|
1
|
Liu X, Zhang S, Qiu H, Xie ZQ, Tang WF, Chen Y, Wei X. Investigation of high-mobility group box 1 variants with lymph node status and colorectal cancer risk. World J Gastrointest Oncol 2025; 17:102584. [PMID: 40235898 PMCID: PMC11995333 DOI: 10.4251/wjgo.v17.i4.102584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 12/31/2024] [Accepted: 01/22/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Accumulating studies indicated that maintain nuclei homeostasis was deemed to the protective factors for the occurrence of cancer. Thus, high-mobility group box 1 (HMGB1) might influence the risk and poorer prognoses of colorectal cancer (CRC). AIM This study was designed to investigate whether HMGB1 polymorphisms influence the risk and lymph node metastasis (LNM) of CRC. METHODS Firstly, we designed an investigation with 1003 CRC patients and 1303 cancer-free controls to observe whether HMGB1 rs1412125 T > C and rs1045411 C > T SNPs could influence the risk of cancer. Subsequently, we carried out a correlation-analysis to assess whether these SNPs could alter the risk of LNM. RESULTS The current investigation suggested a relationship of HMGB1 rs1412125 SNP with the increased susceptibility of CRC. In a subgroup analysis, our findings suggested that this SNP could enhance an occurrence of CRC in ≥ 61 years, non-drinker and body mass index < 24 kg/m2 subgroups. However, we found that there was null association between HMGB1 rs1412125 SNP and LNM, even in different CRC region. These observations were confirmed by calculating the power value (more than 0.8). The association of HMGB1 rs1045411 C > T SNP with CRC risk and LNM was not found in any compare. CONCLUSION This study highlights a possible association between HMGB1 rs1412125 polymorphism and the increased risk of CRC. In the future, more studies should be conducted to explore HMGB1 rs1412125 polymorphism in relation to CRC development.
Collapse
Affiliation(s)
- Xin Liu
- Department of General Surgery, Changzhou Third People’s Hospital, Changzhou 213001, Jiangsu Province, China
| | - Sheng Zhang
- Department of General Surgery, Changzhou Third People’s Hospital, Changzhou 213001, Jiangsu Province, China
| | - Hao Qiu
- Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Zhi-Qiang Xie
- Department of Clinical Laboratory, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
| | - Wei-Feng Tang
- Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210000, Jiangsu Province, China
| | - Yu Chen
- Department of Medical Oncology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuqing 350014, Fujian Province, China
| | - Xi Wei
- Department of Pathology, Affiliated People’s Hospital of Jiangsu University, Zhenjiang 212002, Jiangsu Province, China
| |
Collapse
|
|
2
|
Houssen M, El-Mahdy R, Samra NE, Tera Y, Nayera Mostafa K, El-Desoky MM, Hisham FA, Hewidy AA, Elmorsey RA, Samaha H, Mahmoud R, Abdelhafez MS. High Mobility Group Box 1 Gene Polymorphism and Serum High Mobility Group Box 1, Interleukin 1 Beta, and Alpha-Klotho Crosstalk in Severe COVID-19 Patients. Immunol Invest 2024; 53:450-463. [PMID: 38318856 DOI: 10.1080/08820139.2023.2299680] [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: 02/07/2024]
Abstract
AIM To evaluate the serum levels of HMGB1, IL1β, and α-klotho in COVID-19 patients with different disease severity, investigate their association with clinicopathological parameters, and to assess HMGB1 rs1045411 polymorphism and its relation with clinical severity. METHODS 120 COVID-19 patients (89 critically ill, 15 severe, and 16 moderately severe) along with 80 healthy control were enrolled.The serum levels of HMGB1,IL1β, and α-klotho were determined by ELISA. The HMGB1 rs1045411 polymorphism was detected by RT- PCR. RESULTS The serum levels of HMGB1, IL1β, and α-klotho were significantly higher in critically ill COVID-19 patients compared to other groups. The HMGB1rs1045411 polymorphism revealed a significant decrease in the percentage of T/T genotypes in COVID-19 patients compared to controls. The (ROC) analysis showed moderate diagnostic potential for serum HMGB1, IL1β, and α-klotho. CONCLUSION The serum HMGB1, IL1β, and α-klotho may be severity markers and promising therapeutic targets for COVID-19 patients.
Collapse
Affiliation(s)
- Maha Houssen
- Biochemistry Department, Faculty of Pharmacy, Damanhour University, Damnhour, Egypt
| | - Rasha El-Mahdy
- Medical Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Nouran E Samra
- Medical Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Yousra Tera
- Clinical Pathology Department, Hematology Unit, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Kamel Nayera Mostafa
- Occupational Health and Industrial Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Manal M El-Desoky
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Fatma Azzahraa Hisham
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Asem A Hewidy
- Chest Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Rehab A Elmorsey
- Chest Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Hala Samaha
- Chest Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Rasha Mahmoud
- Internal Medicine Department, Nephrology and Dialysis Unit, Mansoura University, Mansoura, Egypt
| | - Mona S Abdelhafez
- Medical Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| |
Collapse
|
|
3
|
Plemmenos G, Tzimogianni V, Fili C, Piperi C. Contributing Role of High Mobility Group Box 1 Signaling in Oral Cancer Development and Therapy. Life (Basel) 2023; 13:1577. [PMID: 37511951 PMCID: PMC10381251 DOI: 10.3390/life13071577] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 07/10/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
Oral squamous cell carcinoma (OSCC) is the most frequent type of oral cancer of multifactorial origin, characterized by histological and clinical manifestations. To date, there are no specific biomarkers or treatment modalities available to efficiently manage this neoplasia, demanding further research on the molecular background of OSCC pathology. Elucidation of signal transduction pathways and associated molecules with differential expression and function in OSCC are expected to enhance the future development of molecular targeted therapies. Among signaling proteins with a potential functional role in OSCC, the High Mobility Group Box 1 (HMGB1) protein has stimulated scientific interest due to frequent upregulation, and implication in the progression of many types of head and neck cancer types. HMGB1 is a nuclear nonhistone protein and an extracellularly secreted cytokine that can interact with several signaling molecules implicated in the pathogenic pathways of OSCC. Binding of HMGB1 to specific receptors on OSCC cells such as the receptor of AGE (RAGE) and the toll-like receptor (TLR) has been shown to initiate several intercellular signaling cascades that can promote OSCC growth, invasion, and metastasis, indicating a potential target for patient prognosis and therapeutic approaches. The purpose of this review is to explore the functional role and associated signaling of HMGB1 in OSCC in order to reveal potential therapeutic targeting options.
