title: GLUT1 expression is increased in hepatocellular carcinoma and promotes tumorigenesis.
abstract: Accelerated glycolysis is one of the biochemical characteristics of cancer cells. The glucose transporter isoform 1 (GLUT1) gene encodes a key rate-limiting factor in glucose transport into cancer cells. However, its expression level and functional significance in hepatocellular cancer (HCC) are still disputed. Therefore, we aimed to analyze the expression and function of the GLUT1 gene in cases of HCC. We found significantly higher GLUT1 mRNA expression levels in HCC tissues and cell lines compared with primary human hepatocytes and matched nontumor tissue. Immunohistochemical analysis of a tissue microarray of 152 HCC cases revealed a significant correlation between Glut1 protein expression levels and a higher Ki-67 labeling index, advanced tumor stages, and poor differentiation. Accordingly, suppression of GLUT1 expression by siRNA significantly impaired both the growth and migratory potential of HCC cells. Furthermore, inhibition of GLUT1 expression reduced both glucose uptake and lactate secretion. Hypoxic conditions further increased GLUT1 expression levels in HCC cells, and this induction was dependent on the activation of the transcription factor hypoxia-inducible factor-1alpha. In summary, our findings suggest that increased GLUT1 expression levels in HCC cells functionally affect tumorigenicity, and thus, we propose GLUT1 as an innovative therapeutic target for this highly aggressive tumor.
authors.affiliation: University of Regensburg, Department of Internal Medicine I, D-93042 Regensburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Amann
authors.forename: Ulrike
authors.initials: U
authors.lastname: Maegdefrau
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Abbas
authors.initials: A
authors.lastname: Agaimy
authors.forename: Jörg
authors.initials: J
authors.lastname: Marienhagen
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Weiss
authors.forename: Oliver
authors.initials: O
authors.lastname: Stoeltzing
authors.forename: Christina
authors.initials: C
authors.lastname: Warnecke
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schölmerich
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oefner
authors.forename: Marina
authors.initials: M
authors.lastname: Kreutz
authors.forename: Anja K
authors.initials: AK
authors.lastname: Bosserhoff
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
mesh_terms: D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D014162:Transfection
chemical_list: D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; C495677:SLC2A1 protein, human