Kindlin-2在上皮性卵巢癌中调节雌激素受体α表达的作用及其机制研究

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Most patients present at an advanced stage and the disease commonly relapse after primary surgery and chemotherapy. Relapsed ovarian cancer is not curable and has little responses to chemotherapy at the expense of toxicities that may diminish quality of life. Anti-estrogen therapy has provided effective palliation with relatively little toxicity in hormone-sensitive cancers. However, there are few effective markers to guide therapy. Kindlin-2 is a novel integrin-binding adaptor protein. Our previous research found that expression of Kindlin-2 decreased in serous EOC，and low Kindlin-2 expression predicted poor overall and progression-free survivals in serous EOC patients. We also found that Kindlin-2 up-regulated the expression of ERα which correlated to the survival time in other studies. These results indicated that Kindlin-2 may participate in the regulation of ERα. Our lab found that Kindlin-2 up-regulated the expression of DNMTs in breast cancer cells. Kindlin-2 interacted with DNMT3A and both of them co-occupied the promoter of miRNA-200 family and resulted in the CpG island hyper-methylation and significant down-regulation of the expression of miR-200 family. We found that Kindlin-2 also up-regulated the expression of DNMTs in EOC cells. So we proposed a hypothesis that Kindlin-2 may facilitate the methylation of the promoters of microRNAs which regulated ERα through the interaction with DNMTs and then up-regulated the expression of ERα in EOC cells. We aim to clarify the exact mechanism through which Kindlin-2 up-regulated ERα. Then we will investigate the effects of regulation of ERα by Kindlin-2 on EOC cells migration, invasion, peritoneal dissemination and anti-estrogen therapeutic sensitivity. Furthermore, we will discuss the clinical significance of the regulation of ERα by Kindlin-2 in EOC patients. Our research will offer new potential markers for guiding therapy and predicting prognosis.

上皮性卵巢癌（EOC）是致死率最高且易复发的妇科肿瘤。化疗药副作用大且易耐药，激素治疗不良反应轻且有一定疗效，但缺乏有效标记物指导治疗。Kindlin-2是新发现的衔接蛋白，我们前期研究发现，Kindlin-2在EOC细胞中上调ERα，Kindlin-2或ERα低表达的患者预后差，提示Kindlin-2和ERα可能存在调控关系。Kindlin-2在乳腺癌细胞和EOC细胞中均可上调甲基转移酶DNMTs。两者相互作用促乳腺癌细胞miRNA-200家族启动子甲基化。因此本项目假设在EOC细胞中Kindlin-2通过DNMTs甲基化能调节ERα表达的microRNAs而上调ERα。本项目在分子、细胞和实验动物中研究Kindlin-2调节ERα表达的机制及其对EOC细胞转移和激素治疗敏感性的影响；通过临床标本揭示Kindlin-2调节ERα表达的临床意义，为EOC提供潜在标记物来指导治疗及判断预后。

上皮性卵巢癌是妇科肿瘤中死亡率最高的肿瘤。化疗药副作用大且易耐药，激素治疗缺乏有效标记物指导治疗。本研究组试图通过研究Kindlin-2与ERα的关系，探讨二者和激素治疗的联系，为临床提供潜在标记物。但在实施过程中困难比较多，目前的卵巢癌细胞分类混乱，适合于做实验的细胞较少，ERα阳性的上皮性卵巢癌细胞就更少。在现有的一株卵巢癌细胞稳定过表达Kindlin-2后结果与预期不符。虽然尝试了很多办法，但都没有获得实质性进展，非常遗憾。同时期尝试做了其他的实验，获得了一些结果。其中1篇文章已经被接收，另1篇文章修改稿审稿中，还有1篇文章在审稿中，这些文章均标注此基金号。接收文章摘要如下：.偏头痛是一种慢性神经血管性疾病，患病率高，社会经济负担较重。2012年全球疾病负担研究显示，偏头痛为全球第8大以及女性第4大负担最重的疾病。体育运动常常会加剧偏头痛发作，此类病人生活质量较差，学习、工作和生活会受到严重影响。虽然对偏头痛的发病机制进行了大量研究，但其确切机制尚未完全阐明，针对偏头痛的药物有很多，但疗效一般，而且副作用也比较大。因此急需寻找新的偏头痛生物标记物来指导治疗。本研究通过液相色谱-质谱对偏头痛病人血清进行代谢组学检查，筛选偏头痛病人潜在的生物标记物。主成分分析（PCA）和正交偏最小二乘判别分析（orthoPLS-DA）显示偏头痛病人与正常健康人的代谢物有差别。火山图分析发现偏头痛病人有10种代谢物显著低于正常人，其中1种是5-羟色胺，其余均为氨基酸。代谢途径分析发现色氨酸代谢（5-羟色胺代谢）、精氨酸和脯氨酸代谢以及氨基酰-tRNA合成途径是偏头痛病人变化最大的代谢途径，受试者工作特征曲线（ROC）分析显示氨基乙酰基-L-脯氨酸、N-甲基-DL-丙氨酸和L-蛋氨酸是偏头痛潜在的敏感而特异的生物标记物。这三个代谢物可能和传统的偏头痛生物标记物5-羟色胺一样特异，或者比5-羟色胺更特异，我们推测通过调控这些代谢产物或代谢途径可能帮助预防和治疗偏头痛。