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Evaluation of the role of hexokinase type II in cellular proliferation and apoptosis using human hepatocellular carcinoma cell lines.

 Keun Jae Ahn  ;  Hee Sung Hwang  ;  Jeon Han Park  ;  Seong Hye Bang  ;  Won Jun Kang  ;  Mijin Yun  ;  Jong Doo Lee 
 JOURNAL OF NUCLEAR MEDICINE, Vol.50(9) : 1525-1532, 2009 
Journal Title
Issue Date
Apoptosis ; Carcinoma, Hepatocellular/diagnostic imaging* ; Carcinoma, Hepatocellular/enzymology* ; Cell Line, Tumor ; Cell Proliferation ; Fluorodeoxyglucose F18/pharmacokinetics* ; Hexokinase/metabolism* ; Humans ; Liver Neoplasms/diagnostic imaging* ; Liver Neoplasms/enzymology* ; Radionuclide Imaging ; Radiopharmaceuticals/pharmacokinetics
hepatocellular carcinoma ; hexokinase ; F-FDG uptake ; PI3K/Akt signaling ; prognosis
The (18)F-FDG uptake pattern on PET could be an indicator of the prognosis and aggressiveness of various tumors, including hepatocellular carcinoma (HCC). Hexokinase, especially hexokinase type II (HKII), plays a critical role in (18)F-FDG uptake in rapidly growing tumors. We established a stable cell line overexpressing HKII by the transfection of full DNA of HKII to HCC cells (SNU449) that express low levels of HKII and investigated how (18)F-FDG uptake mechanisms, especially overexpression of HKII, are linked to tumor proliferation mechanisms.

METHODS: The HKII gene was stably transfected to SNU449 cells with an expression vector. HKII expression in the cells was verified by reverse-transcriptase polymerase chain reaction, Western blot analysis, adenosine triphosphate (ATP) and lactate production, (18)F-FDG uptake measurement, and confocal microscopy. Cellular proliferation activity and response to the anticancer drug cisplatin were evaluated by cell counting using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. For the evaluation of molecular pathways involved in tumor proliferation, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway was investigated.

RESULTS: The stable cell line produced HKII effectively, but expression of other enzymes or transporters for glycolysis, such as glucose-6-phosphatase (G6Pase), HKI and III, and glucose transporter type 1 and 2 (Glut-1 and Glut-2), did not show any changes. (18)F-FDG uptake was significantly increased after transfection. ATP and lactate production was also increased after transfection. Overexpressed HKII was associated with mitochondria on confocal microscopy. Cells with overexpression of HKII, compared with the nontransfected cell line, showed 1.5- to 2-fold higher cell survival and resistance to the anticancer agent cisplatin (2- to 8-fold). In the molecular study, the activated form of Akt was increased after transfection, and PI3K inhibitor dissociated the mitochondrial HKII to the cytoplasm. In addition, the adenosine monophosphate-activated protein kinase (AMPK) pathway is also involved in Akt signaling.

CONCLUSION: HKII plays an important role in (18)F-FDG uptake and tumor proliferation by both the PI3K-dependent and the PI3K-independent Akt signal pathways; therefore, the (18)F-FDG uptake pattern on a PET scan can be a surrogate marker of prognosis in HCC.
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1. College of Medicine (의과대학) > Dept. of Dermatology (피부과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
Yonsei Authors
Kang, Won Jun(강원준) ORCID logo https://orcid.org/0000-0002-2107-8160
Park, Jeon Han(박전한) ORCID logo https://orcid.org/0000-0001-9604-3205
Ahn, Keun Jae(안근재)
Yun, Mi Jin(윤미진) ORCID logo https://orcid.org/0000-0002-1712-163X
Lee, Jong Doo(이종두)
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