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MiR-181c sensitizes ovarian cancer cells to paclitaxel by targeting GRP78 through the PI3K/Akt pathway

Cancer Gene Therapy volume 29, pages 770–783 (2022)Cite this article

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Abstract

Primary cytoreductive surgery with platinum-taxane-based chemotherapy is the standard treatment for ovarian cancer (OC) patients; however, resistance to chemotherapy is a contributing factor to OC mortality. Paclitaxel (PTX), the most widely used taxane, has become the first-line drug against OC. The molecular mechanism of PTX resistance is different from that of platinum-based agents and is still not completely elucidated. Our previous study showed that glucose-regulated protein 78 (GRP78) is involved in the resistance of OC cells to PTX. However, little is known regarding endogenous inhibitors of this gene. MicroRNAs (miRNAs) play critical roles in the regulation of gene expression; therefore, we sought to identify miRNA(s) with potential to target GRP78 under the hypothesis that miRNA(s) could serve as potential therapeutic targets. Here, we show that miR-181c, predicted to target GRP78, was downregulated in PTX-resistant OC cells and tissues. MiR-181c downregulated GRP78 expression and induced apoptosis by directly targeting its 3′-untranslated region (UTR). Overexpression of miR-181c sensitized resistant OC to PTX by inhibiting the PI3K/Akt pathway in vitro and in vivo. Taken together, our findings indicate that the delivery of miR-181c can efficiently suppress GRP78 expression and GRP78-mediated PTX resistance in OC and suggest that this strategy has therapeutic potential.

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Fig. 1: GRP78 enhances paclitaxel resistance in ovarian cancer cells.
Fig. 2: Evidence of the inverse regulation of GRP78 by miR-181c.
Fig. 3: Deregulation of miR-181c is associated with paclitaxel sensitivity in ovarian cancer cells.
Fig. 4: GRP78 is a target of miR-181c.
Fig. 5: The silencing or overexpression of GRP78 reverses the effect of miR-181c on paclitaxel resistance.
Fig. 6: MiR-181c downregulation activates PI3K/Akt signalling.
Fig. 7: MiR-181c sensitises A2780/PTX cells to paclitaxel in vivo.

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Funding

This study was supported by the National Natural Science Foundation of China (No. 81602273).

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  1. These authors contributed equally: Li-ying Zhang, Jia-ying Yu

Authors and Affiliations

  1. Department of Obstetrics and Gynaecology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China

    Li-ying Zhang, Jia-ying Yu, Ran-ran Zhu, Hong-xian Liu, Xin-yu Wang, Ting-ting Yang & Yi-ning Guo

  2. Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China

    Yan-long Leng

  3. Department of Pharmaceutics, School of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, China

    Jing-ling Tang

  4. Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China

    Xin-chen Zhang

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Zhang, Ly., Yu, Jy., Leng, Yl. et al. MiR-181c sensitizes ovarian cancer cells to paclitaxel by targeting GRP78 through the PI3K/Akt pathway. Cancer Gene Ther 29, 770–783 (2022). https://doi.org/10.1038/s41417-021-00356-y

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