ENST00000449602调控胃癌侵袭转移及化疗耐药的机制研究

The prognosis of advanced-stage gastric cancer patients remains to be dismal and tumor recurrence, metastasis and therapeutic resistance are the key reasons for the failure of treatment. Thus, it is of great importance to illustrate the molecular mechanisms of tumor recurrence, metastasis and therapeutic resistance. At present, more and more studies show that tumor stem cells are closely related to tumor development, metastasis and therapeutic resistance. In our previous research, we identified the lncRNAs that are differentially expressed in gastric cancer compared with normal tissues. ENST0000044960 was found to be upregulated in gastric cancer tissues and play an important role in proliferation, invasion, chemoresistance and stem-like properties of gastric cancer cells. According to the initial experiment data, we hypothesized that ENST00000449602 stabilized STAT3 protein via inferencing COP1-mediated STAT3 degradation, thus, activated STAT3 were recruited to the promoter of OCT4 and transactived its transcription. We will explore the role of ENST0000044960 in gastric cancer proliferation, invasion and chemoresistance on the level of patient species, cancer cell and animal models. This study will cast new light on mechanisms of gastric cancer proliferation, invasion and chemoresistance as ENST0000044960 might be a novel therapeutic target.

进展期胃癌患者的预后目前仍不够理想，肿瘤复发、转移及化疗耐药是患者治疗失败的重要原因，因此探索其相关分子机制就显得尤为重要。目前越来越多研究认为肿瘤干细胞与肿瘤的发生发展、复发转移及药物抵抗密切相关。我们前期利用芯片筛查胃癌组织相对于正常组织差异性表达的lncRNA:我们发现lncRNA ENST00000449602在胃癌组织中异常增高，并且可促进胃癌细胞增殖、侵袭转移及化疗耐药并且在肿瘤干细胞特性的维持中发挥着重要作用。根据初步实验结果，我们提出假说： ENST00000449602通过干扰COP1对STAT3的泛素化降解从而促进STAT3蛋白的稳定，活化的STAT3转移至细胞核内，结合至Oct4启动子区域从而促进Oct4的转录激活，提高Oct4的表达水平。本研究将从ENST00000449602这个新视点为揭示胃癌侵袭转移及治疗耐药机制奠定基础，为胃癌的治疗提供新的思路。

长链非编码RNA(lncRNA)在肿瘤的发生发展中起重要作用，但目前机制尚未完全阐明。我们利用人体胃癌组织及细胞系，探索lncRNA-GCAWKR在胃癌中的促癌作用。利用原位杂交检测42例胃癌患者中GCAWKR的表达水平，利用qRT-PCR检测123例胃癌患者组织中表达水平。调控胃癌细胞系中GCAWKR表达水平，并进行相关生物学及分子机制分析。GCAWKR在胃癌组织中表达水平显著高于正常组织，且表达水平与肿瘤大小、淋巴结转移、TNM分期及患者预后相关。GCAWKR可对胃癌细胞增值及侵袭产生影响。在分子机制上，GCAWKR与WDR5及KAT2A结合，并作为WDR5/KAT2A复合物的分子链接，调控WDR5/KAT2A复合物在靶基因启动子区域的结合。因此，我们的数据揭示了一个新的lncRNA在胃癌中促癌作用的分子机制，可以作为胃癌新的治疗靶点。