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Overexpression of Hexokinase 1 as a poor prognosticator in human colorectal cancer

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Tumor Biology

Abstract

It has been suggested that hexokinase 1 (HK1) is involved in tumorigenesis. However, the expression dynamics of HK1 and its prognostic significance in human colorectal cancer (CRC) still remain unclear. The aim of the present study was to investigate the expression of HK1 and its prognostic significance in CRC. In this study, immunohistochemical analysis was used to examine the expression dynamics of HK1 in CRC tissues from two independent cohorts. Receiver operating characteristic curve analysis, Kaplan–Meier curves, and Cox regression analysis were utilized to investigate the prognostic significance. Results showed that a high expression of HK1 was observed in 106 of 393 (27.0 %) and 69 of 229 (30.1 %) of CRC in the training cohort and validation cohort, respectively. Further correlation analyses indicated that the increased HK1 expression was strongly correlated with the pN classification and TNM stage. Both cohorts showed a close association between the overexpression of HK1 and poorer overall survival. Importantly, multivariate analysis identified HK1 expression in CRC as an independent prognostic factor. Overexpression of HK1 may act as a significant biomarker of poor prognosis for patients with CRC.

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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. Mitry E, Rachet B, Quinn MJ, Cooper N, Coleman MP. Survival from cancer of the rectum in England and Wales up to 2001. Br J Cancer. 2008;99 Suppl 1:S30–2.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Brenner H, Bouvier AM, Foschi R, Hackl M, Larsen IK, Lemmens V, et al. Progress in colorectal cancer survival in Europe from the late 1980s to the early 21st century: the EUROCARE study. Int J Cancer. 2012;131:1649–58.

    Article  CAS  PubMed  Google Scholar 

  4. Wu XR, He XS, Chen YF, Yuan RX, Zeng Y, Lian L, et al. High expression of CD73 as a poor prognostic biomarker in human colorectal cancer. J Surg Oncol. 2012;106:130–7.

    Article  CAS  PubMed  Google Scholar 

  5. Zou Y, Chen Y, Wu X, Yuan R, Cai Z, He X, et al. CCL21 as an independent favorable prognostic factor for stage III/IV colorectal cancer. Oncol Rep. 2013;30:659–66.

    CAS  PubMed  Google Scholar 

  6. Smith TA. Mammalian hexokinases and their abnormal expression in cancer. Br J Biomed Sci. 2000;57:170–8.

    CAS  PubMed  Google Scholar 

  7. Pastorino JG, Hoek JB. Hexokinase II: the integration of energy metabolism and control of apoptosis. Curr Med Chem. 2003;10:1535–51.

    Article  CAS  PubMed  Google Scholar 

  8. Hooft L, van der Veldt AA, van Diest PJ, Hoekstra OS, Berkhof J, Teule GJ, et al. [18F]fluorodeoxyglucose uptake in recurrent thyroid cancer is related to hexokinase i expression in the primary tumor. J Clin Endocrinol Metab. 2005;90:328–34.

    Article  CAS  PubMed  Google Scholar 

  9. Millon SR, Ostrander JH, Brown JQ, Raheja A, Seewaldt VL, Ramanujam N. Uptake of 2-NBDG as a method to monitor therapy response in breast cancer cell lines. Breast Cancer Res Treat. 2011;126:55–62.

    Article  CAS  PubMed  Google Scholar 

  10. Oparina NY, Snezhkina AV, Sadritdinova AF, Veselovskii VA, Dmitriev AA, Senchenko VN, et al. Differential expression of genes that encode glycolysis enzymes in kidney and lung cancer in humans. Genetika. 2013;49:814–23.

    PubMed  Google Scholar 

  11. Battifora H. The multitumor (sausage) tissue block: novel method for immunohistochemical antibody testing. Lab Investig. 1986;55:244–8.

    CAS  PubMed  Google Scholar 

  12. Zlobec I, Steele R, Terracciano L, Jass JR, Lugli A. Selecting immunohistochemical cut-off scores for novel biomarkers of progression and survival in colorectal cancer. J Clin Pathol. 2007;60:1112–6.

    Article  PubMed  Google Scholar 

  13. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4.

    Article  CAS  PubMed  Google Scholar 

  14. Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, et al. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol. 2009;27:186–92.

    Article  PubMed  Google Scholar 

  15. Nosho K, Baba Y, Tanaka N, Shima K, Hayashi M, Meyerhardt JA, et al. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol. 2010;222:350–66.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Huang Y, Li W, Chu D, Zheng J, Ji G, Li M, et al. Overexpression of matrix metalloproteinase-21 is associated with poor overall survival of patients with colorectal cancer. J Gastrointest Surg. 2011;15:1188–94.

    Article  PubMed  Google Scholar 

  17. Lin KY, Tai C, Hsu JC, Li CF, Fang CL, Lai HC, et al. Overexpression of nuclear protein kinase CK2 alpha catalytic subunit (CK2alpha) as a poor prognosticator in human colorectal cancer. PLoS One. 2011;6, e17193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lin AY, Chua MS, Choi YL, Yeh W, Kim YH, Azzi R, et al. Comparative profiling of primary colorectal carcinomas and liver metastases identifies LEF1 as a prognostic biomarker. PLoS One. 2011;6, e16636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Oronsky BT, Oronsky N, Fanger GR, Parker CW, Caroen SZ, Lybeck M, et al. Follow the ATP: tumor energy production. A perspective. Anticancer Agents Med Chem. 2014.

