Distinct temporospatial expression patterns of glycolysis-related proteins in human hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) represents the sixth most frequent human cancer worldwide and is characterized by rapid progression as well as resistance to systemic chemotherapy. Recently, glycolysis has emerged as a potent driving force of tumor growth and therapy failure. The precise role of glycolysis for the pathogenesis of human HCC has not been elucidated thus far. Therefore, we have conducted a comprehensive analysis of the expression patterns of central glycolysis-related factors [glucose transporter-1 and -2 (Glut-1 and Glut-2), phosphoglycerate kinase-1 (PGK-1) and hypoxia-inducible factor-1alpha (HIF-1alpha)] in a large cohort of benign and malignant human liver samples. PGK-1 protein and gene expression was scant in normal liver, elevated in cirrhotic livers and most intense in HCC. Strong immunoreactivity of Glut-2 was noted in cirrhotic livers, whereas in HCC it was only expressed in 50% of examined cases. Strikingly, PGK-1 as well as Glut-2 protein expression was indicative of poor patient prognosis. Glut-1 protein was absent in neoplastic hepatocytes but prominent in tumor-associated endothelial cells. Specific nuclear staining of HIF-1alpha was noted in only 12% of HCC samples. Our data point toward a tumor-promoting function of glycolysis in HCC and establish PGK-1 as an independent prognostic parameter. Furthermore, the endothelial-specific expression of Glut-1 makes a special dependence of vessels on glucose reasonable to assume. In summary, we believe our analysis warrants the validation of glycolytic inhibitors as innovative treatment approaches of human HCC.
Medizinische Klink mit Schwerpunkt Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.
Katjana
K
Daskalow
David
D
Pfander
Wilko
W
Weichert
Nadine
N
Rohwer
Armin
A
Thelen
Peter
P
Neuhaus
Sven
S
Jonas
Bertram
B
Wiedenmann
Christoph
C
Benckert
Thorsten
T
Cramer
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D006019:Glycolysis; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D010735:Phosphoglycerate Kinase / Q000378:metabolism; D055815:Young Adult
D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D010735:Phosphoglycerate Kinase