본문 바로가기
KERD
논문KCI 등재

Prognostic Significance of Glycolytic Metabolic Change Related to HIF-1α in Oral Squamous Cell Carcinomas

2

조회

0

다운로드

0

인용

0

참고문헌

키워드

주제분류병리학

초록

Background : Growing tumors adapt to a hypoxic environment and increase anaerobic glycolysis. This metabolic switch is related to aggressive behavior. We investigated the relationship between glycolytic metabolism biomarkers associated with hypoxia-inducible factor (HIF)-1α and prognosis. Methods : We performed immunohistochemical staining of HIF-1a, pyruvate dehydrogenase kinase (PDK) 1 and lactate dehydrogenase (LDH) 5 in 74 patients with oral squamous cell carcinoma (SCC) who had received curative radical resection. Results : High reactivity of HIF-1α, PDK 1 and LDH 5 was observed in 29 (39.2%), 32 (43.2%) and 54 (73.0%) patients, respectively. Expression levels of the three biomarkers were significantly correlated. All three markers were highly expressed in 16 (21.6%) patients. Elevated expression of the three markers was associated with increased invasiveness (p = 0.043) and recurrence (p = 0.017) of tumors. In survival analysis, upregulation of the three markers was additionally associated with shorter disease free survival (DFS, p = 0.001) and overall survival (OS, p = 0.002). High expression of all three markers was a strong independent prognostic factor for DFS (p = 0.030) and OS (p = 0.026). Conclusions : Oral SCC with altered glycolytic metabolism exhibits a more invasive and aggressive phenotype. Our results indicate that glycolytic metabolism biomarkers related to HIF-1α may be independent prognostic factors in patients with oral SCC.

Abstract

Background : Growing tumors adapt to a hypoxic environment and increase anaerobic glycolysis. This metabolic switch is related to aggressive behavior. We investigated the relationship between glycolytic metabolism biomarkers associated with hypoxia-inducible factor (HIF)-1α and prognosis. Methods : We performed immunohistochemical staining of HIF-1a, pyruvate dehydrogenase kinase (PDK) 1 and lactate dehydrogenase (LDH) 5 in 74 patients with oral squamous cell carcinoma (SCC) who had received curative radical resection. Results : High reactivity of HIF-1α, PDK 1 and LDH 5 was observed in 29 (39.2%), 32 (43.2%) and 54 (73.0%) patients, respectively. Expression levels of the three biomarkers were significantly correlated. All three markers were highly expressed in 16 (21.6%) patients. Elevated expression of the three markers was associated with increased invasiveness (p = 0.043) and recurrence (p = 0.017) of tumors. In survival analysis, upregulation of the three markers was additionally associated with shorter disease free survival (DFS, p = 0.001) and overall survival (OS, p = 0.002). High expression of all three markers was a strong independent prognostic factor for DFS (p = 0.030) and OS (p = 0.026). Conclusions : Oral SCC with altered glycolytic metabolism exhibits a more invasive and aggressive phenotype. Our results indicate that glycolytic metabolism biomarkers related to HIF-1α may be independent prognostic factors in patients with oral SCC.

참고문헌 (29)

