|
1
|
Eskuri M, Kemi N, Helminen O, Huhta H, Kauppila JH. Toll-like receptors 1, 2, 4, 5, and 6 in gastric cancer. Virchows Arch 2024; 485:655-664. [PMID: 37750927 DOI: 10.1007/s00428-023-03635-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 08/20/2023] [Accepted: 08/23/2023] [Indexed: 09/27/2023]
Abstract
Toll-like receptors (TLRs) are expressed on both immune cells and tumor cells, triggering both anti-tumor and pro-tumor responses. Therefore, TLRs have potential as prognostic biomarkers and immunotherapeutic targets. The aim of this study was to investigate TLR1, TLR2, TLR4, TLR5, and TLR6 expression and association with clinicopathological variables and survival in gastric cancer. Immunohistochemical study on cancer specimens from 564 resected gastric cancer patients was performed using tissue microarrays. The association between patient survival and TLR expression was calculated with Cox regression adjusted for confounding factors. Patients with high cytoplasmic TLR2 expression had significantly poorer 5-year survival than the low cytoplasmic TLR2 expression group in multivariate analysis (adjusted HR 1.38, 95% CI 1.11-1.71), and this estimate was similar in intestinal type (adjusted HR 1.33, 95% CI 0.98-1.80) and diffuse type (adjusted HR 1.48, 95% CI 1.06-2.05) histology subgroups. Patients with high cytoplasmic TLR6 expression group had significantly better 5-year survival compared with low cytoplasmic TLR6 expression group in multivariate analysis (adjusted HR 0.74, 95% CI 0.60-0.91). In the subgroup analysis of diffuse type of histology, the 5-year survival was better in high cytoplasmic TLR6 expression group in multivariable analysis (HR 0.62, 95% CI 0.46-0.83). In the intestinal type of histology subgroup, no significant differences between the groups were present. TLR1, TLR4, and TLR5 expression were not associated with 5-year survival. In conclusion, cytoplasmic TLR2 and TLR6 expression seem to have independent prognostic impact in gastric cancer, while TLR1, TLR4, and TLR5 do not.
Collapse
Affiliation(s)
- Maarit Eskuri
- Cancer and Translational Medicine Research Unit, Medical Research Center, University of Oulu and Oulu University Hospital, Aapistie 5, P.O. Box 5000, 90014, Oulu, Finland.
| | - Niko Kemi
- Cancer and Translational Medicine Research Unit, Medical Research Center, University of Oulu and Oulu University Hospital, Aapistie 5, P.O. Box 5000, 90014, Oulu, Finland
| | - Olli Helminen
- Cancer and Translational Medicine Research Unit, Medical Research Center, University of Oulu and Oulu University Hospital, Aapistie 5, P.O. Box 5000, 90014, Oulu, Finland
| | - Heikki Huhta
- Cancer and Translational Medicine Research Unit, Medical Research Center, University of Oulu and Oulu University Hospital, Aapistie 5, P.O. Box 5000, 90014, Oulu, Finland
| | - Joonas H Kauppila
- Cancer and Translational Medicine Research Unit, Medical Research Center, University of Oulu and Oulu University Hospital, Aapistie 5, P.O. Box 5000, 90014, Oulu, Finland
- Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| |
Collapse
|
|
2
|
Um S, Lee J, Kim SJ, Cho KA, Kang KS, Kim SH. Xinghamide A, a New Cyclic Nonapeptide Found in Streptomyces xinghaiensis. Mar Drugs 2023; 21:509. [PMID: 37888444 PMCID: PMC10608500 DOI: 10.3390/md21100509] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/15/2023] [Accepted: 09/25/2023] [Indexed: 10/28/2023] Open
Abstract
Xinghamide A (1), a new nonapeptide, was discovered in Streptomyces xinghaiensis isolated from a halophyte, Suaeda maritima (L.) Dumort. Based on high-resolution mass and NMR spectroscopic data, the planar structure of 1 was established, and, in particular, the sequence of nine amino acids was determined with ROESY and HMBC NMR spectra. The absolute configurations of the α-carbon of each amino acid residue were determined with 1-fluoro-2,4-dinitrophenyl-l-and -d-leucine amide (Marfey's reagents) and 2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl isothiocyanate, followed by LC-MS analysis. The anti-inflammatory activity of xinghamide A (1) was evaluated by inhibitory abilities against the nitric oxide (NO) secretion and cyclooxygenase-2 (COX-2) expression in lipopolysaccharide (LPS)-stimulated RAW264.7 cells.
Collapse
Affiliation(s)
- Soohyun Um
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Republic of Korea; (S.U.); (J.L.); (K.A.C.)
| | - Jaeyoun Lee
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Republic of Korea; (S.U.); (J.L.); (K.A.C.)
| | - Sung Jin Kim
- College of Korean Medicine, Gachon University, Seongnam 13120, Republic of Korea; (S.J.K.); (K.S.K.)
| | - Kyung A Cho
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Republic of Korea; (S.U.); (J.L.); (K.A.C.)
| | - Ki Sung Kang
- College of Korean Medicine, Gachon University, Seongnam 13120, Republic of Korea; (S.J.K.); (K.S.K.)
| | - Seung Hyun Kim
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Republic of Korea; (S.U.); (J.L.); (K.A.C.)
| |
Collapse
|
|
3
|
Liu M, Hu Z, Wang C, Zhang Y. The TLR/MyD88 signalling cascade in inflammation and gastric cancer: the immune regulatory network of Helicobacter pylori. J Mol Med (Berl) 2023; 101:767-781. [PMID: 37195446 DOI: 10.1007/s00109-023-02332-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 05/02/2023] [Accepted: 05/04/2023] [Indexed: 05/18/2023]
Abstract
Helicobacter pylori-induced chronic gastritis represents a well-established risk factor for gastric cancer (GC). However, the mechanism by which chronic inflammation caused by H. pylori induces the development of GC is unclear. H. pylori can influence host cell signalling pathways to induce gastric disease development and mediate cancer promotion and progression. Toll-like receptors (TLRs), as pattern recognition receptors (PRRs), play a key role in the gastrointestinal innate immune response, and their signalling has been implicated in the pathogenesis of an increasing number of inflammation-associated cancers. The core adapter myeloid differentiation factor-88 (MyD88) is shared by most TLRs and functions primarily in H. pylori-triggered innate immune signalling. MyD88 is envisioned as a potential target for the regulation of immune responses and is involved in the regulation of tumourigenesis in a variety of cancer models. In recent years, the TLR/MyD88 signalling pathway has received increasing attention for its role in regulating innate and adaptive immune responses, inducing inflammatory activation and promoting tumour formation. In addition, TLR/MyD88 signalling can manipulate the expression of infiltrating immune cells and various cytokines in the tumour microenvironment (TME). In this review, we discuss the pathogenetic regulatory mechanisms of the TLR/MyD88 signalling cascade pathway and its downstream molecules in H. pylori infection-induced-associated GC. The focus is to elucidate the immunomolecular mechanisms of pathogen recognition and innate immune system activation of H. pylori in the TME of inflammation-associated GC. Ultimately, this study will provide insight into the mechanism of H. pylori-induced chronic inflammation-induced GC development and provide thoughts for GC prevention and treatment strategies.
Collapse
Affiliation(s)
- Meiqi Liu
- Medical School, Cancer Research Institute, University of South China, Chang Sheng Xi Avenue 28, Hengyang City, Hunan, 421001, China
| | - Zhizhong Hu
- Medical School, Cancer Research Institute, University of South China, Chang Sheng Xi Avenue 28, Hengyang City, Hunan, 421001, China
| | - Chengkun Wang
- Medical School, Cancer Research Institute, University of South China, Chang Sheng Xi Avenue 28, Hengyang City, Hunan, 421001, China.
| | - Yang Zhang
- Medical School, Cancer Research Institute, University of South China, Chang Sheng Xi Avenue 28, Hengyang City, Hunan, 421001, China.
| |
Collapse
|
|
4
|
Zheng H, Wu P, Bonnet PA. Recent Advances on Small-Molecule Antagonists Targeting TLR7. Molecules 2023; 28:molecules28020634. [PMID: 36677692 PMCID: PMC9865772 DOI: 10.3390/molecules28020634] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/28/2022] [Accepted: 12/30/2022] [Indexed: 01/11/2023] Open
Abstract
Toll-like receptor 7 (TLR7) is a class of pattern recognition receptors (PRRs) recognizing the pathogen-associated elements and damage and as such is a major player in the innate immune system. TLR7 triggers the release of pro-inflammatory cytokines or type-I interferons (IFN), which is essential for immunoregulation. Increasing reports also highlight that the abnormal activation of endosomal TLR7 is implicated in various immune-related diseases, carcinogenesis as well as the proliferation of human immunodeficiency virus (HIV). Hence, the design and development of potent and selective TLR7 antagonists based on small molecules or oligonucleotides may offer new tools for the prevention and management of such diseases. In this review, we offer an updated overview of the main structural features and therapeutic potential of small-molecule antagonists of TLR7. Various heterocyclic scaffolds targeting TLR7 binding sites are presented: pyrazoloquinoxaline, quinazoline, purine, imidazopyridine, pyridone, benzanilide, pyrazolopyrimidine/pyridine, benzoxazole, indazole, indole, and quinoline. Additionally, their structure-activity relationships (SAR) studies associated with biological activities and protein binding modes are introduced.
Collapse
Affiliation(s)
- Haoyang Zheng
- Faculty of Pharmacy, Montpellier University, 34093 Montpellier, France
| | - Peiyang Wu
- School of Life Sciences, Shanghai Normal University, Shanghai 200234, China
| | - Pierre-Antoine Bonnet
- Institut des Biomolécules Max Mousseron IBMM, Ecole Nationale Supérieure de Chimie de Montpellier ENSCM, Montpellier University, Centre National de La Recherche Scientifique CNRS, 34093 Montpellier, France
- Correspondence:
| |
Collapse
|
|
5
|
Jain S, Dhall A, Patiyal S, Raghava GPS. In Silico Tool for Identification, Designing, and Searching of IL13-Inducing Peptides in Antigens. Methods Mol Biol 2023; 2673:329-338. [PMID: 37258925 DOI: 10.1007/978-1-0716-3239-0_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Interleukins are a distinctive class of molecules exhibiting various immune signaling functions. Immunoregulatory cytokine, Interleukin 13 (IL13), is primarily synthesized by activated T-helper 2 cells, mast cells, and basophils. IL13, is known to stimulate many allergic and autoimmune diseases, such as asthma, rheumatoid arthritis, systemic sclerosis, ulcerative colitis, airway hyperresponsiveness, glycoprotein hypersecretion, and goblet cell hyperplasia. In addition to such disorders, IL13 also leads to carcinogenesis by inhibiting tumor immunosurveillance. Due to its role in various diseases, predicting IL13-inducing peptides or regions in a protein is vital to designing safe protein vaccines and therapeutics. IL13pred is an in silico tool which aids in identifying, predicting, and designing IL13-inducing peptides. The IL13pred web server and standalone package is easily accessible at ( https://webs.iiitd.edu.in/raghava/il13pred/ ).
Collapse
Affiliation(s)
- Shipra Jain
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India
| | - Anjali Dhall
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India
| | - Sumeet Patiyal
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India
| | - Gajendra P S Raghava
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India.
| |
Collapse
|
|
6
|
Ping W, Hong S, Xun Y, Li C. Comprehensive Bioinformatics Analysis of Toll-Like Receptors (TLRs) in Pan-Cancer. BIOMED RESEARCH INTERNATIONAL 2022; 2022:4436646. [PMID: 35937402 PMCID: PMC9352480 DOI: 10.1155/2022/4436646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 06/20/2022] [Accepted: 07/14/2022] [Indexed: 11/18/2022]
Abstract
Background To conduct a comprehensive bioinformatics analysis on the transcriptome signatures of Toll-like receptors (TLRs) in pan-cancer. Materials and methods. A total of 11,057 tissues consisting of 33 types of carcinoma in The Cancer Genome Atlas (TCGA) were retrieved, and then we further explored the correlation between TLRs' expression with tumorigenesis, immune infiltration, and drug sensitivity. We conducted a comprehensive bioinformatics analysis on TLR1 to 10 in pan-cancer, including differential expression analysis between normal and tumor tissues, differential immune subtype correlation, survival analysis, tumor immune infiltration estimating, stemness indices correlation, and drug responses correlation. Results TLR2 was highly expressed in most types of tumors. TLR9 was hardly expressed compared to other TLR genes, which lead to TLR9 showing less correlation with both immune-estimate scores and stromal-estimate scores. All the TLRs were related with immune subtype of tumor samples that all of them were differentially expressed in differential immune subtype samples. The expression of TLRs was positively related with immune-estimate scores and stromal-estimate scores in almost all types of tumor. The expression of TLRs was negatively correlated with mRNA expression-based stemness scores (RNAss) in nearly almost type of tumors except kidney renal clear cell carcinoma (KIRC) and also negatively correlated with DNA methylation-based stemness scores (DNAss) in many types of tumors except adrenocortical carcinoma (ACC), cholangiocarcinoma (CHOL), KIRC, acute myeloid leukemia (LAML), low-grade glioma (LGG), testicular germ cell tumors (TGCT), thyroid carcinoma (THCA), thymoma (THYM), and uveal melanoma (UVM). The expression of TLR9 was significantly positively correlated with the drug sensitivity of fluphenazine, alectinib, carmustine, and 7-hydroxystaurosporine. TLR7 was significantly positively correlated with the drug sensitivity of alectinib. Conclusions Our study reveals the significant role of TLRs family in pan-cancer and provides potential therapeutic strategies of cancer.
