Table 1.
Role of HMGB family members in carcinogenesis.
| Hallmarks | HMGB family | Key findings | References |
|---|---|---|---|
| Angiogenesis | HMGB 1 | HMGB1 can promote the expression of neuropilin-1, VEGFA, VEGF receptors -1 and -2 to induce angiogenesis. | van Beijnum et al.65 |
| HMGB1 can promote the expression of PDGF to induce angiogenesis. | van Beijnum et al.65 | ||
| HMGB1 binds to RAGE to activate NF-κB and then induces angiogenesis. | van Beijnum et al.66 | ||
| Metastasis | HMGB 1 | HMGB1 binds to RAGE and mediates EMT via MMP-7, phosphor-NF-kB and Snail. | Zhu et al.67 |
| HMGB1 binds to RAGE and mediates EMT via the production of NF-kB, p65, iNOS, MMP-9 and phosphorylation of Rac-1, ERK1/2 and AKT. | Kuniyasu et al.68 | ||
| HMGB1 binds to TLR4 and upregulates downstream MAPK and PI3K signaling pathways. | Sharma et al.69 | ||
| Secreted HMGB1 targets other stromal cells, whose released factors can cause ECM proteolytic degradation. | Gialeli et al.70 | ||
| miR-218 can inhibit the expression of HMGB1 and metastasis. | Zhang et al.71 | ||
| miR-325-3p can suppress the expression of HMGB1 and metastasis. | Yao et al.72 | ||
| miR-142-3p can inhibit the expression of HMGB1 and metastasis. | Xiao and Liu73 | ||
| HMGB 2 | HMGB2 correlates with OCT4 and retains the pluripotent gene expression signature. LncCRCMSL plays as a guide and directs the cytoplasmic maintenance of HMGB2. | Han et al.74 | |
| vIRF1 promotes cell migration by p53- and lnc-OIP5-AS1-mediated downregulation of miR-218-5p, leading to increased expression levels of HMGB2. | Li et al.75 | ||
| miR-329 downregulates HMGB2 via the β-catenin pathway, leading to invasion and metastasis in melanoma. | Mo et al.76 | ||
| HMGB 3 | miR-758 regulates HMGB3, leading to the inhibition of migration, and promotes apoptosis of NSCLC cells. | Zhou et al.22 | |
| miR-513b inhibits the invasion and promotes the apoptosis by negatively targeting HMGB3 and mTOR signaling in NSCLC cells. | Wang et al.77 | ||
| Overexpression of miR-200b targets HMGB3 protein and inhibits HCC cell migration. | Wang et al.19 | ||
| Overexpression of miR-205-5p leads to downregulation of HMGB3 and lower abilities in proliferation and metastasis. | Yamada et al.78 | ||
| miR-532-5p directly targets HMGB3 and downregulates Wnt/β-catenin signaling, inhibiting the proliferation and invasion of bladder cancer cells. | Xie et al.79 | ||
| In CRC, HMGB3 promotes growth and migration by regulating Wnt/β-catenin pathway via c-Myc and MMP-7. | Zhang et al.80 | ||
| Proliferation | HMGB 2 | HMGB2 upregulates the AR-YY1 mediated transcription and interacts with HOX10, contributing to the proliferation in prostate cancers. | Barreiro-Alonso et al.81 |
| HMGB2 transcriptionally regulates LDHB and FBP1 and then regulates the Warburg effect, promoting the proliferation and glycolysis of breast cancer. | Fu et al.21 | ||
| HMGB2 upregulates p53 or potentiates Wnt/β-catenin signaling. This can be suppressed by anti-human EGFR2 antibody via the AKT pathway. | Kwon et al.82 | ||
| HMGB2 activates AKT signaling pathway, resulting in the proliferation of cervical carcinoma. | Zhang et al.83 | ||
| Senescence | HMGB 2 | HMGB2-TOP1cc-cGAS axis regulates SASP and assists cytoplasmic chromatin recognition, enabling response to immune checkpoint blockade. | Zhao et al.84 |
| Biogenesis can stimulate HMGB1’s dsDNA sensing pathway, which can be repressed by p53. | Bianco and Mohr85 | ||
| HMGB2 binds to the SASP gene promoter area, preventing HP1α protein recruitment. | Völp et al.86 | ||
| Drug resistance | HMGB 2 | HMGB2 protein migrates from the cytosol to the nucleus, where it can bind to cis-Pt-DNA adducts in genomic DNA and activates repair system under cisplatin treatment. | van Beijnum et al.87 |
| A complex including HMGB2 and the coactivator SRC-1 binds to the promoter of DDX18, leading to the chemical resistance. | van Beijnum et al.65 | ||
| miR-23b-3p inhibits autophagy via regulating ATG12 and HMGB2 and sensitizes GC cells to chemotherapeutic treatment. | van Beijnum et al.66 | ||
| HMGB2 might be involved in the regulation of p53 and MMP-2/TIMP2 and results in the resistance to TMZ chemotherapy. | Lin et al.88 | ||
| HMGB 3 | HMGB3 deletion attenuates ATR/CHK1/p-CHK1 DNA damage signaling pathway and increases apoptosis and sensitivity to cisplatin. | Xiao and Liu73 | |
| EGb 761 can sensitize 5FUR CRC cells by inhibiting the EMT phenotype and suppressing HMGB3 expression via the Wnt/β-catenin pathway. | Gialeli et al.70 | ||
| Hypoxia | HMGB 3 | HOTTIP deficiency represses glycolysis under hypoxic conditions partly by targeting miR-615-3p/HMGB3 axis in NSCLC cells. | Abraham et al.89 |
| Silence of HMGB3 attenuates HIF1α and inhibits cell proliferation. HMGB3 silence also suppresses the expression of Nanog, SOX2 and OCT-4 genes/proteins. | Barreiro-Alonso et al.81 |
EMT, epithelial-mesenchymal transition; GC, gastric cancer; HMGB, high mobility group box; NSCLC, non small cell lung carcinoma; PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol 3-kinase; TMZ, temozolomide.