Role of cell-cycle turnover and oxidative stress in telomere shortening and cellular senescence in patients with chronic hepatitis C.
BACKGROUND
In addition to the telomere shortening that occurs with cell division, oxidative stress can damage or shorten telomeres and induce a condition termed premature senescence, possibly before telomeres become critically short. We investigated the effects of cell-cycle turnover and oxidative stress on cellular senescence in hepatitis C virus (HCV)-related chronic liver injury.


METHODS
Using quantitative fluorescence in situ hybridization, the telomere lengths of hepatocytes in biopsy specimens from HCV-positive patients were estimated. We assessed clinicopathological parameters that reflect cell-cycle turnover, including Ki-67 positive index, serum alanine aminotransferase (ALT) level and degree of fibrosis, and also oxidative stress-related parameters, such as 8-hydroxy-2'-deoxyguanosine (8-OHdG) expression. Nuclear size and DNA content of hepatocytes were measured as morphological features of senescence.


RESULTS
Telomere shortening correlated with the degree of cell turnover, hepatic fibrosis and morphological features of aging cells. Furthermore, the rate of telomere shortening per year was positively correlated with fibrosis progression. In cases of no or mild fibrosis, telomere lengths of positive patients were generally shorter than those of 8-OHdG-negative patients, and this trend achieved statistical significance in advanced-stage fibrosis. HCV carriers with persistently normal serum ALT level (PNAL) showed significantly longer telomeres than patients with active hepatitis and mild fibrosis. There was no significant difference in telomere lengths between HCV carriers with PNAL and normal controls.


CONCLUSIONS
Cell-cycle turnover is the primary mechanism of telomere shortening, and can induce fibrosis progression and cellular senescence. However, oxidative stress can be an accelerator of senescence, especially in advanced-stage fibrosis.
Sekoguchi
Satoru
S
Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan. ssekoguchi@ybb.ne.jp
Nakajima
Tomoki
T
Moriguchi
Michihisa
M
Jo
Masayasu
M
Nishikawa
Taichiro
T
Katagishi
Tatsuo
T
Kimura
Hiroyuki
H
Minami
Masahito
M
Itoh
Yoshito
Y
Kagawa
Keizo
K
Tani
Yoichi
Y
Okanoue
Takeshi
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002453:Cell Cycle; D016922:Cellular Senescence; D005260:Female; D019698:Hepatitis C, Chronic / Q000378:metabolism* / Q000473:pathology*; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D016615:Telomere / Q000378:metabolism*