ARTICLE
Auteur(s) : Christiane
Brahimi-Horn, Jacques Pouysségur
Institute of Signaling, Developmental Biology and Cancer
Research, CNRS UMR 6543, University of Nice, Centre A. Lacassagne,
33 avenue Valombrose, 06189 Nice
Hypoxia in physiology and pathophysiology
Oxygen homeostasis is an essential component of mammalian existence
and is controlled through respiratory and cardiac responses.
Hypoxia, a low level of oxygen in tissues, induces a signalling
pathway of which the transcription factor the hypoxia-inducible
factor (HIF) is a key element. HIF is a heterodimeric factor
composed of an alpha subunit that possesses a remarkably short
half-life in the presence of oxygen (less than five minutes) but is
stable and active in the absence of oxygen, and a beta subunit that
is oxygen independent. Hypoxia is a condition encountered in
embryogenesis in which hypoxic signalling is considered to be
necessary for normal development. In fact, the knockout of HIF in
mice is embryonic lethal (around embryonic day 10) and embryos show
cardiac and vascular abnormalities. A dysfunction in cellular
oxygen homeostasis is also central to a number of
pathophysiological situations and in particular in cancer (table 1(
Table 1 )). In these situations HIF
drives the cellular response by activating or repressing genes
possessing varied functions.
Table 1 Pathophysiological situations in which a
hypoxic environment is involved in disease processes
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Hypoxia in disease
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Ischemic diseases (cerebral, cardiovascular)
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Diabetes
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Atherosclerosis
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Inflammatory disorders
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Psoriasis
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Pre-eclampsia
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Chronic obstructive pulmonary disease (COPD)
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Cancer
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Tumour cell response to hypoxia
A rapidly growing tumour mass quickly outstrips its vasculature and
thus lacks oxygen and nutrients. Oxygen partial pressures
(PO2) as low as 1-10 mmHg have been observed in solid
tumours [1]. This diminished level of oxygen leads to the
stabilisation and activation of the transcription factor HIF, for
hypoxia-inducible factor, which in turn induces the transcription
of genes such as the vascular endothelial growth factor-A (VEGF-A)
( (figure 1) ).
The product of this gene, together with a number of other proteins
such as angiopoietin-2, stimulate the formation of new vessels that
migrate into the tumour mass, a process termed angiogenesis, and
thereby re-establish oxygen and nutritional homeostasis [2]. The
binding of HIF to the VEGF-A promoter, although a key action in
induction, is not the only means of controlling VEGF-A expression.
Regulation of mRNA stability through the stress-activated kinase
p38 and translation by internal ribosome entry site (IRES)
sequences also controls expression [3, 4]. This is important since
hypoxia and nutrient depletion inhibit classic cap-dependent
translation and only mRNA containing IRES are translated. In this
way translation of VEGF-A is ensured under stress conditions as is
the alpha subunit of HIF 1, which also contains IRES sequences.
VEGF-A levels are also increased through the activation of the
Ras→MEK→ERK pathway phosphorylation of the transcription factor Sp1
and its binding to the proximal region of the promoter of VEGF-A
[3]. Finally, HIF1α phosphorylation upregulates expression possibly
by favouring access of RNA polymerase II to the VEGF-A promoter
[3].
The inhibition of angiogenesis, in particular through the
blockade of VEGF, is being actively investigated in the clinic as a
means to inhibit this circumvention mechanism that allows cells to
survive [2, 5]. However, the neo-vessels formed are often defective
and possess an abnormal structure, which may subsequently favour a
return to hypoxic conditions. The hypoxic microenvironment of
tumours is also known to limit the effectiveness of chemo- and
radio-therapy; the abnormal or absent vasculature does not permit
the access of chemicals to individual tumour cells and oxygen is
required for optimal irradiation-induced DNA damage.
