癌基因FAM83B驱动上皮性卵巢癌顺铂耐药的分子机制及其临床价值

Chemotherapy is one of the main methods for the treatment of epithelial ovarian cancer. Cisplatin-resistance is an obstacle to its therapeutic effect. Herein, TCGA data showed that the expression of oncogene FAM83B was highly expressed in the tissues of patients with drug resistance, and the high expression of FAM83B showed an earlier recurrence of ovarian cancer patients. Further, we found that overexpression of FAM83B can enhance the anti-apoptosis ability of tumor cells, improve the drug pump level of tumor cells to chemotherapy drug, and elevate the level of drug pump out and DNA damage repair both in vivo/in vitro assays. At the same time, by using bioinformatic analysis, we found that FAM83B can improve the anti-apoptosis ability of tumor cells to chemotherapeutic drugs by activate Wnt/β-catenin signaling pathway. In the current project, we will combine in vivo and in vitro experimental systems with data from clinical samples, in order to investigate the multi-dimensional mechanisms of FAM83B -induced ovarian cancer chemo-resistence metastasis. Our work may help provide novel therapeutic targets for epithelial ovarian cancer treatment.

化疗是上皮性卵巢癌治疗的主要方法之一，铂耐药是影响其治疗效果的关键。我们通过TCGA大样本量数据分析发现癌基因FAM83B在耐药的上皮性卵巢癌病人组织中高表达，且其高表达的病人复发更早。进一步通过体内/体外实验我们发现FAM83B表达上调可提高上皮性卵巢癌细胞对化疗药物的抗凋亡能力和癌细胞DNA损伤修复能力；同时，结合生物信息学分析，我们发现FAM83B可激活Wnt/β-Catenin信号通路提高癌细胞泵药水平以及DNA损伤修复能力进而提高其对化疗药物的抗凋亡能力。本项目将承前启后，采用体内体外研究体系同时结合临床样本，深入探讨FAM83B通过激活上述信号通路提高癌细胞的抗凋亡能力，导致肿瘤耐药的分子机制及其临床意义，为预测上皮性卵巢癌耐药及治疗提供新的分子靶点。

顺铂耐药是卵巢癌预后不良的重要原因，了解其调节机制对于开发新的治疗方法和药物至关重要。本项目发现 FAM83B 水平低的卵巢癌患者存活时间较短，顺铂耐药的组织也具有低 FAM83B 水平，这表明 FAM83B 可能抑制顺铂耐药。通过体内外实验证实，FAM83B过表达抑制顺铂耐药，表现为卵巢癌细胞增殖和生长速度增加，细胞凋亡率降低，而FAM83B敲低则促进顺铂耐药。具体分子机制分析显示FAM83B与APC相互作用抑制Wnt通路活性，引起卵巢癌顺铂耐药。同时，结合临床样本分析提示 FAM83B 水平与 Wnt 通路活性呈阴性，证实 FAM83B 抑制 Wnt 通路活性。为卵巢癌诊治提供新的分子靶点和新的理论基础，以期改善卵巢癌患者生存预后。