Yokota Takashi, Suda Takeshi, Igarashi Masato, Kuroiwa Takashi, Waguri Nobuo, Kawai Hirokazu, Mita Yusaku, Aoyagi Yutaka
Division of Gastroenterology and Hepatology, Department of Cellular Function, Graduate School of Medical and Dental Science, Niigata University, Niigata, Japan.
Cancer. 2003 Jul 1;98(1):110-8. doi: 10.1002/cncr.11428.
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.
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.
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.
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.
尽管最近发现了染色体间端粒长度变异，但端粒维持异质性的作用尚未确立。本研究调查了染色体间端粒长度变异在癌症进展与端粒长度调节关联方面的意义。
对20例手术切除的肝细胞癌标本（HCC）、相应的癌旁肝组织标本（NCL）以及10例无癌的慢性肝病肝组织标本（DOC）进行了末端限制片段（TRF）评估。平均TRF长度（TRF-A）定义为最大强度点。较短和较长的TRF长度（TRF-S和TRF-L）定义为包含90%TRF分布的长度以上。比率（TRF-L - TRF-S）/TRF-A定义为端粒长度离散度。
HCC标本中的离散度显著大于NCL标本（P = 0.012），NCL标本中的离散度显著大于DOC标本（P = 0.048）。HCC中的TRF-A和TRF-S显著短于NCL（P = 0.0026，P = 0.0010）。在1年内HCC复发的7例患者中，TRF-A和TRF-S显著短于1年后复发的10例患者（P = 0.018，P = 0.0097）。端粒重复结合因子1在TRF-L延长的HCC中上调，而人端粒酶逆转录酶在TRF-S较短的HCC中表达更高。
这些结果表明，端粒长度在慢性肝病过程中通过优先增加较短端粒而发生变化，其长度是HCC恶性潜能的良好指标。端粒长度变异可能是肝癌发生过程中端粒维持的关键密码。