Collapse
Affiliation(s)
- Wei Ping
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, 430030 Wuhan, China
| | - Senyuan Hong
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, 430030 Wuhan, China
| | - Yang Xun
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, 430030 Wuhan, China
| | - Cong Li
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, 430030 Wuhan, China
| |
Collapse
|
|
7
|
Abdel-Wahab BA, Alkahtani SA, Alqahtani AA, Hassanein EHM. Umbelliferone ameliorates ulcerative colitis induced by acetic acid via modulation of TLR4/NF-κB-p65/iNOS and SIRT1/PPARγ signaling pathways in rats. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:37644-37659. [PMID: 35066822 DOI: 10.1007/s11356-021-18252-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 12/16/2021] [Indexed: 06/14/2023]
Abstract
Ulcerative colitis (UC) is a common chronic, idiopathic inflammatory bowel disease associated with inflammatory perturbation and oxidative stress. Umbelliferone (UMB) is a potent anti-inflammatory and antioxidant coumarin derivative. Depending on the possible mechanisms, we aimed to explore and elucidate the therapeutic potential of UMB on UC-inflammatory response and oxidative injury-induced via intrarectal administration of acetic acid (AA) in rats. Animals were assigned into four groups: control group, UMB (30 mg/kg, oral)-treated group, AA-induced colitis model group (2 ml of AA; 3% v/v), and colitis treated with UMB group. The results showed that UMB improved macroscopic and histological tissue injury caused by the AA. Mechanistically, UMB reduced the elevated colonic TNF-α, IL-6, MPO, and VCAM-1 and downregulated the gene and protein expression of TLR4, NF-κB, and iNOS signaling factors, exhibiting potent anti-inflammatory effects. Moreover, UMB upregulated the gene and protein expression of both SIRT1 and PPARγ signaling pathways, thereby inhibiting both oxidative injury and inflammatory response. Conclusively, UMB protected rats against AA-induced UC by suppressing the TLR4/NF-κB-p65/iNOS signaling pathway and promoting the SIRT1/PPARγ signaling. Our results showed the effectiveness of UMB in alleviating the pathogenesis of UC and introduced it as a possible therapeutic applicant for clinical application.
Collapse
Affiliation(s)
- Basel A Abdel-Wahab
- Department of Pharmacology, College of Pharmacy, Najran University, Najran, Kingdom of Saudi Arabia.
- Department of Medical Pharmacology, College of Medicine, Assiut University, Assiut, Egypt.
| | - Saad A Alkahtani
- Department of Clinical Pharmacy, College of Pharmacy, Najran University, Najran, Kingdom of Saudi Arabia
| | - Abdulsalam A Alqahtani
- Department of Pharmaceutics, College of Pharmacy, Najran University, Najran, Kingdom of Saudi Arabia
| | - Emad H M Hassanein
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
| |
Collapse
|
|
8
|
Tegtmeyer N, Linz B, Yamaoka Y, Backert S. Unique TLR9 Activation by Helicobacter pylori Depends on the cag T4SS, But Not on VirD2 Relaxases or VirD4 Coupling Proteins. Curr Microbiol 2022; 79:121. [PMID: 35239059 PMCID: PMC8894178 DOI: 10.1007/s00284-022-02813-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 02/15/2022] [Indexed: 11/30/2022]
Abstract
The genomes of the gastric bacterial pathogen Helicobacter pylori harbor multiple type-IV secretion systems (T4SSs). Here we analyzed components of three T4SSs, the cytotoxin-associated genes (cag) T4SS, TFS3 and TFS4. The cag T4SS delivers the effector protein CagA and the LPS-metabolite ADP-heptose into gastric epithelial cells, which plays a pivotal role in chronic infection and development of gastric disease. In addition, the cag T4SS was reported to facilitate conjugative transport of chromosomal bacterial DNA into the host cell cytoplasm, where injected DNA activates intracellular toll-like receptor 9 (TLR9) and triggers anti-inflammatory signaling. Canonical DNA-delivering T4SSs in a variety of bacteria are composed of 11 VirB proteins (VirB1-11) which assemble and engage VirD2 relaxase and VirD4 coupling proteins that mediate DNA processing and guiding of the covalently bound DNA through the T4SS channel. Nevertheless, the role of the latter components in H. pylori is unclear. Here, we utilized isogenic knockout mutants of various virB (virB9 and virB10, corresponding to cagX and cagY), virD2 (rlx1 and rlx2), virD4 (cag5, traG1/2) and xerD recombinase genes in H. pylori laboratory strain P12 and studied their role in TLR9 activation by reporter assays. While inactivation of the structural cag T4SS genes cagX and cagY abolished TLR9 activation, the deletion of rlx1, rlx2, cag5, traG or xerD genes had no effect. The latter mutants activated TLR9 similar to wild-type bacteria, suggesting the presence of a unique non-canonical T4SS-dependent mechanism of TLR9 stimulation by H. pylori that is not mediated by VirD2, VirD4 and XerD proteins. These findings were confirmed by the analysis of TLR9 activation by H. pylori strains of worldwide origin that possess different sets of T4SS genes. The exact mechanism of TLR9 activation should be explored in future studies.
Collapse
Affiliation(s)
- Nicole Tegtmeyer
- Department of Biology, Chair of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058, Erlangen, Germany
| | - Bodo Linz
- Department of Biology, Chair of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058, Erlangen, Germany
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Japan
| | - Steffen Backert
- Department of Biology, Chair of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058, Erlangen, Germany.
| |
Collapse
|
|
9
|
Sultan AM, Shenouda R, Sultan AM, Shehta A, Nabiel Y. The Relation Between Host TLR9 -1486T/C, rs187084 Gene Polymorphisms and Helicobacter pylori cagA, sodB, hsp60, and vacA Virulence Genes among Gastric Cancer Patients. Pol J Microbiol 2022; 71:35-42. [PMID: 35635169 PMCID: PMC9152911 DOI: 10.33073/pjm-2022-003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 12/19/2021] [Indexed: 12/26/2022] Open
Abstract
To identify the associations between different genotypes of TLR9 -1486T/C (rs187084) with gastric cancer patients and reveal their relation to Helicobacter pylori virulence genes (cagA, sodB, hsp60 and vacA). Patients with gastric cancer were recruited to our study, diagnosed both endoscopically and histopathologically. H. pylori were isolated from gastric samples by culture and PCR amplification of the glmM gene. Virulence genes cagA, sodB, hsp60, and vacA were detected by multiplex PCR. Blood samples were used for genotyping of TLR9 -1486T/C (rs187084) by PCR-RFLP. Out of 132 patients with gastric cancer, 106 (80.3%) were positive for H. pylori. A similar number of healthy participants was recruited as controls. The prevalence of cagA, sodB, hsp60, and vacA genes among H. pylori was 90.6%, 70.8%, 83.0%, and 95.3%, respectively. The vacA gene alleles had a prevalence of 95.3% for vacAs1/s2, 52.8% for vacAm1, and 42.5% for vacAm2. The CC genotype of TLR9 -1486T/C had a significantly higher frequency in gastric cancer patients when compared to healthy participants (p = 0.045). Furthermore, the CC genotype demonstrated a significant association with H. pylori strains carrying sodB, hsp60, and vacAm1 virulence genes (p = 0.021, p = 0.049, and p = 0.048 respectively). Patients with CC genotype of TLR9 -1486T/C (rs187084) might be at higher risk for the development of gastric cancer, and its co-existence with H. pylori strains carrying sodB, hsp60, or vacAm1 virulence genes might have a synergistic effect in the development of gastric cancer. Further studies on a wider scale are recommended.
Collapse
Affiliation(s)
- Amira M. Sultan
- Medical Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ragy Shenouda
- Medical Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ahmad M. Sultan
- Gastroenterology Surgical Center, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ahmed Shehta
- Gastroenterology Surgical Center, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Yasmin Nabiel
- Medical Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| |
Collapse
|
|
10
|
Hang Z, Lei T, Zeng Z, Cai S, Bi W, Du H. Composition of intestinal flora affects the risk relationship between Alzheimer's disease/Parkinson's disease and cancer. Biomed Pharmacother 2021; 145:112343. [PMID: 34864312 DOI: 10.1016/j.biopha.2021.112343] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/09/2021] [Accepted: 10/13/2021] [Indexed: 02/08/2023] Open
Abstract
An increasing number of epidemiological studies have shown that there is a significant inverse relationship between the onset of Alzheimer's disease/Parkinson's disease (AD/PD) and cancer, but the mechanism is still unclear. Considering that intestinal flora can connect them, we tried to explain this phenomenon from the intestinal flora. This review briefly introduced the relationship among AD/PD, cancer, and intestinal flora, studied metabolites or components of the intestinal flora and the role of intestinal barriers and intestinal hormones in AD/PD and cancer. After screening, a part of the flora capable of participating in the occurrence processes of the three diseases at the same time was obtained, the abundance changes of the special flora in AD/PD and various types of cancers were summarized, and they were classified according to the flora function and abundance, which in turn innovatively and reasonably explained the fact that AD/PD and cancer showed certain antagonism in epidemiological statistics from the perspective of intestinal flora. This review also proposed that viewing the risk relationship between diseases from the perspective of intestinal flora may provide new research ideas for the treatment of fecal microbiota transplantation (FMT) and related diseases.
Collapse
Affiliation(s)
- Zhongci Hang
- Daxing Research Institute, University of Science and Technology Beijing, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, China
| | - Tong Lei
- Daxing Research Institute, University of Science and Technology Beijing, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, China
| | - Zehua Zeng
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, China
| | - Shanglin Cai
- Daxing Research Institute, University of Science and Technology Beijing, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, China
| | - Wangyu Bi
- Daxing Research Institute, University of Science and Technology Beijing, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, China
| | - Hongwu Du
- Daxing Research Institute, University of Science and Technology Beijing, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, China.
| |
Collapse
|
|
11
|
The human fungal pathogen Malassezia and its role in cancer. FUNGAL BIOL REV 2021. [DOI: 10.1016/j.fbr.2021.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
|
|
12
|
Xu Q, Li T, Chen H, Kong J, Zhang L, Yin H. Design and optimisation of a small-molecule TLR2/4 antagonist for anti-tumour therapy. RSC Med Chem 2021; 12:1771-1779. [PMID: 34778778 PMCID: PMC8528216 DOI: 10.1039/d1md00175b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Accepted: 08/19/2021] [Indexed: 11/21/2022] Open
Abstract
In anti-tumour therapy, the toll-like receptor 2/4 (TLR2/4) signalling pathway has been a double-edged sword. TLR2/4 agonists are commonly considered adjuvants for immune stimulation, whereas TLR2/4 antagonists demonstrate more feasibility for anti-tumour therapy under specific chronic inflammatory situations. In individuals with cancer retaliatory proliferation and metastasis after surgery, blocking the TLR2/4 signalling pathway may produce favourable prognosis for patients. Therefore, here, we developed a small-molecule co-inhibitor that targets the TLR2/4 signalling pathway. After high-throughput screening of a compound library containing 14 400 small molecules, followed by hit-to-lead structural optimisation, we finally obtained the compound TX-33, which has effective inhibitory properties against the TLR2/4 signalling pathways. This compound was found to significantly inhibit multiple pro-inflammatory cytokines released by RAW264.7 cells. This was followed by TX-33 demonstrating promising efficacy in subsequent anti-tumour experiments. The current results provide a novel understanding of the role of TLR2/4 in cancer and a novel strategy for anti-tumour therapy.
