Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_53_библиотеки_им_акад_М_И_Перельмана
.pdf
TLRs are expressed on a wide range of immune and non-immune cells in which
results in production of different immune compounds such as cytokines, interleukins
(ILs), interferons (IFNs), etc. Moreover, the TLRs are expressed on the surface of
different tumor cells and regulate the activity and met abolism of tumor growth
directly and indirectly in versatile types of cancers such as breast and prostate
cancers. Therefore, the TLRs have a pivotal role in both progression and treatment
of different cancers (Fig. 9.2) (Behzadi 2020; Behzadi et al. 2016, 2019; Boozari
et al. 2019; Huang et al. 2018; Javaid and Choi 2020; Ohadian Moghadam and
Nowroozi 2019; Pradere et al. 2014; Saghazadeh and Rezaei 2020).
In this regard, immune cells comprising dendritic cells (DCs), macrophages
(MΦs), B-cells, T-cell subsets, mast cells, neutrophils and non-immune cells includ-
ing parenchymal-, endothelial-, and epithelial cells and fibroblasts express TLRs.
Interestingly, TLR molecules may lead to maturate DCs. TLR glycop roteins are
molecules that act as bridges which connect the innate into the adaptive immune
system (Behzadi and Behzadi 2016; Boozari et al. 2019; Dajon et al. 2017; Javaid
and Choi 2020; Nissar et al. 2017; Pradere et al. 2014).
Based on amino acid sequencing, the TLR molecules expressed in human body
are categorized into five families of TLRs 2 (involving TLR members of 1, 2, 6, 10),
3 (TLR3), 4 (TLR4), 5 (TLR5), and 9 (comprising TLR members of 7, 8, and 9). The
extracellular TLR molecules of 1, 2, 5, 6, and 10 are expressed on the surface of the
cells (plasma membrane), while the intracellular TLR molecules of 3, 7, 8, and 9 are
expressed within the intracellular organelles such as endosomes, lysosomes, and
endoplasmic reticulum (ER). Due to this fact TLR 4 molecule, a bi-functional
glycoprotein is expressed as extracellular and intracellular molecule (Angrini et al.
2020; Behzadi and Behzadi 2016; Behzadi et al. 2019; Javaid and Choi 2020;
Saghazadeh and Rezaei 2020).
TLRs are structurally consisted of three domains including an IL-1 receptor
(IL-1R)-like (Toll/IL-1R (TIR)) cytoplasmic (intracellular) domain (a conserved
and homolog signaling domain located in C-terminal), an extracellular domain
with leucine rich repeat (LRR) motifs (comprising 24 amino acids) which is situated
in N-terminal and mediates the linkage of TLR molecule with the related ligands and
a transmembrane domain. The LRR motifs are responsible for the horseshoe-shaped
structure of TLR molecules via construction of an α-helix and a β-strand conforma-
tion which are separated by a loop (Fig. 9.3). The TLR horseshoe structure normally
happens after TLR-ligand connection. Moreover, the extracellular domain of TLR
molecule is able to link to its suitable ligand (e.g., PAMPs, DAMPs, and XAMPS)
via some co-receptor molecules of CD14, CD36, and myeloid differentiation factor
2 (MD-2) (Behzadi and Behzadi 2016; Javaid and Choi 2020; Kawasaki and Kawai
2014; Medvedev 2013; Ohto et al. 2012; Saghazadeh and Rezaei 2020; Wang et al.
2020).
By recognition of the related ligand, the spatial structure of TLR molecule
transfigures to have a successful linkage with the ligand. In this regard, hetero-
(TLR2/1, TLR2/6, TLR2/10) or homodimers (TLR3/3, TLR4/4, TLR5/5) and reori-
entation (TLRs 7, 8, and 9) occur and the TIR domains are triggered to interact with
the related intracellular adaptors including five downstream signaling adaptor
296 P. Behzadi
https://t.me/medicina_free
proteins (such as myeloid differentiation primary response protein 88 (MyD88),
sterile α- and armadillo motif-containing protein (SARM), TIR domain-containing
adaptor inducing IFN-β (TRIF/TCAM1)), TIR domain-containing adaptor protein
(TIRAP/Mal), and TRIF-related adaptor molecule (TRAM/TICAM2). Due to this
fact, the TLRs (excluding TLR3 and endosomal TLR4) activate the signaling
pathway of canonical MyD88-dependent. The TRIF dependent signaling pathway
which is a non-canonical one induces nuclear translocation of transcription factors.