Collapse
Affiliation(s)
- Grigorios Plemmenos
- School of Dentistry, National and Kapodistrian University of Athens, 2 Thivon Str, Goudi, 11527 Athens, Greece
| | - Valentini Tzimogianni
- Department of Biology, Medical School, National and Kapodistrian University of Athens, 75 M. Asias Street, 11527 Athens, Greece
| | - Christina Fili
- Medicine and Surgery, Department of Pharmacy and Medicine, Sapienza Universita di Roma, Piazzale Aldo Moro 5, 00185 Roma, Italy
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 M. Asias Street, 11527 Athens, Greece
| |
Collapse
|
|
4
|
Żurek M, Rzepakowska A, Kotuła I, Demkow U, Niemczyk K. Serum expression of Vascular Endothelial-Cadherin, CD44, Human High mobility group B1, Kallikrein 6 proteins in different stages of laryngeal intraepithelial lesions and early glottis cancer. PeerJ 2022; 10:e13104. [PMID: 35462765 PMCID: PMC9029362 DOI: 10.7717/peerj.13104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 02/22/2022] [Indexed: 01/12/2023] Open
Abstract
Background The study was designed to evaluate the potential validity and utility of selected molecular markers in serum samples from patients with specific stages of laryngeal intraepithelial lesions that could serve as diagnostic tools in differentiation of benign and dysplastic lesions from invasive pathologies. Methods Prospective study included 80 consecutive patients with vocal fold lesions treated at the single otorhinolaryngology centre. All participants had surgical resection of the lesion. Blood samples were collected from each patient before the surgery. Final diagnosis was confirmed on histopathological examination and included 39 (48.75%) non-dysplastic lesions, eight (10%) low-grade dysplasia, six (7.5%) high-grade dysplasia and 27 (33.75%) invasive cancers. The ELISA procedures were performed according to the manufacturer's instruction. Individual serum concentration of selected proteins was reported in ng/ml: Vascular Endothelial-Cadherin Complex (VE-cad), CD44, Human High mobility group protein B1(HMGB1), Kallikrein 6. Results The highest mean levels of HMGB1, KLK6 and VE-cad were detected in sera of patients with low-grade dysplasia (81.14, 24.33, 14.17 respectively). Soluble CD44 was the most elevated in patients with non-dysplastic lesions (2.49). The HMGB1, KLK6 and VE-cad serum levels were increasing from non-dysplastic to low-grade dysplasia and followed by the decrease for high-grade dysplasia and invasive cancer, however the differences were not significant (p-values 0.897, 0.354, 0.1 respectively). Patients' serum had the highest CD44 concentration in non-dysplastic and low-grade dysplasia with the following decrease through high-grade dysplasia and invasive cancer. GERD symptomatic patients had higher levels of KLK6 and CD44 than other patients (p-value 0.06 and 0.084 respectively). There were no significant differences of biomarkers levels related to patients' gender (p-value from 0.243 to 1) or smoking status (p-value from 0.22 to 0.706). Conclusions VE-cad, HMGB1, CD44 and KLK6 did not prove to be reliable biomarkers implicating malignant potential within vocal fold hypertrophic intraepithelial lesions.
Collapse
Affiliation(s)
- Michał Żurek
- Department of Otorhinolaryngology Head and Neck Surgery, Medical University of Warsaw, Warsaw, Poland,Doctoral School, Medical University of Warsaw, Warsaw, Poland
| | - Anna Rzepakowska
- Department of Otorhinolaryngology Head and Neck Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Iwona Kotuła
- Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Medical University of Warsaw, Warsaw, Poland
| | - Urszula Demkow
- Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Medical University of Warsaw, Warsaw, Poland
| | - Kazimierz Niemczyk
- Department of Otorhinolaryngology Head and Neck Surgery, Medical University of Warsaw, Warsaw, Poland
| |
Collapse
|
|
5
|
Cao H, Guo D. Association of High-Mobility Group Box 1 (HMGB1) Gene Polymorphisms with Susceptibility and Better Survival Prognosis in Chinese Han Neonatal Necrotizing Enterocolitis. Med Sci Monit 2021; 27:e930015. [PMID: 34054124 PMCID: PMC8176785 DOI: 10.12659/msm.930015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND High-mobility group box 1 (HMGB1) plays a crucial role in a variety of diseases, including neonatal necrotizing enterocolitis (NEC). The purpose of this study was to investigate the association of HMGB1 gene single-nucleotide polymorphisms (SNPs) with susceptibility and survival prognosis in Chinese Han neonates with NEC. MATERIAL AND METHODS The HMGB1 gene rs1360485, rs1045411, and rs2249825 site SNPs were genotyped in all participants. The mRNA expression of serum HMGB1 was examined using quantitative reverse transcription-polymerase chain reaction. The correlation of the HMGB1 rs1360485 SNP with NEC neonatal survival prognosis was evaluated by univariate analysis and logistic multivariate regression analysis. RESULTS The TC and CC genotype and C allele distribution frequencies of the rs1360485 SNP were lower in the NEC group, and the differences were statistically significant (all P<0.05). Individuals carrying the TC and CC genotype or C allele had a low risk of being affected by NEC. However, the genotype and allele distributions of rs1045411 and rs2249825 were not significantly different between the patient and control groups (P>0.05). NEC neonates with HMGB1 gene rs1360485 site mutations had lower mRNA levels of serum HMGB1 than those with rs1360485 site wild-type, and the rs1360485 genotypes TC and CC could independently predict better survival outcomes in NEC neonates. CONCLUSIONS This study demonstrated that the rs1360485 SNP of the HMGB1 gene is associated with susceptibility of NEC in neonates, and the rs1360485 genotypes TC and CC may affect HMGB1 expression and are associated with the survival prognosis of neonates with NEC.
