Gas6/Axl调控ERS信号通路介导食管鳞癌发生及转移的机制研究

Esophageal squamous cell carcinoma (ESCC) is a common digestive system malignancy, but with limited treatment. Growth arrest-specific gene 6 (Gas6) is a key regulator of multiple signaling pathways closely involved in tumor proliferation and metastasis. We firstly indicate that activated endoplasmic reticulum stress (ERS) effectively sensitizes ESCC to endogenous substances-mediated apoptosis. Furthermore, we identify that: ① compared with the adjacent normal tissues, Gas6 and its receptor Axl are significantly upregulated in ESCC tissues; ② after the upregulation of Gas6, the tumorigenic ability of EC109 cell was significantly enhanced in nude mouse; and Gas6 overexpression was associated with downregulation of CHOP; ③ melatonin plays an anti-cancer effect against EC109 cell accompanied by a downregulation of Gas6 expression. The above evidence strongly suggests that Gas6/Axl may be an important positive regulatory pathway in the tumorigenesis and metastasis of ESCC. Therefore, the present study aims to systematically investigate the mechanism and relationship between Gas6/Axl and ERS in the progress of ESCC, meanwhile to elucidate the role of both in the process of the anti-cancer effect of melatonin on ESCC, with various research objects, including Gas6 gene interferential and transgenic cells as well as the Gas6 gene knockout mouse model. The project will provide a new theoretical and experimental basis for pathogenesis of ESCC and design of melatonin-based therapeutic strategies agains ESCC.

食管鳞癌（ESCC）是常见的消化系统恶性肿瘤，但治疗方法有限。生长停滞特异基因6（Gas6）是细胞信号转导的关键调节枢纽，与肿瘤的发生及转移密切相关。申请人前期发现激活内质网应激（ERS）敏化内源性物质的抗ESCC作用；还发现：①ESCC组织中Gas6及其受体Axl表达明显升高；②上调Gas6后，EC109细胞裸鼠皮下成瘤能力明显增强，且Gas6过表达伴随CHOP表达下调；③褪黑素抑制EC109细胞伴随Gas6表达下调。以上证据强烈提示： Gas6/Axl可能是介导ESCC发生及转移重要的正性调控通路。本项目拟采用Gas6基因干扰和转基因的细胞及Gas6基因敲除小鼠模型，研究证实Gas6/Axl和ERS在ESCC进展中所扮演的角色及上下游关系，同时关注两者在褪黑素抗ESCC过程中的作用形式，为寻找全新的ESCC发病机制和开发以褪黑素为基础的抗ESCC治疗策略奠定理论基础。

恶性肿瘤疾病是当今社会的常见病、多发病，不仅占用大量医疗资源，而且给人类健康事业的进步带来了极大的阻碍。探索有效的治疗方法对提高人口生活质量、降低社会经济负担具有深远意义。褪黑素对机体多系统行使正常功能具有广泛的调控作用。褪黑素作为内源性多效应的生理活性物质已经可以通过人工化学方式进行合成，且目前的工艺路线相对成熟、生产成本较低、产品质量较好，获得了较好社会效益和经济效益。Gas6/Axl和ERS通路在某些肿瘤发病过程中具有交互关系，且目前多项研究证实两者可能受褪黑素的调控。本项目证明食管鳞癌中Gas6/Axl和ERS之间的相互联系，并揭示上调Gas6具有促进肿瘤细胞进展的作用；同时表明褪黑素抑制食管鳞癌过程中伴随有阻断Gas6/Axl信号通路，并进一步激活ERS相关的线粒体氧化反应，从而增加食管鳞癌细胞凋亡。本项目的设计和实施将有利于肿瘤领域，尤其是消化系统恶性疾病分支研究的进步。同时，本项目为研究“Gas6/Axl-ERS信号通路介导的食管鳞癌的发病机制”提供新的立论佐证，继而为开发“以褪黑素为核心的抗食管鳞癌治疗策略”奠定药理学基础，具有重要的临床意义和社会价值。