Then the IFN regulatory factors of 3 and 7 (IRF3 and IRF7) lead to produce type
1 IFN as the main product. The TRIF dependent signaling pathway is inhibited by
the SARM in human body. The activation of MyD88-depe ndent signaling pathway
leads to induction of a number of proteins including nuclear translocation of
transcription factors, nuclear factor (NF)-κB, mitogen-activated protein kinases
(MAPKs), adaptor protein-1 (AP-1), and cyclic Adenosine Mono Phosphate
(cAMP) response element binding protein (CREB). The activation of this signaling
pathway results in expression of the genes belonging to pro-inflammatory cytokines.
The TLRs of 3 and endosomal 4 activate TRIF signaling pathway; moreover, the
extracelluar TLR4 is able to induce the canoni cal pathways of MyD88 and TIRAP
dependent, while the intracellular TLR4 triggers the non-canonical pathways of
TRAM and TRIF (Fig. 9.4) (Angrini et al. 2020; Ayala-Cuellar et al. 2019; Basith
et al. 2011, 2012; Ernst et al. 2019; Gajdács and Behzadi 2020; Javaid and Choi
2020; Kawasaki and Kawai 2014; O'neill et al. 2013; Saghazadeh and Rezaei 2020).
Fig. 9.3 The horseshoe structure of TL4. α-helices and β-strands are separated by a loop (4G8A
PDB file) (Ohto et al. 2012)
9 The Role of Toll-Like Receptor (TLR) Polymorphisms in Urinary Bladder Cancer 297
https://t.me/medicina_free
In normal and healthy individuals, the TLRs of urothelial cells are produced
against uropathogenic microorganisms including uropathogenic Escherichia coli
(UPEC), uropathogenic Klebsiella pneumoniae (UPKP), uropathogenic Proteus
mirabilis (UPPM) and uropathogenic Candida albicans (UPCA) as common
uropathogens. Hence, in the presence of uropathogens (and their related
components) the urinary tract TLRs involving TLR2 (the related ligands are bacte-
rial LPS and fungal zymosan), TLR4 (the related ligands are bacterial LPS and Type
I and P fimbriae), and TLR5 (the related ligand is flagellin) induce the MyD88-
dependent signaling pathway to produce transcription factors of NF-κB (for TLR2),
NF-κB, IRF3, and IRF7 (for TLR4), and NF-κB (for TLR5). This signaling pathway
results in inflammatory cytokines (Fig. 9.4). In parallel with this feature, the urinary
tract TLRs may act against tumor cells in which may lead to maturation of antigen
presenting cells (APCs). In follow, APCs produce and secrete different cytokines
including IL-6, IL-12, tumor necrosis factor-α (TNF-α), and INFs. These cytokines
trigger natural killer cells (NK cells) and cytotoxic T lymphocytes (CTLs) to remove
tumor cells. However, in people with oncogenic predisposing factor(s) the
Fig. 9.4 The MyD88-dependent and TRIF-dependent pathways
298 P. Behzadi
https://t.me/medicina_free
expression of TLRs on tumor cells upregulates the expression of pro-angiogenic
factors (e.g., Transforming growth factor-β (TGF-β) and vascular endothelial growth
factor (VEFG)), other growth factors, pro-inflammatory cytokines and compounds
(e.g., IL-6, IL-12, and nitric oxide), and anti-apoptotic proteins (it is reported that
those tumor cells which go through apoptotic process are able to disseminate
DAMPs which are relating to tumor progression).
This process may lead to evoke more immune cells which results in tumor
progression and metastasis. Hence, TLR agonists are able to support the presence
of malignant cells and even promote their resistance against chemotherapy; how-
ever, the TLR ligands have suppressive effect on tumor growth. In addition, there are
four types of factors which affect the expression of TLR molecules including animal
factor (age, breed, immunity condition, sex, and species), external factors (such as
diet, light, and temperature), genetic factors (copy number variants, SNPs, DNA
duplication, DNA deletion, promoter sequences), and internal factors (e.g., apopto-
sis, cell cycle, epithelial-mesenchy mal transition (EMT), inflammation, and migra-
tion) (Behzadi and Behzadi 2016; Behzadi et al. 2019, 2020; Ohadian Moghadam
and Nowroozi 2019; Sarshar et al. 2020; Vidya et al. 2018).
