MAL2基因65(R22)G单碱基删失突变激活WNT信号通路靶点ASCL2调控结直肠癌肝转移的机制研究

已知高达50%结直肠癌患者会发生肝转移，是导致患者死亡的主要原因之一，但结直肠癌肝转移确切驱动基因及作用机制迄今不详。我们前期研究发现：mal T细胞分化蛋白2编码基因MAL2只在四期肠癌中发生65(R22)G单碱基删失突变。MAL2可抑制人肠癌LOVO细胞的侵袭转移能力、皮下移植瘤的生长与肝转移灶数量及下调ASCL2的表达，鉴于ASCL2可通过影响WNT信号通路在肠癌肝转移过程中发挥重要作用。据此，我们提出假说：MAL2可介导WNT信号通路靶点ASCL2调控结直肠癌肝转移。本研究拟从分子、细胞和裸鼠水平，利用肠癌细胞模型、患者肠癌标本、MAL2突变或过表达裸鼠，以qRT-PCR、Western blot、蛋白质免疫共沉淀等方法，探讨MAL2在肠癌肝转移发生过程中的功能和作用。本研究将从MAL2这个新视点为揭示肠癌转移的发生机制提供新思路，并为临床上治疗肠癌肝转移提供了一个新靶点。

As high as 50% colorectal cancer (CRC) patients display liver metastasis, which is one of the major reasons cause their death. However, the driver gene and molecular mechanism remain elusive. We found that MAL2 mutated (65 del G) mainly in CRC stage IV. Additionally, MAL2 was the regulatory network hub gene by using WGCNA through interrogating 409 CRC transcriptomes. Overexpression of MAL2 inhibited invasion and metastasis of LOVO cells, growth of subcutaneous transplanted tumor, the number of metastatic liver focus, and down-regulated ASCL2 that is associated with liver metastasis. We thus hypothesize that MAL2 mutant promotes CRC metastasis via up-regulating ASCL2. The proposal will use CRC cell lines and cancer tissue samples to explore the role of MAL2 in CRC liver metastasis. In short, the study results will reveal that MAL2 might be a novel CRC liver metastasis treatment target, providing new insights into the role of MAL2 in CRC liver metastasis.