Synergistic antitumor effect of HMGB2 targeting combined with MDM2 inhibitor in diffuse intrinsic pontine glioma therapy.
AI interpretation is pending for this paper.
Open original publication →What the AI sees
Not AI summarized yet.
Research significance
Pending deeper interpretation.
Source abstract
Diffuse intrinsic pontine glioma (DIPG) is a brain malignancy in children with a dismal prognosis. The high mobility group box 2 (HMGB2) is a member of the HMGB family of chromatin-associated proteins, and is identified as a potential oncogene in various cancers. However, the effects of HMGB2 in DIPG remains unclear. In this study, we observed aberrant expression of HMGB2 in multiple cancer types, with its expression level being negatively correlated with clinical outcomes across pan-cancers. High expression of HMGB2 was determined in DIPG cells, but not in primary brainstem neural progenitor cells (PPCs). Knockdown of HMGB2 significantly inhibited the DIPG cell proliferation and induced cell apoptosis. Intriguingly, bulk RNA sequencing revealed that inhibition of HMGB2 upregulated p53 protein expression and enhanced the activity of p53-p21 axis. Combining HMGB2 inhibitor with a p53-MDM2 inhibitor RG7388 resulted in a synergistic suppression of DIPG cell growth and promoted cell apoptosis by activating the tumor suppressor p53 and p21 expressions in vitro. The animal studies demonstrated that the combination treatment significantly inhibited tumor growth and prolonged the survival of mice bearing orthotopic DIPG tumors. These findings demonstrate that HMGB2 acts as an oncogene in DIPG tumorigenesis, and targeting HMGB2 combined with MDM2 inhibitor provides a novel preclinical basis for the development of DIPG therapeutic strategies.