MAEL负向调控miR-7激活EGFR通路促进结直肠癌细胞的生长和转移

Colorectal cancer(CRC) is one of the most common malignant tumor of the digestive system. It is generally accepted that CRC pathogenesis is a long-term process involving accumulation of multiple genetic alterations. Herein, we aim to explore the molecular biological mechanisms of CRC initiation and progression. We have been committed to investigating MAEL function in digestive neoplasms and have found MAEL is a new candidate oncogene. Previously, overexpression of MAEL was frequently detected in 48.9%（44/90）CRC tissues and significantly associated with poor outcome (P=0.014). Functional study demonstrated that MAEL promoted cell growth and migration and further study found that MAEL enhanced EGFR activity. MAEL protein contains HMG-box domain which is able to bind to the promoter region of miR-7 and repress its expression in drosophila. To prove this relationship in human, we found the binding site of MAEL HMG-box domain in miR-7 promoter by bioinformatics analysis. Moreover, negative correlation of MAEL and miR-7 expression was shown in CRC cell lines and tissues. As is known that miR-7 is able to target EGFR and its downstream molecules to decrease the activity of EGFR pathway. In this study, we will investigate whether MAEL can bind to the promoter of miR-7 and inhibit its expression in CRC, which may probably raise the ability of cell growth and migration of CRC cell lines by activating EGFR/Ras/Raf/MEK/ERK1/2 and EGFR/PI3K/Akt pathways. Furthermore, we will also explore if MAEL silence exert a synergistic effect with cetuximab and resensitize CRC cell lines with Ras mutation to cetuximab. All these expected results would render new way to anti-CRC therapy in clinic.

结直肠癌（CRC）是最常见的消化系统恶性肿瘤之一，CRC的发生为多基因参与的过程，从基因水平可了解CRC发生发展的分子机制。本课题组一直致力于MAEL在消化系统肿瘤中的研究，发现MAEL蛋白在48.9%（44/90）的CRC组织中表达上调且与患者的不良预后相关。过表达MAEL可促进CRC细胞的生长和迁移，并激活EGFR通路。我们发现miR-7启动子中有MAEL蛋白的结合位点，且MAEL与miR-7表达水平在CRC细胞及组织中呈负相关。本项目拟进一步研究MAEL是否可与miR-7的启动子结合并抑制其表达，以及如何通过miR-7激活EGFR通路并促进CRC细胞的生长和转移。此外，还将探索MAEL的沉默是否可与Cetuximab发挥协同效应，恢复Ras突变细胞系对Cetuximab治疗的敏感性。

结直肠癌(CRC)是最常见的消化系统恶性肿瘤之一，CRC的发生为多基因参与的过程，从基因水平可了解CRC发生发展的分子机制。本课题组一直致力于MAEL在消化系统肿瘤中的研究，发现MAEL蛋白在48.9%(44/90)的CRC组织中表达上调且与患者的不良预后相关。体外过表达MAEL可促进CRC细胞的增殖、克隆形成和迁移能力，减少细胞的衰老，体内过表达MAEL可促进CRC细胞的裸鼠成瘤能力。过表达MAEL还可激活CRC细胞的EGFR通路。MAEL蛋白可定位于应激小体，RIP-Seq提示MAEL蛋白可结合miRNA、piRNA和tsRNA，且应激时结合的tsRNA显著升高，IP-质谱分析提示在应激条件下MAEL蛋白可结合YB1蛋白。本项目拟进一步研究MAEL是否可参与应激，通过对tsRNA的调控发挥转录后调控，进而影响肠癌的发生发展及耐药。