Wang

    2. Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

      Jiujie Cui & Ming Quan

    3. Shanghai Key Laboratory of Pancreatic Diseases, Shanghai, 200080, People’s Republic of China

      Jiujie Cui, Ming Quan, Weihua Jiang, Hai Hu, Feng Jiao, Ning Li, Ziliang Jin, Lei Wang, Yu Wang & Liwei Wang

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    1. Jiujie Cui
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    Correspondence to Liwei Wang.

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    Jiujie Cui and Ming Quan have contributed equally to this work.

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    Cui, J., Quan, M., Jiang, W. et al. Suppressed expression of LDHB promotes pancreatic cancer progression via inducing glycolytic phenotype. Med Oncol 32, 143 (2015). https://doi.org/10.1007/s12032-015-0589-8

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    • DOI: https://doi.org/10.1007/s12032-015-0589-8

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