The dual role and therapeutic potential of high-mobility group box 1 in cancer

He, Si Jia; Cheng, Jin; Xiao, Feng; Yu, Yang; Tian, Ling; Huang, Qian

doi:10.18632/oncotarget.17885

Cited by 104 publications

(125 citation statements)

References 137 publications

(182 reference statements)

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“…In addition to promoting cancer cell death directly, inhibiting HMGB1 with sivelestat could also have additional paracrine effects in cancer. HMGB1 released from dying cells following injury like radiation or chemotherapy could stimulate proliferation of living cells via an apoptosis-stimulated tumor repopulation mechanism named the "Phoenix Rising" pathway (38,39). Inhibition of HMGB1, either with the small-molecule inhibitor glycyrrhizin or by deletion of HMGB1 expression and function with CRISPR/Cas9 technology, abrogated proliferation of living cancer cells through reduction of phospho-ERK activation (39).…”

Section: Discussionmentioning

confidence: 99%

Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome

Kam

Piryani

McCall

et al. 2019

Clinical Cancer Research

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Purpose: Myelodysplastic syndrome (MDS) is associated with a dysregulated innate immune system. The purpose of this study was to determine whether modulation of the innate immune system via high mobility group box-1 (HMGB1) could reduce cell viability in MDS.Experimental Design: We quantified HMGB1 in an MDS cell line MDS-L and in primary MDS cells compared with nonmalignant hematopoietic cells. We performed loss-offunction studies of HMGB1 using pooled siRNAs and a small-molecule inhibitor sivelestat compared with standard chemotherapy. We measured levels of engraftment of MDS-L cells in NOD-scidIL2Rg null (NSG) mice following treatment with sivelestat. Mechanistically, we interrogated cell survival pathways and 45 targets within the NFkB pathway using both protein analysis and a proteome profiler array.Results: We discovered that HMGB1 had increased expression in both MDS-L cells and in primary CD34 þ MDS cells compared with healthy CD34 þ hematopoietic cells. Sivelestat impaired MDS cell expansion, increased cellular death, and spared healthy hematopoietic cells. MDS-L marrow engraftment is reduced significantly at 17 weeks following treatment with sivelestat compared with control mice. Treatment of CD34 þ MDS cells with sivelestat and azacitidine or decitabine was additive to increase apoptotic cell death compared with chemotherapy alone. Sivelestat promoted apoptosis with increased expression of PUMA, activated caspase 3, and increased DNA double-strand breaks. Inhibition of HMGB1 reduced levels of Toll-like receptors (TLR) and suppressed activation of NFkB in MDS-L cells.Conclusions: Inhibition of HMGB1 could promote MDS cell death and alter innate immune responses via suppression of NFkB pathways.

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Section: Discussionmentioning

confidence: 99%

Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome

Kam

Piryani

McCall

et al. 2019

Clinical Cancer Research

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“…This indirect effect occurs via Hmgb1, which we show to be elaborated downstream of Ifnγ. Hmgb1 is a non-histone chromatin binding protein and a member of the alarmin family (43,44). It is known to function as a mediator of inflammatory processes by binding to its receptors including RAGE and a subset of TLRs (44).…”

Section: Discussionmentioning

confidence: 99%

“…Hmgb1 is a non-histone chromatin binding protein and a member of the alarmin family (43,44). It is known to function as a mediator of inflammatory processes by binding to its receptors including RAGE and a subset of TLRs (44). HMGB1 has been shown to be present in MDS marrow plasma at greater than three times the levels seen in normal marrow plasma (45,46), similar to the levels seen in the TIRAP model presented here, providing functional relevance to the role of HMGB1 in BMF syndromes.…”

Section: Discussionmentioning

confidence: 99%

TIRAP drives myelosuppression through an Ifnγ-Hmgb1 axis that disrupts the marrow microenvironment

Ibrahim

Gopal

Fuller

et al. 2020

Preprint

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Activation of inflammatory pathways is associated with bone marrow failure syndromes, but how specific molecules impact on the marrow microenvironment is not well elucidated. We report a novel role for the miR-145 target, Toll/Interleukin-1 receptor domain containing adaptor protein (TIRAP), in driving bone marrow failure. We show that TIRAP is overexpressed in various types of myelodysplastic syndromes (MDS), and suppresses all three major hematopoietic lineages.. Constitutive expression of TIRAP in hematopoietic stem/progenitor cells (HSPC) promotes upregulation of Ifnγ, leading to bone marrow failure. Myelopoiesis is suppressed through Ifnγ-Ifnγr-mediated release of the alarmin, Hmgb1, which disrupts the marrow endothelial niche. Deletion of Ifnγ or Ifnγr blocks Hmgb1 release and is sufficient to reverse the endothelial defect and prevent myelosuppression. In contrast, megakaryocyte and erythroid production is repressed independently of the Ifnγ receptor. Contrary to current dogma, TIRAP-activated Ifnγ-driven marrow suppression is independent of T cell function or pyroptosis.In the absence of Ifnγ, TIRAP drives myeloproliferation, implicating Ifnγ in suppressing the transformation of bone marrow failure syndromes to myeloid malignancy. These findings reveal novel, non-canonical roles of TIRAP, Hmgb1 and Ifnγ function in the marrow microenvironment,and provide insight into the pathophysiology of preleukemic syndromes.AGGGTCTACGGGGCAATTT; rev-ACAGTCCGTTTCCGGAGTT); mFasL (for-TTTAACAGGGAACCCCCACT; rev-GATCACAAGGCCACCTTTCT); mIfna (for-GACTTTGGATTCCCGCAGGAGAAG; rev-CTGCATCAGACAGCCTTGCAGGTC); mIfnab (for-CCTGCTGGCTGTGAGGAAAT; rev-CTCACTCAGACTTGCCAGCA); mHmgb1 (for-GTTCTGAGTACCGCCCCAAA; rev-GTAGGCAGCAATATcCTTCTC); mIL-4 (for-TTGAACGAGGTCACAGGAGA; rev-AAATATGCGAAGCACCTTGG); mIL-17a (for-CGCAAAAGTGAGCTCCAGA; rev-TGAGCTTCCCAGATCACAGA); mIL-1rn (for-GTGAGACGTTGGAAGGCAGT; rev-GCATCTTGCAGGGTCTTTTC); mTNFSF11 (for-GACTCCATGAAAACGCAGGT; rev-CCCACAATGTGTTGCAGTTC); mIL-13 (for-TGTGTCTCTCCCTCTGACCC; rev-CACACTCCATACCATGCTGC); mIL-1a (for-AGCGCTCAAGGAGAAGACC; rev-CCAGAAGAAAATGAGGTCGG); mIL-27 (for-GTGACAGGAGACCTTGGCTG; rev-AGCTCTTGAAGGCTCAGGG); mCSF1 (for-CCAGGATGAGGACAGACAGG; rev-GGTAGTGGTGGATGTTCCCA); mCCL2 (for-AGGTCCCTGTCATGCTTCTG; rev-GGGATCATCTTGCTGGTGAA); mIL-23a (for-TTGTGACCCACAAGGACTCA; rev-AGGCTCCCCTTTGAAGATGT); mIfna13 (for-CTTTGGATTCCCACAGGAGA; rev-TTCCATGCAGCAGATGAGTC); mIfna2 (for-GCAGATCCAGAAGGCTCAAG; rev-GGTGGAGGTCATTGCAGAAT); mGAPDH (for-TGCAGTGGCAAAGTGGAGAT; rev-TTTGCCGTGAGGAGTCATA); hIFNγR1 (for-CCAGGGTTGGACAAAAAGAA; rev-CGGGATCATAATCGACTTCC); hIFNγR2 (for-TGACAATGCCTTGGTTTCAA; rev-ATCAGCGATGTCAAAGGGAG); mCamp (for-GCTGTGGCGGTCACTATCAC; rev-TGTCTAGGGACTGCTGGTTGA); mTmsb10 (for-CCGGACATGGGGGAAATCG; rev-CCTGTTCAATGGTCTCTTTGGTC); mTmsb4x (for-ATGTCTGACAAACCCGATATGGC; rev-CCAGCTTGCTTCTCTTGTTCA); mAnxa6 (for-

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“…Cancer cell death is commonly induced by therapeutics and is referred to as immunogenic cell death, as it can lead to antitumor immune responses (Galluzzi et al, 2017). Major DAMPs in this case include the translocation of calreticulin to the cell surface, the secretion of ATP, and the release of high-mobility group box 1 (HMGB1) protein (Elliott et al, 2009;Garg et al, 2012;He et al, 2017;Obeid et al, 2007).…”

Section: Innate Immune Sensing and Activationmentioning

confidence: 99%

Unfolding innate mechanisms in the cancer microenvironment: The emerging role of the mesenchyme

Koliaraki

Henriques

Prados

et al. 2020

Journal of Experimental Medicine

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Innate mechanisms in the tumor stroma play a crucial role both in the initial rejection of tumors and in cancer promotion. Here, we provide a concise overview of the innate system in cancer and recent advances in the field, including the activation and functions of innate immune cells and the emerging innate properties and modulatory roles of the fibroblastic mesenchyme. Novel insights into the diverse identities and functions of the innate immune and mesenchymal cells in the microenvironment of tumors should lead to improved anticancer therapies.

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The dual role and therapeutic potential of high-mobility group box 1 in cancer

Cited by 104 publications

References 137 publications

Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome

Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome

TIRAP drives myelosuppression through an Ifnγ-Hmgb1 axis that disrupts the marrow microenvironment

Unfolding innate mechanisms in the cancer microenvironment: The emerging role of the mesenchyme

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