Collapse
Affiliation(s)
- Qun Xu
- School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorous chemistry and Chemical Biology (Ministry of Education), Tsinghua University Beijing 100084 China
| | - Tian Li
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University Beijing 100070 China
| | - Hekai Chen
- School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorous chemistry and Chemical Biology (Ministry of Education), Tsinghua University Beijing 100084 China
| | - Jun Kong
- School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorous chemistry and Chemical Biology (Ministry of Education), Tsinghua University Beijing 100084 China
| | - Liwei Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University Beijing 100070 China
| | - Hang Yin
- School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorous chemistry and Chemical Biology (Ministry of Education), Tsinghua University Beijing 100084 China
- Tsinghua-Peking Center for Life Sciences, Tsinghua University Beijing 100084 China
- Beijing Advanced Innovation Center for Structural Biology, Tsinghua University Beijing 100084 China
| |
Collapse
|
|
13
|
Toll-Like Receptors (TLRs): Structure, Functions, Signaling, and Role of Their Polymorphisms in Colorectal Cancer Susceptibility. BIOMED RESEARCH INTERNATIONAL 2021; 2021:1157023. [PMID: 34552981 PMCID: PMC8452412 DOI: 10.1155/2021/1157023] [Citation(s) in RCA: 174] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/04/2021] [Accepted: 08/19/2021] [Indexed: 12/14/2022]
Abstract
Toll-like receptors (TLRs) are the important mediators of inflammatory pathways in the gut which play a major role in mediating the immune responses towards a wide variety of pathogen-derived ligands and link adaptive immunity with the innate immunity. Numerous studies in different populations across the continents have reported on the significant roles of TLR gene polymorphisms in modulating the risk of colorectal cancer (CRC). CRC is one of the major malignancies affecting the worldwide population and is currently ranking the third most common cancer in the world. In this review, we have attempted to discuss the structure, functions, and signaling of TLRs in comprehensive detail together with the role played by various TLR gene SNPs in CRC susceptibility.
Collapse
|
|
14
|
Expression of TLR1, TLR3 and TLR7 genes remarkably down-regulated from erosion to peptic ulcer and gastric cancer development. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
|
|
15
|
T. G. S, Raghunandan R. Insilico Insight into the Association between Polycyclic Aromatic Hydrocarbons and Human Toll like Receptor in Progression of Esophageal Carcinogenesis. Polycycl Aromat Compd 2021. [DOI: 10.1080/10406638.2021.1964990] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Sreeja T. G.
- Department of Chemistry, Velu Thampi Memorial Nair Service Society College, Dhanuvachapuram, University of Kerala, Thiruvananthapuram, Kerala, India
- Department of Chemistry and Research Centre, Mahatma Gandhi College, University of Kerala, Thiruvananthapuram, Kerala, India
| | - Resmi Raghunandan
- Department of Chemistry and Research Centre, Mahatma Gandhi College, University of Kerala, Thiruvananthapuram, Kerala, India
- Department of Chemistry, Nair Service Society College, Nilamel, University of Kerala, Thiruvananthapuram, Kerala, India
| |
Collapse
|
|
16
|
Meliț LE, Mărginean CO, Săsăran MO, Mocan S, Ghiga DV, Bogliş A, Duicu C. Innate immunity - the hallmark of Helicobacter pylori infection in pediatric chronic gastritis. World J Clin Cases 2021; 9:6686-6697. [PMID: 34447815 PMCID: PMC8362532 DOI: 10.12998/wjcc.v9.i23.6686] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 06/14/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Innate immunity was found to be associated with both persistence of Helicobacter pylori (H. pylori) infection and increased risk of gastric cancer. AIM To identify the risk factors associated with H. pylori infection and to establish the role of TLR9 rs352140 in suppressing or promoting inflammation related to this infection in children. METHODS We performed a study of 155 children with digestive symptoms, who were divided into two groups according to the histopathological exam: Group 1 - 48 children with H. pylori-induced chronic gastritis, and Group 2 - control group. RESULTS Rural area and poor living conditions were significantly associated with H. pylori chronic gastritis (P = 0.0042/P < 0.0001). Both positive immunoglobulin A anti H. pylori and the rapid urease test were significantly associated with H. pylori infection (P < 0.0001). Significantly higher values of leukocytes and neutrophils within the peripheral blood were found in children with H. pylori chronic gastritis (P = 0.111/P = 0.284). We found a significant positive correlation between the variant TT genotype of TLR9 rs352140 polymorphism and both leucocytes and neutrophils (P = 0.0225/P = 0.0292). CONCLUSION Variant TT genotype carriers of the TLR9 rs352140 gene polymorphism might have a more severe degree of inflammation.
Collapse
Affiliation(s)
- Lorena Elena Meliț
- Department of Pediatrics I, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology Târgu Mureș, Târgu Mureș 540136, Romania
| | - Cristina Oana Mărginean
- Department of Pediatrics I, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology Târgu Mureș, Târgu Mureș 540136, Romania
| | - Maria Oana Săsăran
- Department of Pediatrics III, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology Târgu Mureș, Târgu Mureș 540136, Romania
| | - Simona Mocan
- Department of Pathology, Emergency County Hospital Târgu Mureș, Târgu Mureș 540139, Romania
| | - Dana Valentina Ghiga
- Scientific Medical Research Methodology, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology Târgu Mureș, Târgu Mureș 540136, Romania
| | - Alina Bogliş
- Department of Genetics, Center for Advanced Medical and Pharmaceutical Research, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology Târgu Mureș, Târgu Mureș 540136, Romania
| | - Carmen Duicu
- Department of Pediatrics I, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology Târgu Mureș, Târgu Mureș 540136, Romania
| |
Collapse
|
|
17
|
Vimal J, Himal I, Kannan S. Role of microbial dysbiosis in carcinogenesis & cancer therapies. Indian J Med Res 2021; 152:553-561. [PMID: 34145094 PMCID: PMC8224166 DOI: 10.4103/ijmr.ijmr_1026_18] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The human body supports a heterogeneous population of microorganisms. Every microorganism has the ability to contribute to the unique microenvironment around it. The aim of this review is to discuss the changes in the microbial population and their relative abundance across different ecosystems of the human body, the interactions within the microbial communities, metabolites they secrete to their external environment, their immunomodulatory functions, their signal transduction pathways and how these respond to environmental stimuli such as various diets, alcohol and drug consumption, smoking and finally suggest new therapeutic approaches. The microbiota may leads to cancer through inflammation mediated mechanisms which modulate immune responses, or produce carcinogenic metabolites and genotoxins, or deregulate cell proliferative signalling pathways. The identification of these molecular mechanisms in carcinogenesis may lead to better treatment strategies. In this review we have tried to explore the changes in microbial composition between cancer and normal tissues and what molecular mechanisms provide a connecting link between microbial dysbiosis and cancer.
Collapse
Affiliation(s)
- Joseph Vimal
- Laboratory of Cell Cycle Regulation & Molecular Oncology, Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, Kerala, India
| | - Iris Himal
- Laboratory of Cell Cycle Regulation & Molecular Oncology, Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, Kerala, India
| | - S Kannan
- Laboratory of Cell Cycle Regulation & Molecular Oncology, Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, Kerala, India
| |
Collapse
|
|
18
|
Beilmann-Lehtonen I, Hagström J, Mustonen H, Koskensalo S, Haglund C, Böckelman C. High Tissue TLR5 Expression Predicts Better Outcomes in Colorectal Cancer Patients. Oncology 2021; 99:589-600. [PMID: 34139707 DOI: 10.1159/000516543] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 04/13/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Colorectal cancer (CRC), the third most common cancer globally, caused 881,000 cancer deaths in 2018. Toll-like receptors (TLRs), the primary sensors of pathogen-associated molecular patterns and damage-associated molecular patterns, activate innate and adaptive immune systems and participate in the development of an inflammatory tumor microenvironment. We aimed to explore the prognostic value of TLR3, TLR5, TLR7, and TLR9 tissue expressions in CRC patients. METHODS Using immunohistochemistry, we analyzed tissue microarray samples from 825 CRC patients who underwent surgery between 1982 and 2002 at the Department of Surgery, Helsinki University Hospital, Finland. After analyzing a pilot series of 205 tissue samples, we included only TLR5 and TLR7 in the remainder of the patient series. We evaluated the associations between TLR5 and TLR7 tissue expressions, clinicopathologic variables, and survival. Using the Kaplan-Meier method, we generated survival curves, determining significance using the log-rank test. Univariate and multivariate survival analyses relied on the Cox proportional hazards model. RESULTS The 5-year disease-specific survival was 55.9% among TLR5-negative (95% confidence interval [CI] 50.6-61.2%) and 61.9% (95% CI 56.6-67.2%; p = 0.011, log-rank test) among TLR5-positive patients. In the Cox multivariate survival analysis adjusted for age, sex, stage, location, and grade, positive TLR5 immunoexpression (hazard ratio [HR] 0.74; 95% CI 0.59-0.92; p = 0.007) served as an independent positive prognostic factor. TLR7 immunoexpression exhibited no prognostic value in the survival analysis across the entire cohort (HR 0.97; 95% CI 0.78-1.20; p = 0.754) nor in subgroup analyses. CONCLUSIONS We show for the first time that a high TLR5 tumor tissue expression associates with a better prognosis in CRC patients.
Collapse
Affiliation(s)
- Ines Beilmann-Lehtonen
- Department of Transplantation and Liver Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Jaana Hagström
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Department of Oral Pathology and Radiology, University of Turku, Turku, Finland
| | - Harri Mustonen
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Selja Koskensalo
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Caj Haglund
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Camilla Böckelman
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| |
Collapse
|
|
19
|
Cuzzubbo S, Mangsbo S, Nagarajan D, Habra K, Pockley AG, McArdle SEB. Cancer Vaccines: Adjuvant Potency, Importance of Age, Lifestyle, and Treatments. Front Immunol 2021; 11:615240. [PMID: 33679703 PMCID: PMC7927599 DOI: 10.3389/fimmu.2020.615240] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 12/23/2020] [Indexed: 12/13/2022] Open
Abstract
Although the discovery and characterization of multiple tumor antigens have sparked the development of many antigen/derived cancer vaccines, many are poorly immunogenic and thus, lack clinical efficacy. Adjuvants are therefore incorporated into vaccine formulations to trigger strong and long-lasting immune responses. Adjuvants have generally been classified into two categories: those that ‘depot’ antigens (e.g. mineral salts such as aluminum hydroxide, emulsions, liposomes) and those that act as immunostimulants (Toll Like Receptor agonists, saponins, cytokines). In addition, several novel technologies using vector-based delivery of antigens have been used. Unfortunately, the immune system declines with age, a phenomenon known as immunosenescence, and this is characterized by functional changes in both innate and adaptive cellular immunity systems as well as in lymph node architecture. While many of the immune functions decline over time, others paradoxically increase. Indeed, aging is known to be associated with a low level of chronic inflammation—inflamm-aging. Given that the median age of cancer diagnosis is 66 years and that immunotherapeutic interventions such as cancer vaccines are currently given in combination with or after other forms of treatments which themselves have immune-modulating potential such as surgery, chemotherapy and radiotherapy, the choice of adjuvants requires careful consideration in order to achieve the maximum immune response in a compromised environment. In addition, more clinical trials need to be performed to carefully assess how less conventional form of immune adjuvants, such as exercise, diet and psychological care which have all be shown to influence immune responses can be incorporated to improve the efficacy of cancer vaccines. In this review, adjuvants will be discussed with respect to the above-mentioned important elements.
Collapse
Affiliation(s)
- Stefania Cuzzubbo
- Université de Paris, PARCC, INSERM U970, 75015, Paris, France.,Laboratoire de Recherches Biochirurgicales (Fondation Carpentier), Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France
| | - Sara Mangsbo
- Ultimovacs AB, Uppsala, Sweden.,Department of Pharmaceutical Biosciences, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Divya Nagarajan
- Department of Immunology, Genetics and Clinical pathology Rudbeck laboratories, Uppsala University, Uppsala, Sweden
| | - Kinana Habra
- The School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom.,The John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Alan Graham Pockley
- The John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom.,Centre for Health, Ageing and Understanding Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Stephanie E B McArdle
- The John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom.,Centre for Health, Ageing and Understanding Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| |
Collapse
|
|
20
|
Cui L, Wang X, Zhang D. TLRs as a Promise Target Along With Immune Checkpoint Against Gastric Cancer. Front Cell Dev Biol 2021; 8:611444. [PMID: 33469538 PMCID: PMC7813757 DOI: 10.3389/fcell.2020.611444] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 12/07/2020] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer (GC) is one of the most common cancers in the world, and the incidence of gastric cancer in Asia appears to increase in recent years. Although there is a lot of improvement in treatment approaches, the prognosis of GC is poor. So it is urgent to search for a novel and more effective treatment to improve the survival rate of patients. Both innate immunity and adaptive immunity are important in cancer. In the innate immune system, pattern recognition receptors (PRRs) activate immune responses by recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Toll-like receptors (TLRs) are a class of pattern recognition receptors (PRRs). Many studies have reported that TLRs are involved in the occurrence, development, and treatment of GC. Therefore, TLRs are potential targets for immunotherapy to gastric cancer. However, gastric cancer is a heterogeneous disorder, and TLRs function in GC is complex. TLRs agonists can be potentially used not only as therapeutic agents to treat gastric cancer but also as adjuvants in conjunction with other immunotherapies. They might provide a promising new target for GC treatment. In the review, we sort out the mechanism of TLRs involved in tumor immunity and summarize the current progress in TLRs-based therapeutic approaches and other immunotherapies in the treatment of GC.
Collapse
Affiliation(s)
- Lin Cui
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Xiuqing Wang
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Dekai Zhang
- Center for Infectious and Inflammatory Diseases, Texas A&M University, Houston, TX, United States
| |
Collapse
|
|
21
|
Rai N, Singh AK, Keshri PK, Barik S, Kamble SC, Singh SK, Kumar R, Mishra P, Kotiya D, Gautam V. Probiotics for Management of Gastrointestinal Cancers. PROBIOTIC RESEARCH IN THERAPEUTICS 2021:191-209. [DOI: 10.1007/978-981-15-8214-1_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
22
|
Espinosa-Sánchez A, Suárez-Martínez E, Sánchez-Díaz L, Carnero A. Therapeutic Targeting of Signaling Pathways Related to Cancer Stemness. Front Oncol 2020; 10:1533. [PMID: 32984007 PMCID: PMC7479251 DOI: 10.3389/fonc.2020.01533] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 07/16/2020] [Indexed: 12/11/2022] Open
Abstract
The theory of cancer stem cells (CSCs) proposes that the different cells within a tumor, as well as metastasis deriving from it, are originated from a single subpopulation of cells with self-renewal and differentiation capacities. These cancer stem cells are supposed to be critical for tumor expansion and metastasis, tumor relapse and resistance to conventional therapies, such as chemo- and radiotherapy. The acquisition of these abilities has been attributed to the activation of alternative pathways, for instance, WNT, NOTCH, SHH, PI3K, Hippo, or NF-κB pathways, that regulate detoxification mechanisms; increase the metabolic rate; induce resistance to apoptotic, autophagic, and senescence pathways; promote the overexpression of drug transporter proteins; and activate specific stem cell transcription factors. The elimination of CSCs is an important goal in cancer therapeutic approaches because it could decrease relapses and metastatic dissemination, which are main causes of mortality in oncology patients. In this work, we discuss the role of these signaling pathways in CSCs along with their therapeutic potential.
Collapse
Affiliation(s)
- Asunción Espinosa-Sánchez
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
- CIBER de Cancer, Madrid, Spain
| | - Elisa Suárez-Martínez
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
- CIBER de Cancer, Madrid, Spain
| | - Laura Sánchez-Díaz
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
- CIBER de Cancer, Madrid, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
- CIBER de Cancer, Madrid, Spain
| |
Collapse
|
|
23
|
Bartolini I, Risaliti M, Ringressi MN, Melli F, Nannini G, Amedei A, Muiesan P, Taddei A. Role of gut microbiota-immunity axis in patients undergoing surgery for colorectal cancer: Focus on short and long-term outcomes. World J Gastroenterol 2020; 26:2498-2513. [PMID: 32523307 PMCID: PMC7265137 DOI: 10.3748/wjg.v26.i20.2498] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 03/27/2020] [Accepted: 05/13/2020] [Indexed: 02/06/2023] Open
Abstract
Human body is colonized by a huge amount of microorganisms mostly located in the gastrointestinal tract. These dynamic communities, the environment and their metabolites constitute the microbiota. Growing data suggests a causal role of a dysbiotic microbiota in several pathologies, such as metabolic and neurological disorders, immunity dysregulations and cancer, especially the well-studied colorectal cancer development. However, many were preclinical studies and a complete knowledge of the pathogenetic mechanisms in humans is still absent. The gut microbiota can exert direct or indirect effects in different phases of colorectal cancer genesis. For example, Fusobacterium nucleatum promotes cancer through cellular proliferation and some strains of Escherichia coli and Bacteroides fragilis produce genotoxins. However, dysbiosis may also cause a pro-inflammatory state and the stimulation of a Th17 response with IL-17 and IL-22 secretion that have a pro-oncogenic activity, as demonstrated for Fusobacterium nucleatum. Microbiota has a crucial role in several stages of postoperative course; dysbiosis in fact seems related with surgical site infections and Enterococcus faecalis (and other collagenase-producers microbes) are suggested as a cause of anastomotic leak. Consequently, unbalanced presence of some species, together with altered immune response may also have a prognostic role. Microbiota has also a substantial role in effectiveness of chemotherapy, chemoresistance and in the related side effects. In other words, a complete knowledge of the fine pathological mechanisms of gut microbiota may provide a wide range of new diagnostic tools other than therapeutic targets in the light of tailored medicine.
Collapse
Affiliation(s)
- Ilenia Bartolini
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Matteo Risaliti
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Maria Novella Ringressi
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Filippo Melli
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Giulia Nannini
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Paolo Muiesan
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Antonio Taddei
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| |
Collapse
|
|
24
|
Sit WY, Chen YA, Chen YL, Lai CH, Wang WC. Cellular evasion strategies of Helicobacter pylori in regulating its intracellular fate. Semin Cell Dev Biol 2020; 101:59-67. [PMID: 32033828 PMCID: PMC7102552 DOI: 10.1016/j.semcdb.2020.01.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 01/27/2020] [Indexed: 12/19/2022]
Abstract
Helicobacter pylori colonizes human stomach mucosa and its infection causes gastrointestinal diseases with variable severity. Bacterial infection stimulates autophagy, which is a part of innate immunity used to eliminate intracellular pathogens. Several intracellular bacteria have evolved multipronged strategies to circumvent this conserved system and thereby enhance their chance of intracellular survival. Nonetheless, studies on H. pylori have produced inconsistent results, showing either elevated or reduced clearance efficiency of intracellular bacteria through autophagy. In this review, we summarize recent studies on the mechanisms involved in autophagy induced by H. pylori and the fate of intracellular bacteria.
Collapse
Affiliation(s)
- Wei Yang Sit
- Biomedical Science and Engineering Center, National Tsing Hua University, Hsinchu, Taiwan; Institute of Molecular and Cellular Biology & Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Yu-An Chen
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Lun Chen
- Biomedical Science and Engineering Center, National Tsing Hua University, Hsinchu, Taiwan; Institute of Molecular and Cellular Biology & Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Chih-Ho Lai
- Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan; Department of Microbiology, School of Medicine, China Medical University, Taichung, Taiwan; Department of Nursing, Asia University, Taichung, Taiwan; Molecular Infectious Disease Research Center, Department of Pediatrics, Chang Gung Memorial Hospital, Linkuo, Taiwan.
| | - Wen-Ching Wang
- Biomedical Science and Engineering Center, National Tsing Hua University, Hsinchu, Taiwan; Institute of Molecular and Cellular Biology & Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
| |
Collapse
|
|
25
|
Javaid N, Choi S. Toll-like Receptors from the Perspective of Cancer Treatment. Cancers (Basel) 2020; 12:E297. [PMID: 32012718 PMCID: PMC7072551 DOI: 10.3390/cancers12020297] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 01/22/2020] [Accepted: 01/25/2020] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) represent a family of pattern recognition receptors that recognize certain pathogen-associated molecular patterns and damage-associated molecular patterns. TLRs are highly interesting to researchers including immunologists because of the involvement in various diseases including cancers, allergies, autoimmunity, infections, and inflammation. After ligand engagement, TLRs trigger multiple signaling pathways involving nuclear factor-κB (NF-κB), interferon-regulatory factors (IRFs), and mitogen-activated protein kinases (MAPKs) for the production of various cytokines that play an important role in diseases like cancer. TLR activation in immune as well as cancer cells may prevent the formation and growth of a tumor. Nonetheless, under certain conditions, either hyperactivation or hypoactivation of TLRs supports the survival and metastasis of a tumor. Therefore, the design of TLR-targeting agonists as well as antagonists is a promising immunotherapeutic approach to cancer. In this review, we mainly describe TLRs, their involvement in cancer, and their promising properties for anticancer drug discovery.
Collapse
Affiliation(s)
| | - Sangdun Choi
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea;
| |
Collapse
|
|
26
|
Susi MD, Lourenço CDM, Rasmussen LT, Payão SLM, Rossi AFT, Silva AE, Oliveira-Cucolo JGD. Toll-like receptor 9 polymorphisms and Helicobacter pylori influence gene expression and risk of gastric carcinogenesis in the Brazilian population. World J Gastrointest Oncol 2019. [DOI: 10.4251/wjgo.v11.i11.0000] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
|
|
27
|
Susi MD, Lourenço Caroline DM, Rasmussen LT, Payão SLM, Rossi AFT, Silva AE, Oliveira-Cucolo JGD. Toll-like receptor 9 polymorphisms and Helicobacter pylori influence gene expression and risk of gastric carcinogenesis in the Brazilian population. World J Gastrointest Oncol 2019; 11:998-1010. [PMID: 31798780 PMCID: PMC6883180 DOI: 10.4251/wjgo.v11.i11.998] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 07/26/2019] [Accepted: 08/28/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Toll-like receptors (TLRs) are the first line of host defense, and are involved in Helicobacter pylori (H. pylori) recognition and activation of both inflammatory and carcinogenic processes. The presence of single nucleotide polymorphisms (SNPs) in genes that activate the immune response may modulate the risk of precancerous lesions and gastric cancer (GC). Among them, Toll-like receptor 9 (TLR9) polymorphisms have emerged with a risk factor of infectious diseases and cancer, however the studies are still inconclusive.
AIM To evaluate whether TLR9 rs5743836 and rs187084 SNPs contribute to the risk of gastric carcinogenesis, and its influence on mRNA expression.
METHODS A case-control study was conducted to evaluate two TLR9 SNPs (TLR9-1237 TC-rs5743836 and TLR9-1486 CT-rs187084) in chronic gastritis (CG) and GC patients. A total of 609 DNA samples of peripheral blood [248 CG, 161 GC, and 200 samples from healthy individuals (C)] were genotyped by polymerase chain reaction-restriction fragment length polymorphism. All samples were tested for the H. pylori infection using Hpx1 and Hpx2 primers. Quantitative polymerase chain reaction by TaqMan® assay was used to quantify TLR9 mRNA from fresh gastric tissues (48 GC, 26 CG, and 14 C).
RESULTS For TLR9-1237, the TC + CC or CC genotypes were associated with a higher risk of GC than C [recessive model odds ratio (OR) = 5.01, 95% confidence interval (CI): 2.52-9.94, P < 0.0001], and the CG (recessive model OR =4.63; 95%CI: 2.44-8.79, P < 0.0001) groups. For TLR9-1486, an association between the CT + TT genotypes and increased risk of both GC (dominant model OR = 2.72, 95%CI: 1.57-4.72, P < 0.0001) and CG (dominant model OR = 1.79, 95%CI: 1.15-2.79, P = 0.0094) was observed when compared to the C group. Moreover, the presence of TLR9-1237 TC/CC + TLR9-1486 CC genotypes potentiate the risk for this neoplasm (OR = 18.57; 95%CI: 5.06-68.15, P < 0.0001). The TLR9 mRNA level was significantly higher in the GC group (RQ = 9.24, P < 0.0001) in relation to the CG group (RQ = 1.55, P = 0.0010) and normal mucosa (RQ = 1.0). When the samples were grouped according to the polymorphic genotypes and the presence of H. pylori infection, an influence of TLR9-1237 TC + CC polymorphic genotypes (P = 0.0083) and H. pylori infection (P < 0.0001) was observed on the upregulation of mRNA expression.
CONCLUSION Our findings show that TLR9 rs5743836 and rs187084 polymorphisms are associated with a higher risk of carcinogenesis gastric, and that TLR9 mRNA levels can be modulated by TLR9-1237 TC + CC variant genotypes and H. pylori infection.