  1. Chen AY, "Changes in treatment of advanced oropharyngeal cancer,1985-2001", Laryngoscope, 117, pp.16~21 (2007)
  2. Stell PM, "Cancer of the head and neck:are we doing any better?", Lancet, 2, pp.1127~ (1985)
  3. Vaupel P, "Treatment resistance of solid tumors:role of hypoxia and anemia", Med Oncol, 18, pp.243~259 (2001)
  4. Nordsmark M, "Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy:an international multi-center study", Radiother Oncol, 77, pp.18~24 (2005)
  5. Semenza GL, "Targeting HIF-1 for cancer therapy", Nat Rev Cancer, 3, pp.721~732 (2003)
  6. Warburg O, "On the origin of cancer cells", Science, 123, pp.309~314 (1956)
  7. Semenza GL, "Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1", J Biol Chem, 269, pp.23757~3763 (1994)
  8. Semenza GL, "HIF-1 mediates the Warburg effect in clear cell renal carcinoma", J Bioenerg Biomembr, 39, pp.231~234 (2007)
  9. Koukourakis MI, "Lactate dehydrogenase 5 expression in operable colorectal cancer:strong association with survival and activated vascular endothelial growth factor pathway-a report of the Tumour Angiogenesis Research Group", J Clin Oncol, 24, pp.4301~4308 (2006)
  10. Lukacova S, "The impact of hypoxia on the activity of lactate dehydrogenase in two different pre-clinical tumour models", Acta Oncol, 47, pp.941~947 (2008)
  11. Wigfield SM, "PDK-1 regulates lactate production in hypoxia and is associated with poor prognosis in head and neck squamous cancer", Br J Cancer, 98, pp.1975~1984 (2008)
  12. Kim JW, "HIF-1-mediated expression of pyruvate dehydrogenase kinase:a metabolic switch required for cellular adaptation to hypoxia", Cell Metab, 3, pp.177~185 (2006)
  13. Aebersold DM, "Expression of hypoxiainducible factor-1alpha:a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer", Cancer Res, 61, pp.2911~2916 (2001)
  14. Koukourakis MI, "Hypoxia inducible factor(HIf1alpha and HIF2alpha)and carbonic anhydrase 9(CA9)expression and response of head-neck cancer to hypofractionated and accelerated radiotherapy", Int J Radiat Biol, 84, pp.47~52 (2008)
  15. Lartigau E, "Oxygenation of head and neck tumors", Cancer, 71, pp.2319~2325 (1993)
  16. Lartigau E, "Variations in tumour oxygen tension(pO2)during accelerated radiotherapy of head and neck carcinoma", Eur J Cancer, 34, pp.856~861 (1998)
  17. Pentenero M, "Importance of tumor thickness and depth of invasion in nodal involvement and prognosis of oral squamous cell carcinoma:a review of the literature", Head Neck, 27, pp.1080~1091 (2005)
  18. Cohen NA, "Dysregulation of hypoxia inducible factor-1alpha in head and neck squamous cell carcinoma cell lines correlates with invasive potential", Laryngoscope, 114, pp.418~423 (2004)
  19. Sahlgren C, "Notch signaling mediates hypoxia-induced tumor cell migration and invasion", Proc Natl Acad Sci U S A, 105, pp.6392~6397 (2008)
  20. Gatenby RA, "Why do cancers have high aerobic glycolysis?", Nat Rev Cancer, 4, pp.891~899 (2004)
  21. Lu H, "Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1", J Biol Chem, 280, pp.41928~1939 (2005)
  22. Katsuta M, "Correlation of hypoxia inducible factor-1alpha with lymphatic metastasis via vascular endothelial growth factor-C in human esophageal cancer", Exp Mol Pathol, 78, pp.123~130 (2005)
  23. Liang X, "Hypoxia inducible factor-alpha expression correlates with vascular endothelial growth factor-C expression and lymphangiogenesis", angiogenesis in oral squamous cell carcinoma, 2008, pp.28, 1659~1666
  24. Koukourakis MI, "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, 89, pp.877~885 (2003)
  25. Gatenby RA, "Acidmediated tumor invasion:a multidisciplinary study", Cancer Res, 66, pp.5216~5223 (2006)
  26. Elstrom RL, "Akt stimulates aerobic glycolysis in cancer cells", Cancer Res, 64, pp.3892~3899 (2004)
  27. Amornphimoltham P, "Persistent activation of the Akt pathway in head and neck squamous cell carcinoma:a potential target for UCN-01", Clin Cancer Res, 10, pp.4029~4037 (2004)
  28. Zhong H, "Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor", phosphatidylinositol 3-kinase, AKT, pp.FRAP pathway in human prostate cancer cells:implications for tumor angiogenesis and therapeutics, Cancer Res[DOI]
  29. Winter SC, "The relation between hypoxiainducible factor(HIF)-1alpha and HIF-2alpha expression with anemia and outcome in surgically treated head and neck cancer", Cancer, 107, pp.757~766 (2006)

관련 논문AI추천

Glucose Transporter-1 Expression in Squamous Cell Carcinoma of the Tongue김석진, 최윤석, Bong Kyung Shin, Byung Soo Kim, Dae Sik Kim, Hye Jin Shin, Jung Woo Choi, Jun Suk Kim, Kwang-Yoon Jung, Sang Won Shin, Seh Jong Park, Seung-Kuk Baek, Yeul Hong Kim, Yong Park대한암학회 · Cancer Research and Treatment2007 · 제39권 제3호The Clinicopathological Significance of Tissue Levels of Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor in Gastric CancerJoo Ho Lee, Ki-Nam Shim, Kwon Yoo, Seong-Eun Kim, Sung-Ae Jung거트앤리버 소화기연관학회협의회 · Gut and Liver2009 · 제3권 제2호Prognostic Relevance of the Expression of CA IX, GLUT-1, and VEGF in Ovarian Epithelial Cancers김경빈, 김지연, 박도윤, 박원용, 설미영, 신동훈, 이정희, 이창훈, 최경운대한병리학회 · Journal of Pathology and Translational Medicine2012 · 제46권 제6호The Influence of Glycolytic Enzyme Expression on the Aggressiveness of Papillary Thyroid Carcinoma Using TCGA DataChung Woong Youn, Jeong Jong Ju, Kang Sang-Wook, Kim Daham, Kim Jin Kyong, Kim Won Woong, Lee Jandee, Nam Kee-Hyun대한내분비외과학회 · Journal of Endocrine Surgery2025 · 제25권 제1호Correlation between glucose transporter type-1 expression and 18F-FDG uptake on PET in oral cancer김문영, 김철환대한구강악안면외과학회 · 대한구강악안면외과학회지2012 · 제38권 제4호Expression of vascular endothelial growth factor in oral squamous cell carcinoma김경욱, 김석곤, Seung-Goo Park대한구강악안면외과학회 · 대한구강악안면외과학회지2015 · 제41권 제1호

이 간행물의 다른 논문 (17건)