ABSTRACT
Pyroptosis, a newly discovered mode of programmed cell death (PCD), is important in the regulation of cancer development. High mobility group box 1 (HMGB1) is a non-histone nuclear protein that is closely related to tumor development and chemotherapy resistance. However, whether endogenous HMGB1 regulates pyroptosis in neuroblastoma remains unknown. Here, we showed that HMGB1 showed ubiquitous higher expression in SH-SY5Y cells and clinical tumors, and was positively correlated with the risk factors of patients with neuroblastoma. Knockdown of GSDME or pharmacological inhibition of caspase-3 blocked pyroptosis and cytosolic translocation of HMGB1. Moreover, knockdown of HMGB1 inhibited cisplatin (DDP) or etoposide (VP16)-induced pyroptosis by decreasing GSDME-NT and cleaved caspase-3 expression, resulting in cell blebbing and LDH release. Knockdown of HMGB1 expression increased the sensitivity of SH-SY5Y cells to chemotherapy and switched pyroptosis to apoptosis. Furthermore, the ROS/ERK1/2/caspase-3/GSDME pathway was found to be functionally connected with DDP or VP16-induced pyroptosis. Hydrogen peroxide (H2O2, a ROS agonist) and EGF (an ERK agonist) promoted the cleavage of GSDME and caspase-3 in DDP or VP16 treatment cells, both of which were inhibited by HMGB1 knockdown. Importantly, these data were further supported by the in vivo experiment. Our study suggests that HMGB1 is a novel regulator of pyroptosis via the ROS/ERK1/2/caspase-3/GSDME pathway and a potential drug target for therapeutic interventions in neuroblastoma.
ABSTRACT
OBJECTIVES: To study the clinical features of children with rhabdomyosarcoma (RMS) and the influencing factors for prognosis. METHODS: A retrospective analysis was performed on the clinical and follow-up data of 20 children with RMS who were admitted to the Department of Pediatric Hematology, Xiangya Hospital of Central South University, from June 2014 to September 2020. RESULTS: The most common clinical symptoms of the 20 children with RMS at the first visit were painless mass (13/20, 65%), exophthalmos (4/20, 20%), and abdominal pain (3/20, 15%). According to the staging criteria of Intergroup Rhabdomyosarcoma Study Group (IRSG), there was 1 child (5%) with stage I RMS, 4 (20%) with stage II RMS, 9 (45%) with stage III RMS, and 6 (30%) with stage IV RMS. The median follow-up time was 19 months for the 20 children (range: 3-93 months), with a 2-year overall survival (OS) rate of 79.5% (95%CI: 20.1-24.3) and a 2-year event-free survival (EFS) rate of 72.0% (95%CI: 19.5-23.9). Pleomorphic RMS was associated with the reduced 2-year OS rate (P<0.05), and distant metastasis, IRSG stage IV RMS, and high-risk RMS were associated with the reduced 2-year EFS rate (P<0.05). CONCLUSIONS: RMS has no specific clinical symptoms at the first visit, with painless mass as the most common symptom. Distant metastasis, IRSG stage, and risk degree may be associated with the prognosis of children with RMS.