Cells have developed means of adapting to hypoxic stress but
cell death is also a characteristic of the hypoxic response. As yet
there is no clear-cut understanding of the choice between cell
survival and cell death in hypoxia (for review see [6]) possibly
because the duration and severity of a hypoxic stress may vary in
tumours and because HIF induces both pro- and anti-apoptotic cell
proteins, responsible for apparently opposite responses. The
microenvironment of tumours may be fundamental in determining cell
survival/death. The protein Bcl-2/adenovirus EIB
19 kD-interacting protein 3 (BNIP3) that contains a BH3 only
domain is involved in cell death and is also a HIF target. However,
growth factor removal, acidosis or glucose deprivation may be
required to obtain induction of BNIP3-mediated cell death [6].
Overview of the regulation of the stability and activity of
HIF
The hypoxia signalling pathway is composed of several steps
starting with oxygen depletion, then HIFα stability, nuclear
translocation, dimerisation with HIFβ, binding to DNA, interaction
with co-activators, and finishing with induction or repression of a
myriad of genes. HIF is a dimer of alpha and beta subunits, for
each of which there are three isoforms numbered 1 to 3. HIF1 is the
most studied to date but more and more data is available concerning
HIF2 and its specificity in gene induction compared to HIF1. Much
less is known about HIF3. Considerable similarity exists in the
mechanism of regulation of the different alpha subunits. These
alpha subunits are extremely unstable in the presence of oxygen,
due to hydroxylation, on two proline residues in the oxygen
dependent degradation domain (ODDD) of the protein, by oxygen-,
2-oxoglutarate- and iron-dependent prolyl hydroxylase domain (PHD)
proteins ( (figure
2) ). The hydroxylation of the HIFα protein causes
interaction with the von Hippel-Lindau (VHL) protein, a component
of an E3 ubiquitin ligase complex. This interaction results in the
covalent attachment of chains of the small globular protein
ubiquitin to lysine residues on HIFα. Decoration of HIF with
ubiquitin chains earmarks it for degradation by a multiprotease
complex called the 26S proteasome. Thus, in the presence of oxygen,
once HIF is produced it is hydroxylated, ubiquitinated and
degraded. However, in the absence of oxygen the PHDs that use
oxygen in the hydroxylation reaction are inactive and consequently
HIF “escapes” hydroxylation, ubiquitination and reaches a higher
steady state level. However, stability does not necessarily mean
activity. Hydroxylation of HIFα on an asparagine residue by another
oxygen- and iron-dependent hydroxylases termed factor inhibiting
HIF1 (FIH) inhibits its transcriptional activity by abrogating
interaction with a co-activator CBP/p300. Thereby oxygen imposes a
double lock on HIF through control of both stability and activity.
Once stabilised, HIFα rapidly translocates to the nucleus and binds
its partner HIFβ; the latter is constitutively synthesized and its
stability is not influenced by the level of oxygen. Together they
bind to target genes through a recognition DNA sequence,
5′-RCGTG-3′, referred to as a hypoxia-response element (HRE).
Finally, the co-activator CBP/p300 interacts with the C-TAD of HIFα
and transcriptional activity is initiated. Thereby, in the absence
of oxygen where the hydroxylases PHD and FIH are inactive, HIF
modulates the expression of genes involved in functions such as
angiogenesis, metabolism, invasion/metastasis and
apoptosis/survival ( (figure 3) ). At least 60
HIF-dependent genes have been recognized to date [7].
HIFα driven to destruction by the prolyl hydroxylase domain
proteins
The secret behind the instability of HIFα remained intact from the
time of its discovery in 1991 [8] until 2001 when it was revealed
that posttranslational hydroxylation by iron- and 2-oxoglutarate
dependent dioxygenases was the key to HIF1α destruction [9, 10]. In
1991 Greg Semenza and colleagues discovered that the incubation of
liver cells in hypoxia resulted in the induction of the EPO gene.
Any sportsman knows that a similar increase in EPO in the blood
occurs with increasing altitude that parallels a decrease in the
level of oxygen. A nuclear factor extracted from hypoxic cells,
appropriately termed the hypoxia-inducible factor (HIF), was
identified through binding to and induction of the transcription of
the EPO gene. HIF was subsequently shown to be expressed in a large
number of cell types and to be rapidly (two to four hours)
stabilised in an atmosphere of less than 5% (40 mm Hg) oxygen.