Collapse
Affiliation(s)
- Manoela Dias Susi
- Department of Graduate-Level Research, USC-Sacred Heart University, Bauru 17011-970, SP, Brazil
| | | | - Lucas Trevizani Rasmussen
- Department of Genetics and Molecular Biology, FAMEMA-Marilia Medical School, Marília 17519-030, SP, Brazil
| | - Spencer Luis Marques Payão
- Department of Genetics and Molecular Biology, FAMEMA-Marilia Medical School, Marília 17519-030, SP, Brazil
| | - Ana Flávia Teixeira Rossi
- Department of Biology, São Paulo State University-UNESP, São José do Rio Preto 15054-000, SP, Brazil
| | - Ana Elizabete Silva
- Department of Biology, São Paulo State University-UNESP, São José do Rio Preto 15054-000, SP, Brazil
| | - Juliana Garcia de Oliveira-Cucolo
- Department of Molecular, Biological and Genetics and Molecular Biology Research Unit – UPGEM, Faculty of Medicine of São José do Rio Preto – FAMERP, São José do Rio Preto 15090-000, SP, Brazil
| |
Collapse
|
|
28
|
Pandey NO, Chauhan AV, Raithatha NS, Patel PK, Khandelwal R, Desai AN, Choxi Y, Kapadia RS, Jain ND. Association of TLR4 and TLR9 polymorphisms and haplotypes with cervical cancer susceptibility. Sci Rep 2019; 9:9729. [PMID: 31278284 PMCID: PMC6611874 DOI: 10.1038/s41598-019-46077-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 06/21/2019] [Indexed: 12/13/2022] Open
Abstract
Single nucleotide polymorphisms (SNPs) in TLR genes may serve as a crucial marker for early susceptibility of various cancers including cervical cancer. The present study was therefore designed to ascertain the role of TLR4 and TLR9 SNPs and haplotypes to hrHPV infection and cervical cancer susceptibility. The study included 110 cervical cancer biopsies and 141 cervical smears from age-matched healthy controls of Gujarati ethnicity of Western India. hrHPV 16 and 18 were detected using Real-time PCR. Eight SNPs, four each in TLR4 and TLR9 were analyzed using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism and Allele-Specific PCR. HPV 16 and 18 were detected in 68% cervical cancer cases. TLR4 rs4986790, rs1927911 and TLR9 rs187084 showed association with HPV 16/18 infection. CC and CT genotypes of TLR4 rs11536889 and rs1927911 respectively, and TC, CC genotypes of TLR9 rs187084, as well as minor alleles of TLR4 rs4986790 and TLR9 rs187084, were associated with the increased risk of cervical cancer. Stage-wise analysis revealed TLR9 rs187084 and rs352140 to be associated with early-stage cancer. TLR4 haplotype GTAC and TLR9 haplotype GATC were associated with the increased risk of cervical cancer while TLR4 haplotype GCAG was associated with the decreased risk. TLR4 haplotype GCAG and TLR9 haplotype GATC showed association with increased susceptibility to hrHPV infection. In conclusion, the present study revealed association of TLR4 and TLR9 polymorphisms and haplotypes with hrHPV infection and cervical cancer risk. Further evaluation of a larger sample size covering diverse ethnic populations globally is warranted.
Collapse
Affiliation(s)
- Nilesh O Pandey
- P D Patel Institute of Applied Sciences, Charotar University of Science and Technology (CHARUSAT), Changa, Anand, India
| | - Alex V Chauhan
- P D Patel Institute of Applied Sciences, Charotar University of Science and Technology (CHARUSAT), Changa, Anand, India
| | - Nitin S Raithatha
- Department of Obstetrics and Gynaecology, Pramukh Swami Medical College, Shree Krishna Hospital, Karamsad, Anand, India
| | - Purvi K Patel
- Department of Obstetrics and Gynaecology, Sir Sayajirao General Hospital and Medical College, Vadodara, India
| | - Ronak Khandelwal
- Department of Obstetrics and Gynaecology, Sir Sayajirao General Hospital and Medical College, Vadodara, India
| | - Ajesh N Desai
- Department of Obstetrics & Gynaecology, GMERS Medical College and Hospital, Ahmedabad, India
| | - Yesha Choxi
- Department of Obstetrics & Gynaecology, GMERS Medical College and Hospital, Ahmedabad, India
| | - Rutul S Kapadia
- Department of Obstetrics & Gynaecology, GMERS Medical College and Hospital, Ahmedabad, India
| | - Neeraj D Jain
- P D Patel Institute of Applied Sciences, Charotar University of Science and Technology (CHARUSAT), Changa, Anand, India.
| |
Collapse
|
|
29
|
Ganji L, Alebouyeh M, Shirazi MH, Zali MR. Comparative transcriptional analysis for Toll-like receptors, inflammatory cytokines, and apoptotic genes in response to different cytolethal-encoding and noncoding isolates of Salmonella enterica and Campylobacter jejuni from food and human stool. Microb Pathog 2019; 133:103550. [PMID: 31112773 DOI: 10.1016/j.micpath.2019.103550] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Revised: 05/16/2019] [Accepted: 05/17/2019] [Indexed: 12/24/2022]
Abstract
Diversity of Campylobacter and Salmonella strains in interaction with epithelial cells may explain distinct modes of the pathogenesis, varying from mild watery to severe inflammatory diarrhea. We analyzed impact of this diversity, in relation to carriage and expression of cytholethal distending toxin B (cdtB), on alteration of IL-8, TNF-α, TLR2, TLR4, TLR5, CASP3 mRNA and cytokine levels in HT-29 cell line. A diversity was observed for induction of genes among different strains. Great diversity in IL-8 induction was detected between cdtB+ and cdtB- strains. Early analysis showed down-regulation of TNF-α, mostly among cdtB+ strains. Any increase or decrease in expression of TLR2 in the cdtB-C. jejuni strains was orderly correlated with increase or decrease of TLR4 and TNF-α. Up-regulation of CASP3 was followed by upregulation of TLR2, -4 and/or TNF-α, regardless to the cdtB status. In conclusion, induction of inflammatory response could mediate by distinct C. jejuni and S. enterica strains by several ways.
Collapse
Affiliation(s)
- Leila Ganji
- Department of Pathobiology, School of Public Health, University of Medical Sciences, Tehran, Iran; Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Research Center of Health Reference Laboratory, Ministry of Health and Medical Education, Tehran, Iran
| | - Masoud Alebouyeh
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Pediatric Infections Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohammad Hassan Shirazi
- Department of Pathobiology, School of Public Health, University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Science, Tehran, Iran
| |
Collapse
|
|
30
|
Du Q, Zhu C, Shang Q, Mao H, Li X, Huang Y, Du N. A study on the correlation of MyD88 expression with gastric cancer. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:4836-4844. [PMID: 31949558 PMCID: PMC6962909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 08/28/2018] [Indexed: 06/10/2023]
Abstract
OBJECTIVE The myeloid differentiation factor-88 (MyD88) plays a key role in mediating the innate immune signal transduction of toll-like receptor (TLR) and interleukin-1 (IL-1) family members, and it also participates in the regulation of tumorigenesis in various cancer models Our study sought to determine whether there is any correlation with MyD88 and the development of gastric cancer and, if such a correlation exists, to find out whether it can be used to improve the prognosis of gastric cancer patients. PATIENTS AND METHODS The expression of MyD88 in 108 cases of gastric cancer specimens, 15 cases of adenoma, and 15 cases of normal mucosa was detected by immunohistochemistry, and the correlations of the MyD88 expression with clinicopathologic changes (including disease-free survival [DFS] and overall survival [OS] were analyzed. The level of MyD88 was detected in well-differentiated MGC-803 and poorly-differentiated BGC-823 cell lines by qPCR and western blot. The expression of MyD88 was then measured by western blot after the treatment of an MyD88 overexpression vector or MyD88 inhibitor. Cell proliferation was determined by overexpression or suppression of MyD88. RESULTS In clinical cases, MyD88 was highly expressed in 23% of patients with gastric cancer as compared to those in normal mucosa and adenoma. There was a significant correlation of MyD88 overexpression with gastric metastasis (P<0.01). The overexpression of MyD88 significantly promoted the proliferation of MGC-803 and BGC-823 cell lines in gastric cancer. According to the single factor analysis, a high expression of MyD88 was strongly associated with poor DFS and OS (P<0.01), and MyD88 was an independent prognostic factor of OS. CONCLUSION This study demonstrates that a high expression of MyD88 is associated with the gastric cancer patients with liver metastasis, and facilitates the proliferation of gastric cancer cells. MyD88 is an independent predictive factor for the poor prognosis of gastric cancer patients, which provides a potential tool for future clinical diagnosis.
Collapse
Affiliation(s)
- Qiupeng Du
- Department of Gastroenterology, Beijing First Hospital of Integrated Chinese and Western Medicine Beijing 100026, China
| | - Chenchen Zhu
- Department of Gastroenterology, Beijing First Hospital of Integrated Chinese and Western Medicine Beijing 100026, China
| | - Qingqing Shang
- Department of Gastroenterology, Beijing First Hospital of Integrated Chinese and Western Medicine Beijing 100026, China
| | - Haiyan Mao
- Department of Gastroenterology, Beijing First Hospital of Integrated Chinese and Western Medicine Beijing 100026, China
| | - Xiaoyun Li
- Department of Gastroenterology, Beijing First Hospital of Integrated Chinese and Western Medicine Beijing 100026, China
| | - Yingchun Huang
- Department of Gastroenterology, Beijing First Hospital of Integrated Chinese and Western Medicine Beijing 100026, China
| | - Na Du
- Department of Gastroenterology, Beijing First Hospital of Integrated Chinese and Western Medicine Beijing 100026, China
| |
Collapse
|
|
31
|
Pucułek M, Machlowska J, Wierzbicki R, Baj J, Maciejewski R, Sitarz R. Helicobacter pylori associated factors in the development of gastric cancer with special reference to the early-onset subtype. Oncotarget 2018; 9:31146-31162. [PMID: 30123433 PMCID: PMC6089554 DOI: 10.18632/oncotarget.25757] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 06/22/2018] [Indexed: 02/07/2023] Open
Abstract
Nowadays, gastric cancer is one of the most common neoplasms and the fourth cause of cancer-related death on the world. Regarding the age at the diagnosis it is divided into early-onset gastric carcinoma (45 years or younger) and conventional gastric cancer (older than 45). Gastric carcinomas are rarely observed in young population and rely mostly on genetic factors, therefore provide the unique model to study genetic and environmental alternations. The latest research on early-onset gastric cancer are trying to explain molecular and genetic basis, because young patients are less exposed to environmental factors predisposing to cancer. In the general population, Helicobacter pylori, has been particularly associated with intestinal subtype of gastric cancers. The significant association of Helicobacter pylori infection in young patients with gastric cancers suggests that the bacterium has an etiologic role in both diffuse and intestinal subtypes of early-onset gastric cancers. In this paper we would like to ascertain the possible role of Helicobacter pylori infection in the development of gastric carcinoma in young patients. The review summarizes recent literature on early-onset gastric cancers with special reference to Helicobacter pylori infection.
