NOB1促进卵巢癌发生发展的作用机制研究

Ovarian cancer is one of the major gynecologic malignant tumors with the top ranking mortality rate in China. In our preliminary data, we found that the ribosome assembly factor NIN1/RPN12 binding protein 1 (NOB1) is overexpressed in human ovarian cancer tissue and has a promoting effect on ovarian cancer cells. However, targeting NOB1 can effectively inhibit the growth and invasion of ovarian cancer cells, suggesting that NOB1 is a potential therapeutic target for ovarian cancer. In this proposed study, we will investigate the mechanisms by which NOB1 promotes ovarian cancer and NOB1-mediated targeted therapy. We hypothesized that NOB1 promotes ubiquitination of proteins by ubiquitin proteolytic pathway and subsequently inhibits endoplasmic reticulum (ER) stress and autophagy, ultimately promoting ovarian cancer progression. We will use cellular and animal models to 1) elucidate the molecular mechanism of NOB1-mediated regulation of ER stress-autophagy axis in ovarian cancer cells; 2) assess the effect and mechanism of NOB1 on the progression of ovarian cancer tumors as well as NOB1-related targeting therapy. This study will provide new concept and therapeutic targets for patients with ovarian cancer.

卵巢癌是妇科生殖系统三大恶性肿瘤之一，死亡率居妇科恶性肿瘤之首。我们的前期研究发现：核糖体装配因子NIN1/RPN12结合蛋1(NOB1)在人卵巢癌组织中过表达并具有促癌作用，而靶向NOB1能有效抑制卵巢癌细胞的生长和侵袭。因此，NOB1可能是一个潜在的卵巢癌治疗靶点。本课题将对NOB1的促癌机制及靶向治疗进行深入的研究。在本项目中，我们提出了“NOB1高表达促进泛素蛋白水解酶通路对泛素化蛋白的降解，并抑制内质网应激和自噬，最终促进卵巢癌生长”的假设。我们将利用细胞和动物模型：1）阐明在卵巢癌细胞中NOB1介导的内质网应激-自噬轴调控的分子机制；2）评估NOB1对卵巢癌肿瘤生长进展的影响及机制和靶向治疗的效力。本项目的完成将为卵巢癌发生发展的研究提供新的理论及治疗靶点。

核糖体装配因子NIN1/RPN12结合蛋1（NOB1）在人妇科肿瘤组织中的过表达，使其成为了一个潜在的妇科肿瘤治疗靶点。因此，本课题组对NOB1的促癌机制及靶向治疗进行了深入地研究。在对卵巢癌细胞系与NOB1表达的相关性进行研究后，本项目进一步以宫颈癌细胞系为研究对象，利用Western blot、RT-PCR、CCK法和流式细胞术等技术，从细胞分子和组织水平验证NOB1在宫颈癌发生中的作用，并探讨了miR-612与NOB1表达的调控关系在宫颈癌发生发展中的生物学作用。通过研究，发现NOB1在卵巢癌组织中的高表达与临床病理特征无显著关联，明确了NOB1促进宫颈癌发生的作用及其分子机制，并阐明了miR-612对宫颈癌发生、发展过程的生物学效应以及miR-612在宫颈癌中对NOB1表达的作用，揭示了宫颈癌治疗的潜在预后生物标志物和分子靶点，为妇科肿瘤的防治提供新思路。