HMGB1 as a therapeutic target in disease Xue, Jiaming; Suarez, Joelle S.; Minaai, Michael ...
Journal of cellular physiology,
20/May , Letnik:
236, Številka:
5
Journal Article
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High‐mobility group box 1 (HMGB1) was initially recognized as a ubiquitous nuclear protein involved in maintaining the nucleosome integrity and facilitating gene transcription. HMGB1 has since been ...reevaluated to be a prototypical damage‐associated molecular pattern (DAMP) protein, and together with its exogenous counterpart, pathogen‐associated molecular pattern (PAMP), completes the body's alarmin system against disturbances in homeostasis. HMGB1 can be released into the extracellular matrix (ECM) by either granulocytes or necrotic cells to serve as a chemotaxis/cytokine during infection, endotoxemia, hypoxia, ischemia–reperfusion events, and cancer. Different isoforms of HMGB1 present with distinctive physiological functions in ECM—fully‐reduced HMGB1 (all thiol) acts as the initial damage signal to recruit circulating myeloid cells, disulfide HMGB1 behaves as a cytokine to activate macrophages and neutrophils, and both signals are turned off when HMGB1 is terminally oxidized into the final sulfonate form. Targeting HMGB1 constitutes a favorable therapeutic strategy for inflammation and inflammatory diseases. Antagonists such as ethyl pyruvate inhibit HMGB1 by interfering with its cytoplasmic exportation, while others such as glycyrrhizin directly bind to HMGB1 and render it unavailable for its receptors. The fact that a mixture of different HMGB1 isoforms is present in the ECM poses a challenge in pinpointing the exact role of an individual antagonist. A more discriminative probe for HMGB1 may be necessary to advance our knowledge of HMGB1, HMGB1 antagonists, and inflammatory‐related diseases.
Graphical
High‐mobility group box 1 (HMGB1) has captured much attention as a prototypical damage‐associated molecular pattern molecule that actively participates in inflammation, inflammatory diseases, and cancer. Targeting HMGB1 has been proven successful in treating inflammation and inflammatory diseases, especially in sepsis, sterile inflammation, autoimmune diseases, and cancer. Continued efforts in the field of HMGB1 can help to fill the gaps in our knowledge and bring HMGB1 antagonists closer to the next step of targeted clinical use.
Among more than 200
-mutant families affected by the "BAP1 cancer syndrome," nearly all individuals inheriting a
mutant allele developed one or more malignancies during their lifetime, mostly uveal ...and cutaneous melanoma, mesothelioma, and clear-cell renal cell carcinoma. These cancer types are also those that, when they occur sporadically, are more likely to carry somatic biallelic
mutations. Mechanistic studies revealed that the tumor suppressor function of BAP1 is linked to its dual activity in the nucleus, where it is implicated in a variety of processes including DNA repair and transcription, and in the cytoplasm, where it regulates cell death and mitochondrial metabolism. BAP1 activity in tumor suppression is cell type- and context-dependent. BAP1 has emerged as a critical tumor suppressor across multiple cancer types, predisposing to tumor development when mutated in the germline as well as somatically. Moreover,
has emerged as a key regulator of gene-environment interaction.
.
BRCA1-associated protein 1 (BAP1) is a potent tumor suppressor gene that modulates environmental carcinogenesis
1
-
3
. All carriers of inherited heterozygous germline
BAP1
inactivating mutations (
...BAP1
+/-
)
developed one and often several
BAP1
-/-
malignancies in their lifetime
4
, mostly malignant mesothelioma (MM), uveal melanoma (UVM)
2
,
5
, etc
6
-
10
. Moreover,
BAP1
acquired biallelic mutations are frequent in human cancers
8
,
11
-
14
. BAP1 tumor suppressor activity has been attributed to its nuclear localization where BAP1 helps maintaining genome integrity
15
-
17
. The possible activity of BAP1 in the cytoplasm was unknown. Cells with reduced levels of BAP1 exhibit chromosomal abnormalities and decreased DNA repair by homologous recombination
18
, indicating that BAP1 dosage is critical. Cells with extensive DNA damage should die and not grow into malignancies. We discovered that BAP1 localizes at the endoplasmic reticulum (ER). Here BAP1 binds, deubiquitylates and stabilizes type-3 inositol-1,4,5-trisphosphate-receptor (IP3R3), modulating calcium (Ca
2+
) release from the ER into the cytosol and mitochondria, promoting apoptosis. Reduced levels of BAP1 in
BAP1
+/-
carriers caused reduction of both IP3R3 levels and Ca
2+
flux, preventing
BAP1
+/-
cells that had accumulated DNA damage from executing apoptosis. A higher fraction of cells exposed to either ionizing or ultraviolet radiation, or to asbestos, survived genotoxic stress resulting in a higher rate of cellular transformation. We propose that the high incidence of cancers in
BAP1
+/-
carriers results from the combined reduced nuclear and cytoplasmic BAP1 activities. Our data provide a mechanistic rationale for the powerful ability of BAP1 to regulate gene-environment interaction.
Mesothelioma has long been associated with the exposure to asbestos, which was largely used in manufacturing activities. Toxicology studies
in vitro
and
in vivo
demonstrated that asbestos fibers were ...carcinogenic, and epidemiology studies revealed that asbestos exposure was paralleled by the increase in the incidence of mesothelioma and related mortality rates. More recently, the role of chronic inflammation and the molecular mechanisms involved in carcinogenesis by mineral fibers were elucidated following the discovery of the roles of HMGB1 and inflammasome. A change of paradigm was the discovery of a prevalence of mesotheliomas attributable to inherited mutations of cancer susceptibility genes. The discovery of
BAP1
as a predisposition gene for the development of familial mesothelioma and other cancers implemented genome studies in patients with mesothelioma and routine clinical surveys in individuals at risk to identify germline mutations associated with cancers included in the BAP1 syndrome. A further progress in the approach to asbestos-related malignancy was the adoption of combined genetics and environmental analyses according to the model of gene-environment (GxE) interactions. This review aims at updating on the most recently discovered mechanisms of tumorigenesis and the pivotal role of GxE interactions.
Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma, and because mesothelioma clustering is observed in some families, we searched for genetic predisposing ...factors. We discovered germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1) in two families with a high incidence of mesothelioma, and we observed somatic alterations affecting BAP1 in familial mesotheliomas, indicating biallelic inactivation. In addition to mesothelioma, some BAP1 mutation carriers developed uveal melanoma. We also found germline BAP1 mutations in 2 of 26 sporadic mesotheliomas; both individuals with mutant BAP1 were previously diagnosed with uveal melanoma. We also observed somatic truncating BAP1 mutations and aberrant BAP1 expression in sporadic mesotheliomas without germline mutations. These results identify a BAP1-related cancer syndrome that is characterized by mesothelioma and uveal melanoma. We hypothesize that other cancers may also be involved and that mesothelioma predominates upon asbestos exposure. These findings will help to identify individuals at high risk of mesothelioma who could be targeted for early intervention.
Breast cancer 1-associated protein 1 (BAP1) is a nuclear deubiquitinase that regulates gene expression, transcription, DNA repair, and more. Several findings underscore the apparent driver role of ...BAP1 in malignant mesothelioma (MM). However, the reported frequency of somatic BAP1 mutations in MM varies considerably, a discrepancy that appeared related to either methodological or ethnical differences across various studies.
To address this discrepancy, we carried out comprehensive genomic and immunohistochemical (IHC) analyses to detect somatic BAP1 gene alterations in 22 frozen MM biopsies from U.S. MM patients.
By combining Sanger sequencing, multiplex ligation-dependent probe amplification, copy number analysis, and cDNA sequencing, we found alteration of BAP1 in 14 of 22 biopsies (63.6%). No changes in methylation were observed. IHC revealed normal nuclear BAP1 staining in the eight MM containing wild-type BAP1, whereas no nuclear staining was detected in the 14 MM biopsies containing tumor cells with mutated BAP1. Thus, IHC results were in agreement with those obtained by genomic analyses. We then extended IHC analysis to an independent cohort of 70 MM biopsies, of which there was insufficient material to perform molecular studies. IHC revealed loss of BAP1 nuclear staining in 47 of these 70 MM biopsies (67.1%).
Our findings conclusively establish BAP1 as the most commonly mutated gene in MM, regardless of ethnic background or other clinical characteristics. Our data point to IHC as the most accessible and reliable technique to detect BAP1 status in MM biopsies.
Cell division and organismal development are exquisitely orchestrated and regulated processes. The dysregulation of the molecular mechanisms underlying these processes may cause cancer, a consequence ...of cell-intrinsic and/or cell-extrinsic events. Cellular DNA can be damaged by spontaneous hydrolysis, reactive oxygen species, aberrant cellular metabolism or other perturbations that cause DNA damage. Moreover, several environmental factors may damage the DNA, alter cellular metabolism or affect the ability of cells to interact with their microenvironment. While some environmental factors are well established as carcinogens, there remains a large knowledge gap of others owing to the difficulty in identifying them because of the typically long interval between carcinogen exposure and cancer diagnosis. DNA damage increases in cells harbouring mutations that impair their ability to correctly repair the DNA. Tumour predisposition syndromes in which cancers arise at an accelerated rate and in different organs - the equivalent of a sensitized background - provide a unique opportunity to examine how gene-environment interactions influence cancer risk when the initiating genetic defect responsible for malignancy is known. Understanding the molecular processes that are altered by specific germline mutations, environmental exposures and related mechanisms that promote cancer will allow the design of novel and effective preventive and therapeutic strategies.
Human malignant mesothelioma is an aggressive and highly lethal cancer that is believed to be caused by chronic exposure to asbestos and erionite. Prognosis for this cancer is generally poor because ...of late-stage diagnosis and resistance to current conventional therapies. The damage-associated molecular pattern protein HMGB1 has been implicated previously in transformation of mesothelial cells. Here we show that HMGB1 establishes an autocrine circuit in malignant mesothelioma cells that influences their proliferation and survival. Malignant mesothelioma cells strongly expressed HMGB1 and secreted it at high levels in vitro. Accordingly, HMGB1 levels in malignant mesothelioma patient sera were higher than that found in healthy individuals. The motility, survival, and anchorage-independent growth of HMGB1-secreting malignant mesothelioma cells was inhibited in vitro by treatment with monoclonal antibodies directed against HMGB1 or against the receptor for advanced glycation end products, a putative HMGB1 receptor. HMGB1 inhibition in vivo reduced the growth of malignant mesothelioma xenografts in severe-combined immunodeficient mice and extended host survival. Taken together, our findings indicate that malignant mesothelioma cells rely on HMGB1, and they offer a preclinical proof-of-principle that antibody-mediated ablation of HMBG1 is sufficient to elicit therapeutic activity, suggesting a novel therapeutic approach for malignant mesothelioma treatment.
Asbestos causes malignant transformation of primary human mesothelial cells (HM), leading to mesothelioma. The mechanisms of asbestos carcinogenesis remain enigmatic, as exposure to asbestos induces ...HM death. However, some asbestos-exposed HM escape cell death, accumulate DNA damage, and may become transformed. We previously demonstrated that, upon asbestos exposure, HM and reactive macrophages releases the high mobility group box 1 (HMGB1) protein that becomes detectable in the tissues near asbestos deposits where HMGB1 triggers chronic inflammation. HMGB1 is also detectable in the sera of asbestos-exposed individuals and mice. Searching for additional biomarkers, we found higher levels of the autophagy marker ATG5 in sera from asbestos-exposed individuals compared to unexposed controls. As we investigated the mechanisms underlying this finding, we discovered that the release of HMGB1 upon asbestos exposure promoted autophagy, allowing a higher fraction of HM to survive asbestos exposure. HMGB1 silencing inhibited autophagy and increased asbestos-induced HM death, thereby decreasing asbestos-induced HM transformation. We demonstrate that autophagy was induced by the cytoplasmic and extracellular fractions of HMGB1 via the engagement of the RAGE receptor and Beclin 1 pathway, while nuclear HMGB1 did not participate in this process. We validated our findings in a novel unique mesothelial conditional HMGB1-knockout (HMGB1-cKO) mouse model. Compared to HMGB1 wild-type mice, mesothelial cells from HMGB1-cKO mice showed significantly reduced autophagy and increased cell death. Autophagy inhibitors chloroquine and desmethylclomipramine increased cell death and reduced asbestos-driven foci formation. In summary, HMGB1 released upon asbestos exposure induces autophagy, promoting HM survival and malignant transformation.
A
bstract
We critically analyze the body of results that hints to the existence of New Physics from possible violations of lepton universality observed by the LHCb experiment in the
μ/e
ratios
R
K
...and
R
K
∗
to the
g −
2 lepton anomalies. The analysis begins with a theoretical, in depth, study of the
μ/e
ratios
R
K
and
R
K
∗
as well as the process
B
s
→ μ
+
μ
−
. Here we consider the impact of complex Wilson coefficients and derive constraints on their imaginary and real parts. We then move to a comprehensive comparison with experimental results. We show that, by fitting a single Wilson coefficient, the deviations from the Standard Model are at the 4
.
7
σ
level when including only the hadronic insensitive observables while it increases to 6
.
1
σ
when including also the hadronic sensitive ones. When switching on all relevant Wilson coefficients and combining both hadronic sensitive and insensitive data into the fit, the deviation from the Standard Model peaks at 7
.
2
σ
and decreases at the 4
.
9
σ
level if we assume that the central values of
R
K
and
R
K
∗
are taken to be unity. We further estimate other unaccounted for SM contributions and show that their inclusion still requires New Physics to fit the data. We then introduce the
g −
2 lepton anomalies as well as the most recent
W
-mass results. Different theoretical models are considered that can explain the discrepancies from the Standard Model. In the final part of our work we estimate the impact of the forthcoming data from LHCb (coming from LHC Run3) and Belle II, when it will have accumulated about 5
ab
−
1
.
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