胃癌细胞快速增殖和永生化需要端粒长度维持，而端粒长度的维持又需要端粒酶活性保持或端粒延长替代机制激活。高迁移率族蛋白-1 (HMGB1）在肿瘤恶性演变进展的多个环节扮演着关键作用，我们前期研究证实胃癌等多种人类癌症存在高比例HMGB1过表达，并与胃癌预后相关。初步研究表明HMGB1与端粒长度正相关，可能通过调控端粒酶活性或激活端粒延长替代机制等途径，在肿瘤细胞端粒长度维持中发挥作用，但相关研究仅仅起步。基于此，本课题以胃癌为切入点，将研究内容设定为：①应用胃癌组织标本和细胞系，分析HMGB1表达与端粒长度相关性。②通过干预HMGB1作用，明确胃癌细胞中HMGB1参与端粒长度维持的生物学作用；③利用基因芯片等高通量筛选技术，探讨胃癌细胞中HMGB1参与维持端粒长度的分子机制。本课题的实施将促进以HMGB1和端粒为切入点的肿瘤分子机制研究，为以HMGB1和端粒为靶向的肿瘤治疗研究打下基础。

Telomere integrity is the crucial mechanism and marker of chromatin stability, and it is also the key factor in malignant mutation maintenance and overgrowth of gastric cancer cells. HMGB1 has recently emerged as a key factor in the pathogenesis of various diseases, placing it in the center of our modern understanding of cancer biology. The recent studies have showed that HMGB1 could affect the telomere length and telomerase activity, but the studies are rare, especially in cancer cells. In our work, HMGB1 overexpression was found in various cancerous tissues, including gastric adenocarcinoma. Furthermore, HMGB1 overexpression positively associated with cancer-free survival of resectable gastric adenocarcinomas. We also found that the constitutive telomere shortening andγ-radiation-induced telomerase activity in peripheral blood lymphacytes were associated with the elevated GC risk. The further preliminary study indicated HMGB1 expression was associated with the hTERT mRNA expression. Based on our preliminary work, we present the study to reveal the biological functions and molecular mechanisms of HMGB1 in the maintenance of telomere integrity. The main research contents include: 1) through detecting the HMGB1 expression, telomere length and telomerase activity in cancer tissues and cells, to assess the association of HMGB1 expression and telomere integrity. 2) Through influencing HMGB1 expression, to explicit the biological functions of HMGB1 on telomere integrity. 3) Through high-throughput screening techniques, just as gene chip, shRNA library screening, ChIP and phage-displaying polypeptides library, to investigate the hTERT expression dependent and non-dependent mechanism of HMGB1 regulation of telomere integrity. The associated study will reveal the biological functions of HMGB1 in the maintenance of telomere integrity, deepen the mechanism study associated with HMGB1 and telomere, and accelerate the therapeutic study targeting HMGB1 and telomere.