LncRNA KCNQ1OT1 promotes oxaliplatin resistance of ovarian cancer cells through upregulating Bmi1 by sponging miR-128-3p

The long non-coding RNA (lncRNA) KCNQ1OT1 exerts oncogenic functions in human cancers, including ovarian cancer (OC). However, the potential role and detailed mechanism of KCNQ1OT1 in modulating chemoresistance in OC remain unclear. Herein, it showed that KCNQ1OT1 expression was upregulated in OC tissues and tissues from oxaliplatin (OHP)-resistant OC patients. KCNQ1OT1 exhibited oncogenic functions in OVCAR3 and A2780 OC cell lines with increased sensitivity of drug-resistant OC cells against OHP. miR-128-3p was identified as a target of KCNQ1OT1 which negatively regulated the expression levels of the former. Overexpression of miR-128-3p reversed the oncogenic effects of KCNQ1OT1 in OC cells and OHP sensitivity. miR-128-3p main target B lymphoma Mo-MLV insertion region 1 homolog (Bmi1) and negatively regulated its expression, while later positively regulated by KCNQ1OT1. The mouse xenograft tumor experiments in vitro and in vivo have demonstrated that KCNQ1OT1 promoted OC progression and oxaliplatin resistance by upregulating Bmi1 by involving miR-128-3p. Taken together, KCNQ1OT1 acts as a molecular target to bind miR-128-3p and regulates the expression levels of Bim1 in cancer cells that consequently promote tumor progression and OHP resistance in OC. The KCNQ1OT1-miR-128-3p-Bmi1 pathway may represent novel targets for OC treatment.长链非编码RNA（long non-coding RNA，lncRNA）KCNQ1OT1在包括卵巢癌（ovarian cancer，OC）在内的人类恶性肿瘤中发挥致癌功能。然而，KCNQ1OT1在卵巢癌化疗耐药调控中的潜在作用与具体机制仍不明确。本研究发现，KCNQ1OT1在卵巢癌组织以及奥沙利铂（oxaliplatin，OHP）耐药卵巢癌患者的组织中表达上调。KCNQ1OT1在OVCAR3与A2780卵巢癌细胞系中发挥致癌功能，且可提高耐药卵巢癌细胞对奥沙利铂的敏感性。本研究鉴定出微小RNA-128-3p（microRNA-128-3p，miR-128-3p）是KCNQ1OT1的靶标，且KCNQ1OT1可负向调控miR-128-3p的表达水平。过表达miR-128-3p可逆转KCNQ1OT1在卵巢癌细胞中的致癌效应，并恢复其对奥沙利铂的敏感性。miR-128-3p的核心靶基因为B细胞淋巴瘤Mo-MLV插入区1同源物（B lymphoma Mo-MLV insertion region 1 homolog，Bmi1），并可负向调控其表达；而KCNQ1OT1可正向调控Bmi1的表达。体内外小鼠异种移植瘤实验证实，KCNQ1OT1可通过靶向miR-128-3p上调Bmi1的表达，进而促进卵巢癌进展与奥沙利铂耐药。综上，KCNQ1OT1可作为分子靶点结合miR-128-3p，调控癌细胞中Bmi1的表达水平，进而促进卵巢癌的肿瘤进展与奥沙利铂耐药。KCNQ1OT1-miR-128-3p-Bmi1通路有望成为卵巢癌治疗的新型靶点。