The role of HMGB1 and its isoforms in the pathogenesis of malignant mesothelioma

Malignant Mesothelioma (MM) is cancer associated with mesothelial cells, which compose pleural and peritoneal tissues. MM results from mineral fiber exposure and has a long, asymptomatic incubation period, causing an extremely poor prognosis for most. High mobility group box protein 1 (HMGB1), a protein released from damaged and dying cells, is mechanistically linked to the malignant transformation and proliferation of mesothelial cells. The goals of this study are verifying whether HMGB1 is required for MM pathogenesis and determining which HMGB1 isoforms are released after mineral fiber exposure. Results showed overall macrophage levels were elevated in mice with wildtype (WT) vs. HMGB1KO (knock out) phenotypes, highlighting the chemoattractant nature of HMGB1, proving it plays a role in MM pathogenesis. Mice unable to produce acetylated HMGB1 had significantly lower levels of inflammatory M1 macrophages (commonly present in MM) compared to individuals producing all isoforms, suggesting the latter, acetylated HMGB1-secreting group developed MM. Finally, mice producing nonacetylated HMGB1 had significantly more M2 macrophages and fewer neutrophils and overall macrophages compared to mice unable to produce any isoform; the combination of fewer inflammatory cells and increased anti-inflammatory cells in mice producing nonacetylated HMGB1 indicates the isoform is not directly associated with MM, but may be prevalent when at-risk patients develop the disease, as shown in past research. Understanding the role of HMGB1 and its isoforms in MM pathogenesis and verifying past results helps improve effectiveness of patient screening; HMGB1 isoforms may serve as diagnostic biomarkers, potentially resulting in earlier diagnoses and improved prognoses