Collapse
Affiliation(s)
- Huiling Cao
- Department of Neonatology, Weifang People's Hospital, Weifang, Shandong, China (mainland)
| | - Defeng Guo
- Department of Gastroenterology, Weifang People's Hospital, Weifang, Shandong, China (mainland)
| |
Collapse
|
|
6
|
Xia Q, Tao P, Xu J. Association of Polymorphism rs1045411 in the HMGB1 Gene with Cancer Risk: Evidence from a Meta-analysis. Int J Med Sci 2021; 18:1348-1355. [PMID: 33628090 PMCID: PMC7893572 DOI: 10.7150/ijms.52181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 01/04/2021] [Indexed: 11/19/2022] Open
Abstract
The high-mobility group box protein 1 (HMGB1) rs1045411 polymorphism has been demonstrated to be associated with cancer risk in some studies. However, the results regarding this topic are inconsistent. A meta-analysis was applied to elucidate the association between the HMGB1 rs1045411 polymorphism and cancer risk. Ten relevant studies were subjected to our analysis, and pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. In total, of 3,918 cases and 5,296 controls were included in this study. The pooled ORs were calculated using a random-effects or fixed-effects model according to the heterogeneity. The pooled results revealed that TT genotype was significantly related to increased cancer risk in the comparisons of TT vs. CC+TC (OR=1.35; 95% CI: 1.09-1.67; p=0.005). Though no statistical significance was achieved between HMGB1 rs1045411 polymorphism and cancer risk in other four genetic models (T vs. C: OR=1.08, 95% CI 0.90-1.30; TC vs. CC: OR=1.01, 95% CI 0.82-1.24; CC vs. TC+TT: OR=0.95, 95% CI 0.77-1.18; TT vs. CC: OR=1.42; 95% CI 0.98-2.05), a trend of increased risk could be drawn. In the subgroup analysis by type of malignancy and ethnicity, no obvious difference was found in the tumour risk regarding the HMGB1 rs1045411 polymorphism amongst the cancer types except for breast cancer (OR=1.94; 95% CI: 1.05-3.59; p=0.03) and hepatocellular carcinoma (OR=1.82; 95% CI: 1.15-2.88; p=0.01), while rs1045411 polymorphism was positively associated with risks of cancer amongst Hans (OR=1.37; 95% CI: 1.11-1.69; p=0.004) rather than Caucasians (OR=0.89; 95% CI: 0.26-3.02; p=0.01). These results suggest that the HMGB1 rs1045411 polymorphism might be associated with increased cancer risk.
Collapse
Affiliation(s)
- Quansong Xia
- Department of Clinical Laboratory, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, China
| | - Pengzuo Tao
- Department of Clinical Laboratory, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, China
| | - Juan Xu
- Department of Internal Medicine, The People's Hospital of Guandu District, Kunming 650200, China
| |
Collapse
|
|
7
|
Carron J, Torricelli C, Silva JK, Queiroz GSR, Ortega MM, Lima CSP, Lourenço GJ. microRNAs deregulation in head and neck squamous cell carcinoma. Head Neck 2020; 43:645-667. [PMID: 33159410 DOI: 10.1002/hed.26533] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 09/30/2020] [Accepted: 10/23/2020] [Indexed: 12/24/2022] Open
Abstract
Head and neck (HN) squamous cell carcinoma (SCC) is the eighth most common human cancer worldwide. Besides tobacco and alcohol consumption, genetic and epigenetic alterations play an important role in HNSCC occurrence and progression. microRNAs (miRNAs) are small noncoding RNAs that regulate cell cycle, proliferation, development, differentiation, and apoptosis by interfering in gene expression. Expression profiling of miRNAs showed that some miRNAs are upregulated or downregulated in tumor cells when compared with the normal cells. The present review focuses on the role of miRNAs deregulations in HNSCC, enrolled in risk, development, outcome, and therapy sensitivity. Moreover, the influence of single nucleotide variants in miRNAs target sites, miRNAs seed sites, and miRNAs-processing genes in HNSCC was also revised. Due to its potential for cancer diagnosis, progression, and as a therapeutic target, miRNAs may bring new perspectives in HNSCC understanding and therapy, especially for those patients with no or insufficient treatment options.
Collapse
Affiliation(s)
- Juliana Carron
- Laboratory of Cancer Genetics, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Caroline Torricelli
- Laboratory of Cancer Genetics, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Janet K Silva
- Laboratory of Cancer Genetics, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Gabriela S R Queiroz
- Laboratory of Cancer Genetics, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Manoela M Ortega
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University, Bragança Paulista, Brazil
| | - Carmen S P Lima
- Laboratory of Cancer Genetics, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Gustavo J Lourenço
- Laboratory of Cancer Genetics, School of Medical Sciences, University of Campinas, Campinas, Brazil
| |
Collapse
|
|
8
|
Chou YE, Yang PJ, Lin CY, Chen YY, Chiang WL, Lin PX, Huang ZY, Huang M, Ho YC, Yang SF. The Impact of HMGB1 Polymorphisms on Prostate Cancer Progression and Clinicopathological Characteristics. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17197247. [PMID: 33023053 PMCID: PMC7579148 DOI: 10.3390/ijerph17197247] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/24/2020] [Accepted: 10/01/2020] [Indexed: 02/06/2023]
Abstract
Prostate cancer is one of the major cancers of the genitourinary tract. High-mobility group box 1 (HMGB1) was suggested as a promising therapeutic target for prostate cancer. In this study, we aim to elucidate the associations of HMGB1 single nucleotide polymorphisms (SNPs) with prostate cancer susceptibility and clinicopathological characteristics. The HMGB1 SNPs rs1412125, rs2249825, rs1045411, and rs1360485 in 579 prostate cancer patients and 579 cancer-free controls were analyzed with real-time polymerase chain reactions (real-time PCR). All of the data were evaluated with SAS statistical software. Our results showed that the HMGB1 rs1045411 T allele genotype was significantly associated with advanced pathologic T stage (odds ratio (OR) = 1.433, 95% confidence interval (CI) = 1.021–2.012; p = 0.037) and pathologic N1 stage (OR = 2.091, 95% CI = 1.160–3.767; p = 0.012), and the rs1360485 polymorphic CT + TT genotype was associated with pathologic Gleason grade group (4 + 5) (OR = 1.583, 95% CI = 1.017–2.462; p = 0.041), pathologic T stage (3 + 4) (OR = 1.482, 95% CI = 1.061–2.070; p = 0.021), and pathologic N1 stage (OR = 2.131, 95% CI = 1.178–3.852; p = 0.011) compared with their wild-type carriers. In conclusion, our results revealed that the HMGB1 SNPs were associated with the clinical status of prostate cancer. The HMGB1 SNPs may have the potential to predict prostate cancer disease progression.
Collapse
Affiliation(s)
- Ying-Erh Chou
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (Y.-E.C.); (P.-J.Y.)
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan;
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Po-Jen Yang
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (Y.-E.C.); (P.-J.Y.)
