Toll-like receptor 3 (TLR3) is an endosomal receptor expressed in several immune and epithelial cells. Recent studies have highlighted its expression also in solid tumors, including prostate cancer (PCa), and have described its role primarily in the proinflammatory response and induction of apoptosis. It is up-regulated in some castration-resistant prostate cancers. However, the role of TLR3 in prostate cancer progression remains largely unknown. The current study experimentally demonstrated that exogenous TLR3 activation in PCa cell lines leads to a significant induction of secretion of the cytokines IL-6, IL-8, and interferon-β, depending on the model and chemoresistance status. Transcriptomic analysis of TLR3-overexpressing cells revealed a functional program that is enriched for genes involved in the regulation of cell motility, migration, and tumor invasiveness. Increased motility, migration, and invasion in TLR3-overexpressing cell line were confirmed by several in vitro assays and using an orthotopic prostate xenograft model in vivo. Furthermore, TLR3-ligand induced apoptosis via cleavage of caspase-3/7 and poly (ADP-ribose) polymerase, predominantly in TLR3-overexpressing cells. These results indicate that TLR3 may be involved in prostate cancer progression and metastasis; however, it might also represent an Achilles heel of PCa, which can be exploited for targeted therapy.

• MeSH
• apoptóza MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prostaty * patologie   MeSH
• poly I-C farmakologie   MeSH
• prostata patologie   MeSH
• toll-like receptor 3 * genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVE: The TLR3/cGAS-STING-IFN signaling has recently been reported to be disturbed in colorectal cancer due to deregulated expression of the genes involved. Our study aimed to investigate the influence of potential regulatory variants in these genes on the risk of sporadic colorectal cancer (CRC) in a Czech cohort of 1424 CRC patients and 1114 healthy controls. METHODS: The variants in the TLR3, CGAS, TMEM173, IKBKE, and TBK1 genes were selected using various online bioinformatic tools, such as UCSC browser, HaploReg, Regulome DB, Gtex Portal, SIFT, PolyPhen2, and miRNA prediction tools. RESULTS: Logistic regression analysis adjusted for age and sex detected a nominal association between CRC risk and three variants, CGAS rs72960018 (OR: 1.68, 95% CI: 1.11-2.53, P-value = .01), CGAS rs9352000 (OR: 2.02, 95% CI: 1.07-3.84, P-value = .03) and TMEM173 rs13153461 (OR: 1.53, 95% CI: 1.03-2.27, P-value = .03). Their cumulative effect revealed a threefold increased CRC risk in carriers of 5-6 risk alleles compared to those with 0-2 risk alleles. Epistatic interactions between these genes and the previously genotyped IFNAR1, IFNAR2, IFNA, IFNB, IFNK, IFNW, IRF3, and IRF7 genes, were computed to test their effect on CRC risk. Overall, we obtained nine pair-wise interactions within and between the CGAS, TMEM173, IKBKE, and TBK1 genes. Two of them remained statistically significant after Bonferroni correction. Additional 52 interactions were observed when IFN variants were added to the analysis. CONCLUSIONS: Our data suggest that epistatic interactions and a high number of risk alleles may play an important role in CRC carcinogenesis, offering novel biological understanding for the CRC management.

• MeSH
• dospělí MeSH
• genetická epistáze * MeSH
• genotypizační techniky MeSH
• interferony genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• karcinogeneze genetika   MeSH
• kinasa I-kappa B genetika   MeSH
• kohortové studie MeSH
• kolon diagnostické zobrazování   patologie   MeSH
• kolonoskopie MeSH
• kolorektální nádory diagnóza   genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové proteiny genetika   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nukleotidyltransferasy genetika   MeSH
• protein-serin-threoninkinasy genetika   MeSH
• regulace genové exprese u nádorů * MeSH
• rektum diagnostické zobrazování   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• signální transdukce genetika   MeSH
• studie případů a kontrol MeSH
• toll-like receptor 3 genetika   MeSH
• výpočetní biologie MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH

Morbilliviruses, such as Cetacean morbillivirus (CeMV) or Phocine distemper virus (PDV), represent a growing threat for marine mammals on both hemispheres. Because free-ranging animal populations strongly rely on natural resistance mechanisms, innate immunity-related genes and virus cell entry receptor genes may represent key factors involved in susceptibility to CeMV in Cetaceans. Using the next generation sequencing technology, we have sequenced 11 candidate genes in two model species, Stenella coeruleoalba and Phocoena phocoena. Suitable single nucleotide polymorphism markers of potential functional importance, located in genes coding for basigin (BSG, CD147), the signaling lymphocyte activating molecule (SLAMF1), the poliovirus-related receptor-4 (NECTIN4, PVRL4), toll-like receptors 3, 7, 8 (TLR3, TLR7, TLR8), natural resistance-associated macrophage protein (SLC11A1) and natural cytotoxicity triggering receptor 1 (NCR1), were identified in each model species, along with MHC-DQB haplotypes unique for each species. This set of molecular markers represents a potentially useful tool for studying host genetic variation and susceptibility to morbillivirus infection in Cetaceans as well as for studying functionally important genetic diversity of selected Cetacean populations.

• MeSH
• basigin genetika   imunologie   MeSH
• biologické markery metabolismus   MeSH
• delfíni rodu Stenella genetika   imunologie   virologie   MeSH
• exprese genu MeSH
• genetická predispozice k nemoci * MeSH
• histokompatibilita - antigeny třídy II genetika   imunologie   MeSH
• infekce viry z rodu Morbillivirus genetika   imunologie   virologie   MeSH
• jednonukleotidový polymorfismus * MeSH
• molekuly buněčné adheze genetika   imunologie   MeSH
• Morbillivirus imunologie   patogenita   MeSH
• Phocoena genetika   imunologie   virologie   MeSH
• proteiny přenášející kationty genetika   imunologie   MeSH
• receptor 1 spouštějící přirozenou cytotoxicitu genetika   imunologie   MeSH
• SLAMF1 protein genetika   imunologie   MeSH
• toll-like receptor 3 genetika   imunologie   MeSH
• toll-like receptor 7 genetika   imunologie   MeSH
• toll-like receptor 8 genetika   imunologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Due to the persisting threat of development of new highly pathogenic influenza A subtypes, a mucosal vaccination which would induce a potent and cross-protective reaction is desirable. We succeeded in mucosal immunization of mice with an inactivated influenza A virus by using delipidated Bacillus firmus (DBF) as adjuvant. The mechanism of adjuvant effect was followed in NALT by comparing the response after intranasal immunization by inactivated influenza virus type A (H1N1) alone, adjuvant alone (DBF), or by a mixture of virus+DBF. Expression of selected gene groups was tested via qPCR at 7 different time-points: cytokines (IL-2, IFN-γ, IL-4, IL-6, and IL-10), type I interferons (IFN-α4, IFN-α11, IFN-α12, and IFN-β), toll-like receptors (TLR2, TLR3, TLR7, and TLR9), iNOS and CCR7. Intranasally administered DBF and the mixture of virus+DBF induced an elevated expression of IFN-γ, IL-6 and IL-10 cytokines, type I interferons, iNOS, and pDC markers in NALT. Multimarker qPCR data was analyzed by relative quantification and by principal component analysis. DBF has been shown to be a very efficient adjuvant for the stimulation of innate immunity after IN immunization. DBF accelerated, increased, and prolonged the antiviral response.

• MeSH
• adjuvancia imunologická aplikace a dávkování   MeSH
• analýza hlavních komponent MeSH
• aplikace intranazální MeSH
• Bacillus imunologie   MeSH
• časové faktory MeSH
• cytokiny genetika   MeSH
• exprese genu účinky léků   MeSH
• imunizace metody   MeSH
• interferon typ I genetika   MeSH
• interleukin-10 genetika   MeSH
• interleukin-2 genetika   MeSH
• lymfoidní tkáň metabolismus   MeSH
• membránové glykoproteiny genetika   MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nazofarynx metabolismus   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• synergismus léků MeSH
• toll-like receptor 2 genetika   MeSH
• toll-like receptor 3 genetika   MeSH
• toll-like receptor 7 genetika   MeSH
• toll-like receptor 9 genetika   MeSH
• toll-like receptory genetika   MeSH
• vakcíny proti chřipce aplikace a dávkování   imunologie   MeSH
• virus chřipky A, podtyp H1N1 imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH