HIF-1α-URG11-E-Cadherin信号通路在胃癌侵袭转移中的作用机制研究

To invatigate the molecular mechanism of gastric cancer metastasis is important for improving the patients'survival.URG11, novle gene firstly coloned by our group,was found to be highly-expressed in tumour tissue and crucial for tumour cell proliferation as well as cell cycle.Furthermore,it was found that URG11 expressed remarkably higher in primary tumour tissues of gastric cancer patients with metastasis than those without metastasis.Meanwhile,the research on gasstric cancer cell lines also confirmed that URG11 could promote the invasive and metastasitic abilities of tumor cell.However,the molecular mechanism is not yet clearly elucidated.Our previous study found that URG11 was significantly upregulated in hypoxia condition, resulting in the suppression of E-Cadehrin. Moreover, biological informatic analysis revealed that there were three hypoxia-induced factor-1α(HIF-1α) binding components in the promoter area of URG11.Hence,our hypothesis is that URG11 is a target gene of HIF-1α, and URG11 can facilitate the invasion and metastasis of gastric cancer mediated by HIF-1α through inhibiting E-Cadherin. Thus,this study may provide valuable insights in clarifying the function of URG11 and the molecular mechanism of gastric cancer invasion and metastasis.

探究胃癌侵袭转移分子机制对提高胃癌生存率具有重要价值。URG11（Up Regulated Gene 11）是申请者所在课题组最先克隆出的一个新基因，申请者前期研究显示其在肿瘤组织高表达，并与肿瘤生长、细胞周期等密切相关。课题组近期发现URG11在有转移胃癌组织中表达显著高于无转移胃癌组织，细胞水平研究显示URG11可促进胃癌侵袭转移，但分子机制未完全阐明，同时，缺氧可使URG11的表达显著提高，过表达URG11可抑制E-Cadehrin，结合申请者近期经生物信息学研究发现URG11启动子区有3个缺氧诱导因子1α( hypoxia-inducible factor-1α, HIF-1α)的结合元件。因此推测：URG11是HIF-1α的一个靶基因，URG11通过抑制E-Cadherin表达介导HIF-1α促胃癌侵袭转移功能。本研究对阐明URG11基因的功能及其在胃癌侵袭转移中的分子机制

前期研究发现URG11与肿瘤生长、细胞周期、侵袭转移等相关，但具体分子机制有待阐明。本项目进一步在前期研究基础上探索了URG11在胃癌发生发展中的作用，及其分子机制。项目总体进展顺利并取得了部分重要成果。发现干扰URG11后胃癌细胞发生了显著的增殖抑制、细胞周期阻滞，并伴有凋亡增加。进一步分子机制的研究发现，干扰URG11后p27发生明显下调，联合干扰URG11和p27可产生抑制胃癌细胞的叠加效应，该策略有望成为抑制胃癌的新选择；发现URG11、HIF-1α及E-Cadherin三者相关，URG11可调控HIF-1α和E-Cadherin的表达，进而调控细胞活性，在炎性调控、糖代谢、能量代谢等通路中可能发挥着多重的重要作用，为进一步阐明其功能奠定了重要基础。