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan;
- Department of Family and Community Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Chia-Yen Lin
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan;
- Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung 407, Taiwan
| | - Yen-Yu Chen
- School of Medical Applied Chemistry, Chung Shan Medical University, Taichung 402, Taiwan;
| | - Whei-Ling Chiang
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 402, Taiwan; (W.-L.C.); (P.-X.L.); (Z.-Y.H.)
| | - Pei-Xuan Lin
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 402, Taiwan; (W.-L.C.); (P.-X.L.); (Z.-Y.H.)
| | - Zih-Yun Huang
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 402, Taiwan; (W.-L.C.); (P.-X.L.); (Z.-Y.H.)
| | - Matthew Huang
- White Oaks Secondary School, Oakville, ON L6H 1Z5, Canada;
| | - Yung-Chuan Ho
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- School of Medical Applied Chemistry, Chung Shan Medical University, Taichung 402, Taiwan;
- Correspondence: (Y.-C.H.); (S.-F.Y.)
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan;
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- Correspondence: (Y.-C.H.); (S.-F.Y.)
| |
Collapse
|
|
9
|
Li L, Liu Y, Li X, Qiu C. Insights into the genetic basis of HMGB1 in atrial fibrillation in a Chinese Han population. Cardiovasc Diagn Ther 2020; 10:388-395. [PMID: 32695619 DOI: 10.21037/cdt.2019.12.07] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Background Atrial fibrillation (AF) is the most common cardiac arrhythmia. High mobility group box 1 (HMGB1) has been demonstrated to be involved in AF, but the genetic relationship between them is not clear yet. Here, we investigated the genetic association between functional variants in HMGB1 and AF in a Chinese Han population. Methods Two common variants (the promoter one rs1045411T/C and the 3'UTR one rs1412125C/T) in HMGB1 were selected and genotyped in 576 AF patients and 869 control subjects. Traditional risk factors, such as age, gender, the history of smoking, hypertension and diabetes mellitus, were adjusted as covariates using a logistic regression analysis (SPSS, v.21.0). The haplotypic analysis was performed using SPSS (v.21.0, Inc., Chicago, IL, USA). Results Under the allelic association analysis, neither rs1045411T/C nor rs1412125C/T was associated with AF with all P values >0.05; under the genotypic association analysis, the 3'UTR variant rs1045411T showed a marginally significant association with AF under the recessive model (Padj=0.056, OR =0.42; 95% CI: 0.17-1.02). When divided the studied population by gender, we still found no significant association results between the selected variants and AF with P values more than 0.05; however, when divided the population into subgroups by the age onset of AF, we found that the 3'UTR variant rs1045411T was significantly associated with AF in the late-onset subgroup (Padj=0.009, OR =11.1; 95% CI: 1.82-50.0). Conclusions The 3'UTR variant rs1045411T/C of HMGB1 might influence the risk of late-onset AF in the Chinese Han population, which provides an important target factor for the prevention and treatment study of AF.
Collapse
Affiliation(s)
- Li Li
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.,Department of Emergency Internal Medicine, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang 443000, China
| | - Yang Liu
- Department of Emergency Internal Medicine, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang 443000, China
| | - Xinxin Li
- Department of Emergency Internal Medicine, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang 443000, China
| | - Chunguang Qiu
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| |
Collapse
|
|
10
|
Zhou YK, Li XP, Yin JY, Zou T, Wang Z, Wang Y, Cao L, Chen J, Liu ZQ. Association of variations in platinum resistance-related genes and prognosis in lung cancer patients. J Cancer 2020; 11:4343-4351. [PMID: 32489453 PMCID: PMC7255368 DOI: 10.7150/jca.44410] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 03/29/2020] [Indexed: 01/25/2023] Open
Abstract
Purpose: We aimed to investigate the association of single-nucleotide polymorphisms (SNPs) in HMGB1, REV3L, and NFE2L2 with prognosis in lung cancer patients with platinum-based chemotherapy. Methods: We have recruited 348 lung cancer patients treated with platinum. Log-rank test and Cox regression analysis were used to assess overall survival (OS) and progression-free survival (PFS) among SNP genotypes. Results: The results revealed that patients carrying TC or CC genotype in REV3L rs462779 (HR=0.67, 95% CI=0.51-0.90, P=0.007) and AG or GG genotype in HMGB1 rs1045411 (HR=0.61, 95% CI=0.38-0.99, P=0.046) had a better overall survival. Additionally, carrying TC or TT genotype in rs462779 had a lower risk (OR=0.38, 95% CI=0.17-0.89, P=0.025) of lymph node metastasis, carrying AG or AA genotype in rs1045411 was significantly related to early T stage (OR=0.47, 95% CI=0.29-0.76, P=0.002). In stratified analysis, patients with TC or CC genotype in rs462779 were significantly associated with overall survival in male patients, never-smokers, patients with younger age (≤56), no family history of cancer, adenocarcinoma, advanced stage (stage III or IV), or ECOG PS 0-1. While patients with AG or GG genotype in rs1045411 were significantly associated with overall survival in patients with advanced stage (stage III or IV) or ECOG PS 0-1. Conclusion: Our results indicate that the TC or CC genotype in rs462779 and AG or GG genotype in rs1045411 are contributed to better overall survival. The REV3L rs462779 and HMGB1 rs1045411 may serve as prognosis markers in lung cancer patients with platinum-based chemotherapy.
