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Tumor Biology

, Volume 37, Issue 3, pp 3887–3895 | Cite as

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

  • Xiaosheng He
  • Xutao Lin
  • Muyan Cai
  • Xiaobin Zheng
  • Lei Lian
  • Dejun Fan
  • Xiaojian Wu
  • Ping Lan
  • Jianping Wang
Original Article

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.

Keywords

Colorectal cancer Hexokinase Prognosis Biomarker 

Notes

Compliance with ethical standards

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

Conflicts of interest

None

Declaration of funding interests

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

References

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMedGoogle Scholar
  2. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. 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.CrossRefPubMedGoogle Scholar
  5. 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.PubMedGoogle Scholar
  6. 6.
    Smith TA. Mammalian hexokinases and their abnormal expression in cancer. Br J Biomed Sci. 2000;57:170–8.PubMedGoogle Scholar
  7. 7.
    Pastorino JG, Hoek JB. Hexokinase II: the integration of energy metabolism and control of apoptosis. Curr Med Chem. 2003;10:1535–51.CrossRefPubMedGoogle Scholar
  8. 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.CrossRefPubMedGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 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.PubMedGoogle Scholar
  11. 11.
    Battifora H. The multitumor (sausage) tissue block: novel method for immunohistochemical antibody testing. Lab Investig. 1986;55:244–8.PubMedGoogle Scholar
  12. 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.CrossRefPubMedGoogle Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 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.CrossRefPubMedGoogle Scholar
  15. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 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.CrossRefPubMedGoogle Scholar
  17. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Dang CV, Semenza GL. Oncogenic alterations of metabolism. Trends Biochem Sci. 1999;24:68–72.CrossRefPubMedGoogle Scholar
  20. 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.Google Scholar
  21. 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.CrossRefPubMedGoogle Scholar
  22. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Colombini M. VDAC structure, selectivity, and dynamics. Biochim Biophys Acta. 1818;2012:1457–65.Google Scholar
  26. 26.
    Takahashi Y, Tateda C. The functions of voltage-dependent anion channels in plants. Apoptosis. 2013;18:917–24.CrossRefPubMedGoogle Scholar
  27. 27.
    Martel C, Wang Z, Brenner C. VDAC phosphorylation, a lipid sensor influencing the cell fate. Mitochondrion. 2014.Google Scholar
  28. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. 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.CrossRefPubMedGoogle Scholar
  32. 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.CrossRefPubMedGoogle Scholar
  33. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Li H, Zeng J, Shen K. PI3K/AKT/mTOR signaling pathway as a therapeutic target for ovarian cancer. Arch Gynecol Obstet. 2014.Google Scholar
  36. 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.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Xiaosheng He
    • 1
    • 2
  • Xutao Lin
    • 1
    • 2
  • Muyan Cai
    • 3
    • 4
  • Xiaobin Zheng
    • 1
    • 2
  • Lei Lian
    • 1
    • 2
  • Dejun Fan
    • 1
    • 2
  • Xiaojian Wu
    • 1
    • 2
  • Ping Lan
    • 1
    • 2
  • Jianping Wang
    • 1
    • 2
  1. 1.Department of Colorectal Surgery, the Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhouChina
  2. 2.Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhouChina
  3. 3.State Key Laboratory of Oncology in South ChinaSun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer MedicineGuangzhouChina
  4. 4.Department of PathologySun Yat-sen University Cancer CenterGuangzhouChina

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