After return of cells to a sea level oxygen concentration (21%
oxygen, 160 mm Hg) the protein is rapidly (within 20 minutes)
degraded and no longer detectable. It was also known that
incubation of cells in the presence of cobalt or iron chelators
leads to stable HIF1α. The explanation for this came with the
discovery of the PHD proteins and the finding that their activity
is dependent on the presence of iron. The PHDs are both Fe(II)- and
2-oxoglutarate-dependent dioxygenases (EC 1.14.11.2). They belong
to the largest known family of non-heme oxidizing enzymes of which
the collagen prolyl-4-hydroxylase is a member. The PHDs have also
been referred to HIF-1a prolyl-4-hydroxylase (HPH) or EGL Nine
(EGLN). There exists three human PHD isoforms and the corresponding
abbreviations for the various homologs are as follows:
PHD1/HPH-3/EGLN2; PHD2/HPH-2/EGLN1; PHD3/HPH-1/EGLN3. The PHDs
hydroxylate two proline residues in the oxygen dependent
degradation domain (ODDD) of HIF-α, proline 402 and 546 in HIF1α.
These enzymes require 2-oxoglutarate (2-OG) (α-ketoglutarate) as
co-substrate and Fe(II) and ascorbate as co-factors. The PHD-Fe(II)
complex first binds 2-OG and then HIFα, which displaces a water
molecule that is coordinated to Fe(II) thereby initiating reaction
with molecular oxygen [10]. The oxidative decarboxylation of 2-OG
then leads to production of succinate and CO2, and a
ferryl species (FeIV = O) that oxidizes HIFα. The specific
silencing by RNA interference of PHD2 but not PHD1 or 3 is
sufficient to stabilise HIF1α in normoxia [11]. This result
indicates that PHD2 is the major oxygen sensor responsible for
maintaining low levels of HIF1α in normoxia.
This posttranslational hydroxylation results in the rapid
attraction to HIFα of the protein von Hippel-Lindau (VHL), a
component of an E3 multiprotein ubiquitin ligase complex, termed
VBC (VHL/elongin B/elongin C). E3 ubiquitin ligases bring about the
covalent attachment of the small protein ubiquitin to a substrate,
in this case HIFα. The ubiquitination of a protein with
multiubiquitin chains is more often a signal for its degradation by
the 26S proteasome, which is a barrel-shaped multiprotein
proteolytic complex that degrades proteins into polypeptides.
The instability of HIFα is also regulated by other proteins such
as Hsp90 and OS9 [12, 13]. OS9 interacts with HIF1α and increases
HIF-a instability by promoting interaction with PHD2 and PHD3
leading to prolyl hydroxylation and thus VHL-dependent
polyubiquitination and proteasomal degradation. In addition, an
acetyltransferase termed arrest-defective-1 (ARD1) was reported to
favour interaction with VHL by direct acetylation of HIF1α [14],
but this has been more recently questioned [15-17]. Our laboratory
has shown that the expression of ARD1 is neither hypoxia nor HIF1-
or -2-dependent and does not effect the stability of HIF1α or -2α
in tumour cells of human origin [16]. Although ARD1 has been
confirmed to interact with HIF1α [15] its role in HIF function
remains to be clarified and any link to tumourigenesis through
increased expression of its partner N-acetyl transferase human
(NATH, also called tubedown or Gal9) requires further investigation
[18, 19].
It is of interest to note that the genes PHD2 and PHD3 but not
PHD1 are themselves subjected to up-regulation in hypoxia [11].
This auto-regulation assures rapid intervention if and when the
cellular oxygen level returns to a level that allows the
hydroxylation reaction to take place. However, the PHDs like HIFα
are also regulated by the ubiquitin-proteasomal system. The E3
ubiquitin ligases Siah1a and Siah2 have been shown to initiate
proteasomal degradation of PDHs [20]. In addition, the genes for
these E3 ligases are also up-regulated in hypoxia via HIF and
thereby limit the levels of PHD1 and 3 under moderate oxygen
deprivation. It is also of interest to note that the co-substrate
2-oxoglutarate required for PHD activity is a component of the
mitochondrial tricarboxylic acid (TCA) cycle. As will be seen
below, the functioning of the TCA cycle is limited under hypoxic
conditions, thus 2-OG may also become limiting making the PDHs
ineffective. In fact, mutations in enzymes of the TCA cycle
including succinate dehydrogenase (SDH) and fumarate dehydrogenase
(FH) (also termed fumarase) are associated with tumourigenesis
[21]. SDH and FH are tumour suppressors and their mutation results
in an accumulation of succinate or fumarate, respectively, which
have been suggested to inactivate the PHDs. This inhibition would
then lead to HIF1α stability and HIF activity and transcription of
downstream genes. A more detailed description of the properties of
these enzymes can be found in a two recent reviews [10, 22].