Collapse
Affiliation(s)
- Yuan-Kang Zhou
- Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South University, Changsha 410008, China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, P. R. China
| | - Xiang-Ping Li
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Ji-Ye Yin
- Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South University, Changsha 410008, China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, P. R. China
| | - Ting Zou
- Department of National Institution of Drug Clinical Trial, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Zhan Wang
- Department of Lung Cancer and Gastroenterology, Hunan Cancer Hospital, Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, 410013, China
| | - Ying Wang
- Department of the Central Laboratory, Hunan Cancer Hospital, Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, 410013, China
| | - Lei Cao
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Juan Chen
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China
- ✉ Corresponding authors: Zhao-Qian Liu, Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008; China; Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078; China. Tel: +86 731 89753845, Fax: +86 731 82354476, E-mail: or Juan Chen, Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008; China. E-mail:
| | - Zhao-Qian Liu
- Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South University, Changsha 410008, China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, P. R. China
- ✉ Corresponding authors: Zhao-Qian Liu, Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008; China; Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078; China. Tel: +86 731 89753845, Fax: +86 731 82354476, E-mail: or Juan Chen, Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008; China. E-mail:
| |
Collapse
|
|
11
|
Liu B, Cao G, Dong Z, Guo T. Effect of microRNA-27b on cisplatin chemotherapy sensitivity of oral squamous cell carcinoma via FZD7 signaling pathway. Oncol Lett 2019; 18:667-673. [PMID: 31289540 PMCID: PMC6540118 DOI: 10.3892/ol.2019.10347] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 02/27/2019] [Indexed: 12/19/2022] Open
Abstract
Effect of microRNA-27b (miR-27b) on cisplatin chemotherapy sensitivity of oral squamous cell carcinoma (OSCC) was investigated to provide a reference for clinical prevention of OSCC cell resistance. The clinical tissues of 34 patients with OSCC-resistant cancer and 28 patients with cisplatin-sensitive OSCC in Nanjing General Hospital were collected. The expression levels of miR-27b and Frizzled-7 (FZD7) in cancer tissues were detected by reverse transcription-quantitative polymerase chain reation (RT-qPCR). After a certain gradient of cisplatin was used to induce stable acquired resistance of OSCC cell line Tca8113/CDDP, a dose of miR-27b was added to construct a cell line overexpressing miR-27b in the drug-resistant cell line. The effect of cisplatin on the proliferation of drug-resistant OSCC cells was detected by colony formation assay. In addition, the scratch test and Transwell formation assay was performed to examine the effect of cisplatin drug stimulation on proliferation and migration of Tca8113/CDDP. Flow cytometry and Hoechst 33258 staining were used to detect the effect of miR-27b on apoptosis of OSCC-resistant cells after cisplatin chemotherapy. The expression level of miR-27b in cancer tissues of patients with drug-resistant OSCC was significantly lower than that of patients with OSCC cisplatin sensitivity (P<0.05). After high expression of miR-27b, the number of clones of drug-resistant OSCC cells after adding cisplatin drugs can be significantly inhibited. The proliferation and migration ability of drug-resistant OSCC was significantly decreased after the addition of cisplatin in miR-27b overexpression (P<0.05). miR-27 mimic enhanced the pro-apoptotic ability of cisplatin drugs (P<0.05). The expression of FZD7 in cisplation-resistant patients was significantly higher (P<0.05). miR-27b significantly inhibited the expression of FZD7 and β-catenin proteins. miR-27b can inhibit the resistance of OSCC to cisplatin drugs, increase apoptosis of cancer cells, and inhibit the proliferation of cancer cells. The mechanism may be related to the inhibition of FZD7/β-catenin signaling pathway activation in drug-resistant cell lines by miR-27b.
Collapse
Affiliation(s)
- Bingyao Liu
- Department of Stomatology, Nanjing General Hospital, Nanjing, Jiangsu 210002, P.R. China
| | - Gang Cao
- Department of Stomatology, Nanjing General Hospital, Nanjing, Jiangsu 210002, P.R. China
| | - Zhen Dong
- Department of Stomatology, Nanjing General Hospital, Nanjing, Jiangsu 210002, P.R. China
| | - Ting Guo
- Department of Endodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
| |
Collapse
|
|
12
|
Wu YL, Chien MH, Chou YE, Chang JH, Liu TC, Tsao TCY, Chou MC, Yang SF. Association of EGFR mutations and HMGB1 genetic polymorphisms in lung adenocarcinoma patients. J Cancer 2019; 10:2907-2914. [PMID: 31281467 PMCID: PMC6590032 DOI: 10.7150/jca.31125] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 04/11/2019] [Indexed: 12/14/2022] Open
Abstract
High-mobility group protein box 1 (HMGB1) is overexpressed and reported to be a prognostic factor in patients with non-small-cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutants play an important role in NSCLC progression. The aim of this study was to explore potential associations between genetic polymorphisms of HMGB1 and EGFR mutations in a cohort that included 280 patients with NSCLC, some of whom were smokers and others who never smoked. Four tagged single-nucleotide polymorphisms (SNPs) of HMGB1 were detected by a TaqMan-based real-time polymerase chain reaction (PCR) in patients. We found that after adjusting for other covariates, NSCLC patients who smoked and who respectively had CG, CT, and TC heterozygotes of HMGB1 rs2249825, rs1045411, and rs1360485, were at lower risk of developing mutant EGFR, compared to those patients with wild-type homozygotes. Moreover, significant inverse associations between the CG and CG + GG genotypes of HMGB1 rs2249825 and the EGFR hotspot mutation, an exon 19 in-frame deletion, were also observed among NSCLC patients. Within patients harboring mutant EGFR, HMGB1 rs1360485 C (TC + CC) allele carriers were at higher risk of developing poorly differentiated cancer types (odds ratio=5.493, 95% confidence interval: 1.130~26.696, p=0.019), compared to patients with TT homozygotes. Furthermore, we found that HMGB1 rs1360485 polymorphisms seemed to be related to susceptibility to developing poorly differentiated cancer linked to tobacco consumption in EGFR mutant patients. In conclusion, our results suggested that HMGB1 variants are significantly inversely associated with EGFR mutations among NSCLC patients who smoked. HMGB1 variants and tobacco consumption might contribute to the pathological development of NSCLC.
Collapse
Affiliation(s)
- Yi-Liang Wu
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Ming-Hsien Chien
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Ying-Erh Chou
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Jer-Hwa Chang
- Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.,Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Tu-Chen Liu
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Chest Medicine, Cheng-Ching General Hospital, Taichung, Taiwan
| | - Thomas Chang-Yao Tsao
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Division of Chest, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Ming-Chih Chou
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| |
Collapse
|
|
13
|
Song W, Tan H, Wang S, Zhang Y, Ding Y. Association of High Mobility Group Box Protein B1 Gene Polymorphisms with Pneumonia Susceptibility and Severity. Genet Test Mol Biomarkers 2018; 23:3-11. [PMID: 30562142 DOI: 10.1089/gtmb.2018.0174] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVE To investigate the relationship between the high mobility group box protein B1 (HMGB1) single nucleotide polymorphisms (SNPs) rs1412125, rs2249825, and rs1045411 with pneumonia in terms of susceptibility, severity, and inflammatory response. METHODS The genotypes of HMGB1 rs1412125 (-1615T > C), rs2249825 (3814C > G), and rs1045411 (2262C > T) loci in 328 patients with community-acquired pneumonia (CAP) and 317 healthy subjects were analyzed by Sanger sequencing. The expression and secretion of the inflammatory cytokines HMGB1, interleukin (IL)-10, tumor necrosis factor-alpha (TNF-α), and IL-6 were determined after lipopolysaccharide (LPS) stimulation of peripheral whole blood cells. RESULTS The risk of CAP was higher in carriers of the mutant HMGB1 rs1412125 and rs2249825 alleles than those that had the wild type alleles (adjusted odds ratio [OR] = 1.241; 95% confidence interval [CI] = 1.061-1.448; p = 0.007; adjusted OR = 1.225; 95% CI = 1.038-1.427; p = 0.016, respectively). Moreover, the mutation-carrying patients with CAP were more likely to develop severe community-acquired pneumonia (SCAP). There was no correlation between the HMGB1 rs1045411 SNP alleles and CAP or SCAP (p > 0.05). The expression and secretion of the inflammatory cytokines HMGB1, IL-10, TNF-α, and IL-6 was significantly higher in LPS-stimulated peripheral blood among patients with mutations at the rs1412125 and rs2249825 loci compared with those with wild type alleles (p < 0.05). The 30-day mortality rates for CAP patients with mutations at the rs1412125 and rs2249825 loci of HMGB1 were significantly higher than those that had wild type alleles. The mortality rate difference between rs1045411 wild-type CAP patients and mutant was not significant (p = 0.789). CONCLUSION SNPs at the rs1412125 and rs2249825 loci of HMGB1 are associated with pneumonia in terms of susceptibility, severity, and inflammatory response.
