E3泛素连接酶PARK2调控EGFR的分子机制及其对肿瘤细胞生长和侵袭的影响

PARK2, as an E3 ubiquitin ligase, plays an important role in the progress of Parkinson disease. Recently, PARK2 has been assumed to be a tumor suppressor gene in the development of cancer and gradually becoming a hot research field. In previous studies, we used SNP-Chip technique to screen copy number abnormality of the whole genome in GBMs, and found that PARK2 localized in the common minimum deleted region (CMDRs) of 6q26-27, which contained only four genes. At the same time, we found that in GBM specimens and cell lines, PARK2 presented lower expression, and patients had a significantly shortened survival time with low PARK2 expression. In recent work, we pointed out PARK2 was associated with the EGFR degradation through ubiquitination pathway, and suggested that PARK2 was involved in the malignant transformation and tumor cell growth by regulating the EGFR. In this study, we will take glioma as a cell model to investigate the regulation mechanism between PARK2 and EGFR: 1) the mechanism of PARK2 inducing ubiquitination of EGFR; 2) regulation of PARK2 on EGFR pathway; 3) the effect of mutation in both of PARK2 and EGFR on correlativity between these two genes; 4)the effects of PARK2 on cell growth and invasion through EGFR pathway, as well as therapeutic strategy of cancer dependences on the correlativity of PARK2 and EGFR. Our studies will help to better clarify the mechanism of PARK2 in the regulation of the cell malignant transformation and inhibition of cell growth.

PARK2作为一种E3泛素连接酶，在帕金森病中发挥重要作用。近来，PARK2在肿瘤发生发展中的功能逐步受到重视。我们利用SNP-Chip对神经胶质瘤全基因组拷贝数进行扫描，PARK2位于染色体6q26-27最小同源缺失片段之中，并发现：1)PARK2缺失与EGFR扩增有显著共存关系；2)低表达PARK2与神经胶质瘤预后差呈明显相关性；3)PARK2过表达抑制细胞生长；4)PARK2通过泛素化途径降解EGFR。本课题将进一步从以下几个方面研究肿瘤中PARK2泛素化调控EGFR分子机制及其对肿瘤细胞生长和侵袭的影响：1)PARK2诱导EGFR泛素化的分子机制；2)PARK2对EGFR通路的调控；3)PARK2突变和EGFR突变对两者之间调控关系的影响；4)PARK2与EGFR的关系对肿瘤生长和治疗的影响。通过该研究，将阐明PARK2调控EGFR的分子机制，及其抑制肿瘤细胞生长和侵袭转移的功能。

我们不仅在胶质瘤当中发现PARK2通过抑制EGFR-AKT信号通路，泛素化降解EGFR蛋白，进而抑制肿瘤的发展。同时我们也发现PARK2在乳腺癌化疗中扮演重要的角色。微管在有丝分裂和细胞分裂过程中起重要作用，是抗癌药物的重要靶点。抗微管药物如多西他赛和长春瑞滨被广泛用于治疗乳腺癌。然而，大约三分之一的乳腺癌患者遭受抗微管药物化疗的副作用，却没有从中受益。如今迫切需要的是开发生物标志物，用于预测抗微管药物对哪些患者有疗效。我们发现，PARK2是一种可以预测乳腺癌中抗微管药物的化疗敏感性的预测因子。PARK2基因编码E3泛素连接酶。34%的乳腺癌患者表现出PARK2缺失。有趣的是，在接受化疗的乳腺癌患者中，PARK2的高表达与良好的生存率呈正相关，而在未接受化疗的患者中则无相关。PARK2过表达使细胞对抗微管药物更敏感，而不改变对DNA损伤药物敏感性。PARK2敲低增加了抗微管药物的耐药性。机制上，PARK2在抗微管药物暴露后显著激活线粒体凋亡通路。这种现象是通过下调抗凋亡蛋白BCL-2来实现的。值得注意的是，PARK2与BCL-2相互作用，并以E3连接酶依赖的方式促进BCL-2的泛素化降解。因此，PARK2在体内外均显著增强了抗微管药物的化疗敏感性，而E3泛素化功能缺失的PARK2突变体则没有这种功能。综上所述，我们发现PARK2是抗微管药物敏感性的一种新型中介物，可用于预测乳腺癌患者对含抗微管药物治疗方案的疗效。