RP11-290F20.3→miR-182-5p→SMAD7影响肺鳞癌侵袭转移的机制研究

Currently, the traditional double medicine scheme containing platinum is still the first line choice for lung squamous cell carcinoma (LUSC), and we are still short of effective targeted agents, specially designed for this deadly disease. In previous researches, our team was trying to screen for survival-related lncRNA→miRNA→mRNA triplet regulatory relations, based on cDNA microarray and RNA sequencing data, and finally we chose RP11-290F20.3→miR-182-5p→SMAD7 for further analysis. Our preliminary research corroborated the regulatory relationship among these three RNAs on the basis of clinical tissues and in vitro experiments. Our preliminary research also indicated that overexpression of RP11-290F20.3 could significantly promote the process of invasion and metastasis in LUSC. Therefore, we proposed the hypothesis that the overexpression of RP11-290F20.3 could promote the transcription and protein level of SMAD7 by competitively binding miR-182, therefore influence the invasion and metastasis of LUSC cells, and further indicate the prognosis of the LUSC patients. We will further consolidate the validity of this triplet regulatory relation and investigate the underlying mechanism upon invasion and metastasis in both in vitro and in vivo levels, in an attempt to discover new therapeutic target and provide promising clinic guidance for LUSC.

肺鳞癌的一线化疗目前仍为传统的含铂双药方案，尚缺乏有效的靶向治疗药物。在前期研究中，我们通过基因芯片及RNA测序等高通量数据，利用生物信息学方法筛选出与肺鳞癌总生存密切相关的lncRNA→miRNA→mRNA三元调控关系： RP11-290F20.3→miR-182-5p→SMAD7，并在临床样本及细胞实验中初步证实了三者的显著相关性。预实验结果表明：RP11-290F20.3高表达可明显促进肺鳞癌细胞的侵袭转移。据此我们提出假说：RP11-290F20.3可通过结合miR-182-5p从而削弱该miRNA对SMAD7表达的抑制，进而促进肺鳞癌侵袭转移的生物学过程，影响患者总生存。本项目将进一步在体外及体内水平验证RP11-290F20.3→miR-182-5p→SMAD7调控关系的可信性，并研究该调控影响肺鳞癌侵袭转移的分子机制，以期为肺鳞癌的治疗提供可能有效的干预靶点。

长链非编码RNA-微小RNA-mRNA三元调控体系在生理和病理过程中发挥多重作用。该三元调控网络在恶性肿瘤中的作用也日益受到重视。有望为肿瘤的诊断、预后或治疗提供新的思路。在本项目中，我们发现了肺癌中存在RP11-290F20.3→hsa-miR-182-5p→SMAD7 的三元调控关系，而且该关系对于肺鳞癌的侵袭转移有重要的影响。我们的发现不仅为更好的理解肺鳞癌的侵袭转移机制提供了新的线索，而且有可能为抑制其侵袭转移提供了一个潜在的治疗靶点。例如，我们可以尝试设计针对RP11-290F20.3的siRNA，再加以合适的载体给药；或者将人工合成的hsa-miR-182-5p小分子模拟物用于肺鳞癌的治疗。后续，我们将继续对该三元调控网络在体内所发挥的作用进行研究。并进一步针对该调控体系的治疗干预策略进行研究。