低表达SLC1A4在卵巢癌顺铂耐药中的作用研究

Study on the Role of Low Expression SLC1A4 in Cisplatin Resistance in Ovarian Cancer

关键词:  溶质载体家族1成员4  卵巢癌  铂类耐药性

Key words:  SLC1A4  ovarian cancer  platinum resistance

摘要:

目的 探讨溶质载体家族1成员4(solute carrier family 1 member 4，SLC1A4)在卵巢癌铂类化疗耐药性中的作用。方法 通过GEO、TCGA数据库分析工具分析SLC1A4在卵巢癌或铂类耐药性卵巢癌中的表达；通过GEO数据库分析SLC1A4在铂类药物处理的卵巢癌细胞系中的表达；通过Kaplan Meier-plotter分析SLC1A4表达量与卵巢癌患者总生存期(overall survival，OS)、无疾病进展生存率(progression free survival，PFS)的相关性；通过DepMap平台分析SLC1A4基因效应与卵巢癌化疗药物敏感相关性；通过流式细胞试验和肿瘤细胞克隆集落形成试验验证低表达SLC1A4介导卵巢癌细胞顺铂耐药；通过TargetScan预测靶向于SLC1A4的微小RNA(miRNA)，并在TCGA数据库卵巢癌样本中验证其相关性；运用COREMINE工具进行文本挖掘分析SLC1A4介导卵巢癌化疗耐药性的生物过程。结果 SLC1A4在卵巢癌患者及铂类耐药性的卵巢癌中的显著降低(P<0.05)，而且与患者的OS、PFS显著相关(P<0.05)；铂类药物处理卵巢癌细胞增加SLC1A4的表达；SLC1A4对卵巢癌的基因效应与铂类药物敏感性正相关；过表达SLC1A4增加顺铂引起的卵巢癌细胞凋亡和减少肿瘤细胞克隆集落形成；hsa-let-7c-5p靶向于SLC1A4并在耐药性卵巢癌患者样本中呈显著负相关。结论 低表达SLC1A4介导卵巢癌铂类耐药性，并且有可能与hsa-let-7c-5p调控有关。

Abstract:

OBJECTIVE To investigate the role of solute carrier family 1 member 4(SLC1A4) in platinum-based chemotherapy resistance in ovarian cancer. METHODS The expression of SLC1A4 in ovarian cancer or platinum-resistant ovarian cancer was analyzed by GEO and TCGA database analysis tools. The expression of SLC1A4 in platinum-treated ovarian cancer cell lines was analyzed by GEO database. The relation of SLC1A4 expression and overall survival(OS) or progression free survival(PFS) in ovarian cancer patients were analyzed by Kaplan Meier-plotter. Correlation between SLC1A4 gene effect and sensitivity to chemotherapeutic agents in ovarian cancer was analyzed through DepMap platform. Low expression of SLC1A4 mediates cisplatin resistance in ovarian cancer cells as verified by flow cytometry and tumor cell clone colony formation assays; prediction of microRNAs(miRNA) targeting SLC1A4 was conducted using TargetScan then validated their correlation in TCGA ovarian cancer samples. Used COREMINE tool to analyze the biological processes of SLC1A4 mediating chemoresistance in ovarian cancer. RESULTS SLC1A4 was significantly reduced in ovarian cancer patients and platinum-resistant ovarian cancer(P<0.05) and significantly correlated with OS and PFS in ovarian cancer patients(P<0.05). SLC1A4 expression was increased in ovarian cancer cells with platinum treatment. The genetic effect of SLC1A4 on ovarian cancer was positively correlated with platinum drug sensitivity. Overexpression of SLC1A4 increased cisplatin-induced apoptosis and reduced tumor cell colony formation in ovarian cancer cells. Hsa-let-7c-5p was targeted to SLC1A4 and significantly negatively correlated in samples from drug-resistant ovarian cancer patients. CONCLUSION Low expression of SLC1A4 mediates platinum drug resistance in ovarian cancer and is potentially associated with hsa-let-7c-5p regulation.