9.7 MyD88-Dependent Pathway
Throughout MyD-dependent pathway, the MyD88 adaptor together with IL-1-
receptor associated kinases (IRAKs) constructs a complex known as Myddosome
(Fig. 9.4). In parallel with Myddosome complex formation, the IRAK1 become
activated (by IRAK4) and then autophosphorylated which lead to TRAF6 and TAK1
activation. The activation of TRAF6 and TGF-activated kinase 1 (TAK1) is the
result of k63-linked polyubiquitination process on them via IRAK1. Finally, activa-
tion of TAK1 results in activation of two pathways of MAPKs and the inhibitor of
kappa light polypeptide gene enhancer in B-cells kinase (IKK)-NF-κB (the IKK
complex involves three compartments of IKKα (catalytic structure), IKKβ (catalytic
structure), and the regulatory structure of IKKγ (NF-kappa B Essential Modulator)
(NEMO)). The activated MAPKs (or MAPK family members including extracellular
signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase (JNK) and p38) trigger
the AP-1 s (AP-1 family transcription factors) activity to modulate the production of
inflammatory cytokines. And in IKK-NF-κB pathway, the NF-κB is transferred into
the nucleus which results in pro-inflammatory responses (Fig. 9.4). The chronic
inflammations occurred by TLRs of 4, 7, 8, and 9 signaling pathway have pro-tumor
effects on cancer cells. In this regard, the activation of TLR4 throughout Myd88-
dependent pathway results in tumor formation and metastasis. Although, TLRs of
4, 7, 8, and 9 support tumor cells by escaping them from immune syst em, apoptotic
resistant and immunosuppressive abilities, TLRs of 3 and 5 signaling pathways
activate the anti-tumor T-cell reactions (Basith et al. 2012; Gajdács and Behzadi
2020; Javaid and Choi 2020; Kawasaki and Kawai 2014; Sughra et al. 2010; Vidya
et al. 2018).
9 The Role of Toll-Like Receptor (TLR) Polymorphisms in Urinary Bladder Cancer 299
https://t.me/medicina_free
9.8 MyD88-Independent (TRIF-Dependent) Pathway
The TRIF-dependent pathway is mediated by TRIF adaptor and this pathway is
continued throughout activated molecules of TRAFs 6 and 3. TRAF6 employs the
kinase molecule of RIP-1 which in follow leads to activation of the cascade of TAK1
complex, NF-κB, MAPKs, AP-1 s, and inflammatory responses, respectively.
Simultaneously, the TRAF3 activates the IKK kinases of TBK1 and IKKi to
phosphorylate IRF3. This process leads to IRF3 dimerization and translocation
into the nucleus. Thereafter, the IFN-I genes are triggered to express the type I
IFN protein in the presence of IRF3 dimers. The pellino family E3 ubiquitin ligases
including Pellino-1 employ RIP-1 to activate NF-κB pathway through TRIF-
dependent pathway. On the other hand, Pellino-1 links to the transcription factor
of Deformed Epidermal Autoregulatory Factor-1 (DEAF-1) to modulate the linkage
of IRF3 to promoter of IFN-β (Fig. 9.4). The NF-κB has pivotal role in regulation of
apoptosis, cell proliferation and transcription (about 200 genes which express
growth and inflammatory responses) processes (Basith et al. 2012; Gajdács and
Behzadi 2020; Javaid and Choi 2020; Kawasaki and Kawai 2014; Wu and Sheng
2015).
9.9 Toll-Like Receptors and Trafficking
TLR molecules are totally biosynthesized within the ER and then are transferred into
the Golgi apparatus for necessary glycosylation. Thereafter, they translocate to their
right positions within the cell via the general chaperone protein of gp96. Indeed,
gp96 is known as an ER-associated paralog of Hsp90 that transfers a wide range of
molecules comprising integrins, several TLRs (including TLR1, TLR2, TLR4,
TLR5, TLR7, and TLR9), etc., to their natural situations and places. The protein
associated with TLR4 (PRAT4A) is another ER resident molecule which contributes
in transferring TLR molecules of 1, 2, 4, 7, and 9 from ER to their places on cell
membrane and within the endosomes. In this regard, TLRs 1, 2, 4 are transferred
upon the cell membrane, while the TLR9 is carried into the endosome. The Unc-93
homolog B1 (Unc-93B1) protein is a multispan transmembrane molecule which
participates in transmission of intracellular TLRs of 3, 7, 8, and 9 into the endosomes
to mediate the signaling processes. The exaggerated activity of TLR7 is controlled
by Unc-93B1 via application of TLR9. Now it is known that, the consequence of the
absence of gp96 protein is the lack of TLR molecules of 1, 2, 3, 4, 5, and 7 on one
hand and misfolding of TLR9 on the other hand. Hence, there are a huge number of
proteins and molecules which co-work as an unite orchestrate to harmonize the
position, structure, and function of TLRs (Kawasaki and Kawai 2014; Medvedev
2013; Vijay 2018).