Collapse
Affiliation(s)
| | | | - Ryszard Wierzbicki
- Department of Surgery with Trauma, Orthopaedic and Urological Subunit, Independent Public Health Care Center of the Ministry of Interior and Administration in Lublin, Poland
- Department of Surgical Oncology, Medical University of Lublin, Poland
| | - Jacek Baj
- Department of Human Anatomy, Medical University of Lublin, Poland
| | | | - Robert Sitarz
- Department of Human Anatomy, Medical University of Lublin, Poland
- Department of Surgery with Trauma, Orthopaedic and Urological Subunit, Independent Public Health Care Center of the Ministry of Interior and Administration in Lublin, Poland
- Department of Surgery, St. John's Cancer Center, Lublin, Poland
| |
Collapse
|
|
32
|
Morgillo F, Dallio M, Della Corte CM, Gravina AG, Viscardi G, Loguercio C, Ciardiello F, Federico A. Carcinogenesis as a Result of Multiple Inflammatory and Oxidative Hits: a Comprehensive Review from Tumor Microenvironment to Gut Microbiota. Neoplasia 2018; 20:721-733. [PMID: 29859426 PMCID: PMC6014569 DOI: 10.1016/j.neo.2018.05.002] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 04/30/2018] [Accepted: 05/01/2018] [Indexed: 12/18/2022]
Affiliation(s)
- Floriana Morgillo
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy.
| | - Marcello Dallio
- Gastroenterologia, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Carminia Maria Della Corte
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Antonietta Gerarda Gravina
- Gastroenterologia, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Giuseppe Viscardi
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Carmelina Loguercio
- Gastroenterologia, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Fortunato Ciardiello
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Alessandro Federico
- Gastroenterologia, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
| |
Collapse
|
|
33
|
Noguti J, Chan AA, Bandera B, Brislawn CJ, Protic M, Sim MS, Jansson JK, Bilchik AJ, Lee DJ. Both the intratumoral immune and microbial microenvironment are linked to recurrence in human colon cancer: results from a prospective, multicenter nodal ultrastaging trial. Oncotarget 2018; 9:23564-23576. [PMID: 29805756 PMCID: PMC5955112 DOI: 10.18632/oncotarget.25276] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 04/08/2018] [Indexed: 12/15/2022] Open
Abstract
Colon cancer (CC) is the third most common cancer diagnosed in the United States and the incidence has been rising among young adults. We and others have shown a relationship between the immune infiltrate and prognosis, with improved disease-free survival (DFS) being associated with a higher expression of CD8+ T cells. We hypothesized that a microbial signature might be associated with intratumoral immune cells as well as DFS. We found that the relative abundance of one Operational Taxonomic Unit (OTU), OTU_104, was significantly associated with recurrence even after applying false discovery correction (HR 1.21, CI 1.08 to 1.36). The final multivariable model showed that DFS was influenced by three parameters: N-stage, CD8+ labeling, as well as this OTU_104 belonging to the order Clostridiales. Not only were CD8+ labeling and OTU_104 significant contributors in the final DFS model, but they were also inversely correlated to each other (p=0.022). Interestingly, CD8+ was also significantly associated with the microbiota composition in the tumor: CD8+ T cells was inversely correlated with alpha diversity (p=0.027) and significantly associated with the beta diversity. This study is the first to demonstrate an association among the intratumoral microbiome, CD8+ T cells, and recurrence in CC. An increased relative abundance of a specific OTU_104 was inversely associated with CD8+ T cells and directly associated with CC recurrence. The link between this microbe, CD8+ T cells, and DFS has not been previously shown.
Collapse
Affiliation(s)
- Juliana Noguti
- Dirks/Dougherty Laboratory for Cancer Research, Department of Translational Immunology, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USA.,Los Angeles Biomedical Research Institute, Harbor - UCLA Medical Center, Torrance, CA, USA
| | - Alfred A Chan
- Dirks/Dougherty Laboratory for Cancer Research, Department of Translational Immunology, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USA.,Los Angeles Biomedical Research Institute, Harbor - UCLA Medical Center, Torrance, CA, USA
| | - Bradley Bandera
- Department of Surgical Oncology. The John Wayne Cancer Institute at Providence St. John's Health Center, Santa Monica, CA, USA
| | - Colin J Brislawn
- Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington, USA
| | - Mladjan Protic
- University of Novi Sad, Faculty of Medicine, Novi Sad, Serbia.,Oncology Institute of Vojvodina, Sremska Kamenica, Serbia
| | - Myung S Sim
- UCLA Department of Medicine, Statistics Core, Los Angeles, CA, USA
| | - Janet K Jansson
- Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington, USA
| | - Anton J Bilchik
- Department of Surgical Oncology. The John Wayne Cancer Institute at Providence St. John's Health Center, Santa Monica, CA, USA
| | - Delphine J Lee
- Dirks/Dougherty Laboratory for Cancer Research, Department of Translational Immunology, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USA.,Los Angeles Biomedical Research Institute, Harbor - UCLA Medical Center, Torrance, CA, USA.,Division of Dermatology, Department of Medicine, Harbor - UCLA Medical Center, Torrance, CA, USA.,David Geffen School of Medicine, University of California - Los Angeles, Los Angeles, CA, USA
| |
Collapse
|
|
34
|
Lam SY, Yu J, Wong SH, Peppelenbosch MP, Fuhler GM. The gastrointestinal microbiota and its role in oncogenesis. Best Pract Res Clin Gastroenterol 2017; 31:607-618. [PMID: 29566903 DOI: 10.1016/j.bpg.2017.09.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 09/03/2017] [Indexed: 02/07/2023]
Abstract
Advances in research techniques have made it possible to map the microbial communities in the gastrointestinal (GI) tract, where the majority of bacteria in the human body reside. Disturbances in these communities are referred to as dysbiosis and have been associated with GI cancers. Although dysbiosis is observed in several GI malignancies, the specific role of these changes has not been understood to the extent of Helicobacter pylori (HP) in gastric cancer (GC). This review will address the bacterial communities along the GI tract, from the oral cavity to the anal canal, particularly focusing on bacterial dysbiosis and carcinogenesis. Just as non-HP bacteria in the stomach may interact with HP in gastric carcinogenesis, the same may hold true for other GI tract malignancies, where an interplay between microbes in carcinogenesis seems conceivable, especially in colorectal cancer (CRC). In the last part of this review we will discuss the potential mechanisms of bacterial dysbiosis in GI carcinogenesis.
Collapse
Affiliation(s)
- S Y Lam
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
| | - J Yu
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences and CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
| | - S H Wong
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences and CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
| | - M P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
| | - G M Fuhler
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
| |
Collapse
|
|
35
|
The role of TLRs in cervical cancer with HPV infection: a review. Signal Transduct Target Ther 2017; 2:17055. [PMID: 29263932 PMCID: PMC5668671 DOI: 10.1038/sigtrans.2017.55] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 06/20/2017] [Accepted: 07/17/2017] [Indexed: 01/01/2023] Open
Abstract
The main cause of cervical cancer is persistent infection with high-risk human papilloma virus (HR-HPV), but not all human papilloma virus (HPV) infections lead to cervical cancer. The key factors that determine the outcome of HPV infection remain poorly understood, and how the host immune system protects against HPV infection is unclear. Toll-like receptors (TLRs) are a group of pattern recognition receptors present in the cytoplasm and cell membrane, and can specifically recognize pathogen-associated molecular patterns. As the key molecules of innate and acquired immunity, TLRs not only play important roles in the immune defense against infectious diseases, but also are involved in the occurrence and development of a variety of malignant tumors. In cervical cancer caused by HR-HPV infection, TLRs have been found to regulate the local immune microenvironment. The role of TLRs in HR-HPV infection and HPV-induced cervical cancer and its relationship with HPV vaccine are reviewed in this article.
Collapse
|
|
36
|
Gao W, Xiong Y, Li Q, Yang H. Inhibition of Toll-Like Receptor Signaling as a Promising Therapy for Inflammatory Diseases: A Journey from Molecular to Nano Therapeutics. Front Physiol 2017; 8:508. [PMID: 28769820 PMCID: PMC5516312 DOI: 10.3389/fphys.2017.00508] [Citation(s) in RCA: 269] [Impact Index Per Article: 33.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2017] [Accepted: 07/03/2017] [Indexed: 12/20/2022] Open
Abstract
The recognition of invading pathogens and endogenous molecules from damaged tissues by toll-like receptors (TLRs) triggers protective self-defense mechanisms. However, excessive TLR activation disrupts the immune homeostasis by sustained pro-inflammatory cytokines and chemokines production and consequently contributes to the development of many inflammatory and autoimmune diseases, such as systemic lupus erythematosus (SLE), infection-associated sepsis, atherosclerosis, and asthma. Therefore, inhibitors/antagonists targeting TLR signals may be beneficial to treat these disorders. In this article, we first briefly summarize the pathophysiological role of TLRs in the inflammatory diseases. We then focus on reviewing the current knowledge in both preclinical and clinical studies of various TLR antagonists/inhibitors for the prevention and treatment of inflammatory diseases. These compounds range from conventional small molecules to therapeutic biologics and nanodevices. In particular, nanodevices are emerging as a new class of potent TLR inhibitors for their unique properties in desired bio-distribution, sustained circulation, and preferred pharmacodynamic and pharmacokinetic profiles. More interestingly, the inhibitory activity of these nanodevices can be regulated through precise nano-functionalization, making them the next generation therapeutics or “nano-drugs.” Although, significant efforts have been made in developing different kinds of new TLR inhibitors/antagonists, only limited numbers of them have undergone clinical trials, and none have been approved for clinical uses to date. Nevertheless, these findings and continuous studies of TLR inhibition highlight the pharmacological regulation of TLR signaling, especially on multiple TLR pathways, as future promising therapeutic strategy for various inflammatory and autoimmune diseases.
Collapse
Affiliation(s)
- Wei Gao
- Department of Respiratory Medicine, Shanghai First People's Hospital, Shanghai Jiaotong University School of MedicineShanghai, China
| | - Ye Xiong
- Department of Respiratory Medicine, Changhai Hospital, Second Military Medical UniversityShanghai, China
| | - Qiang Li
- Department of Respiratory Medicine, Shanghai First People's Hospital, Shanghai Jiaotong University School of MedicineShanghai, China
| | - Hong Yang
- Department of Respiratory Medicine, Shanghai First People's Hospital, Shanghai Jiaotong University School of MedicineShanghai, China
| |
Collapse
|
|
37
|
Spanou E, Kalisperati P, Pateras IS, Papalampros A, Barbouti A, Tzioufas AG, Kotsinas A, Sougioultzis S. Genetic Variability as a Regulator of TLR4 and NOD Signaling in Response to Bacterial Driven DNA Damage Response (DDR) and Inflammation: Focus on the Gastrointestinal (GI) Tract. Front Genet 2017; 8:65. [PMID: 28611823 PMCID: PMC5447025 DOI: 10.3389/fgene.2017.00065] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 05/09/2017] [Indexed: 12/13/2022] Open
Abstract
The fundamental role of human Toll-like receptors (TLRs) and NOD-like receptors (NLRs), the two most studied pathogen recognition receptors (PRRs), is the protection against pathogens and excessive tissue injury. Recent evidence supports the association between TLR/NLR gene mutations and susceptibility to inflammatory, autoimmune, and malignant diseases. PRRs also interfere with several cellular processes, such as cell growth, apoptosis, cell proliferation, differentiation, autophagy, angiogenesis, cell motility and migration, and DNA repair mechanisms. We briefly review the impact of TLR4 and NOD1/NOD2 and their genetic variability in the process of inflammation, tumorigenesis and DNA repair, focusing in the gastrointestinal tract. We also review the available data on new therapeutic strategies utilizing TLR/NLR agonists and antagonists for cancer, allergic diseases, viral infections and vaccine development against both infectious diseases and cancer.
Collapse
Affiliation(s)
- Evagelia Spanou
- Gastroenterology Division, Department of Pathophysiology, “Laikon” General Hospital, University of AthensAthens, Greece
| | - Polyxeni Kalisperati
- Gastroenterology Division, Department of Pathophysiology, “Laikon” General Hospital, University of AthensAthens, Greece
| | - Ioannis S. Pateras
- Department of Histology and Embryology, University of AthensAthens, Greece
| | - Alexandros Papalampros
- 1st Department of Surgery, “Laikon” General Hospital, University of AthensAthens, Greece
| | - Alexandra Barbouti
- Department of Anatomy-Histology-Embryology, University of IoanninaIoannina, Greece
| | - Athanasios G. Tzioufas
- Department of Pathophysiology, “Laikon” General Hospital, University of AthensAthens, Greece
| | | | - Stavros Sougioultzis
- Gastroenterology Division, Department of Pathophysiology, “Laikon” General Hospital, University of AthensAthens, Greece
| |
Collapse
|
|
38
|
Zhou X, Dong T, Fan Z, Peng Y, Zhou R, Wang X, Song N, Han M, Fan B, Jia J, Liu S. Perfluorodecanoic acid stimulates NLRP3 inflammasome assembly in gastric cells. Sci Rep 2017; 7:45468. [PMID: 28367997 PMCID: PMC5377303 DOI: 10.1038/srep45468] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 02/28/2017] [Indexed: 02/07/2023] Open
Abstract
Perfluorodecanoic acid (PFDA), a perfluorinated carboxylic acid, presents in the environment and accumulates in human blood and organs, but its association with tumor promotion are not clear. Given that inflammation plays a significant role in the development of gastric malignancies, we evaluated the effects of PFDA on activation of the inflammasome and inflammation regulation in the gastric cell line AGS. When added to cell cultures, PFDA significantly stimulated IL-1β and IL18 secretion and their mRNA levels compared with control cells. By RT-PCR and western-blot we found that up-regulation of NLRP3 were associated with promotion of IL-1β and IL-18 production. Then expression variation of cIAP1/2, c-Rel and p52 were analyzed, the results demonstrated raised mRNA expression in all the tested genes concomitant with enhanced inflammasome activity after exposure to PFDA. Assays with cIAP2 siRNA and NFκB reporter provided additional evidence that these genes were involved in PFDA-induced inflammasome assembly. Furthermore, increased secretion of IL-1β and IL-18 were detected in stomach of PFDA-treated mice, disorganized alignment of epithelial cells and inflammatory cell infiltration were also observed in the stomach tissues upon PFDA treatment. This study reports for the first time that PFDA regulates inflammasome assembly in human cells and mice tissues.
Collapse
Affiliation(s)
- Xiangyu Zhou
- Department of medical microbiology, School of basic medical science, Shandong University, Jinan, Shandong, 250012, China
| | - Tianyi Dong
- Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
| | - Ziyan Fan
- China National Tobacco Quality Supervision &Test Center, 2 Fengyang Street, Zhengzhou, Henan, 450001, China
| | - Yanping Peng
- Department of medical microbiology, School of basic medical science, Shandong University, Jinan, Shandong, 250012, China
| | - Rongbin Zhou
- Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230027, China
| | - Xiaqiong Wang
- Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230027, China
| | - Ning Song
- Department of medical microbiology, School of basic medical science, Shandong University, Jinan, Shandong, 250012, China
| | - Mingyong Han
- Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
| | - Bingbing Fan
- School of Public Health, Shandong University, Jinan, Shandong, 250012, China
| | - Jihui Jia
- Department of medical microbiology, School of basic medical science, Shandong University, Jinan, Shandong, 250012, China
| | - Shili Liu
- Department of medical microbiology, School of basic medical science, Shandong University, Jinan, Shandong, 250012, China
| |
Collapse
|
|
39
|
Wang X, Yang Y, Huycke MM. Microbiome-driven carcinogenesis in colorectal cancer: Models and mechanisms. Free Radic Biol Med 2017; 105:3-15. [PMID: 27810411 DOI: 10.1016/j.freeradbiomed.2016.10.504] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 10/19/2016] [Accepted: 10/25/2016] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is a leading cause of cancer death and archetype for cancer as a genetic disease. However, the mechanisms for genetic change and their interactions with environmental risk factors have been difficult to unravel. New hypotheses, models, and methods are being used to investigate a complex web of risk factors that includes the intestinal microbiome. Recent research has clarified how the microbiome can generate genomic change in CRC. Several phenotypes among a small group of selected commensals have helped us better understand how mutations and chromosomal instability (CIN) are induced in CRC (e.g., toxin production, metabolite formation, radical generation, and immune modulation leading to a bystander effect). This review discusses recent hypotheses, models, and mechanisms by which the intestinal microbiome contributes to the initiation and progression of sporadic and colitis-associated forms of CRC. Overall, it appears the microbiome can initiate and/or promote CRC at all stages of tumorigenesis by acting as an inducer of DNA damage and CIN, regulating cell growth and death, generating epigenetic changes, and modulating host immune responses. Understanding how the microbiome interacts with other risk factors to define colorectal carcinogenesis will ultimately lead to more accurate risk prediction. A deeper understanding of CRC etiology will also help identify new targets for prevention and treatment and help accelerate the decline in mortality for this common cancer.
Collapse
Affiliation(s)
- Xingmin Wang
- Department of Radiation Oncology, University of Oklahoma Health Sciences Center, USA; Muchmore Laboratories for Infectious Diseases Research, Oklahoma City VA Health Care System, USA
| | - Yonghong Yang
- Gansu Province Children's Hospital, Lanzhou, China; Key Laboratory of Gastrointestinal Cancer, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Mark M Huycke
- Muchmore Laboratories for Infectious Diseases Research, Oklahoma City VA Health Care System, USA; Department of Internal Medicine, PO Box 26901, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73126-0901, USA.
| |
Collapse
|
|
40
|
ElObeid AS, Kamal-Eldin A, Abdelhalim MAK, Haseeb AM. Pharmacological Properties of Melanin and its Function in Health. Basic Clin Pharmacol Toxicol 2017; 120:515-522. [PMID: 28027430 DOI: 10.1111/bcpt.12748] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 12/14/2016] [Indexed: 01/08/2023]
Abstract
The biological pigment melanin is present in most of the biological systems. It manifests a host of biological and pharmacological properties. Its role as a molecule with special properties and functions affecting general health, including photoprotective and immunological action, are well recognized. Its antioxidant, anti-inflammatory, immunomodulatory, radioprotective, hepatic, gastrointestinal and hypoglycaemic benefits have only recently been recognized and studied. It is also associated with certain disorders of the nervous system. In this MiniReview, we consider the steadily increasing literature on the bioavailability and functional activity of melanin. Published literature shows that melanin may play a number of possible pharmacological effects such as protective, stimulatory, diagnostic and curative roles in human health. In this MiniReview, possible health roles and pharmacological effects are considered.
Collapse
Affiliation(s)
- Adila Salih ElObeid
- King Abdullah International Medical Research Centre, National Guard & Health Affairs, Riyadh, Saudi Arabia
| | - Afaf Kamal-Eldin
- Department of Food Science, United Arab Emirates University, AlAin, United Arab Emirates
| | | | - Adil M Haseeb
- Physics and Astronomy Department, King Saud University, Riyadh, Saudi Arabia
| |
Collapse
|
|
41
|
Henson LH, Songsasen N, Waddell W, Wolf KN, Emmons L, Gonzalez S, Freeman E, Maldonado J. Characterization of genetic variation and basis of inflammatory bowel disease in the Toll-like receptor 5 gene of the red wolf and the maned wolf. ENDANGER SPECIES RES 2017. [DOI: 10.3354/esr00790] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
|
|
42
|
TLR4-mediated galectin-1 production triggers epithelial-mesenchymal transition in colon cancer cells through ADAM10- and ADAM17-associated lactate production. Mol Cell Biochem 2016; 425:191-202. [PMID: 27837433 DOI: 10.1007/s11010-016-2873-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 11/02/2016] [Indexed: 12/30/2022]
Abstract
Toll-like receptor 4 (TLR4) activation is a key contributor to the carcinogenesis of colon cancer. Overexpression of galectin-1 (Gal-1) also correlates with increased invasive activity of colorectal cancer. Lactate production is a critical predictive factor of risk of metastasis, but the functional relationship between intracellular lactate and Gal-1 expression in TLR4-activated colon cancer remains unknown. In this study, we investigated the underlying mechanism and role of Gal-1 in metastasis and invasion of colorectal cancer (CRC) cells after TLR4 stimulation. Exposure to the TLR4 ligand lipopolysaccharide (LPS) increased expression of Gal-1, induced EMT-related cytokines, triggered the activation of glycolysis-related enzymes, and promoted lactate production. Gene silencing of TLR4 and Gal-1 in CRC cells inhibited lactate-mediated epithelial-mesenchymal transition (EMT) after TLR4 stimulation. Gal-1-mediated activation of a disintegrin and metalloproteinase 10 (ADAM10) and ADAM 17 increased the invasion activity and expression of mesenchymal characteristics in LPS-activated CRC cells. Conversely, inhibition of ADAM10 or ADAM17 effectively blocked the generation of lactate and the migration capacity of LPS-treated CRC cells. Thus, the TLR4/Gal-1 signaling pathway regulates lactate-mediated EMT processes through the activation of ADAM10 and ADAM17 in CRC cells.
Collapse
|
|
43
|
Tsai WT, Lo YC, Wu MS, Li CY, Kuo YP, Lai YH, Tsai Y, Chen KC, Chuang TH, Yao CH, Lee JC, Hsu LC, Hsu JTA, Yu GY. Mycotoxin Patulin Suppresses Innate Immune Responses by Mitochondrial Dysfunction and p62/Sequestosome-1-dependent Mitophagy. J Biol Chem 2016; 291:19299-311. [PMID: 27458013 DOI: 10.1074/jbc.m115.686683] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Indexed: 01/20/2023] Open
Abstract
Innate immune responses are important for pathogen elimination and adaptive immune response activation. However, excess inflammation may contribute to immunopathology and disease progression (e.g. inflammation-associated hepatocellular carcinoma). Immune modulation resulting from pattern recognition receptor-induced responses is a potential strategy for controlling immunopathology and related diseases. This study demonstrates that the mycotoxin patulin suppresses Toll-like receptor- and RIG-I/MAVS-dependent cytokine production through GSH depletion, mitochondrial dysfunction, the activation of p62-associated mitophagy, and p62-TRAF6 interaction. Blockade of autophagy restored the immunosuppressive activity of patulin, and pharmacological activation of p62-dependent mitophagy directly reduced RIG-I-like receptor-dependent inflammatory cytokine production. These results demonstrated that p62-dependent mitophagy has an immunosuppressive role to innate immune response and might serve as a potential immunomodulatory target for inflammation-associated diseases.
Collapse
Affiliation(s)
- Wan-Ting Tsai
- From the National Institute of Infectious Diseases and Vaccinology
| | - Yin-Chiu Lo
- From the National Institute of Infectious Diseases and Vaccinology
| | - Ming-Sian Wu
- From the National Institute of Infectious Diseases and Vaccinology
| | - Chia-Yang Li
- From the National Institute of Infectious Diseases and Vaccinology, the Department of Genome Medicine, College of Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Yi-Ping Kuo
- From the National Institute of Infectious Diseases and Vaccinology
| | - Yi-Hui Lai
- the Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan, and
| | - Yu Tsai
- From the National Institute of Infectious Diseases and Vaccinology
| | - Kai-Chieh Chen
- From the National Institute of Infectious Diseases and Vaccinology
| | | | - Chun-Hsu Yao
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan Town, Miaoli County 35053, Taiwan
| | - Jinq-Chyi Lee
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan Town, Miaoli County 35053, Taiwan
| | - Li-Chung Hsu
- the Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan, and
| | - John T-A Hsu
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan Town, Miaoli County 35053, Taiwan
| | - Guann-Yi Yu
- From the National Institute of Infectious Diseases and Vaccinology, the Center of Infectious Disease and Signaling Research, National Cheng-Kung University, Tainan 70101, Taiwan
| |
Collapse
|
|
44
|
Huhta H, Helminen O, Kauppila JH, Salo T, Porvari K, Saarnio J, Lehenkari PP, Karttunen TJ. The Expression of Toll-like Receptors in Normal Human and Murine Gastrointestinal Organs and the Effect of Microbiome and Cancer. J Histochem Cytochem 2016; 64:470-82. [PMID: 27370795 PMCID: PMC4971779 DOI: 10.1369/0022155416656154] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 06/01/2016] [Indexed: 12/12/2022] Open
Abstract
Toll-like receptors (TLRs) are innate immune receptors expressed in all parts of the alimentary tract. However, analyses comparing expression in different segments and data on germ-free animals are lacking. Alimentary tract cancers show increased TLR expression. According to the field effect concept, carcinogenetic factors induce subtle cancer predisposing alterations in the whole organ. We studied TLR1 to TLR9 expression in all segments of the alimentary tract from cancer patients’ tumor-adjacent normal mucosa, healthy organ donors, and conventional and germ-free mice by using immunohistochemistry and quantitative PCR. All TLRs were expressed in all segments of the alimentary tract. Expression was most intensive in the small intestine in humans and conventional mice, but germ-free mice showed less expression in the small intestine. TLR expression levels were similar in cancer patients and organ donors. We provide systematic baseline data on the TLR expression in the alimentary tract. Normal epithelium adjacent to tumor seems to have similar TLR expression compared with healthy tissues suggesting absence of any field effect in TLR expression. Accordingly, specimens from cancer patients’ normal tumor-adjacent tissue can be used as control tissues in immunohistochemical TLR studies in gastrointestinal cancer.
