Rab23在皮肤鳞癌细胞自噬促进肿瘤侵袭中的作用及分子机制

Cutaneous squamous cell carcinoma (cSCC) is one of the most common non-melanoma skin cancers worldwide, with a 5-year survival rate of approximately 50 % due to its invasive capacity. Many studies show that autophagy could enhance cell invasion of tumor cells. Our previous work found that Rab23 could enhance cell invasion of squamous cell carcinoma by regulating Rac1. Additionally, we also found that levels of autophagy and Rab23 were increased in cSCC. All of these results strongly suggested that Rab23 may play a key role in the regulation of cell invasion of squamous cell carcinoma promoted by autophagy. However, the molecular mechanism by which Rab23 regulates autophagy and invasion still remains unknown. To verify our hypothesis, the study will be performed from the view of clinical specimens, cell and animal model aspects respectively. Our studies include the following contents. The first is to clarify the function of autophagy promoting cell invasion of squamous cell carcinoma. Then, we will explore the mechanism of Rab23 regulating autophagy in cSCC. Thirdly, we will clarify that Rab23 regulate cell invasion enhanced by autophagy in cSCC to illustrate the key role of Rab23 in the network comprehensively. The anticipated results will provide a theoretical foundation for comprehensively clarifying the function of Rab23, and will be helpful to understand the molecular mechanism of autophagy and invasion, and will also provide new strategy and target for the treatment of squamous cell carcinoma.

皮肤鳞癌侵袭性强、危害大，头颈部鳞癌五年的生存率仅50%。研究表明，肿瘤细胞自噬可明显促进肿瘤的侵袭，但具体机制尚未阐明。我们前期研究发现，小GTP酶Rab23可通过调控Rac1显著促进鳞癌细胞的侵袭，我们还发现，鳞癌组织中在自噬水平明显升高的同时，Rab23的表达也明显增强，这些结果强烈提示Rab23在鳞癌细胞自噬促进肿瘤侵袭中发挥重要作用，但Rab23调控自噬与侵袭的分子机制尚不清楚。本项目拟以皮肤鳞癌为研究对象，从临床标本、细胞水平和动物实验三个方面，进一步明确鳞癌细胞自噬促进肿瘤侵袭的作用，阐明Rab23调控鳞癌自噬的作用机制，探讨Rab23在鳞癌自噬促进肿瘤侵袭中的作用及分子机制，全面阐明Rab23调控鳞癌自噬促进侵袭作用的关键分子及其网络。预期结果将有助于深入认识Rab23的功能及作用机制，有助于全面理解鳞癌细胞自噬与侵袭的分子调控，并为鳞癌侵袭的防治提供新的策略和治疗靶点。

皮肤鳞癌侵袭性强、危害大，头颈部鳞癌五年的生存率仅50%。课题组前期已经发现小GTP 酶Rab23 通过调控Rac1 显著促进鳞癌侵袭，而自噬又与肿瘤的发生、发展及侵袭转移密切相关。本项研究旨在明确鳞癌细胞自噬在侵袭中的关键作用，探讨Rab23 调控鳞癌自噬的作用及机制，重点在阐明Rab23 在鳞癌自噬促进肿瘤侵袭中的作用及分子机制。本研究首先通过生物信息学分析及组织病理学水平均明确了皮肤鳞癌中Rab23与自噬相关分子的相关性。随后我们建立了稳定转染过表达、干涉 Rab23 的鳞癌 Sa3 细胞系，在细胞水平验证了Rab23可以自噬相关蛋白LC3、Beclin1的表达。最后通过研究发现Rab23可能通过下述两种机制参与自噬的调控：○1. Rab23通过调控ERK与AKT/mTOR信号通路○2. Rab23直接参与自噬的囊泡转运。最后，研究发现Rab23促进自噬后是通过抑制初级纤毛生成从而促进鳞癌细胞的侵袭。上述结果将有助于深入认识Rab23的功能及作用机制，有助于全面理解鳞癌细胞自噬与侵袭的分子调控，并为鳞癌侵袭的防治提供新的策略和治疗靶点。