300 P. Behzadi
https://t.me/medicina_free
9.10 Toll-Like Receptors and Urinary Bladder Cancer
The TLR molecules have been recognized as double-edged sword. On one hand,
TLRs act as anti-tumor molecules in healthy people; on the other hand, the expressed
TLRs in tumor cells act as tumorigenic molecules (Angrini et al. 2020; Javaid and
Choi 2020; Ohadian Moghadam and Nowroozi 2019). Depending on the stage and
the type of cancer, the expression of TLRs in tumor cells differs in different
individuals (Angrini et al. 2020; Li et al. 2014a).
The immune system in urinary bladder acts in particular pathway. The
non-specific and physical defense system of urinary bladder depends on production
of natural antimicrobial agents comprising cathelicidin and β-defensin, a significant
layer of mucin which acts as a strong barrier against infectious agents, strong urine
flow during micturition, and the immunosuppressive milieu. Because of immuno-
suppressive condition within urinary bladder tumor microenvironment, the urinary
bladder tumor is able to neutralize the activity of tumor-infiltrating lymphocytes
(TILs) which leads to tumor maintenance. Simultaneously, high expression of
regulatory T cell s (T
regs
) and cytokines like TGF-β and IL-10 (known as Th1
inhibitory cytokines) supports the development and progression of urinary bladder
tumors. Due to this fact, the expression of TLR molecules within tumor cells
activates the relating signaling pathways in which a versatile of proteins and
cytokines are induced and finally results in tumor survival, invasion, development,
progression, and metastasis. Hence, it seems that the TLR signaling pathways in
tumors reprogram the tumor metabolism and growth and reduce the anti-tumor
immune responses (Angrini et al. 2020; deLeeuw et al. 2012; Ingersoll and Albert
2013; Ohadian Moghadam and Nowroozi 2019).
According to previous studies, expression of TLRs and induction of their related
signaling pathways may lead to localization of NF-κB within the cell’s nucleus. The
NF-κB is recognized as tumor promoter which supports the transcription of cell
proliferation genes such as BCL-2, BCL-XL, c-Myb, c-Myc, cyclin D1, cyclin D2,
and cyclooxygenase 2 (COX-2) (Ohadian Moghadam and Nowroozi 2019).
Previous reports indicate that in NMIBCs, the expression of the majority of TLRs
including 2, 3, 4 (extracellular TLR), 4 (intracellular TLR), 5, 7, and 9 is reduced
while in MIBCs only the expression of TLR9 is decreased. Interestingly, the TLR4
has a d ual function which can support the progression or suppression of urinary
bladder tumors. This property supports us to use TLRs as suitable agonists against
BCas (Angrini et al. 2020; Ayari et al. 2011; Li et al. 2017; Ohadian Moghadam and
Nowroozi 2019).
9.11 Single Nucleotide Polymorphism in Toll-Like Receptors
and Urinary Bladder Cancer
TLRs as the key immune molecules have pivotal role in both innate and adaptive
immune responses. They are involved in angiogenesis, cell proliferation, apoptosis,
cell survival, and tissue remodeling and repair mechanisms. Hence, the occurrence
9 The Role of Toll-Like Receptor (TLR) Polymorphisms in Urinary Bladder Cancer 301
https://t.me/medicina_free
of SNPs may lead to imbalanced consequences in cytokines secretion, production,
and harmonic orchestrates of different mechanisms against infectious diseases,
cancers, and inflammations. As mentioned before, SNPs can be seen in different
types of genes which may lead to different cancers such as BCas. In this regard, the
occurrence of SNPs in the genes encoding TLR molecules and the related proteins
and molecules involved in TLR signaling pathways is recognized as an important
genetic predisposing factor for the cancer risk.
