Abstract
The transcription factor c-Myb is vital for cell survival, proliferation, differentiation, and apoptosis. We have previously reported that c-Myb knockdown exacerbates neomycin-induced damage to cochlea cells. However, the function and regulation of c-Myb in the mammalian inner ear remains unclear. Here, we first found that the expression of c-Myb in cochlear HCs was downregulated after cisplatin damage in vivo. Next, to investigate the role of c-Myb in HCs treated with cisplatin, the recombinant virus AAV-ie-CAG-Myb-HA (AAV-c-Myb) that overexpresses c-Myb was constructed and transfected into HCs. The protein expression of c-Myb was effectively up-regulated in cultured cochlear HCs after the virus transfection, which increased cochlear HC viability, decreased HC apoptosis and reduced intracellular reactive oxygen species (ROS) levels after cisplatin injury in vitro. The overexpression of c-Myb in HCs after AAV-c-Myb transfection in vivo also promoted HC survival, improved the hearing function of mice and reduced HC apoptosis after cisplatin injury. Furthermore, c-Myb-HC conditional knockout mice (Prestin; c-Myb-cKO) in which c-Myb expression is downregulated only in cochlear OHCs were generated and the cisplatin-induced HCs loss, apoptosis and hearing deficit were all exacerbated in Prestin; c-Myb-cKO mice treated with cisplatin in vivo. Finally, mechanistic studies showed that upregulation of the PI3K/Akt signaling pathway by c-Myb contributed to the increased HC survival after cisplatin exposure in vitro. The findings from this work suggest that c-Myb might serve as a new target for the prevention of cisplatin-induced HC damage and hearing loss.
Highlights
Hearing loss is a common disabling disease affecting up to 466 million people worldwide, of which sensorineural hearing loss (SNHL) accounts for the vast majority of cases [1]
Expression of c-Myb is observed in outer hair cells (HCs) (OHCs) at postnatal day (P) 14, while only weak expression is seen in the inner HCs (IHCs) at this time, and c-Myb is strongly expressed in both IHCs and OHCs starting from P30
The cisplatin administration in vivo was performed according to our previous report [11], and the auditory brainstem response (ABR) thresholds shift at all frequencies were increased after cisplatin administration in mice compared to the control group (Fig. 1A)
Summary
Hearing loss is a common disabling disease affecting up to 466 million people worldwide, of which sensorineural hearing loss (SNHL) accounts for the vast majority of cases [1]. The ototoxicity induced by cisplatin has been attributed to the formation of double-stranded breaks in DNA, the accumulation of reactive oxygen species (ROS), mitochondrial damage, apoptosis [7–11], and the stimulation of inflammatory responses [12, 13], the exact mechanism of cisplatin ototoxicity is not fully understood, and there are currently no methods for protecting against ototoxicity during cisplatin-based chemotherapy. C-Myb is vital for survival, and knockout of both alleles of the gene results in lethality at embryo day 14 in mice [14, 15], c-Myb has been shown to modulate cell proliferation, differentiation, and apoptosis via protein-protein interactions and through transcriptional regulation of signaling pathways, including phosphatidylinositol 3 kinase (PI3K)/Akt, NF-κB, Wnt, etc. We found that c-Myb is dynamically expressed in mouse cochlea HCs and showed that disruption of c-Myb resulted in the induction of apoptosis, the accumulation of reactive oxygen species (ROS), and the reduction of Bcl-2 expression in HEI-OC1 cells, a HC-like cell line, in response to neomycin injury [21]. The role of c-Myb in cisplatin-induced ototoxicity, as well as the underlying molecular mechanisms, remain unclear
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