HMGB1 expression is linked to unfavorable tumor features and poor prognosis in colorectal cancers

High-mobility group box 1 (HMGB1) is a chromatin-associated protein with a key role in DNA damage repair and genome stability, involved in DNA replication, transcription, and chromatin remodeling. The translocation of HMGB1 from the nucleus to the cytoplasm may confer additional functions regarding the interplay between autophagy, apoptosis and mitochondrial function. By regulating multiple signaling pathways HMGB1 contributes to critical characteristics of cancer cells including inflammation, angiogenesis, proliferation, migration and invasion, as well as tumor energy metabolism. Both increased and reduced expression of HMGB1 have been found to be linked to unfavorable tumor features, presumably depending on its cellular location and tissue type. To gain further insight into the potential significance of HMGB1 in colorectal cancer, a tissue microarray containing 3,456 colorectal cancers was analyzed by immunohistochemistry for nuclear and cytoplasmic HMGB1. A significant nuclear HMGB1 immunostaining was seen in all normal cells of the colorectal epithelium. However, the level of nuclear HMGB1 was variable in cancers. Among 2,601 interpretable cancers, nuclear HMGB1 was completely lost in 8 cases (0.3%) while the staining was 1+ in 179 (6.9%), 2+ in 684 (26.3%), and 3+ in 1,730 (66.5%) tumors. Strong nuclear HMGB1 was significantly linked to distant metastasis (p<0.0001), lymph node metastasis (p=0.0438), blood vessel invasion (p=0.0365), absence of BRAF V600E mutations (p=0.0107), and shortened overall survival (p=0.0118). Nuclear HMGB1 was markedly reduced in mismatch repair (MMR) deficient (43.8% strong) as compared to MMR proficient tumors (73.4%, p<0.0001). Within MMR proficient tumors, high nuclear HMGB1 was linked to V+ (p=0.0089) and L1 status (p=0.0054). Cytoplasmic HMGB1 was less common (16.7%) and unrelated to the histopathologic tumor phenotype. In summary, our data demonstrate that HMGB1 expression is variable in colorectal cancer and that a high nuclear HMGB1 staining level is associated with aggressive tumor features and poor outcome while reduced nuclear HMGB1 is strongly linked to MMR deficiency.