乙酰化酶NAT10调节Tiam1在头颈部鳞癌侵袭转移过程中的机制研究

Invasion and metastasis is important factors which can influent the prognosis of head and neck squamous cell carcinoma (HNSCC). And therefore, the elucidation of mechanism on invasion and metastasis is the key point in anti-cancer therapy. The activation of RhoGTPases, a group of factors that belongs to small GTPases, has been identified as a crucial step for initiation of cytoskeletal remodeling, resulting in formation of protrusions for cell migration such as filopodia, lamellipodia, focal adhesions and stress fibers. In the process, a vast of proteins sequentially are activated or inactivated through direct interaction and protein modification such as phosphorylation and acetylation/or deactylation. In previous studies, we have found that NAT10, an acetyltransferase, could take a translocation from nucleolus to cytoplasm or membrane of colorectal cancer cells under the activation of Wnt/beta-catenin signaling pathway and was closely correlated with the tumor invasion and metastasis. Recent studies also showed the translocation of NAT10 from nucleolus to cytoplasm or membrane in HNSCC such as nasopharyngeal carcinoma and laryngeal squamous cell carcinoma. Tiam1 is a kind of GEFs specific for Rac1 activation, and therefore induce the migration of tumors. Some studies have proved that overexpression of Tiam1 was correlated with invasion and metastasis of HNSCC; however, little is known about the potential prognostic value and molecular mechanisms of Tiam1 in HNSCC. The proposed investigation will further focus on the regulation of NAT10 on the motility and migration of cancer cells. We will explore the interactions between NAT10 and Tiam1, and their influence on the activation of RhoGTPase,the remodeling or assembly of cellular cytoskeleton. The study is believed to provide more clues for uncovering the mechanism of cancer metastasis and more targets for anti-metastasis strategy.

侵袭和转移是头颈部鳞癌预后的重要影响因素。以RhoGTPases激活所诱导的细胞骨架蛋白重组是促进肿瘤细胞侵袭、转移的核心环节，其中蛋白质磷酸化、乙酰化修饰起着重要的调节作用。在前期研究中我们发现人乙酰化酶NAT10的胞浆胞膜易位与结直肠癌Wnt通路激活以及肿瘤的侵袭、转移密切相关。近来实验显示，NAT10在头颈部鳞癌如鼻咽癌、喉癌中也存在由核仁到胞浆胞膜的易位。Tiam1可特异性激活Rac1，参与Tiam1-Rac信号传导通路，从而引起肿瘤细胞的迁移，已有研究证明Tiam1与头颈部鳞癌的浸润转移有关，但其确切机理尚不清楚。本研究拟在此基础上，运用分子细胞生物学、分子病理学等技术，进一步确定NAT10是否通过与Tiam1相互作用，进而激活RhoGTPases、调节细胞骨架重构而促进肿瘤细胞侵袭转移的作用，为深入揭示NAT10调节肿瘤侵袭、转移的分子机制、寻找新的抗肿瘤转移靶点提供线索。

侵袭和转移是恶性肿瘤的重要特征，其中细胞骨架特别是微丝、微管成分起着重要的作用，且细胞的增殖和移行两个方面相互影响。我们的以往研究证明乙酰化酶NAT10具有调节细胞有丝分裂和DNA损伤修复等多种生物学功能。头颈部鳞癌是人体发生的第六大常见恶性肿瘤，研究头颈部鳞癌侵袭和转移的机制是改善其预后的重要途径。在本研究中，我们对乙酰化酶NAT10（N-acetyltransferase 10）与头颈部鳞癌侵袭、转移的相关性、NAT10对细胞骨架重构的调节及机制、抑制NAT10表达对头颈部鳞癌细胞生物学功能的影响等做了一系列的研究。结果表明：（1）NAT10的表达与头颈部鳞癌的分级、分期及预后等密切相关。（2）NAT10的表达增加可促进细胞内RhoGTPase的含量增加，提示NAT10可能通过调节RhoGTPase影响细胞骨架，但是可能不是通过Tiam1发挥作用。（3）NAT10可通过乙酰化微管来提高微管稳定性，并可促使微丝重构，促进细胞伪足形成。（4）NAT10 抑制剂Remodelin可降低NAT10水平并抑制头颈部鳞癌细胞生物学功能。（5）沉默NAT10表达可抑制头颈部鳞癌细胞生物学功能。（6）NAT10促进头颈部鳞癌发生发展的作用可能与PI3K/AKT信号通路有关。总之，本研究深入揭示了乙酰化酶NAT10调节头颈部鳞癌侵袭、转移的作用和机制，为临床诊治提供了潜在的治疗靶点。