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Introduction
Hepatoblastoma (HB) is a malignant liver tumor observed in pediatric patients, the incidence of which has increased by 2.18% annually in patients <20 years of age (1). A total of 90% of patients with liver malignancies and <5 years of age were diagnosed with HB (1). Previously, the main treatment for HB was surgical resection. However, complete tumor resection may only be achieved in a small proportion of patients (1). However, since cisplatin (DDP) was introduced into the treatment regimen, the survival rate had improved markedly (1). DDP is a platinum-based chemotherapeutic that belongs to a class of alkylating agents widely used in the treatment of a variety of pediatric malignancies (2). However, as occurs with the majority of anticancer drugs, treatment resistance and side effects (including hearing loss) in healthy tissues are two major challenges in the use of DDP (2,3). The DDP-associated toxicity is dose-dependent, but inhibition of cancer cell proliferation requires a sufficient dose of DDP. Therefore, there exists a contradiction between chemotherapy efficiency and side effects, meaning that there is an urgent requirement to enhance the sensitivity of DDP chemotherapy.
The anticancer mechanism of DDP is associated with its ability to form inter- and intra-strand DNA crosslinks, which perturb DNA replication and transcription, therefore inducing a replication stress and DNA damage response, eventually resulting in cell cycle arrest and apoptosis (4). Apoptosis induced by DDP can be initiated through two main core signaling pathways, the tumor protein 53-dependent transcription of pro-apoptotic B-cell lymphoma-2 family members (p53 upregulated modulator of apoptosis, phorbol-12-myristate-13-acetate-induced protein 1 and Bcl-associated X) that trigger cell death via the mitochondrial apoptotic pathway and the death receptors (DRs) (5). DRs are receptors of tumor necrosis factor-related apoptosis-inducing ligands (TRAILs), which have five receptors. However, only two of the receptors, DR4 (TRAIL-R1) and DR5 (TRAIL-R2), are capable of effectively transmitting the apoptotic signal (5). A number of studies reported that DDP enhances the sensitivity of TRAIL to the cancer cells by increasing the expression of DR4 and DR5 (6,7), which triggers the relocalization of DR4 and DR5 to the cell membrane and accelerates the internalization of TRAIL (2,6,8). However, DDP can also induce apoptosis through the DR4 and DR5 signaling pathways, which is not dependent on TRAIL and the...