GPR31信号转导机制及其在肿瘤治疗上的应用

12-(S)-HETE,a 12-lipoxygenase metabolite of arachidonic acid, has been demonstrated to evoke a wide variety of cellular responses.For example, 12-(S)-HETE has shown to have a prominent role in cytoskeleton remodeling so as to facilitate cell chemotaxis. Furthermore, addition of exogenous 12-(S)-HETE induces cells to secrete proteinases and vascular endothelial growth factor leading to an angiogenic response . 12-(S)-HETE treatment of cancer cells also enhanced the expression of integrins and fibronectin, which prolong cell survival. In endothelial cells, 12-(S)-HETE induces the non-destructive retraction of monolayers and promotes tumor cell adhesion. Also, the motility of isolated endothelial cells and tube formation is enhanced by 12-(S)-HETE treatment.Recently,Yande Guo et al identified GPR31, a plasma membrane orphan G protein-coupled receptor that displays high affinity for the human 12-lipoxygenase-derived product 12-(S)-HETE.The cloned GPR31 demonstrated high affinity binding for 12-(S)-[(3)H]HETE. Also, 12-(S)-HETE efficiently and selectively stimulated GTPγS coupling in the membranes of 12-HETER-transfected cells. Activating GTPγS coupling with 12-(S)-HETE proved to be both regio- and stereospecific. Also, 12-(S)-HETE/GPR31 interactions lead to activation of ERK1/2, MEK, and NFκB. Moreover, knocking down GPR31 specifically inhibited 12-(S)-HETE-stimulated cell invasion. Thus, GPR31 represents the first identified high affinity receptor for the 12-(S)-HETE hydroxyl fatty acids.Following the cloning and characterization of GPR31 as a high affinity receptor of 12-(S)-HETE, the researchers performed an extensive analysis of array data deposited in the Gene Expression Omnibus (GEO) to examine the potential involvement of 12-HETER in various pathophysiological conditions. They observed that 12-HETER may be dysregulated in several diseases,including malignant megakaryocytes, arthritis, Alzheimer's disease, progressive B-cell chronic lymphocytic leukemia,diabetic nephropathy, high grade astrocytoma, prostate cancer,etc. Also, 12-(S)-HETE is an important signaling molecule which regulates various biological functions . For example,it has been shown that 12-(S)-HETE increases the invasiveness and metastatic potential in prostate tumors and is involved in the carcinogenesis of prostate tumors. However, the pathophysiological roles of 12-(S)-HETE/GPR31 signaling await empirical determinations in the future. Therefore, further studies of the GPR31 will provide mechanistic insights into 12-(S)-HETE-regulated signaling and functions, which may offer potential new therapeutics for a variety of diseases.

12-(S)- HETE作为一种调节生理过程的关键信号分子，调控着多种生物学活动，但其作用机制和作用靶点一直不明。直到2011年Yande Guo 等人发现12-(S)-HETE的作用靶点是G蛋白偶联受体GPR31。目前关于GPR31受体的功能的研究尚处于起步阶段，尤其对其活化后胞内转运机制、其介导的信号转导机制及其对肿瘤细胞的增殖、转移和凋亡作用并没有详细的研究。鉴于GPR31受体多表达于肿瘤细胞中，并在调控多种肿瘤细胞活动中起到关键的调控作用，因此，详细阐明GPR31受体介导的信号转导的分子机制将有助于找到治疗肿瘤疾病的新靶点。本项目将着重阐明GPR31受体活化后胞内转运机制、其介导的信号转导途径及其对肿瘤细胞多种生理活动的调控机制。

12-(S)- HETE作为一种调节生理过程的关键信号分子，调控着多种生物学活动，但其作用机制和作用靶点一直不明。直到2011年Yande Guo 等人发现12-(S)-HETE的作用靶点是G蛋白偶联受体GPR31。目前关于GPR31受体的功能的研究尚处于起步阶段，尤其对其活化后胞内转运机制、其介导的信号转导机制及其对肿瘤细胞的增殖、转移和凋亡作用并没有详细的研究。鉴于GPR31受体多表达于肿瘤细胞中，并在调控多种肿瘤细胞活动中起到关键的调控作用，因此，详细阐明GPR31受体介导的信号转导的分子机制将有助于找到治疗肿瘤疾病的新靶点。本项目将着重阐明GPR31受体活化后胞内转运机制、其介导的信号转导途径及其对肿瘤细胞多种生理活动的调控机制。