Abstract
Cisplatin is widely used for chemotherapy of a variety of malignancies. However, the clinical application of cisplatin is hampered by the resultant irreversible hearing loss due to hair cell apoptosis. To date, no practical regimen to resolve this has been developed. Meanwhile, the role of microRNA in protecting hair cells from cisplatin-induced apoptosis in the inner ear has not been extensively investigated. In this study, we monitored miR-183, -96, and -182 turnover in the cochlea during cisplatin treatment in vitro. We found that overexpression of miR-182, but not miR-183 and -96, improved hair cell survival after 3 μM cisplatin treatment in vitro. We demonstrated that overexpression of miR-182 repressed the intrinsic apoptotic pathway by inhibiting the translation of FOXO3a. Our study offers a new therapeutic target for alleviating cisplatin-induced hair cell apoptosis in a rapid and tissue-specific manner.
Highlights
As the cornerstone of platinum-based chemotherapy regimens, cisplatin is widely used as the first-line treatment of a variety of malignancies, including lung and ovarian cancers and lymphoma.[1,2] The application of cisplatin significantly improves patient survival rates, whether as adjuvant treatment combined with surgery or salvage treatment for unresectable disease.[3,4] the use of cisplatin is severely limited by its unwanted side effects, including ototoxicity and nephrotoxicity, which reduce patient tolerance during treatment and interfere with the long-term quality of life.[5,6] The cytotoxicity of cisplatin is mediated by induction of apoptosis.[7,8]
Cisplatin leads to irreversible hair cell loss, together with damage to both the spiral ganglion and stria vascularis.[6,9,10]
We investigated the extent of hair cell loss according to cisplatin concentration
Summary
As the cornerstone of platinum-based chemotherapy regimens, cisplatin (cis-diamminedichloroplatinum-II; DDP) is widely used as the first-line treatment of a variety of malignancies, including lung and ovarian cancers and lymphoma.[1,2] The application of cisplatin significantly improves patient survival rates, whether as adjuvant treatment combined with surgery or salvage treatment for unresectable disease.[3,4] the use of cisplatin is severely limited by its unwanted side effects, including ototoxicity and nephrotoxicity, which reduce patient tolerance during treatment and interfere with the long-term quality of life.[5,6] The cytotoxicity of cisplatin is mediated by induction of apoptosis.[7,8]. MicroRNAs (miRNAs) are a class of endogenous non-coding RNAs 20–22 nucleotides in length They negatively regulate gene expression at the post-transcriptional level by binding to partially complementary sites in the 3ʹ-untranslated regions (3ʹUTR) of target messenger RNAs (mRNAs). MiRNAs have important roles in regulating many biological processes, such as proliferation, differentiation, and cell death.[13,14] In vertebrates, the expression of the highly conserved miR-183/96/182 cluster (hereafter, miR-183/96/182) is predominant in ciliated sensory organs.[15,16] In the inner ear, their expression is confined to hair cells and the spiral ganglion.[17,18] Previous studies have revealed the importance of miR-183-5p, -96-5p, and -182-5p (hereafter, miR-183, -96, and -182) in hair cell development and maintenance.[19,20] Other studies conducted in cancer cells have reported their anti-apoptotic effects.[21,22] the roles of miR-183, -96, and -182 in protecting hair cells from cisplatininduced apoptosis have not been investigated. MiR-182 might protect inner ear hair cells from cisplatin-induced apoptosis through inhibition of FOXO3a
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