Risk prediction for malignant conversion of oral epithelial dysplasia by hypoxia related protein expression

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Authors: XIANGLAN ZHANG ; SEONHUI HAN ; HYE-YEON HAN ; MI HEON RYU ; KI-YEOL KIM ; EUN-JOO CHOI ; IN-HO CHA ; JIN KIM

MeSH: Antigens, Neoplasm/genetics ; Antigens, Neoplasm/metabolism* ; Biomarkers, Tumor/metabolism ; Carbonic Anhydrase IX ; Carbonic Anhydrases/genetics ; Carbonic Anhydrases/metabolism* ; Carcinoma, Squamous Cell/genetics ; Carcinoma, Squamous Cell/metabolism ; Carcinoma, Squamous Cell/pathology* ; Cell Line ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Cell Transformation, Neoplastic/pathology* ; Disease Progression ; Epithelium/metabolism ; Epithelium/pathology ; Female ; Gene Expression Regulation, Neoplastic ; Glucose Transporter Type 1/genetics ; Glucose Transporter Type 1/metabolism* ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Male ; Middle Aged ; Mouth/metabolism ; Mouth/pathology* ; Mouth Neoplasms/metabolism ; Mouth Neoplasms/pathology* ; Precancerous Conditions/epidemiology ; Precancerous Conditions/metabolism ; Precancerous Conditions/pathology ; Predictive Value of Tests ; Risk Factors

Abstract: AIMS:
Increased aerobic glycolysis is a unique finding in cancers and hypoxia-related proteins are associated with aerobic glycolysis. Therefore, we aimed to investigate whether hypoxia-related proteins can be predictive markers for malignant conversion of oral premalignant lesions with epithelial dysplasia (OED).
METHODS:
Expression of HIF-1α, Glut-1 and CA9 were detected in clinical samples of eight normal oral mucosa, 85 transitional areas of oral squamous cell carcinoma (OSCC) and 28 OED with or without malignant conversion using immunohistochemistry and were also comparatively detected in immortalised human oral keratinocyte (IHOK) and OSCC cell lines under hypoxia using immunoblotting.
RESULTS:
Sequential expression of HIF-1α, Glut-1 and CA9 was found both in transitional areas of OSCC and cell lines of IHOK and OSCC under hypoxia, supporting hypoxia-aerobic glycolysis-acidosis axis. Expression of all proteins showed significant association with malignant conversion of OED and CA9 was an independent risk factor of malignant transformation of OED. But the predictability of malignant transformation was improved when all three proteins were applied together.
CONCLUSION:
High expression of CA9 was an independent predictive marker of malignant conversion. Moreover, the combined application of these three proteins may be useful to assess the risk of malignant conversion of OED.