FOS/MALAT1/miR-497信号环路促进肺腺癌增殖与侵袭的机制研究

As a highly expressed non-coding RNA in lung adenocarcinoma, MALAT1 is closely related to tumor proliferation and invasion. Although it has made considerable progress in the functional study of MALAT1, the specific regulatory mechanism for its high expression in lung cancer and other tumors has not yet clear. Our previous study validated the targeted regulation of the relationship between miR-497 and FOS, and found the FOS inhibition reduced the expression of MALAT1 significantly, thereby leading to increase the expression of miR-497. Therefore, we hypothesized that the above three factors constitute a positive feedback loop signal, which is maybe maintaining the high expressional status of MALAT1 in lung adenocarcinoma cells. In this project, two levels of cells and animals will be intended to detect the binding activity of FOS and upstream promoter region of the MALAT1 by using not only the overexpression and inhibition of FOS and MALAT1,but also the luciferase reporter gene vector system, thus verifying the relationship between FOS and MALAT1 and their effects on miR-497.Furthermore, we will construct the psiCHECK2-miR-497 and MALAT1 overexpression plasmids, and verify the relationship between MALAT1 and miR-497 by co-transfection of the above two kinds of vectors. This project will be contributed to explore the mechanism of tumor cell proliferation and invasion thoroughly, and provide new ideas for the study of cancer treatments.

MALAT1在肺腺癌细胞中高度表达，与肿瘤的增殖与侵袭密切相关。尽管对MALAT1的功能研究已经取得了长足进步，但是对于它在肺癌等恶性肿瘤中高表达的具体调控机制至今尚未明确。我们的前期研究初步验证了miR-497与转录因子FOS的靶向调控关系，发现了FOS表达抑制能显著降低MALAT1的转录，并由此导致miR-497表达升高。因此我们推测，在肺腺癌细胞中MALAT1高表达状态的维持可能是以上三者构成的正反馈信号环路的结果。本项目拟从细胞和动物两个层面，通过FOS和MALAT1的过表达和表达抑制体系，利用荧光素酶报告基因载体检测FOS与MALAT1基因上游启动子区的结合活性。进一步通过构建psiCHECK2-miR-497与MALAT1过表达质粒的共转染验证MALAT1与miR-497的直接作用关系。本课题的研究结果有助于深入探索肿瘤细胞增殖和侵袭的机制，为研究肿瘤的治疗手段提供新的思路。