Collapse
Affiliation(s)
- Weiwei Song
- 1 Department of Critical Care Medicine, Zibo Central Hospital, Zibo, China
| | - Haibo Tan
- 1 Department of Critical Care Medicine, Zibo Central Hospital, Zibo, China
| | - Shifu Wang
- 1 Department of Critical Care Medicine, Zibo Central Hospital, Zibo, China
| | - Yun Zhang
- 1 Department of Critical Care Medicine, Zibo Central Hospital, Zibo, China
| | - Yueping Ding
- 2 Department of Intensive Care Unit, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| |
Collapse
|
|
14
|
Associations between HMGB1 gene polymorphisms and susceptibility and clinical outcomes in Chinese Han sepsis patients. Gene 2018; 687:23-29. [PMID: 30423384 DOI: 10.1016/j.gene.2018.11.027] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Revised: 10/02/2018] [Accepted: 11/08/2018] [Indexed: 01/27/2023]
Abstract
OBJECTIVES High mobility group box 1 protein (HMGB1) is an important late inflammatory mediator in the body. In recent years, studies have found that it plays an important pathogenic role in various diseases such as sepsis. However, it is unclear whether the genetic variation of the HMGB1 gene is related to the susceptibility to sepsis. This study investigated the relationship between susceptibility and outcome of the HMGB1 gene rs2249825, rs1045411, and rs1360485 single nucleotide polymorphisms (SNPs) in Chinese Han patients with sepsis. METHODS The HMGB1 gene rs2249825, rs1045411, and rs1360485 genotypes were detected by the direct sequencing method in 345 patients with sepsis and 345 healthy controls. Serum HMGB1 levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS The HMGB1 gene rs2249825 and rs1045411 site SNPs were associated with sepsis risk, but the rs1360485 site SNP was not associated with sepsis risk. Subjects with the HMGB1 gene rs2249825 and rs1045411 site mutations had higher serum HMGB1 levels, and patients with mutant genotype sepsis had higher APACHE II scores and lower 30-day survival rates. There were no correlations among the rs1360485 site SNP, sepsis risk, and patient 30-day survival. CONCLUSION The HMGB1 gene rs2249825 and rs1045411 site SNPs are associated with susceptibility and outcomes of Chinese Han patients with sepsis. The rs2249825 locus C allele and the rs1045411 locus A allele are high risk factors for sepsis and severity in the Chinese Han population, and are associated with adverse outcomes in patients with sepsis.
Collapse
|
|
15
|
No association between HMGB1 polymorphisms and cancer risk: evidence from a meta-analysis. Biosci Rep 2018; 38:BSR20180658. [PMID: 30049847 PMCID: PMC6123066 DOI: 10.1042/bsr20180658] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 07/05/2018] [Accepted: 07/18/2018] [Indexed: 12/13/2022] Open
Abstract
The aim of the present study was to determine whether High mobility group box 1 (HMGB1) polymorphism was associated with cancer susceptibility. PubMed, Embase, and ISI Web of Science were extensively searched without language restriction. Data were extracted using a standardized data collection sheet after two reviewers scanned studies independently. The association between HMGB1 polymorphism and cancer risks was indicated as odds ratio (OR) along with its related 95% confidence interval (95%CI). Meta-analysis was conducted via RevMan 5.3 software. A total of ten studies comprising 4530 cases and 5167 controls were included in our study. Meta-analysis revealed no statistical association between rs1045411, rs1360485, rs1412125, or rs2249825 polymorphisms in HMGB1 gene and risk of cancer, either did subgroup analysis of rs1045411 stratified by cancer types and ethnic groups. Our results revealed no statistical association between current four polymorphism loci and cancer risks, suggesting that the attempt of applying HMGB1 variants as a therapeutic target or a prognosis predictor might still require a second thought. However, HMGB1 is deemed to play pleiotropic roles in cancers, we strongly call for large-scale studies with high evidence level to uncover the exact relationship between HMGB1 gene variants and cancer progression.
Collapse
|
|
16
|
Wu CZ, Zheng JJ, Bai YH, Xia P, Zhang HC, Guo Y. HMGB1/RAGE axis mediates the apoptosis, invasion, autophagy, and angiogenesis of the renal cell carcinoma. Onco Targets Ther 2018; 11:4501-4510. [PMID: 30122942 PMCID: PMC6078191 DOI: 10.2147/ott.s167197] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background High mobility group box 1 protein (HMGB1) is a sort of non-histone protein in chromatin, which plays an important role in tumor proliferation, invasion, and immune escape. HMGB1-RAGE (receptor for advanced glycation end products) interactions have been reported to be important in a number of cancers. Methods CCK8, flow cytometry and qRT-PCR were used to detected cell viability, apoptosis and gene expression, respectively. Results In the present study, we demonstrated that HMGB1/RAGE axis regulated the cell proliferation, apoptosis, and invasion of the renal cell carcinoma (RCC). Further, we discovered that HMGB1/RAGE axis increased the expression of autophagic proteins LC3 and Beclin-1 in RCC. Finally, we used a coculture model of human umbilical vein endothelial cells with RCC cell lines to find out that HMGB1 also increased the expression of VEGF and VEGFR2 in human umbilical vein endothelial cells. An in vivo study further confirmed that HMGB1 knockdown inhibited RCC tumor growth. Conclusion Our results illustrated that HMGB1/RAGE axis mediated RCC cell viability, apoptosis, invasion, autophagy, and angiogenesis, which provides a novel theoretical basis for using HMGB1 as the target in RCC.
