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Condyloma acuminatum (CA) is a sexually
transmitted infection resulting from certain types of human papillomavirus
(HPV). The manifestation of this infection may be found anywhere within the
anal or genital area, frequently on external surfaces of the body, including
the penile shaft, scrotum or labia majora as well as on internal surfaces like
the urethra orifice, vagina, cervix or anus. Humans are the only natural host
of HPV, which shows high tissue specificity and usually results from
micro-trauma of the skin or mucosa through which the virus can infect the
germinal keratinocytes. There exist many therapeutic options for the treatment
of warts, such as topical imiquimod, cryotherapy, surgical excision and
electrocautery. While all of these treatments show varying degrees of
effectiveness, each possesses their own limitations. Recent evidence has
indicated that thermotherapy, a method of heating local tissue to achieve a
therapeutic effect, has been successful in the treatment of HPV-infected skin
lesions. Here, we summarizes the possible mechanisms of local hyperthermia in
the treatment of CA and briefly introduce the tools and methods involved in the
application of this procedure.
Keywords: Hyperthermia,
Immune response, Condyloma acuminatum, Human papilloma virus
INTRODUCTION
CYTOKINES
Hyperthermia induces
a significant increase in the transcriptional expression of interferon in CA
Hyperthermia induces a significant increase in transcriptional
expressions of interferon (IFN)-α, IFN-β and IFN-γ, in a temperature-dependent
manner in CA [3]. IFNs, which can exert anti-viral, immunomodulatory and
anti-cancer effects [4], comprise a small group of highly bioactive
glycoproteins produced by human and animal cells when stimulated by pathogens
or microorganisms. They consist of three different sub-types: type I IFNs
(i.e., IFN-α/β) that are produced in virally infected cells and type II IFN
(i.e., IFN-γ) that is not virus inducible and restricted to mitogen- or
cytokine-activated lymphoid cells such as T-lymphocytes and natural killer (NK)
cells. Type III interferon (IFN-λ) plays an important role in antifungal
responses of neutrophils [5]. IFN-α and β transduce their signals through the
sequential activation of IFN-α/β receptor (IFNAR) (with two subunits, IFNAR1
and IFNAR2)-associated Janus tyrosine kinases Jak1 and Tyk2, leading to
tyrosine phosphorylation and activation of Stat1 and Stat2. Activated
Stat1/Stat2 heterodimers then translocate to the nucleus, where they associate
with the IFN regulatory factor IRF-9 to form an active complex (known as
ISGF-3) on the IFN-stimulatory response element (ISRE). ISG blocks viral
replication by presenting antigens and inhibiting viral RNA transcription or
translation to establish antiviral responses in target cells [6]. OAS1 and PKR
(one of the ISGs) are two main enzymes involved in antiviral activity in
interferon-related pathways. It has been reported that hyperthermia up-regulates
the expression of PKR and OASI and inhibits the proliferation of HPV virus [7].
The IFN-α/β receptor-related kinases, STAT1 and STAT2 are significantly
increased after hyperthermia in CA.
Local hyperthermia
decreases the expression of CCL-20 in CA
The mRNA expressions of CCL-20 in CA specimens were found to be
significantly increased as compared with that in normal skin. Local
hyperthermia at 42°C and 45°C significantly decreased these mRNA levels of
CCL-20 [8]. CCL-20, a member of the chemokine family, participates in the
migration of dendritic and T cells, plays a role in tumor immunity and
autoimmune diseases and exerts robust broad-spectrum antimicrobial activity.
CCL20 also plays an important role in regulating Langerhans cells (LCs) and
their precursors to enter the epidermis [9]. CCL-20 expression was reported to
be increased by TNF-a and IL-1a in oral squamous cell carcinomas, intestinal
epithelial cells and keratinocytes [10]. Local hyperthermia reduces the
expression of IL-α in CA tissue, followed by a decrease in the expression of
CCL-20, thereby decreasing the number of epidermal LCs and promoting the
migration of LCs to dermal lymph nodes. The chemokines CCL21 and CCL19,
secreted by lymph node cells guide LCs to enter the T-cell region through CCL7
on the surface of LCs. LCs present antigens to antigen-specific T cells and
stimulate immune effects of anti-viruses, which is conducive to the treatment
of CA [8].