Up to date, the occurrence of SNPs in TLRs genes and their importance in
prevalence of BCas have not been studied so well. Different SNPs in association
with TLR genes—in a wide range of cancers including prostate cancer, lymphoma,
breast cancer, nasopharyngeal cancer cervical cancer, etc.,—have been investigated
and a mass of SNPs have been recognized. Interestingly, the outcome of the
occurrence of SNPs in TLR genes is very different; from changing in protein
structure and receptor activity to predisposing for different types of cancers with
versatile frequencies. The occurrence of SNPs results in different consequences
involving amino acid substitution, alteration of proteins activities and functions,
affecting splicing process and changes in enhancer sequences and structures and
stability of the mRNA molecules, changes in transcription factor binding motifs,
altering the efficacy of enhancers and repressors, interference in translation process
by changing the structure of initial codons, adaptor activities, etc.
(Afsharimoghaddam et al. 2016; Angrini et al. 2020; Gomaz et al. 2012; Kutikhin
2011).
9.11.1 TLR1
9.11.1.1 Structure and Function
The molecules of TLR1 and 2 and then TLRs 3, 4, and 5 are known as the first
recognized human TLRs (hTLRs). The TLR 1 as an extracellular TLR is able to
heterodimerize with TLRs of 2 and 10, respectively, to construct the heterodimers of
TLR1/TLR2 and TLR1/TLR10. TLR1—as well as TLR2, TLR6, and TLR10—
belongs to TLR2 family and its gene is located on chromosomal position of 4p14
within the cluster gene of TLR10-TLR1-TLR6. TLR1 molecules link to Triacyl
lipoproteins and are expressed by innate immune cells such as eosinophils,
macrophages (MΦs), monocytes, myeloid DCs, natural killer (NK) cells,
neutrophils, plasmocytoid DCs, and adaptive immune cells like B cells. The
non-immune cells including endothelial- and epithelial cells express TLR1
molecules, too (Table 9.2). (Behzadi and Behzadi 2016; Behzadi et al. 2019;
Boozari et al. 2019; Dajon et al. 2017; Huang et al. 2018; Saghazadeh and Rezaei
2020; Wang et al. 2020).
The bioinformatic investigations have been revealed the presence of hydrophobic
pockets within the structure of TLRs of 1 and 2 which enable them to bind to the
agonists such as Pam
3
CSK
4
(a triacylated lipopeptide) and CU-T12–9. Pam
3
CSK
4
links to TLR1 and TLR2 via an amide bound lipid chain and two ester-bound lipid
chains, respectively, which leads to heterodimerization of TLR1/TLR2 and
302 P. Behzadi
https://t.me/medicina_free
activation of the related signaling pathway. The agonis t of CU-T12–9 links to TLR1
throughout hydrogen bonds while the linkage between CU-T12-9 and TLR1/TLR2
is hydrophobic. The latter supports the formation of TLR1/TLR2 heterodimers. The
linkage of the agonist of SMU-Z1 (with high specificity and low toxicity) with
TLR1/TLR2 heterodimer leads to activation of NF-κB pathway. The SMU-Z1
activates the anti-tumor signaling pathway of TLR1/TLR2 against leukemia. The
CU-CPT22 is known as the TLR1/TLR2 antagonist which competes with
Pam
3
CSK
4
to link to TLR1/TLR2 heterodimer to inactivate it. Expression of
TLR1 genes increases in multiple myeloma cells (Basith et al. 2012; Behzadi and
Behzadi 2016; Behzadi et al. 2019; Wang et al. 2020).
9.11.1.2 TLR1 SNPs and Their Role
The TLR genes of 1, 6, and 10 create a unite gene cluster of TLR10-TLR1-TLR6
which located on 4p14 position of the genomic chromosome (Table 9.2). The minor
allele of TLR1-rs7696175 (C > T) is placed at the adjacent of TLR10-TLR1-TLR6
(TLR1-TLR6) gene promoters. The occurrence of this SNP may increase the risk of
breast cancer. Moreover, several SNPs in TLR1 gene are reported which may lead to
formation of T1805G (rs5743618) (leading to colon cancer) and rs4833095 (leading
to gastric cancer in patients infected by Helicobacter pylori (H. pylori). -7202A/G
(rs5743551), -6399C/T (rs5743556), and -833C/T (rs5743604) are the recognized
TLR1 gene SNPs which are in association prostate cancer. The SNP of rs4833103
(C > A) in the neighborhood of TLR1 gene reduces the risk of tumor development
regarding non-Hodgki n ’ s lymphoma (NHL) (Gomaz et al. 2012; Khan et al. 2016;
Semlali et al. 2018; Yeyeodu et al. 2013).
