CDH1通过调控ARHI表达影响下咽癌侵袭转移的分子机制

Invasion and metastasis is the major cause of death in patients with hypopharyngeal carcinoma. CDH1, a pivotal adhesion molecule that regulates intercellular junction, plays an important role in the invasion and metastasis of hypopharyngeal carcinoma. However, the elaborate mechanism is unclear. Our preliminary Chip data suggested that ARHI was greatly down-regulated when CDH1 was silenced. And the decreased expression of CDH1 coupled with ARHI down-regulation in metastatic samples of hypopharyngeal cancer. Therefore, we propose that CDH1 affects the invasion and metastasis of hypopharyngeal carcinoma via regulating ARHI expression. Based on our previous research, we will use molecular and cell biology methods to explore the mechanism that CDH1 modulates ARHI expression through the transcription factors E2F1/4. Then, besides in vitro and in vivo assays, clinical tissue samples of hypopharyngeal cancer will be utilized to investigate the function of ARHI on CDH1-regulated invasion and metastasis of hypopharyngeal cancer. Finally, the effects of ARHI on p-STAT3, MMPs and Fascin family members will be studied to explore the molecular mechanism of CDH1-regulated hypopharyngeal carcinoma metastasis. We believe that this study will reveal the regulatory network of key molecules in hypopharyngeal carcinoma metastasis, thereby developing specific biomarkers and providing novel drug targets for its clinical treatment.

侵袭转移是造成下咽癌患者死亡的主要原因，CDH1作为细胞间连接的重要粘附分子在下咽癌侵袭转移中发挥重要作用，但具体作用机制未知。我们前期芯片实验发现沉默CDH1表达后，ARHI表达下调，并且下咽癌术后转移标本低表达CDH1的同时ARHI表达降低。因此提出假说：CDH1可能通过调控ARHI表达影响下咽癌的侵袭转移。基于前期基础，本项目拟利用分子细胞生物学方法阐明CDH1通过转录因子E2F1/4调控ARHI表达的分子机制；采用体外与体内实验并结合下咽癌临床标本资源分析ARHI在CDH1调控下咽癌侵袭转移中的作用；最终探讨ARHI通过影响p-STAT3、MMPs或Fascin家族蛋白参与CDH1调控下咽癌侵袭转移的分子机制。期望通过该研究揭示下咽癌转移的分子调控网络，以此寻找下咽癌转移的分子标记物，为临床治疗提供新靶点。

侵袭转移是造成下咽癌患者死亡的主要原因，CDH1作为细胞间连接的重要粘附分子在下咽癌侵袭转移中发挥重要作用，但具体作用机制未知。本课题以下咽癌临床标本作为研究出发点，利用分子与细胞生物学技术，从分子表达调控角度深入探讨CDH1通过调控ARHI表达影响下咽癌增殖与转移的作用机制。我们研究发现下咽癌术后转移标本低表达CDH1的同时ARHI表达降低，统计分析显示二者表达呈正相关。分子调控机制研究表明沉默CDH1能够降低转录因子Sp1表达，继而在转录水平下调ARHI。下咽癌临床标本分析显示ARHI与下咽癌N分期、远处转移以及生存预后密切相关，进一步体内外实验结果证实ARHI抑制下咽癌增殖与转移，并且能够削弱CDH1表达下调引起的下咽癌增殖与转移能力的增强。最后，课题组利用转录组测序发现FOXP4可能作为ARHI下游靶分子参与CDH1对下咽癌增殖转移的调控。本项目的研究为深入了解下咽癌转移调控网络奠定了基础，为探寻下咽癌转移相关生物分子标志物与治疗靶标提供了理论依据。在本项目资助下发表SCI论文4篇，另有1篇正在撰稿中。本项目培养博士研究生1名、硕士研究生2名。