VR1的Y738位点磷酸化在皮肤癌发生中的作用与机制研究

Skin cancer is one of the most common cancers in the world. It can be categoried in two major sub-type, namely, Melanoma and Non-melanoma skin cancer. Recent evidences suggested that many of the membrane proteins, such as VDR, ERBB1 and VR1, were associated with the tumorigenesis of skin cancer. VR1 (Vanilloid Receptor) is a member of the TRP(Transient Receptor Potential) singal pathway and the activation of VR1 was reported to interfere with the growth of tumor cells, suggesting an anti-tumor effect in certain tumors. However, VR1 was also found to be highly expressed in types of tumors together with some pro-tumorigenic factors. These findinds suggested that VR1 can be aberrantly activated, leading to a inhibition of the anti-tumor effect, even to a pro-tumorigenic effect. Furthermore, our previous findings also revealed that Y738 of VR1 can be phosphorylated by an pro-tumorigenic factor, ERBB1, which was highly expressed in types of cancers..Thus, we hypothesized that the phosphorylation of VR1 by ERBB1 may alter the activity and functionality of VR1, which interfered with the anti-tumor effect of VR1 and led to an activation of the downstream pro-tumorigenic signal pathways. In this study, based on our previous findings, we will further investigate the influence on the activity and functionality of VR1 by the phosphorylation at Y738 and unravel the downstream pathways and its effect in the tumorigenesis of skin cancer.

皮肤癌是现今世界上较常见的癌症之一，主要分为皮肤恶性黑色素瘤和非黑色素瘤皮肤癌两个类型。研究表明皮肤癌的发生与表皮细胞中多种膜受体蛋白相关，如VDR、ERBB1及VR1等。VR1是TRP通路中的成员之一，其激活与肿瘤细胞的生长抑制相关，说明VR1在一些肿瘤中具有抑癌作用。然而VR1也被发现在多种肿瘤中伴随一些促癌基因呈高表达，提示在某种机制下，其抗肿瘤作用可能会被抑制甚至变为促肿瘤作用。我们的前期研究表明，VR1的Y738位点可被ERBB1磷酸化，而后者在多种肿瘤中高表达，并且呈现促肿瘤作用。.由此我们假设，ERBB1对VR1的磷酸化，可能改变VR1的活性及功能，抑制VR1的抗肿瘤作用，甚至激活肿瘤发生相关的下游信号通路。本课题将在前期研究的基础上，进一步探索该位点磷酸化对VR1的活性及通道功能的影响，阐明相关的下游信号通路，及其在皮肤癌发生发展中的作用、机制和意义。

皮肤癌是现今世界上较为常见的癌症之一。研究表明皮肤癌的发生与表皮细胞中多种膜受体蛋白相关，如VDR、ERBB1及VR1等。VR1是TRP通路中的成员之一，其在一些肿瘤中具有抑癌作用。然而VR1也被发现在多种肿瘤中伴随一些促癌基因呈高表达。提示在某种机制下，如VR1的异常激活，其抗肿瘤作用可能会受抑制甚至变为促肿瘤作用。我们的前期研究表明，对VR1的Tyr738位点可被ERBB1磷酸化，而后者在多种肿瘤中高表达并呈现促肿瘤作用。.为探讨VR1在肿瘤发生发展过程中的作用及相关机制，本项目深入研究了VR1与ERBB1的相互作用，并确定了VR1的Y738位点可以被ERBB1磷酸化，同时，VR1和ERBB1在部分肿瘤中呈现共表达，从而提示VR1 Y738位点的磷酸化可能与肿瘤的发生发展相关。本项目进而通过全细胞膜片钳和钙离子荧光标记技术研究了该位点与VR1通道功能的关系、通过对470个皮肤癌患者数据的统计学分析确定了VR1与皮肤癌的发生、发展、预后以及长期存活率的相关性。本项目还通过大量体外细胞实验证实了当Y738位点发生突变时，VR1的肿瘤抑制能力减弱，肿瘤细胞的增殖能力、侵袭能力以及形成克隆的能力均得到恢复，而这一过程与VR1的通道功能无关。同时通过转录组测序和生物信息学分析，发现多个与肿瘤发生发展相关的信号通路，如IL-6及MAPK等，与VR1密切相关。.本项目进一步研究了VR1在肿瘤发生发展中的作用和机制，阐明了部分相关的下游信号通路，为VR1相关的皮肤癌的诊断与靶向治疗提供新的靶点和重要实验证据。同时，本项目已经按计划发表了标注项目资助的SCI论文3篇，核心期刊论文1篇，1篇SCI论文在投稿中，同时另有1名参与项目的硕士研究生顺利毕业，已经完成了项目预期的学术目标。