The “bicephalous” nature of HIF-α transcriptional activity
Few transcription factors have two domains controlling their
transcriptional activity and for those that do little is know about
the significance of this duplication. HIFα possesses two
transcriptional activation domains (TAD) in its C-terminal part,
referred to as the C-terminal and N-terminal TADs ( (figure 4) ). Only about
20% amino acid similarity exists between the two TADs. As indicated
above the oxygen-sensor FIH hydroxylates the C-TADs leading to
inhibition of its activity. A differential in the Km of
the PHDs and FIH has been reported suggesting that the PDHs are
more readily inactivated by a drop in the oxygen level below
normoxic levels than FIH. Thus as tumour cells are progressively
distanced from blood vessels the PHD activity will decline leading
to accumulation of HIFα but with a lock on the C-TAD due to
maintenance at this oxygen level of FIH activity ( (figure 4) ). However, if a
gene requires only N-TAD activity it will be activated under these
conditions. As the oxygen level drops further both PHD and FIH will
be inhibited and genes requiring full N-TAD and C-TAD activity will
be induced. Using either cells stably silenced, by RNA
interference, for FIH or cells overexpressing FIH i.e. unlocking or
locking the C-TAD, our laboratory recently examined the role of the
two TAD of HIFα [23]. 26 HIF-dependent genes were examined and
almost equal numbers subsequently grouped into genes sensitive or
insensitive to FIH; reflecting their dependence or lack of
dependence on one or both TADs along a hypoxic gradient.
FIH hydroxylation leading to inhibition of interaction of HIF-α
with the co-activator CBP/p300 is probably the major mechanism
regulating the transcriptional activity of HIF. However, a number
of other forms of posttranslational modifications including
phosphorylation and S-nitrosation may induce HIF transcriptional
activity while modification with the small ubiquitin-related
modifier (SUMO) may repress activity [19, 24]. In addition, a
number of proteins including CBP/p300 interacting transactivator
with ED-rich tail 2 (CITED) [25], inhibitor of growth family member
4 (IGN4) [26] and VHL-associated KREB-A domain containing protein
(VHLaK) [27] have been shown to associate with HIF and repress its
transcriptional activity. Such posttranslational modifications and
interactions may bring into play the balance between histone
acetylation and deacetylation. Acetylation, occurring on lysine
residues of histones, brings about a change in charge leading to a
more acidic and thus stronger DNA binding state. Thus, in general,
acetylation by Histone Acetyltransferases (HAT) and deacetylation
by histone deacetylases (HDAC) correlated, respectively, with
activation and repression of transcription. In fact, the major
co-activator CBP (CREB binding protein) and its paralog p300
possess HAT activity. This is also the case for another
co-activator protein steroid hormone receptor co-activator-1
(SRC-1) that binds HIF.
Tumour metabolism leading to acidosis and cell
survival/death
It has been know for quite some time that tumours possess an
extracellular pH that is lower, more acidic, than that of normal
tissue (6.2-6.8 versus 7.2-7.4). This is considered to be the
consequence of a high rate of glucose uptake accompanied by
elevated glucose consumption i.e. glycolysis (for review see [28]).
Otto Warburg discovered in the 1920s that tumours, unlike normal
cells, converted glucose to pyruvate and then to lactate, even in
the presence of abundant amounts of oxygen (the “Warburg effect”) (
(figure 5) ).
This is synonymous with the metabolic pathway used by muscle tissue
when oxygen is low. Normal cells also convert glucose to pyruvate
but in contrast transport it to the mitochondria where it enters
the TCA cycle (or citric acid cycle, or Krebs cycle) and undergoes
oxidative phosphorylation. This catabolic pathway produces a much
higher level of ATP but requires oxygen for mitochondrial
respiration. Thus, hypoxic tumour cells in order to obtain enough
ATP increase their rate of glycolysis through active HIF that
induces the expression of glucose transporters such as GLUT1 and
the enzymes involved in glycolysis. By inhibiting HIF1α
degradation, pyruvate could also further enhance the rate of
glycolysis. HIF also drives the reversible conversion of pyruvate
to lactate by the HIF-target gene lactate dehydrogenase A (LDH-A)
that is up-regulated in transformed cells. In this way highly
proliferating cells with a high-energy demand rapidly dispose of a
supply of ATP. However, the consequence is an overload in lactate
and CO2 that contributes to the decrease in the
extracellular pH. The lactate produced is excreted from cells
through a H+/lactate cotransporter, the monocarboxylate
transporter (MCT), leading to a decrease in the extracellular pH of
tumours [29]. At least one MCT, MCT4 has been shown to be
up-regulated in hypoxia in a HIF-dependent manner [30]. A parallel
increase in the expression of the HIF-induced enzyme carbonic
anhydrase (CA), a membrane-bound ectoenzyme that catalyzes the
reversible conversion of CO2 to carbonic acid, is also
observed. In fact, the expression of the CA IX isoform correlates
so well with hypoxia that it is being considered as a marker of
hypoxic conditions in certain tumour types. Consequently,
substantial interest is also being shown in the immunohistochemical
detection of CA IX in tumour sections for prognostic purposes. The
HCO3 formed enters cells through the action of the
bicarbonate/Cl family of exchangers that re-equilibrate the
intracellular pH (pHi). The growth factor activatable- and
amilioride-sensitive Na+/H+ exchanger (NHE1)
also contributes to pHi-regulation [31]. Manipulation of tumour
acidosis and/or glycolysis in Ras transformed fibroblasts by
deletion of the genes for respectively NHE1 or PGI (phosphoglucose
isomerase) has demonstrated potential in reducing tumour
progression [32].
In fact, the characteristic increase in glucose uptake by solid
tumours is being exploited in the clinic. The administration to
patients of non-metabolisable, radioactive glucose [fluorine-18]
2-deoxy-2-fluoro-D-glucose (FDG), and its detection by positron
emission tomography (PET) in solid tumours is now considered to be
an important predictor in determining the aggressiveness of a
number of types of tumours. However, a direct correlation between
FDG accumulation and hypoxic regions is not always observed [33]
and points to heterogeneity in the level of oxygenation of
different tumours that possibly reflects variations in
vascularization.
However, modifications in both the c-myc oncogene and Akt kinase
pathways have been shown to activate glucose metabolism [28]. c-myc
induced up-regulation of the glucose transporter GLUT1 as well as
several glycolytic enzymes and lactate dehydrogenase A leading to
lactate overproduction. The AKT oncogene also induced glucose
metabolism and AKT-expressing cells required glucose for survival.
Thus oncogenes, which are usually considered to be involved in
cancer cell proliferation and survival, together with HIF may also
be involved in modulating tumour metabolism.
Mammalian target of rapamycin (mTOR), a critical regulator of
protein translation, is activated by growth factors, hormones,
amino acids and extracellular components leading to cell growth and
survival [34]. Activation by growth factors occurs through the
Ras/ERK and PI3K/Akt pathways that are recognized as fundamental in
growth control and survival. In situations adverse for cell
proliferation such as energy or growth factor depletion, or hypoxia
mTOR is inhibited resulting in a slowing of protein synthesis and
energy conservation [4, 35]. Hypoxia down-regulates mTOR via the
TSC1/2 complex through the up-regulation of the HIF-target gene
REDDI (also called RTP801). Mutations in the tumour suppressor
TSC1/2 leads to tuberous sclerosis complex, a syndrome
characterised by the formation of benign tumours called hamartomas.
TSC1/2 is also regulated by the tumour suppressor phosphatase and
tensin (PTEN) gene and loss of function mutations in this gene lead
to the accumulation of HIF1α possibly through the activation of
mTOR, which has independently been shown to stabilise HIF1α. These
observations provide evidence for an auto-regulatory loop linking
hypoxia, tumour metabolism and cell survival. However, the ultimate
in cell survival must be macroautophagy, a last chance mechanism
that allows cells to feed on themselves when nutrients are
exhausted. Macroautophagy is a process of bulk degradation of
cytoplasmic proteins or organelles within a lysosomal/vaculolar
system, which is also regulated through the PI3K/Akt/mTOR pathway
[36]. Although little information is available concerning
macroautophagy in hypoxia this process may be of fundamental
importance in tumourigenesis and may implicate, as discussed in
[4], the induction of HIF target genes such as the pro-apoptotic
gene BNIP3. Thus, depending on the intensity and duration of
hypoxic exposure of cells and their metabolic status, cells may be
driven toward either cell survival or cell death.
Hypoxia-inducible factor in tumorigenesis and metastasis
The VHL gene implicated in HIF1α degradation is in fact a tumour
suppressor and mutations leading to loss of function are associated
with renal cell carcinoma (RCC) and VHL disease, a familial cancer
syndrome. As a consequence HIF1α is stable and active in RCC cells
and tumours are highly vascularized. VHL disease is characterised
by the presence of blood vessel tumours (haemangioblastomas) of the
central nervous system and retina that are often associated with
tumours such as RCC. These characteristics provide a strong link
between HIF, angiogenesis and tumourigenesis, which is further
reinforced by observations of increased expression of HIF1α in
different primary and metastatic tumour types. The acidic
microenvironment resulting sequential to HIF activation may
contribute not only to tumourigenesis but also to metastasis.
Disruption of cell-cell and cell-extracellular matrix contacts
promotes cell migration through basement membranes and stromal
tissue into the blood and lymphatic system on the road to
metastasis. A substantial number of proteins involved in these
processes including: vimentin, fibronectin, keratins 14, 18, 19,
matrix metalloproteinase 2, cathepsin D, urokinase plasminogen
activator receptor are HIF-induced [7]. The loss of expression of
E-cadherin, a key player in cell adhesion and
epithelium-mesenchymal transition, a hallmark in invasion is also
linked to HIF activation and thus metastasis. The HIF-dependent
gene products of the family of lysyl oxidase (LOX), in particular
LOXL2, induce a conformational change in the nuclear factor Snail
leading to its partial resistance to degradation [37] and
subsequent repression of E-cadherin expression [4]. In addition, a
number of factors promoting cell migration are HIF-target gene
products; these include the autocrine motility factor (also known
as the glycolytic enzyme phosphoglucose isomerase, PGI), the
proto-oncogene receptor tyrosine kinase c-MET and the cytokine
receptor CXCR4 [4].
Ways to fight tumour progression
Anti-VEGF therapy, which targets angiogenesis, is presently viewed
as holding major potential for fighting tumour progression [5].
Other ways, possibly in conjunction with stopping angiogenesis, may
prove effective. Small molecule inhibitors of HIF are being
actively sought. However because of the pleiotropic effects of HIF,
targeting of specific downstream HIF gene products may prove to be
preferable. A better understanding of the metabolism of tumours and
its consequences on cell survival/death should lead to novel
approaches including ways to modulate glycolysis, antagonize pHi
regulation and prevent macroautophagy. Intervention at this level
would hopefully favour a cellular response leading to destruction
of tumour cells.
Acknowledgments
We thank members of the Pouysségur laboratory for sharing with us
their results and comments. We apologize to the many research
groups whose work was cited indirectly by reference to review
articles. This is due to constraints in the number of references
permitted. Readers are referred to two of our recent reviews in
which many of the individual studies are cited [19, 38]. Our
laboratory is funded by grants from the Ligue nationale contre le
cancer (équipe labellisée), the Centre national de la recherche
scientifique (CNRS), the ministère de l’Éducation, de la Recherche
et de la Technologie, and the Institut national de la santé et de
la recherche médicale (Inserm).
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