HMGB3 is Associated With an Unfavorable Prognosis of Neuroblastoma and Promotes Tumor Progression by Mediating TPX2.

Xiaodan Zhong,Songling Zhang,Ying Shi,Junqi Niu,Yutong Zhang,Jian Chang,Yanan Li,Zongmiao Jiang

doi:10.3389/fcell.2021.769547

Abstract

Neuroblastoma (NB) is the most common solid tumor apart from central nervous system malignancies in children aged 0–14 years, and the outcomes of high-risk patients are dismal. High mobility group box 3 (HMGB3) plays an oncogenic role in many cancers; however, its biological role in NB is still unclear. Using data mining, we found that HMGB3 expression was markedly elevated in NB patients with unfavorable prognoses. When HMGB3 expression in NB cell lines was inhibited, cell proliferation, migration, and invasion were suppressed, and HMGB3 knockdown inhibited NB tumor development in mice. RT−PCR was employed to detect mRNA expression of nine coexpressed genes in response to HMGB3 knockdown, and TPX2 was identified. Furthermore, overexpression of TPX2 reversed the cell proliferation effect of HMGB3 silencing. Multivariate Cox regression analysis indicated that HMGB3 and TPX2 might be independent prognostic factors for overall survival and event-free survival, which showed the highest significance (p < 0.001). According to the nomogram predictor constructed, the integration of gene expression and clinicopathological features exhibited better prognostic prediction power. Furthermore, the random forest algorithm and receiver operating characteristic curves also showed that HMGB3 and TPX2 played important roles in discriminating the vital status (alive/dead) of patients in the NB datasets. Our informatics analysis and biological experiments suggested that HMGB3 is correlated with the unfavorable clinical outcomes of NB, and plays an important role in promoting cell growth, proliferation, and invasion in NB, potentially representing a new therapeutic target for tumor progression.

Highlights

Neuroblastoma (NB) is the third most common cancer in children under the age of 15 years, and originates from neural crest-derived sympathetic adrenal precursors, accounting for approximately 7% of pediatric malignancies; it is responsible for nearly 15% of childhood cancer mortality (Ward et al, 2014; Mullassery and Losty, 2016; Zafar et al., High mobility group box 3 (HMGB3) Promotes Neuroblastoma Progression2021)
The results suggested that expression of HMGB3 in all 4 cell lines was high
We analyzed the expression of HMGB1, HMGB2, and HMGB3 in different prognostic groups of NB patients

Summary

Introduction

Neuroblastoma (NB) is the third most common cancer in children under the age of 15 years, and originates from neural crest-derived sympathetic adrenal precursors, accounting for approximately 7% of pediatric malignancies; it is responsible for nearly 15% of childhood cancer mortality (Ward et al, 2014; Mullassery and Losty, 2016; Zafar et al., HMGB3 Promotes Neuroblastoma Progression2021). A study enrolling 240 cases reported a low mutation frequency in NB, less than 20% in total (Pugh et al, 2013) Such relatively uncommon somatic mutations in NB have made it challenging for existing treatment strategies to target frequently mutated oncogenic driver genes. The application of diverse oncogene-targeting drugs, such as CDK4/6 inhibitors (Rihani et al, 2015; Geoerger et al, 2017), AURKA inhibitors (DuBois et al, 2016), and ALK inhibitors (Whittle et al, 2017), has brought some hope to high-risk/refractory/relapsed patients It is still far from sufficient, and novel therapeutic targets are urgently needed

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