9.11.1.3 TLR1 SNP in Urinary Bladder Cancer
No meta-analysis was recognized regarding TLR1 gene SNP contributing in BCa.
9.11.2 TLR2
9.11.2.1 Structure and Function
TLR1 like TLR2 belongs to TLR2 family and its gene is situated on chromosomal
position of 4q32. The TLR2 molecules are able to join whether to each other as
homodimers of TLR2/TLR2 or to bind to TLRs of 1, 6, and 10, respective ly, to
construct the heterodimers of TLR1/TLR2, TLR2/TLR6, and TLR2/TLR10. The
construction of homodimers of TLR2/TLR2 and the heterodimers of TLR1/TLR2,
TLR2/TLR6, and TLR2/TLR10 indicate the close relationship among these TLR
molecules as the members of the TLR2 family. TLR2 molecules link to
Lipoproteins, Glycolipids, bacterial Peptidoglycans, fungal Zymosan, etc. The
TLR1/TLR2 heterodimers are able to distinguish bacterial peptidoglycan, fatty
acids (saturated), and triacylated lipoproteins.
Furthermore, TLR2 molecules are located on the cell surface and are expressed
by the innate immune cells comprising MΦs, mast cells, monocytes, myeloid DCs,
NK cells and neutrophils, and the adaptive immune cells of B and T. TLR2 gene is
9 The Role of Toll-Like Receptor (TLR) Polymorphisms in Urinary Bladder Cancer 303
https://t.me/medicina_free
also expressed by non-immune cells like endothelial- and epithelial cells (Table 9.2).
The TLR2 signaling pathway is able to increase the proliferation activity and
survival of the cancerous cells in gastric cancer in which may lead to enhance the
process of tumor metastasis. The expression of TLR2 gene increases in colon,
ovarian, oral squamous cell, laryngeal, and intestinal adenocarcinomas (Ayala-
Cuellar et al. 2019; Basith et al. 2012; Behzadi and Behzadi 2016; Behzadi et al.
2019; Boozari et al. 2019; Dajon et al. 2017; Huang et al. 2018; Saghazadeh and
Rezaei 2020; Wang et al. 2020).
9.11.2.2 TLR2 SNPs and Their Role
A deletion of 22 bps in promoter region belonging to TLR2 gene from 196 to 174
is recognized as an important TLR2 gene polymorphism which is in association with
breast, cervical, colon, gallbladder, prostate, colorectal, gastric, and hepatocellular
(with the background of hepatitis C virus infection) cancers. However, some studies
indicate that, this polymorphism in TLR2 gene reduces the risk of gastric cancer. The
TLR2ins/del SNP contributes to gastric cancer risk. The TLR2 SNPs including
N199N (rs3804099) and S450S (rs3804100) predispose individuals for gastric,
breast, hepatocellular (N199N rs3804099 C/T and rs3804100 C/T), and papillary
thyroid cancer. Moreover, the C allele of the S450S (rs3804100) SNP in TLR2 gene
is associated with marginal zone lymphoma (MZL) and in particular mucosa-
associated lymphoid tissue (MALT) lymphoma.
This association is probably the reason of the unsuitable TLR2 immune
responses, against pathogenic microorganisms (comprising Borrelia burgdurferi,
Campylobacter jejuni, Chlamydia psittaci, H. pylori and hepatitis C virus) which
results in MALT lymphoma in carriers of C allele of the rs3804100 SNP in TLR2
gene. The SNPs of rs5743704, rs5743708, and rs7656411 in TLR2 are associated
with colon and hepatocellular carcinomas, respec tively. The short and long
GT-microsatellite polymorphism is associated with increase in NF-κB activation,
overexpression of inflammatory mediators participated in tumorigenesis promotion
and colorectal cancer. The short alleles of GT-microsatellite have significant rela-
tionship with reduction of TLR2 gene promoter activity and expression (Gomaz et al.
2012; Khan et al. 2016; Kutikhin 2011; Medvedev 2013; Ranjbar et al. 2017;
Semlali et al. 2018; Vijay 2018).
