NDRG1蛋白调控actin骨架重构对结直肠癌迁移侵袭的影响及其机制研究

Metastasis, which is one of the key risk factors for long-term survival of colorectal cancer (CRC) patients, has gradually become one of the biggest clinical challenge. The metastasis of CRC is a complicated process, in which that cytoskeleton, especially actin cytoskeleton, plays the core effect in regulating cell migration and invasion. Our recent study has demonstrated that the novel tumor suppressor N-myc downstream regulated gene 1 (NDRG1) is able to resist CRC migration and invasion via inhibition of actin filament polymerization, stress fiber assembly, and cell migration as well as invasion through modulating the ROCK1/pMLC2 pathway. Interestingly, we also discovered that, if ROCK1/pMLC2 signaling was blocked, the resistance and inhibition effects of NDRG1 was only partially reversed. This indicates that there probably be other potential signaling pathways which may be involved in NDRG1-mediated actin cytockeleton remodeling. After a series of preliminary experiments, we raise the hypothesis as follows: NDRG1 may further regulate actin cytoskeleton remodeling through modulating p21(CIP1/WAF1)/PAK1/MLCK/pMLC2 signaling pathways; furthermore, this effect may on account of the protein-protein interaction between NDRG1 and the protein kinase C delta (PKCδ). This study may uncover the novel molecular mechanisms underlying the metastasis of CRC. Moreover, it may also provide theoretical evidences for the potential targeted therapy for metastatic CRC cases.

结直肠癌转移是困扰临床医生的一大难题，已经成为影响结直肠癌远期生存的主要因素之一。结直肠癌转移是一复杂的生物学过程，这一过程中，actin骨架重构介导的迁移侵袭起关键作用。本课题组在前期研究中发现，肿瘤抑制基因NDRG1能够通过介导ROCK1/pMLC2信号通路从而抑制actin骨架重构与应力纤维合成，进而抑制结直肠癌细胞迁移侵袭。有趣的是，在上述研究的同时，我们发现，阻断ROCK1/pMLC2信号通路后，这一现象未被完全逆转，提示可能存在NDRG1介导的其他信号通路参与NDRG1对actin骨架重构的调控。通过预实验的进一步验证，我们提出假说：NDRG1可能还通过与PKCδ的相互作用从而介导下游p21(CIP1/WAF1)/PAK1/MLCK/pMLC2信号通路进而介导结直肠癌细胞actin骨架重构。本课题旨在发现结直肠癌转移新机制，为转移性结直肠癌防治提供可能的新靶标及理论依据。

结直肠癌已成为全球，尤其是中国发病率居恶性肿瘤前列的恶性肿瘤之一。据统计约有33%的结直肠癌患者确诊时已进入进展期，约25%的结直肠患者确诊时已经伴有肝转移，目前常规综合治疗手段逐渐已不能满足临床治疗需要。因此，进行结直肠癌侵袭转移相关的分子生物学研究，寻找新的结直肠癌侵袭转移的治疗靶点已经成为当前转移性结直肠癌治疗中急需解决的重要目标之一。在本研究中，我们首次发现并报道了NDRG1通过直接相互作用促进caveolin-1泛素化降解从而抑制结直肠癌细胞骨架重构。我们还发现，NDRG1调控PAK1/MLCK/pMLC2通路进而抑制结直肠癌细胞骨架重构。本研究还首次发现并报道了NDRG1通过直接相互作用调控PKC-δ磷酸化进而调控结直肠癌细胞骨架重构。最后，我们还评估了NDRG1对于直肠癌患者预后的预测价值，发现NDRG1减弱CRC细胞的干细胞特性和自我复制能力，促进奥沙利铂诱导的CRC细胞凋亡，这一作用是通过下调Bcl-2蛋白表达，促进Bcl-2蛋白降解达成的。本研究发现了NDRG1抑制迁移侵袭、调控结直肠癌细胞actin骨架重构的新机制，丰富了NDRG1功能，为转移性结直肠癌的防治提供可能的新靶标及其理论依据。