HYPERTHERMIA-RELATED
APOPTOTIC SIGNALING PATHWAYS
The apoptosis-related
factors - DR4, DR5, Fas, Bax and Bcl-2
Keratinocytes are located in the outermost region of the skin and remain
stable after programmed death, as resulting from pathological conditions and
external stimuli. Apoptosis is mainly regulated by mitochondria and death receptor
pathways, with the Bcl-2 gene family acting as an important regulator of
programmed cell death. The differential expression of anti-versus pro-apoptotic
Bcl-family proteins determines the inherent susceptibility of a given cell to
respond to apoptotic signals. The most important proteins of the Bcl-2 family
are the pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins and this ratio of
Bcl-2/Bax represents a critical factor in the regulation of apoptosis [11]. The
two putative apoptosis-inducing receptor-ligand systems, tumor necrosis factor
(TNF) and CD95, have been shown to play a major role in many physiological and
pathophysiological situations, as they induce apoptosis by activation of their
corresponding receptors, Fas and TNFR-1. TRAIL, a member of the TNF family of
cytokines, has been shown to induce apoptosis in a variety of transformed cell
lines by binding to TRAIL receptors [12] and five distinct receptors for the
TRAIL ligand have been identified: death receptor 4 (DR4), DR5, decoy receptor
1 (DcR1), DcR2 and osteoprotegerin (OPG). DR4 and DR5 contain death domains
(DD) in their cytoplasmic region that can mediate cell apoptosis upon binding
with the membrane form of TRAIL or with the soluble TRAIL [12]. In CA tissue,
expression of the anti-apoptotic effects of Bcl-2 are decreased while that of
the pro-apoptotic effects of Bax are increased after local hyperthermia at
42-45℃. In addition, expressions of Fas, DR4 and DR5 are increased after these
same local hyperthermia conditions, indicating that the death receptor promotes
apoptosis through activation of death receptor pathways [13]. Accordingly,
hyperthermia promotes apoptosis within HPV infected cells by affecting the
expression of DR4, DR5, Fas, Bax and Bcl-2 and, in this way, plays an antiviral
immune role.
EFFECT OF LOCAL
HYPERTHERMIA ON CELLULAR FUNCTIONS
Local hyperthermia
induces migrational maturation of Langerhans cells (LCs) in CA
It has been reported that local hyperthermia induces migrational
maturation of Langerhans cells in CA [14]. LCs is dendritic cells (DCs) within
the epidermis. These cells possess a robust ability to absorb and present
antigens, but a weak ability to stimulate T-cell activation. When the antigen
enters the epidermis, it induces epidermal cells to secrete a number of
cytokines, among which interleukin (IL)-1β and tumor necrosis factor alpha
(TNF-α) stimulate LCs migration to the dermis. Within the dermis, lymphatic
endothelial cells secrete the chemokine, CCL21, which attracts LCs into
lymphatic vessels and then enables these cells to flow into lymph nodes through
the chemokine receptor CCR7 located on the surface of LCs. The LCs surface
molecule, CCR7, interacts with the chemokine, CCL21 and CCL19, secreted by
lymph node cells to induce LCs to enter the T-cell region. LCs present antigens
to antigen-specific T-cells, and, in this way, play an immune role. Local
hyperthermia, as administered at fever ranges, promotes the migration and
activation of LCs in mice [15]. We have found similar effects of hyperthermia
when administered in temperatures above that of fever ranges [14]. Further,
local hyperthermia at 42 and 45°C concomitantly produces an increase in the
expression of CCR7 and a decrease in the expression of CCR6, both of which are
prerequisites for transport of LCs to regional lymph nodes [16].
HYPERTHERMIA
INCREASES EDITING EFFICIENCY OF THE HPV GENE
Hyperthermia changes
the nucleic acid composition of the HPV E2 gene
Although the E2 gene constitutes only a small portion of the total viral
genome, E2 plays an important role in replication and transcription of HPV by
binding to specific cognate sequences in the viral genome [17]. APOBEC, a
family member which can induce cytosine deaminase activity within humans,
consists of 11 members and is a natural defender of the human body. The
antiviral agents of APOBEC, A3A and A3G, were initially identified as factors
involved with limiting HIV-1 infection [18]. Recently, results from several
high-profile studies have suggested that APOBEC3-mediated mutagenesis is highly
enriched in HPV-positive cervical and head-and-neck cancers [19]. In addition,
two antiviral agents of the human APOBEC3A (A3A) and A3G genes have been shown
to be expressed in epithelial cells and both are reported to be involved in
editing HPV by inducing a cytidine (C) to uracil (U) hyper mutation [20].
APOBEC can deaminate cytosine on the substrate by binding to DNA and RNA, thus
mutating DNA or RNA. Overall, APOBEC3 exerts a wide range of antiviral
functions and it has been reported that hyperthermia induces a significant
increase of IFN in CA [21]. Such an effect can subsequently positively regulate
APOBEC3 expression [22], to increases the expression of APOBEC A3 A and A3G in
HPV infected cells. APOBEC both mutates the E2 gene of HPV (G→A, C→T) and
destroys the function of the E2 gene which may, in part, serve as the basis for
its thermotherapy effect in CA [23].
Hyperthermia changes
HPV-6/11 E6 and E7 genes
In response to treatment with varying temperatures, we found that the
expressions of HPV-6 E6/E7 and HPV-11 E6/E7 decreased as a function of
increasing temperature [24]. Accordingly, this hyperthermia-induced reduction
of E6 and E7 expression and inhibition of HPV proliferation may result from
enhancing the effects of interferons and/or inhibiting viral gene replication [24].