Collapse
Affiliation(s)
- Heikki Huhta
- Departments of Pathology, University of Oulu, Oulu, Finland (HH, OH, JHK, KP, TJK),Surgery, University of Oulu, Oulu, Finland (HH, OH, JHK, JS, PPL),Medical Research Center Oulu, Oulu, Finland (HH, OH, JHK, TS, JS, PPL, TJK),Oulu University Hospital, Oulu, Finland (HH, OH, JHK, TS, JS, PPL, TJK)
| | - Olli Helminen
- Departments of Pathology, University of Oulu, Oulu, Finland (HH, OH, JHK, KP, TJK),Surgery, University of Oulu, Oulu, Finland (HH, OH, JHK, JS, PPL),Medical Research Center Oulu, Oulu, Finland (HH, OH, JHK, TS, JS, PPL, TJK),Oulu University Hospital, Oulu, Finland (HH, OH, JHK, TS, JS, PPL, TJK)
| | - Joonas H Kauppila
- Departments of Pathology, University of Oulu, Oulu, Finland (HH, OH, JHK, KP, TJK),Surgery, University of Oulu, Oulu, Finland (HH, OH, JHK, JS, PPL),Medical Research Center Oulu, Oulu, Finland (HH, OH, JHK, TS, JS, PPL, TJK),Oulu University Hospital, Oulu, Finland (HH, OH, JHK, TS, JS, PPL, TJK)
| | - Tuula Salo
- Dentistry, University of Oulu, Oulu, Finland (TS),Medical Research Center Oulu, Oulu, Finland (HH, OH, JHK, TS, JS, PPL, TJK),Oulu University Hospital, Oulu, Finland (HH, OH, JHK, TS, JS, PPL, TJK)
| | - Katja Porvari
- Departments of Pathology, University of Oulu, Oulu, Finland (HH, OH, JHK, KP, TJK)
| | - Juha Saarnio
- Surgery, University of Oulu, Oulu, Finland (HH, OH, JHK, JS, PPL),Medical Research Center Oulu, Oulu, Finland (HH, OH, JHK, TS, JS, PPL, TJK),Oulu University Hospital, Oulu, Finland (HH, OH, JHK, TS, JS, PPL, TJK)
| | - Petri P Lehenkari
- Surgery, University of Oulu, Oulu, Finland (HH, OH, JHK, JS, PPL),Anatomy and Cell biology, University of Oulu, Oulu, Finland (PPL),Medical Research Center Oulu, Oulu, Finland (HH, OH, JHK, TS, JS, PPL, TJK),Oulu University Hospital, Oulu, Finland (HH, OH, JHK, TS, JS, PPL, TJK)
| | - Tuomo J Karttunen
- Departments of Pathology, University of Oulu, Oulu, Finland (HH, OH, JHK, KP, TJK),Medical Research Center Oulu, Oulu, Finland (HH, OH, JHK, TS, JS, PPL, TJK),Oulu University Hospital, Oulu, Finland (HH, OH, JHK, TS, JS, PPL, TJK)
| |
Collapse
|
|
45
|
Russo E, Taddei A, Ringressi MN, Ricci F, Amedei A. The interplay between the microbiome and the adaptive immune response in cancer development. Therap Adv Gastroenterol 2016; 9:594-605. [PMID: 27366226 PMCID: PMC4913328 DOI: 10.1177/1756283x16635082] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
The data from different studies suggest a bacterial role in cancer genesis/progression, often modulating the local immune response. This is particularly so at the mucosal level where the bacterial presence is strong and the immune system is highly reactive. The epithelial surfaces of the body, such as the skin and mucosa, are colonized by a vast number of microorganisms, which represent the so-called normal microbiome. Normally the microbiome does not cause a proinflammatory response because the immune system has developed different strategies for the tolerance of commensal bacteria, but when these mechanisms are impaired or new pathogenic bacteria are introduced into this balanced system, the immune system reacts to the microbiome and can trigger tumor growth in the intestine. In this review, we discuss the potential role of the bacterial microbiome in carcinogenesis, focusing on the direct and indirect immune adaptive mechanisms, that the bacteria can modulate in different ways.
Collapse
Affiliation(s)
- Edda Russo
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Antonio Taddei
- Department of Surgery and Translational Medicine (DCMT), University of Florence, Florence, Italy
| | - Maria Novella Ringressi
- Department of Surgery and Translational Medicine (DCMT), University of Florence, Florence, Italy
| | - Federica Ricci
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine – Section of Internal Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
| |
Collapse
|
|
46
|
Pandolfi F, Altamura S, Frosali S, Conti P. Key Role of DAMP in Inflammation, Cancer, and Tissue Repair. Clin Ther 2016; 38:1017-28. [PMID: 27021609 DOI: 10.1016/j.clinthera.2016.02.028] [Citation(s) in RCA: 126] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2016] [Revised: 02/29/2016] [Accepted: 02/29/2016] [Indexed: 12/30/2022]
Abstract
PURPOSE This review aimed to take stock of the current status of research on damage-associated molecular pattern (DAMP) protein. We discuss the Janus-faced role of DAMP molecules in inflammation, cancer, and tissue repair. The high-mobility group box (HMGB)-1 and adenosine triphosphate proteins are well-known DAMP molecules and have been primarily associated with inflammation. However, as we shall see, recent data have linked these molecules to tissue repair. HMGB1 is associated with cancer-related inflammation. It activates nuclear factor kB, which is involved in cancer regulation via its receptor for advanced glycation end-products (RAGE), Toll-like receptors 2 and 4. Proinflammatory activity and tissue repair may lead to pharmacologic intervention, by blocking DAMP RAGE and Toll like receptor 2 and 4 role in inflammation and by increasing their concentration in tissue repair, respectively. METHODS We conducted a MEDLINE search for articles pertaining to the various issues related to DAMP, and we discuss the most relevant articles especially (ie, not only those published in journals with a higher impact factor). FINDINGS A cluster of remarkable articles on DAMP have appeared in the literature in recent years. Regarding inflammation, several strategies have been proposed to target HMGB1, from antibodies to recombinant box A, which interacts with RAGE, competing with the full molecule. In tissue repair, it was reported that the overexpression of HMGB1 or the administration of exogenous HMGB1 significantly increased the number of vessels and promoted recovery in skin-wound, ischemic injury. IMPLICATIONS Due to the bivalent nature of DAMP, it is often difficult to explain the relative role of DAMP in inflammation versus its role in tissue repair. However, this point is crucial as DAMP-related treatments move into clinical practice.
Collapse
Affiliation(s)
- Franco Pandolfi
- Department of Internal Medicine, School of Medicine, Catholic University, Rome, Italy.
| | - Simona Altamura
- Department of Internal Medicine, School of Medicine, Catholic University, Rome, Italy
| | - Simona Frosali
- Department of Internal Medicine, School of Medicine, Catholic University, Rome, Italy
| | - Pio Conti
- Postgraduate Medical School, Chieti University, Chieti, Italy
| |
Collapse
|
|
47
|
Skierucha M, Milne ANA, Offerhaus GJA, Polkowski WP, Maciejewski R, Sitarz R. Molecular alterations in gastric cancer with special reference to the early-onset subtype. World J Gastroenterol 2016; 22:2460-2474. [PMID: 26937134 PMCID: PMC4768192 DOI: 10.3748/wjg.v22.i8.2460] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 11/06/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023] Open
Abstract
Currently, gastric cancer (GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possible factors that stimulate the pro-carcinogenic activity of important genes. These factors include genetic susceptibility expressed in a single-nucleotide polymorphism, various acquired mutations (chromosomal instability, microsatellite instability, somatic gene mutations, epigenetic alterations) and environmental circumstances (e.g., Helicobcter pylori infection, EBV infection, diet, and smoking). Most of the aforementioned pathways overlap, and authors agree that a clear-cut pathway for GC may not exist. Thus, the categorization of carcinogenic events is complicated. Lately, it has been claimed that research on early-onset gastric carcinoma (EOGC) and hereditary GC may contribute towards unravelling some part of the mystery of the GC molecular pattern because young patients are less exposed to environmental carcinogens and because carcinogenesis in this setting may be more dependent on genetic factors. The comparison of various aspects that differ and coexist in EOGCs and conventional GCs might enable scientists to: distinguish which features in the pathway of gastric carcinogenesis are modifiable, discover specific GC markers and identify a specific target. This review provides a summary of the data published thus far concerning the molecular characteristics of GC and highlights the outstanding features of EOGC.
Collapse
|
|
48
|
Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-κB and NFAT transcriptional pathways. Proc Natl Acad Sci U S A 2015; 113:434-9. [PMID: 26712011 DOI: 10.1073/pnas.1517642113] [Citation(s) in RCA: 136] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription factor activity and was sensitive to inhibition of calcineurin-dependent NFAT activation. However, calcineurin/NFAT regulation did not contribute to constitutive expression elsewhere or to inflammatory COX-2 induction at any site. These data address the mechanisms driving constitutive COX-2 and suggest that by targeting transcription it may be possible to develop antiinflammatory therapies that spare the constitutive expression necessary for normal homeostatic functions, including those important to the cardiovascular-renal system.
Collapse
|
|
49
|
Sung H, Camargo MC, Yu K, Weinstein SJ, Morgan DR, Albanes D, Rabkin CS. Association of 4p14 TLR locus with antibodies to Helicobacter pylori. Genes Immun 2015; 16:567-70. [PMID: 26312625 PMCID: PMC4670272 DOI: 10.1038/gene.2015.33] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 07/20/2015] [Accepted: 07/21/2015] [Indexed: 12/31/2022]
Abstract
A genome-wide association study among Europeans related polymorphisms of the Toll-like receptor (TLR) locus at 4p14 and the Fcγ receptor 2a locus at 1q23.3 to Helicobacter pylori serologic status. We replicated associations of 4p14 but not 1q23.3 with anti-Helicobacter pylori antibodies in 1402 Finnish males. Importantly, our analysis clarified that the phenotype affected by 4p14 is quantitative level of these antibodies rather than association with seropositivity per se. In addition, we annotated variants at 4p14 as expression quantitative trait loci (eQTL) associated with TLR6/10 and FAM114A1. Our findings suggest that 4p14 polymorphisms are linked to host immune response to H. pylori infection but not to its acquisition.
Collapse
Affiliation(s)
- Hyuna Sung
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - M Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Kai Yu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Stephanie J. Weinstein
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Douglas R. Morgan
- Division of Gastroenterology, Vanderbilt University, Nashville, TN, USA
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Charles S Rabkin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| |
Collapse
|
|
50
|
Coulombe G, Rivard N. New and Unexpected Biological Functions for the Src-Homology 2 Domain-Containing Phosphatase SHP-2 in the Gastrointestinal Tract. Cell Mol Gastroenterol Hepatol 2015; 2:11-21. [PMID: 28174704 PMCID: PMC4980741 DOI: 10.1016/j.jcmgh.2015.11.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Accepted: 11/10/2015] [Indexed: 12/13/2022]
Abstract
SHP-2 is a tyrosine phosphatase expressed in most embryonic and adult tissues. SHP-2 regulates many cellular functions including growth, differentiation, migration, and survival. Genetic and biochemical evidence show that SHP-2 is required for rat sarcoma viral oncogene/extracellular signal-regulated kinases mitogen-activated protein kinase pathway activation by most tyrosine kinase receptors, as well as by G-protein-coupled and cytokine receptors. In addition, SHP-2 can regulate the Janus kinase/signal transducers and activators of transcription, nuclear factor-κB, phosphatidyl-inositol 3-kinase/Akt, RhoA, Hippo, and Wnt/β-catenin signaling pathways. Emerging evidence has shown that SHP-2 dysfunction represents a key factor in the pathogenesis of gastrointestinal diseases, in particular in chronic inflammation and cancer. Variations within the gene locus encoding SHP-2 have been associated with increased susceptibility to develop ulcerative colitis and gastric atrophy. Furthermore, mice with conditional deletion of SHP-2 in intestinal epithelial cells rapidly develop severe colitis. Similarly, hepatocyte-specific deletion of SHP-2 induces hepatic inflammation, resulting in regenerative hyperplasia and development of tumors in aged mice. However, the SHP-2 gene initially was suggested to be a proto-oncogene because activating mutations of this gene were found in pediatric leukemias and certain forms of liver and colon cancers. Moreover, SHP-2 expression is up-regulated in gastric and hepatocellular cancers. Notably, SHP-2 functions downstream of cytotoxin-associated antigen A (CagA), the major virulence factor of Helicobacter pylori, and is associated with increased risks of gastric cancer. Further compounding this complexity, most recent findings suggest that SHP-2 also coordinates carbohydrate, lipid, and bile acid synthesis in the liver and pancreas. This review aims to summarize current knowledge and recent data regarding the biological functions of SHP-2 in the gastrointestinal tract.
Collapse
Key Words
- CagA, cytotoxin-associated gene A
- ERK, extracellular signal-regulated kinases
- FGF, fibroblast growth factor
- GI, gastrointestinal
- HCC, hepatocellular carcinoma
- IBD, inflammatory bowel disease
- IEC, intestinal epithelial cell
- JMML, juvenile myelomonocytic leukemia
- KO, knockout
- MAPK, mitogen-activated protein kinase
- NF-κB, nuclear factor-κB
- PI3K, phosphatidyl-inositol 3-kinase
- PTP, protein tyrosine phosphatase
- PTPN11
- RAS, rat sarcoma viral oncogene
- epithelium
- gastrointestinal cancer
- inflammation
Collapse
Affiliation(s)
| | - Nathalie Rivard
- Correspondence Address correspondence to: Nathalie Rivard, PhD, 3201, Jean Mignault, Sherbrooke, Quebec, Canada, J1E4K8.3201Jean Mignault, SherbrookeQuebecCanada, J1E4K8
| |
Collapse
|