Collapse
Affiliation(s)
- Cun-Zao Wu
- Department of Transplantation Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China,
| | - Jian-Jian Zheng
- Department of Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yong-Heng Bai
- Department of Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Peng Xia
- Department of Transplantation Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China,
| | - Hai-Cong Zhang
- Department of Pathology, The Fifth Hospital of Shijiazhuang, Shijiazhuang, China
| | - Yong Guo
- Department of Transplantation Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China,
| |
Collapse
|
|
17
|
High-mobility group box 1 protein (HMGB1) gene polymorphisms and cancer susceptibility: A comprehensive meta-analysis. Clin Chim Acta 2018; 483:170-182. [PMID: 29730397 DOI: 10.1016/j.cca.2018.04.042] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 04/30/2018] [Accepted: 04/30/2018] [Indexed: 02/07/2023]
Abstract
AIM The role of HMGB1 polymorphisms in cancer predisposition remains unclear. This meta-analysis was performed assess four HMGB1 polymorphisms (rs1045411, rs2249825, rs1360485 and rs1412125) in cancer risk. METHODS We searched published studies till January 2018 from EMBASE, PubMed, Google scholar, and Cochrane library. Thereafter, the statistical software "R" was used to calculate Pooled Odds Ratios (OR), and 95% confidence intervals (CI) for assessment of association between different HMGB1 polymorphisms and cancer risk. RESULT In this meta-analysis we used eight studies totaling 7017 subjects. HMGB1 rs1045411 polymorphism in recessive model (OR 1.4159, 95% CI 0.9197-2.1798, P = 0.1142) and homozygous model (OR 1.4157, 95% CI 0.8711-2.3006, P = 0.1606) emerged as a risk factor for cancer development. Dominant model in rs2249825 polymorphism (OR: 0.8954) and rs1412125 polymorphism (OR: 0.9029) emerged as protective factors. Statistical significance was not achieved for any genetic model. Begg's test and Egger's test for all analysis suggested no publication bias. CONCLUSION This is the first meta-analysis exploring the association of four HMGB1 polymorphisms with cancer. Although polymorphism rs1045411 emerged as a risk candidate, additional studies are suggested to confirm these findings.
Collapse
|
|
18
|
Jiang M, Li X, Quan X, Li X, Zhou B. Single Nucleotide Polymorphisms in HMGB1 Correlate with Lung Cancer Risk in the Northeast Chinese Han Population. Molecules 2018; 23:E832. [PMID: 29617336 PMCID: PMC6017634 DOI: 10.3390/molecules23040832] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 03/26/2018] [Accepted: 04/01/2018] [Indexed: 12/18/2022] Open
Abstract
Lung cancer is the principal cause of cancer-associated deaths. HMGB1 has been reported to be associated with tumorigenesis. This study aimed to investigate the relationship between rs1412125 and rs1360485 polymorphisms in HMGB1 and the risk and survival of lung cancer. 850 cases and 733 controls were included. Logistic regression analysis and survival analysis were performed to investigate the association between SNPs and the risk and survival of lung cancer. Crossover analysis was used to analyze the interaction between SNPs and tobacco exposure. Results indicated that rs1412125 polymorphism was associated with lung cancer risk, especially with the risk of lung adenocarcinoma and small cell lung cancer. Carriers with CT and CC genotypes had a decreased risk of lung cancer (CT + CC vs.TT: adjusted OR = 0.736, p = 0.004). Similar results were obtained in the stratification analysis for non-smokers and female population. For rs1360485 polymorphism, AG and GG genotypes could decrease the risk of lung adenocarcinoma and female lung cancer by 0.771-fold and 0.789-fold. However, no significant interaction between polymorphisms and tobacco exposure or association between SNPs and the survival of lung cancer was observed. This study indicated polymorphisms in HMGB1 may be a novel biomarker for female lung adenocarcinoma risk.
Collapse
Affiliation(s)
- Min Jiang
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110122, China.
- Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Province Department of Education, Shenyang 110122, China.
| | - Xuelian Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110122, China.
- Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Province Department of Education, Shenyang 110122, China.
| | - Xiaowei Quan
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110122, China.
- Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Province Department of Education, Shenyang 110122, China.
| | - Xiaoying Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110122, China.
- Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Province Department of Education, Shenyang 110122, China.
| | - Baosen Zhou
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110122, China.
- Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Province Department of Education, Shenyang 110122, China.
| |
Collapse
|
|
19
|
Zeng J, Yi X, Liu H, Yang Y, Duan Y, Chen H. Polymorphisms in four microRNAs and risk of oral squamous cell cancer: a meta-analysis. Oncotarget 2018; 9:8695-8705. [PMID: 29492228 PMCID: PMC5823596 DOI: 10.18632/oncotarget.24211] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 12/05/2017] [Indexed: 02/05/2023] Open
Abstract
Objectives Single nucleotide polymorphisms in microRNAs (microRNA-196a2 rs11614913, microRNA-146a rs2910164, microRNA-149 rs2292832 and microRNA-499 rs3746444) have been inconsistently associated with risk for oral squamous cell cancer (OSCC). This meta-analysis aimed to assess the correlation between microRNA polymorphisms and susceptibility to OSCC. Materials and Methods Free words were used to search for the relevant studies without language limitations in electronic databases including PubMed, Embase, Web of Science and SCOPUS through June 15, 2017. Odds ratios (ORs) were calculated to investigate the effects of microRNA polymorphisms on oral cancer risk. Results Eleven studies were included. Analysis under the recessive model of microRNA-146a (CC vs GG+CG) showed significant differences (ORs = 0.874, P = 0.041). The G allele and the GG genotype of microRNA-499 were associated with OSCC risk (ORs >1, P < 0.05). MicroRNA-196a2 rs11614913 and microRNA-149 polymorphisms appeared to have no relationship with OSCC risk (P > 0.05). In the sensitivity analysis, there was a significant association between the TT genotype of microRNA-196a2 and OSCC risk (TT vs TC + CC, ORs < 1, P < 0.05). Conclusions There may be no significant relationship between microRNA-149 polymorphisms and OSCC risk, and the CC genotype of microRNA-146a may have protective effects against oral cancer. However, the G allele and the GG genotype of microRNA-499 may increase OSCC risk.