RELATED PROTEINS
DNAJA4
The expression of heat shock protein is closely related to the
pathophysiology of stress as can occur with elevated body temperature [25]. As
one of the members of the DNAJ protein family, DNAJA4, with a molecular weight
around 40 kDa, has been shown to function as a co-chaperone for HSP70 through
its J domain and, in this way, can stimulate ATP-hydrolysis activity [26]. DNAJA4
can be induced in HaCaT cells, foreskin and CA tissues subjected to hyperthermia,
as demonstrated at both transcriptional and translational levels [27].
Interestingly, the HPV E7 oncoprotein was reported to bind DnaJA3 to facilitate
viral carcinogenesis [28]. Although no direct evidence exists showing
associations between DNAJA4 and HPV oncoproteins, given the highly conserved
structure among DnaJ protein family members, DNAJA4 may likely function as
DNAJA3 in response to HPV infection. As a heat shock protein, DNAJA4 may
provide a protective role in cells undergoing active proliferation and may also
be utilized by HPV-infected keratinocytes to survive under conditions of
hyperthermia. Nuclear Factor-kappa B (NF-kB) is an important transcription
factor which initiates the transcription of multiple genes related to inflammation,
immunity and cell survival and serves as a hyperthermia-responsive protein
whose activity is altered during heat shock [29]. As increased HSP70 alters
NF-kB activity [30], hyperthermia-induced heat shock proteins may be one of the
regulators of cellular proliferation, immune responses and inflammation via the
NF-kB pathway. Hyperthermia can induce the activity of NF-kB in keratinocytes,
especially in keratinocytes lacking DNAJA4 [27]. The findings that DNAJA4 was
up regulated by 44℃ hyperthermia treatment, a deficiency of which reduced HaCaT
cell proliferation and altered cytokine expression, indicate effects which
favor anti-viral activity, mainly through a NF-kB dependent pathway. In this
way, DNAJA4 may serve as a very promising therapeutic target whose inhibition
could contribute to the therapeutic efficacy of local hyperthermia treatment
against HPV-infectious diseases.
Surviving
Calcium influx is required for the activation of cellular function.
Store-operated calcium entry (SOCE) mediates calcium influx through a calcium
release-activated calcium (CRAC) channel, which represents a principal calcium
entry mechanism in non-excitable cells. Composed of Orai molecules in the
plasma membrane, CRAC channels are activated by stromal interaction molecules
(STIM) located in the membrane of the endoplasmic reticulum (ER). STIM proteins
monitor changes in calcium concentrations within the ER and activate Orai
molecules. There are two subtypes of STIM proteins, STIM1 and STIM2 [31]. STIM1
is an ER calcium sensor that responds to depleted levels of ER calcium.
Decreases in ER calcium concentrations induce STIM1 multimerization and
translocation into puncta close to the plasma membrane where STIM1 multimers
bind to and activate the Orai channel, leading to a massive influx of calcium.
During events related to immunity, calcium regulates cytoskeleton remodeling,
release of vesicle contents and transcriptional changes. In addition, increased
sustained cytosolic calcium results in cellular activation or apoptosis [32]. STIM1,
which typically induces a robust calcium influx, is often over expressed in
human cancers such as melanoma tissues, multiple melanoma cell lines, and
cervical cancer [33]. Physiological processes such as the regulation of
reactive oxygen species (ROS), mitochondrial damage and calcium overload can
all influence apoptosis [34]. Calcium overload may damage mitochondria and
result in the activation of the apoptotic signaling cascade [34]. It has been
demonstrated that hyperthermia can activate CRAC channels and increase calcium
influx. While such an effect can promote cell apoptosis in non-HPV infected
cells, this process is not as obvious in HPV infected cells [35]. Caspase-3 is
the essential death protease and final executor of calcium signaling, involved
in the apoptotic pathway. Surviving, a member of the inhibitor of apoptosis
protein (IAP) family, is abundantly expressed in some malignancies, but
undetectable in normal adult tissues. Survive in binds to caspase-3 and
inhibits caspase activity in cells exposed to a diverse array of apoptotic
stimuli [36]. Survive in expression is likely to be regulated by HPV, as
survive in expression levels are strongly dependent on continuous HPV E6/E7
expression and HPV E6/E7 is reported to trans activate the survivin promoter [37].
Based on these findings, we hypothesize that inhibition of this over expression
of survive in may further improve the therapeutic effects of hyperthermia
treatment in HPV-infected lesions.
SUMMARY
Here we present a review on the methods and mechanisms of local
hyperthermia for the treatment of CA. We report that local hyperthermia has
been shown to be successfully in the treatment of HPV infected skin lesions.
The procedure is easy to apply and is associated with high cure and low
recurrence rates. However, details regarding the molecular mechanisms of
hyperthermia within the immune system remain a challenge for future
investigation. This review summarizes several important aspects on the effects
of hyperthermia in HPV infected cells and tissues. Such information will help
in identifying the mechanisms of hyperthermia and serve as a foundation for
procedures that can be used to optimize the conditions of local hyperthermia
for the treatment of viral warts, tumors and other diseases.
FUNDING
This work was supported by the National Natural Science Foundation of
China (81673070, 81872538) and 111 Project (D18011).
CONFLICT OF INTERESTS
The authors declare that they have no conflict of interest.
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