  21. Bryson JM, Coy PE, Gottlob K, Hay N, Robey RB. Increased hexokinase activity, of either ectopic or endogenous origin, protects renal epithelial cells against acute oxidant-induced cell death. J Biol Chem. 2002;277:11392–400.

    Article  CAS  PubMed  Google Scholar 

  22. Azoulay-Zohar H, Israelson A, Abu-Hamad S, Shoshan-Barmatz V. In self-defence: hexokinase promotes voltage-dependent anion channel closure and prevents mitochondria-mediated apoptotic cell death. Biochem J. 2004;377:347–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sun L, Shukair S, Naik TJ, Moazed F, Ardehali H. Glucose phosphorylation and mitochondrial binding are required for the protective effects of hexokinases I and II. Mol Cell Biol. 2008;28:1007–17.

    Article  CAS  PubMed  Google Scholar 

  24. Maldonado EN, Lemasters JJ. Warburg revisited: regulation of mitochondrial metabolism by voltage-dependent anion channels in cancer cells. J Pharmacol Exp Ther. 2012;342:637–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Colombini M. VDAC structure, selectivity, and dynamics. Biochim Biophys Acta. 1818;2012:1457–65.

    Google Scholar 

  26. Takahashi Y, Tateda C. The functions of voltage-dependent anion channels in plants. Apoptosis. 2013;18:917–24.

    Article  CAS  PubMed  Google Scholar 

  27. Martel C, Wang Z, Brenner C. VDAC phosphorylation, a lipid sensor influencing the cell fate. Mitochondrion. 2014.

  28. Rathmell JC, Fox CJ, Plas DR, Hammerman PS, Cinalli RM, Thompson CB. Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival. Mol Cell Biol. 2003;23:7315–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bhatia B, Potts CR, Guldal C, Choi S, Korshunov A, Pfister S, et al. Hedgehog-mediated regulation of PPARgamma controls metabolic patterns in neural precursors and shh-driven medulloblastoma. Acta Neuropathol. 2012;123:587–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wolf A, Agnihotri S, Munoz D, Guha A. Developmental profile and regulation of the glycolytic enzyme hexokinase 2 in normal brain and glioblastoma multiforme. Neurobiol Dis. 2011;44:84–91.

    Article  CAS  PubMed  Google Scholar 

  31. Clatot F, Gouerant S, Mareschal S, Cornic M, Berghian A, Choussy O, et al. The gene expression profile of inflammatory, hypoxic and metabolic genes predicts the metastatic spread of human head and neck squamous cell carcinoma. Oral Oncol. 2014;50:200–7.

    Article  CAS  PubMed  Google Scholar 

  32. Li W, Xu Z, Hong J, Xu Y. Expression patterns of three regulation enzymes in glycolysis in esophageal squamous cell carcinoma: association with survival. Med Oncol. 2014;31:118.

    Article  CAS  PubMed  Google Scholar 

  33. Tsouko E, Khan AS, White MA, Han JJ, Shi Y, Merchant FA, et al. Regulation of the pentose phosphate pathway by an androgen receptor-mTOR-mediated mechanism and its role in prostate cancer cell growth. Oncogenesis. 2014;3, e103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Paplomata E, O’Regan R. The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers. Ther Adv Med Oncol. 2014;6:154–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li H, Zeng J, Shen K. PI3K/AKT/mTOR signaling pathway as a therapeutic target for ovarian cancer. Arch Gynecol Obstet. 2014.

  36. Beck JT, Ismail A, Tolomeo C. Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway: an emerging treatment strategy for squamous cell lung carcinoma. Cancer Treat Rev. 2014;40:980–9.

    Article  CAS  PubMed  Google Scholar 

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Author notes

    Authors and Affiliations

    1. Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, Guangzhou, 510655, China

      Xiaosheng He, Xutao Lin, Xiaobin Zheng, Lei Lian, Dejun Fan, Xiaojian Wu, Ping Lan & Jianping Wang

    2. Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Road, Guangdong, Guangzhou, 510655, China

      Xiaosheng He, Xutao Lin, Xiaobin Zheng, Lei Lian, Dejun Fan, Xiaojian Wu, Ping Lan & Jianping Wang

    3. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangdong, Guangzhou, 510060, China

      Muyan Cai

    4. Department of Pathology, Sun Yat-sen University Cancer Center, Guangdong, Guangzhou, 510060, China

      Muyan Cai

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    1. Xiaosheng He
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    2. Xutao Lin
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    9. Jianping Wang
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    Correspondence to Jianping Wang.

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    This study was approved by the IRB of the Sixth Affiliated Hospital and Cancer Center, Sun Yat-sen University.

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    Declaration of funding interests

    This work is supported by the National Natural Science Foundation of China (81400604).

    Additional information

    Xiaosheng He, Xutao Lin and Muyan Cai contributed equally to this work.

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    He, X., Lin, X., Cai, M. et al. Overexpression of Hexokinase 1 as a poor prognosticator in human colorectal cancer. Tumor Biol. 37, 3887–3895 (2016). https://doi.org/10.1007/s13277-015-4255-8

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    • DOI: https://doi.org/10.1007/s13277-015-4255-8

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