转录因子CUTL1通过SRC和ADAM22调控恶性黑素瘤转移的机制研究

Transcription factors are showed to play crucial roles in malignant melanoma (MM). In the previous studies, we found that CUTL1 could affect the proliferation of MM by targeting cyclins. Further studies showed that CUTL1 was associated with tumor cell motility of MM, but the underlying mechanisms remained unclear. By the preliminary studies, we noticed that SRC and ADAM22 might be the downstream targets of CUTL1, and knockdown of either CUTL1 or ADAM22 could induce the re-organization of cytoskeleton. There were also reports showing that CUTL1 was associated with Rho GTPase proteins. Meanwhile, CUTL1 was reported to up-regulate SRC while SRC could transactivate ADAM22. On the basis of information above, we speculated that CUTL1 might regulate ADAM22 directly or indirectly by SRC. This project is aimed to further reveal the mechanism of CUTL1 in regulation of MM metastasis, and we will also focus on investigate how ADAM22 participate the regulation of cytoskeleton. This program could raise evidence for CUTL1 serving as a potential therapeutic target in future.

转录因子在恶性黑素瘤的发生发展中发挥重要调控作用。本课题组既往发现转录因子CUTL1可通过调节细胞周期蛋白促进恶性黑素瘤的增殖。进一步研究发现CUTL1的升高还可促进恶性黑素瘤的转移，但机制不清。预实验提示：1. SRC和ADAM22可能是CUTL1的潜在下游分子；2. SRC和ADAM22与CUTL1呈一致性变化；下调CUTL1和ADAM22后可诱导细胞骨架的重组。文献提示：1. CUTL1可通过Rho GTPase影响细胞骨架；2. CUTL1可以非转录激活的方式上调SRC，后者可转录激活ADAM22。由此我们推测CUTL1可能直接或通过SRC间接调控ADAM22，从而调节恶性黑素瘤的转移。本项目拟进一步明确CUTL1对恶性黑素瘤转移的调控，并阐明ADAM22是否通过其相互作用分子调控细胞骨架。该项目有助于深化对恶性黑素瘤的认识，其发现的相关分子可为恶性黑素瘤的治疗提供新的治疗靶标。