Risques Rosa Ana, Lai Lisa A, Brentnall Teresa A, Li Lin, Feng Ziding, Gallaher Jasmine, Mandelson Margaret T, Potter John D, Bronner Mary P, Rabinovitch Peter S
Department of Pathology, University of Washington, Seattle, Washington, USA.
Gastroenterology. 2008 Aug;135(2):410-8. doi: 10.1053/j.gastro.2008.04.008. Epub 2008 Apr 15.
BACKGROUND & AIMS: Telomere shortening is implicated in cancer and aging and might link these 2 biologic events. We explored this hypothesis in ulcerative colitis (UC), a chronic inflammatory disease that predisposes to colorectal cancer and in which shorter telomeres have been associated with chromosomal instability and tumor progression.
Telomere length was measured by quantitative polymerase chain reaction in colonocytes and leukocytes of 2 different sets of UC patients and compared with normal controls across a wide range of ages. For a subset of patients, telomere length was measured in epithelium and stroma of right and left colon biopsy specimens. A third set of biopsy specimens was analyzed for phosphorylation of histone H2AX (gammaH2AX), a DNA damage signal, by immunofluorescence and for telomere length by quantitative fluorescence in situ hybridization. Relationships between telomere length, gammaH2AX intensity, age, disease duration, and age of disease onset were explored.
Colonocyte telomeres shorten with age almost twice as rapidly in UC patients as in normal controls. This extensive shortening occurs within approximately 8 years of disease duration. Leukocyte telomeres are slightly shorter in UC patients than in controls, but telomeres of colon stromal cells are unaffected. gammaH2AX intensity is higher in colonocytes of UC patients than in controls and is not dependent on age or telomere length.
Colonocytes of UC patients show premature shortening of telomeres, which might explain the increased and earlier risk of cancer in this disease. Shorter leukocyte telomeres and increased gammaH2AX in colonocytes might reflect oxidative damage secondary to inflammation.
端粒缩短与癌症和衰老相关，可能将这两个生物学事件联系起来。我们在溃疡性结肠炎（UC）中探讨了这一假说，UC是一种慢性炎症性疾病，易患结直肠癌，且较短的端粒与染色体不稳定和肿瘤进展有关。
通过定量聚合酶链反应测量两组不同UC患者的结肠细胞和白细胞中的端粒长度，并与各年龄段的正常对照进行比较。对于一部分患者，测量左右结肠活检标本上皮和基质中的端粒长度。通过免疫荧光分析第三组活检标本中组蛋白H2AX（γH2AX）的磷酸化情况（一种DNA损伤信号），并通过定量荧光原位杂交分析端粒长度。探讨端粒长度、γH2AX强度、年龄、疾病持续时间和疾病发病年龄之间的关系。
UC患者结肠细胞端粒随年龄缩短的速度几乎是正常对照的两倍。这种广泛的缩短发生在疾病持续约8年的时间内。UC患者白细胞端粒略短于对照，但结肠基质细胞端粒不受影响。UC患者结肠细胞中的γH2AX强度高于对照，且不依赖于年龄或端粒长度。
UC患者的结肠细胞显示端粒过早缩短，这可能解释了该疾病中癌症风险增加且出现更早的原因。较短的白细胞端粒和结肠细胞中γH2AX增加可能反映了炎症继发的氧化损伤。
