Hu Hua, Zhang Yang, Zou Mei, Yang Shuai, Liang Xiao-Qiu
Cancer Research Institute, The Second Affiliated Hospital, University of South China, 421001, Hengyang, Hunan, People's Republic of China.
J Cancer Res Clin Oncol. 2010 Sep;136(9):1407-14. doi: 10.1007/s00432-010-0795-x. Epub 2010 Feb 2.
Telomere dysfunction is believed to be a significant factor in carcinogenesis. To elucidate the carcinogenesis mechanism in gastric cancer, the expression of telomeric proteins and changes in telomere length were investigated during multistage carcinogenesis of gastric cancer.
Tissue samples were obtained during surgical operations from the normal gastric mucosa of 10 patients, the precancerous lesions of 15 patients, the gastric cancer tissues (GC) of 20 patients, and of tumors due to gastric cancer with lymph node metastasis (GCLM) from 5 patients. The expression of TRF1, TRF2, and TIN2 proteins was measured by Western blotting, while the expression of TERT, KU70, and BRCA1 proteins was detected using the immunohistochemical method. The mean telomere length was determined by Southern blotting.
Compared with normal gastric mucosa tissues, the expression of TRF1, TRF2, and TIN2 proteins was significantly higher in precancerous lesions, GC, and GCLM (P < 0.01). The expression of TRF1, TRF2, and TIN2 proteins was significantly higher in GC and GCLM than in precancerous lesions (P < 0.01). The expression of TERT and Ku70 proteins in precancerous lesions and GC tissues was significantly higher than that in normal gastric mucosa tissues (P < 0.01). The expression of TERT and Ku70 proteins in GC tissues was significantly higher than in precancerous lesions (P < 0.01). In normal gastric mucosa, the BRCA1 protein was primarily located in the cell nucleus. In precancerous lesions and GC, the expression of the BRCA1 protein was apparent in the cell cytoplasm. The mean telomere length in precancerous lesions, GC, and GCLM was significantly shorter than that in normal gastric mucosa tissues (P < 0.05). The mean telomere length in GC and GCLM was significantly shorter than that in precancerous lesions (P < 0.05). The mean telomere length in all tissue samples was inversely correlated with the level of TRF1, TRF2, TIN2, TERT, and Ku70 proteins.
Our results suggest that the over-expression of telomeric proteins, TRF1, TRF2, TIN2, TERT, and Ku70, and the transposition of the BRCA1 protein may work together to reduce the telomere length in precancerous lesions and gastric cancer, and could contribute to the multistage carcinogenesis of gastric cancer. These findings offer new insight into the mechanism of carcinogenesis in gastric cancer.
端粒功能障碍被认为是致癌作用中的一个重要因素。为阐明胃癌的致癌机制，在胃癌的多阶段致癌过程中研究了端粒蛋白的表达及端粒长度的变化。
在手术过程中获取了10例患者正常胃黏膜、15例患者癌前病变、20例患者胃癌组织（GC）以及5例伴有淋巴结转移的胃癌肿瘤组织（GCLM）的组织样本。通过蛋白质免疫印迹法检测TRF1、TRF2和TIN2蛋白的表达，采用免疫组织化学方法检测TERT、KU70和BRCA1蛋白的表达。通过Southern印迹法测定平均端粒长度。
与正常胃黏膜组织相比，癌前病变、GC和GCLM中TRF1、TRF2和TIN2蛋白的表达显著更高（P < 0.01）。GC和GCLM中TRF1、TRF2和TIN2蛋白的表达显著高于癌前病变（P < 0.01）。癌前病变和GC组织中TERT和Ku70蛋白的表达显著高于正常胃黏膜组织（P < 0.01）。GC组织中TERT和Ku70蛋白的表达显著高于癌前病变（P < 0.01）。在正常胃黏膜中，BRCA1蛋白主要位于细胞核。在癌前病变和GC中，BRCA1蛋白在细胞质中表达明显。癌前病变、GC和GCLM中的平均端粒长度显著短于正常胃黏膜组织（P < 0.05）。GC和GCLM中的平均端粒长度显著短于癌前病变（P < 0.05）。所有组织样本中的平均端粒长度与TRF1、TRF2、TIN2、TERT和Ku70蛋白的水平呈负相关。
我们的结果表明，端粒蛋白TRF1、TRF2、TIN2、TERT和Ku70的过度表达以及BRCA1蛋白的转位可能共同作用以缩短癌前病变和胃癌中的端粒长度，并可能促成胃癌的多阶段致癌过程。这些发现为胃癌的致癌机制提供了新的见解。
