Telomere length variation and maintenance in hepatocarcinogenesis.
BACKGROUND
Despite the recent discovery of interchromosomal telomere length variation, a role for heterogeneity in telomere maintenance has yet to be established. This study investigated the significance of telomere length variation between chromosomes with respect to the association of cancer progression and telomere length regulation.


METHODS
Terminal restriction fragment (TRF) was evaluated in 20 surgically resected hepatocellular carcinoma specimens (HCC), corresponding noncancerous liver tissue specimens (NCL), and in 10 liver tissue specimens with chronic liver diseases devoid of cancer (DOC). Average TRF length (TRF-A) was defined as the point of maximum intensity. Shorter and longer TRF lengths (TRF-S and TRF-L) were defined as the length above which 90% of TRF distribution was involved. A ratio, (TRF-L-TRF-S)/TRF-A, was defined as telomere length dispersion.


RESULTS
The dispersion was significantly larger in HCC than in NCL specimens (P = 0.012) and in NCL than in DOC (P = 0.048). TRF-A and TRF-S were significantly shorter in HCC than in NCL (P = 0.0026, P = 0.0010). In seven patients in whom HCC recurred within 1 year, TRF-A and TRF-S were significantly shorter than in 10 patients in whom recurrence occurred after 1 year (P = 0.018, P = 0.0097). Telomeric repeat binding factor 1 was up-regulated in HCC with elongated TRF-L, whereas expression of human telomerase reverse transcriptase was greater in HCC with a shorter TRF-S.


CONCLUSIONS
These results suggest that telomere length varied through chronic liver diseases by preferentially increasing shorter telomeres, whose length is a good indicator for malignant potential of HCC. Telomere length variation may be a crucial code in telomere maintenance through hepatocarcinogenesis.
Yokota
Takashi
T
Division of Gastroenterology and Hepatology, Department of Cellular Function, Graduate School of Medical and Dental Science, Niigata University, Niigata, Japan.
Suda
Takeshi
T
Igarashi
Masato
M
Kuroiwa
Takashi
T
Waguri
Nobuo
N
Kawai
Hirokazu
H
Mita
Yusaku
Y
Aoyagi
Yutaka
Y
D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins; D018450:Disease Progression; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D016615:Telomere / Q000235:genetics* / Q000378:metabolism; D035321:Telomeric Repeat Binding Protein 1 / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; D035321:Telomeric Repeat Binding Protein 1; D019098:Telomerase