肿瘤相关巨噬细胞分泌CCL18上调HOTAIR促进食管癌转移

Tumor-associated macrophages (TAMs) plays a critical role in promoting cancer progression and metastasis via producing CCL18 abundantly. But the mechanism of CCL18 functioned in esophageal cancer remains unclear. Long non-coding RNAs (lncRNAs) are an important class of pervasive genes involved in a variety of biological functions that interfere with the expression of proteins, such as HOTAIR, one of the lncRNAs that is overexpressed in cancer. Here we discuss the hypothesis whether tumor-associated macrophages change the expression of lncRNAs, thereby regulating the biological characteristic of cancer cells. From our data before, we confirmed that the expression of HOTAIR can be upregulated by CCL18 from TAMs. In addition, the expression of HOTAIR in esophageal cancer is connective with the prognostic of the patients. In the following days, we want to explore the mechanism of the different expression of HOTAIR regulated by CCL18 in esophageal cancer, what's more, to explain how HOTAIR promotes the metastasis of esophageal cancer cells. This project can contribute to illustrating the mechanism of lncRNAs taking part in the process of TAMs promoting the progression and metastasis of cancer cells, as well as providing the new molecular therapy of targeting to lncRNAs in caner.

肿瘤相关巨噬细胞(TAMs)在恶性肿瘤的发生发展中起到关键作用。我们预实验结果显示TAMs通过分泌CCL18促进食管癌转移，但CCL18作用的分子机制仍未见报道。现有报道及我们的预实验结果显示长非编码RNA HOTAIR在食管癌等恶性肿瘤中异常高表达，并介导肿瘤细胞侵袭转移，但其高表达的原因及分子机制仍未清楚。我们预实验通过建立TAMs与食管癌细胞共培养模型，发现TAMs通过CCL18上调食管癌细胞HOTAIR表达。在此基础上，本课题将进一步阐明CCL18上调HOTAIR表达的分子机制，揭示HOTAIR通过调控蛋白修饰和表达从而促进食管癌细胞转移的分子机理，并验证食管癌标本中CCL18和HOTAIR的表达与患者临床特征和预后的相互关系。本研究将有助于揭示长非编码RNA参与炎症微环境调控肿瘤细胞生物学特性的分子机制，并为靶向长非编码RNA治疗食管癌转移提供理论依据。

肿瘤微环境中的细胞因子在恶性肿瘤的发生发展中起到关键作用，其中由肿瘤相关巨噬细胞或者肿瘤细胞产生的CCL18对肿瘤进展扮演者重要的角色。长链非编码RNA HOTAIR同样广泛参与包括肿瘤发生发展在内的各种生理病理过程，并且发挥着重要的作用。然而，CCL18和HOTAIR的关系以及它们在食管癌的发生发展中的作用机制仍然不清楚。. 我们利用荧光定量PCR、免疫组化、酶联免疫吸附测定和原位杂交来检测食管癌组织及细胞系中CCL18和HOTAIR的表达水平，我们发现CCL18和HOTAIR在食管癌中高表达并且表达越高，食管癌病人生存预后越差。进一步实验提示CCL18与HOTAIR表达水平呈正相关并且CCL18能够上调HOTAIR表达。侵袭实验显示CCL18能增加食管癌细胞的侵袭能力，并且CCL18浓度越高，食管癌细胞侵袭能力越强，但当HOTAIR表达下调时，食管癌细胞侵袭能力减弱。在机制方面，我们发现HOTAIR扮演者“分子海绵”的角色竞争性结合miR-130b，从而通过上调ZEB1来促进食管癌恶性进展。. 我们的研究表明，CCL18可能通过上调HOTAIR表达来促进食管癌的恶性进展，并且HOTAIR的过表达可以通过作为miR-130b海绵来正向调节ZEB1来促进食管癌侵袭和进展，这一发现为早期诊断和有效治疗食管癌提供了新的治疗靶点。