HMMR-AS1/HMMR/C/EBPβ正反馈回路与高级别浆液性卵巢癌顺铂获得性耐药的关系及机制研究

Chemoresistant relapse mainly account for treatment failure to high grade serous ovarian cancer patients. An induction of chemotherapy drugs on EMT-related genes is likely to be the link to connect with recurrence, metastasis and chemoresistance. Analysis of gene microarray results indicate HMMR-AS1 is a chemoresistance associated gene in ovarian cancer, and its expression increases in surgical specimens with preoperative chemotherapy. Changes in cell motility and drug sensitivity of SKOV3 cells are in vitro induced by exposure to cisplatin with the altered expression of some molecules, including HMMR-AS1, HMMR, TWIST1, MMP1, CDH3 and so on. Previous studies have shown that TWIST1 and C/EBPβ can be activated by Erk1/2. Together with the prediction of C/EBPβtranscriptionally regulating HMMR-AS1, we speculate that the HMMR-AS1-HMK-Erk1/2-TWIST1 signal axis regulates EMT and changes the motility and drug sensitivity of SKOV3 cells after cisplatin exposure, while downstream C/EBPβ activation by Erk1/2 forms a positive feedback regulation by transcriptional activating HMMR-AS1 expression. We had better to perform the following assays to confirm the speculation. Investigate the relationship between HMMR-AS1 expression and SKOV3 cell phenotype through cisplatin induction and shRNA interference. Explore the exactly molecular mechanism underlying HMMR-AS1-HMMR-Erk1/2-TWIST1 signal pathway and HMMR-AS1-HMMR-Erk1/2-C/EBPβ positive feedback regulation. Observe the curative effect of cisplatin to transplanted tumor with different HMMR-AS1 expression in nude mice. Assess the relationship between HMMR-AS1 expression and the prognosis of patients. The results of this study will reveal a new mechanism concerning acquired chemoresistance regulated by lncRNA, and provide a theoretical basis for clinical chemotherapy options.

耐药性复发是高级别浆液性卵巢癌治疗失败的最主要原因，化疗药物对EMT调控因子的诱导有望关联复发、转移和耐药。基因芯片结果显示HMMR-AS1为卵巢癌耐药相关基因，且在术前化疗样本中表达上调。顺铂诱导的细胞运动性和药物敏感性改变伴随着HMMR-AS1、HMMR、TWIST1等基因的表达改变。过往研究表明TWIST1和C/EBPβ均可被HMMR激活。我们推测：顺铂作用于卵巢癌细胞后诱导的HMMR-AS1-HMMR-TWIST1信号轴调控EMT，另一方面C/EBPβ被激活进而转录调控HMMR-AS1形成正反馈调节。为证实该推测，拟从分子、细胞、动物、临床四个水平考察：在顺铂诱导和基因干扰条件下HMMR-AS1表达与细胞表型的关系；基因下游信号传递和正反馈调控的分子机制；HMMR-AS1基因表达与顺铂疗效及患者预后的关系。本研究揭示调控卵巢癌获得性耐药的新机制，并为临床化疗方案的选择提供理论依据。

耐药性复发是高级别浆液性卵巢癌治疗失败的最主要原因，化疗药物对EMT调控因子的诱导有望关联复发、转移和耐药。基因芯片结果显示HMMR-AS1为卵巢癌耐药相关基因，且在术前化疗样本中表达上调。顺铂诱导的细胞运动性和药物敏感性改变伴随着HMMR-AS1、ZEB2等基因的表达改变。本研究从分子、细胞、动物、临床四个水平考察：1、在顺铂诱导和基因干扰条件下HMMR-AS1表达与细胞表型的关系；2、基因下游信号传递和正反馈调控的分子机制；3、HMMR-AS1基因表达与顺铂疗效及患者预后的关系。本研究揭示调控卵巢癌获得性耐药的新机制，并为临床化疗方案的选择提供理论依据