Oxidative stress may enhance the malignant potential of human hepatocellular carcinoma by telomerase activation.
OBJECTIVE
Continuous oxidative stress (OS) plays an important role in the progression of chronic liver diseases and hepatocarcinogenesis through telomere shortening in hepatocytes. However, it has not been established how the OS influences the progression of human hepatocellular carcinomas (HCCs). We examined the correlations of OS with telomere length of cancer cells, telomerase activity and other clinicopathological factors in 68 HCCs.


METHODS
The level of 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a marker of OS was examined immunohistochemically and OS was scored in four grades (0-3). The telomere length of cancer cells was measured by quantitative fluorescence in situ hybridization. Telomerase activity was measured by (i) immunodetection of human telomerase reverse transcriptase (hTERT) and (ii) telomere repeat amplification protocol (TRAP) assay. Telomerase related proteins, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and Akt, and other clinicopathological factors were also evaluated.


RESULTS
As the OS grade increased, the average telomere length became significantly shorter in HCCs, especially in the hTERT-negative group. In the state of high-grade OS, hTERT-positive HCC cells showed more proliferative and less apoptotic features compared with hTERT-negative HCC cells. Telomerase activity, as measured by the TRAP assay, was strongly correlated with OS grade in HCCs. Furthermore, a high OS grade was correlated with the downexpression of PTEN and the activation of Akt.


CONCLUSIONS
Oxidative stress enhanced the malignant potential of HCCs through the activation of telomerase, which raises the possibility of using OS as a marker for assessing the clinical state of HCCs.
Nishikawa
Taichiro
T
Kyoto Prefectural University of Medicine Graduate School of Medical Science, Molecular Gastroenterology and Hepatology, Kyoto, Japan. liverresearch2004@yahoo.co.jp
Nakajima
Tomoki
T
Katagishi
Tatsuo
T
Okada
Yoshihisa
Y
Jo
Masayasu
M
Kagawa
Keizo
K
Okanoue
Takeshi
T
Itoh
Yoshito
Y
Yoshikawa
Toshikazu
T
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D018450:Disease Progression; D004789:Enzyme Activation / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D020287:In Situ Nick-End Labeling; D008113:Liver Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere / Q000502:physiology*
D000080242:8-Hydroxy-2'-Deoxyguanosine; D019098:Telomerase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D003849:Deoxyguanosine