4.4 Article

Long noncoding RNA ZEB1-AS1 affects paclitaxel and cisplatin resistance by regulating MMP19 in epithelial ovarian cancer cells

期刊

ARCHIVES OF GYNECOLOGY AND OBSTETRICS
卷 303, 期 5, 页码 1271-1281

出版社

SPRINGER HEIDELBERG
DOI: 10.1007/s00404-020-05858-y

关键词

ZEB1-AS1; Epithelial ovarian cancer; Chemoresistance; MMP19

资金

  1. National Natural Science Foundation of China [81572556, 81402139, 81502307]
  2. Nanjing Medical Science and Technique Development Foundation [YKK17182, QRX17157]
  3. Science and technology development foundation item of Nanjing medical university [NMUB2018123, NMUB2018135]

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The study revealed that ZEB1-AS1 plays a pivotal role in cancer chemoresistance by regulating MMP19, providing a potential target for overcoming drug resistance in ovarian cancer cells.
Purpose The long noncoding RNA (lncRNA) ZEB1-AS1 is reported overexpressed in sensitive ovarian cancer cells A2780 compared with paclitaxel (PTX)-and cisplatin (DDP)- resistant. However, the function and mechanism of ZEB1-AS1 in EOC cells still unknown. Methods We used quantitative real-time PCR (qPCR) to detect ZEB1-AS1 expression in A2780 and A2780/R cells. A combination of siRNA, plasmids, CCK8 and flow cytometry was used to detect the effect of ZEB1-AS1 on ovarian cancer cell A2780 PTX and DDP resistance. Transcriptome sequencing, qPCR, and western blot were used for further mechanistic studies. Results ZEB1-AS1 depletion using siRNA in chemosensitive A2780 cells significantly increased PTX and DDP resistance. In contrast, ZEB1-AS1 overexpression in PTX- and DDP-resistant A2780/resistant (A2780/R) cells reversed the observed drug resistance. Thus, ZEB1-AS1 plays an important role in PTX and DDP resistance in EOC cells. However, quantitative real-time PCR (qPCR) and western blot results suggested that ZEB1-AS1 did not regulate chemoresistance through regulation of ZEB1 protein. We used sequencing to detect mRNA expression changes in A2780 cells after ZEB1-AS1 silencing. The results indicated that MMP19 was the likely downstream factor of ZEB1-AS1. We further examined whether ZEB1-AS1 played an important role in chemoresistance by silencing MMP19 in ZEB1-AS1-overexpressing cells. CCK8 assay results suggested that MMP19 knockdown promoted ZEB1-AS1-induced chemoresistance to PTX and DDP in A2780 cells. Conclusion This study is the first to reveal that ZEB1-AS1 plays a pivotal role in cancer chemoresistance.

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