9.11.2.3 TLR2 SNP in Urinary Bladder Cancer
In a case study done by Singh et al. in which they showed a significant association
between TLR2 allele (ID + DD))196 to 174 del(polymorphism and the BCa risk
in a population of 200 individuals (Singh et al. 2013).
9.11.3 TLR3
9.11.3.1 Structure and Function
TLR3 as an intracellular molecule belongs to TLR3 family and its gene is located on
chromosomal position of 4q35. TLR3 molecules are expressed by innate immune
304 P. Behzadi
https://t.me/medicina_free
cells like myeloid and plasmacytoid DCs and NK cells and the non-immune cells
comprising endothelial- and epithelial cells (Table 9.2). The homodimer of TLR3 is
known as an active viral sensor which in parallel with recognition of viral molecules
of double stranded RNA (dsRNA) activates the apoptosis mechanism (Fig. 9.2), the
pro-inflammatory and type I IFN pathways (Fig. 9.4). The TLR3 molecules are
going to be effective targets regarding anti-viral, anti-tumor, and cancer
immunotherapies. The antagonist of CU-CPT4a can be useful in this regard. The
ligand of poly-inosinic-poly-cytidylic (Poly (I:C)) (a synthetic dsRNA molecule)
directly triggers the TLR-positive process of tumor cell apoptosis or supports the
activities of tumor-infiltrating innate and tumor specific T cells. Due to this fact, the
activation of protein kinases is responsible for prevention of proliferation and
increase of apoptosis process within cancerou s cells in prostate cancer. In contrast,
activation of TLR3 via its ligand of poly-adenylic-poly-uridylic acid (Poly (A:U))
(a synthetic dsRNA molecule) supports cancerous cells by reprogramming their
metabolic pathway in head and neck carcinomas which leads to progression in
tumor growth. The TLR3 gene expression raises up in colon, laryngeal, cervical,
papillary thyroid, oral, nasopharyngeal, hepatocellular, rectal, lung, breast, prostate,
esophageal squamous cell, urinary bladder, and ovarian cancers (Ayala-Cuellar et al.
2019; Basith et al. 2012; Behzadi and Behzadi 2016; Behzadi et al. 2019; Boozari
et al. 2019; Cheng et al. 2014; Dajon et al. 2017; Huang et al. 2018; Javaid and Choi
2020; Saghazadeh and Rezaei 2020; Wang et al. 2020; Yeyeodu et al. 2013).
9.11.3.2 TLR3 SNPs and Their Role
Some SNPs in TLR3 gene have been recognized. The TLR3 gene SNP of
rs10025405 G allele is in association with breast and colorectal cancers. In this
regard, the TLR3 gene SNP of rs10025405 G allele has a five-fold reduction effect on
breast cancer occurrence. The SNP of rs5743312 in TLR3 gene is correlated with
breast, melanoma, and oral cancers. The SNPs of rs11721827 and rs3775292 in
TLR3 gene are in association with rectal and colon cancers, respectively. The
polymorphisms in TLR3 gene including +1234C/T (+1234CT and +1234TT) and
+1377 C > T (rs3775290) are associated with hepatocellular, urinary bladder,
prostate, breast, and cervical cancers, respectively. The result of a study has revealed
that the 11381G/C variant in 3’UTR region of TLR3 gene has association with
cervical cancer. The SNP of 829A > C increases the risk of nasopharyngeal cancer.
Furthermore, the TLR3 SNPs of rs3775291 (relating to breast, colon, oral, mela-
noma, hepatocellular, and nasopharyngeal cancers), rs5743305 (an intronic SNP)
(relating to breast and hepatocellular cancers), rs5743312 (an intronic SNP) (relating
to melanoma, breast, and oral cancers) have significant association with increasing
the risk of cancers (Cheng et al. 2014; Medvedev 2013; Semlali et al. 2018; Yeyeodu
et al. 2013).
9.11.3.3 TLR3 SNP in Urinary Bladder Cancer
In a meta-analysis study done by Cheng et al., the association between TLR3 gene
SNP of rs377529 and the risk of BCa occurrence was recognized. The sample size
included 200 patients (Cheng et al. 2014).
9 The Role of Toll-Like Receptor (TLR) Polymorphisms in Urinary Bladder Cancer 305
https://t.me/medicina_free
Соседние файлы в папке Библиотека им академика М.И. Перельмана