CHD1L调控circ-PTK2翻译蛋白促进卵巢癌转移的机制研究

Epithelial ovarian cancer is the worldwide leading cause of death from gynecological malignancy, with a highly aggressive natural history. Poor prognosis of ovarian cancer is due to the insidious asymptomatic nature of this disease in its early onset, with tumor invasion and metastasis. Protein sequencing analysis showed that chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) belongs to SNF2-like subfamily of the sucrose nonfermenting 2 (SNF2) family, and it is the one to play the role of oncogenic genes in SNF2-like subfamily. Our previous studies have demonstrated that CHD1L gene expression in ovarian cancer metastasis lesions was significantly higher than in ovarian primary lesion, and found that the expression of CHD1L significantly adverse effects the survival of patients with ovarian cancer. Recently, our study found that interfering with the expression of CHD1L in ovarian cancer cells inhibits cell migration, invasion and epithelial-mesenchymal transition (EMT). However, the exact mechanism remains unclear. Through high-throughput sequencing, we found that circ-PTK2 downstream of CHD1L regulates ovarian cancer cell migration and invasion and affects EMT. Bioinformatics analysis showed that circ-PTK2 has the potential to translate proteins. Therefore, we propose that CHD1L, which is over-expressed in ovarian cancer, regulates cellular EMT by a protein translated by circ-PTK2, and thereby promoting ovarian cancer cell metastasis. In this project, we will systematically study the mechanism and function of circ-PTK2 using cell, molecular biology and animal experiments. The relationship between circ-PTK2 expression and clinicopathological features in clinical tissues will also studied. Moreover, the presence of new proteins will be identified by the flag plasmid, antibody and mass spectrometry, and then the mutation circ-PTK2 to detect cell function. Through this project will have a comprehensive and in-depth understanding of the molecular mechanism of CHD1L promotes ovarian cancer metastasis by regulating circ-PTK2 translation of a novel protein. This will provide a new target for treatment of ovarian cancer.

局部侵袭和远处转移是卵巢癌治疗失败的主要原因。CHD1L是癌基因，在多种癌症中表达上调。我们前期研究发现CHD1L在卵巢癌转移灶中的表达显著高于原发灶。我们还发现干扰CHD1L的表达可抑制卵巢癌细胞迁移、侵袭和细胞上皮间质转化（EMT），但其机制仍不明。我们通过高通量测序发现CHD1L下游的circ-PTK2可调节卵巢癌细胞迁移、侵袭，影响细胞EMT。生物信息学分析显示circ-PTK2具有翻译蛋白的潜力。因而我们提出：在卵巢癌中高表达的CHD1L通过circ-PTK2翻译的蛋白调节细胞EMT，从而促进卵巢癌转移。本项目拟在细胞和动物水平验证circ-PTK2的功能，并从临床组织验证其与临床病理因素的相关性，继而通过含flag质粒、抗体和质谱确认新蛋白存在，再突变circ-PTK2检测细胞功能，深层次解析CHD1L调控circ-PTK2翻译蛋白促进卵巢癌转移的分子机制，为治疗提供新的靶点。

侵袭转移是卵巢癌治疗失败的主要原因。探索卵巢癌潜在的预后标记物以及治疗靶点，有助于明确卵巢癌发生发展的机制并开发新的治疗策略。本课题探讨与CHD1L表达相关的circRNA：circ-PTK2，并进一步研究其与卵巢癌发生发展的关系，探索CHD1L通过circRNA参与卵巢癌侵袭转移的分子机制。通过本研究，可为卵巢癌的诊治提供新的理论基础和治疗靶点。根据研究结果我们得出如下结论：CHD1L可通过circ-PTK2的has-miR-639海绵化并释放其对FOXC1的表达从而促进卵巢癌的发生和发展。我们的研究揭示了CHD1L通过circ-PTK2促进卵巢癌侵袭转移的生物学功能以及相应的分子机制。我们的研究发现了一条全新的影响卵巢癌发生发展的新通路，可为卵巢癌的治疗提供新的靶点。