Collapse
Affiliation(s)
- Junfeng Zeng
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaowei Yi
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu,610041, China
| | - Hao Liu
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yi Yang
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yuchen Duan
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hua Chen
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, 610041, China
| |
Collapse
|
|
20
|
Hung SC, Wang SS, Li JR, Chen CS, Yang CK, Chiu KY, Cheng CL, Ou YC, Ho HC, Yang SF. Effect of HMGB1 Polymorphisms on Urothelial Cell Carcinoma Susceptibility and Clinicopathological Characteristics. Int J Med Sci 2018; 15:1731-1736. [PMID: 30588197 PMCID: PMC6299401 DOI: 10.7150/ijms.27901] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 10/18/2018] [Indexed: 12/29/2022] Open
Abstract
The high mobility group box 1 gene (HMGB1) plays a prominent role in cancer progression, angiogenesis, invasion, and metastasis. This study explored the effect of HMGB1 polymorphisms on clinicopathological characteristics of urothelial cell carcinoma (UCC). In total, 1293 participants (431 patients with UCC and 862 healthy controls) were recruited. Four single-nucleotide polymorphisms (SNPs) of HMGB1 (rs1412125, rs1360485, rs1045411, and rs2249825) were assessed using TaqMan real-time polymerase chain reaction assay. The results indicated that individuals carrying at least one T allele at rs1045411 had a lower risk of UCC than those with the wild-type allele [adjusted odds ratio = 0.722, 95% confidence interval (CI) = 0.565-0.924]. Furthermore, female patients with UCC carrying at least one T allele at rs1045411 were at a lower invasive tumor stage than those with the wild-type allele [odds ratio (OR) = 0.396, 95% CI = 0.169-0.929], similar to nonsmoking patients (OR = 0.607, 95% CI = 0.374-0.985). In conclusion, this is the first report on correlation between HMGB1 polymorphisms and UCC risk. Individuals carrying at least one T allele at rs1045411 are associated with a lower risk of UCC and a less invasive disease in women and nonsmokers.
Collapse
Affiliation(s)
- Sheng-Chun Hung
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Shian-Shiang Wang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.,Department of Applied Chemistry, National Chi Nan University, Nantou, Taiwan
| | - Jian-Ri Li
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.,Department of Medicine and Nursing, Hungkuang University, Taichung, Taiwan Taiwan
| | - Chuan-Shu Chen
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Chun-Kuang Yang
- Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Kun-Yuan Chiu
- Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.,Department of Applied Chemistry, National Chi Nan University, Nantou, Taiwan
| | - Chen-Li Cheng
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yen-Chuan Ou
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.,Department of Urology, Tung's Taichung MetroHarbor Hospital, Taichung, Taiwan
| | - Hao-Chung Ho
- Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| |
Collapse
|
|
21
|
Lee HL, Chiou HL, Wang SS, Hung SC, Chou MC, Yang SF, Hsieh MJ, Chou YE. WISP1 genetic variants as predictors of tumor development with urothelial cell carcinoma. Urol Oncol 2017; 36:160.e15-160.e21. [PMID: 29277583 DOI: 10.1016/j.urolonc.2017.11.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 11/11/2017] [Accepted: 11/30/2017] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Urothelial cell carcinoma (UCC) of the urinary bladder is a major malignancy of the genitourinary tract. Etiological factors, such as the environment, ethnicity, genetics, and diet, contribute to UCC carcinogenesis. WNT1-inducible signaling pathway protein 1 (WISP1), also known as CCN4, a cysteine-rich protein belonging to the Cyr61, CTGF, Nov (CCN) family of matricellular proteins, has many developmental functions and might be involved in carcinogenesis. This study investigated WISP1 single-nucleotide polymorphisms to evaluate UCC susceptibility and clinicopathological characteristics. MATERIALS AND METHODS Real-time polymerase chain reaction was used to analyze 4 single-nucleotide polymorphisms of WISP1 in 369 patients with UCC and 738 controls without cancer. RESULTS The results showed that in 128 women with UCC who carried WISP1 rs2929973 (AG + GG) variants had a higher risk of developing an advanced muscle-invasive tumor stage (pT2-pT4, P = 0.007) and a large tumor (T1-T4, P = 0.030). Further analyses revealed that a correlation between the expressions of WISP1 and invasive tumor and large tumor size in urothelial carcinoma was observed in the TCGA (The Cancer Genome Atlas) dataset. CONCLUSIONS Our results indicated that patients with UCC carrying rs2977530 genetic variants (AG + GG) have a higher risk of developing a more invasive tumor stage and a large tumor. WISP1 polymorphisms may serve as a marker or a therapeutic target in UCC.
Collapse
Affiliation(s)
- Hsiang-Lin Lee
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Hui-Ling Chiou
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan; Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Shian-Shiang Wang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Sheng-Chun Hung
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Ming-Chih Chou
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Ming-Ju Hsieh
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
| | - Ying-Erh Chou
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.
| |
Collapse
|
|
22
|
Li Y, Zhu J, Chen L, Hu W, Wang M, Li S, Gu X, Tao H, Zhao B, Ma G, Li K. Genetic predisposition to ischaemic stroke by RAGE and HMGB1 gene variants in Chinese Han population. Oncotarget 2017; 8:100150-100164. [PMID: 29245967 PMCID: PMC5725009 DOI: 10.18632/oncotarget.22112] [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: 06/22/2017] [Accepted: 09/20/2017] [Indexed: 11/25/2022] Open
Abstract
Emerging evidence suggests that the multiligand receptor for advanced glycation end products (RAGE) and its ligand high mobility group box 1 protein (HMGB1) contribute to the pathophysiology of ischaemic stroke (IS). The present study aimed to investigate the association of RAGE and HMGB1 variants with the risk of IS. A total of 1,034 patients and 1,015 age- and sex-matched healthy controls were genotyped to detect five genetic variants of the RAGE gene and four genetic variants of the HMGB1 gene using the Multiplex SNaPshot assay. We found that the rs2070600 variant of RAGE was associated with an increased risk of IS (OR = 1.19, 95% CI: 1.02-1.38, P = 0.043), whereas the rs2249825 variant of HMGB1 was associated with a decreased risk of IS (OR = 0.83, 95% CI: 0.71-0.98, P = 0.041). Further stratification by IS subtypes revealed that the presence of the TT genotype of the RAGE rs2070600 variant confers a higher risk of the large artery atherosclerosis subtype of IS (P = 0.036). Moreover, patients with the variant T allele of the RAGE rs2070600 variant presented with reduced serum soluble RAGE production. Patients carrying the variant G allele of the HMGB1 rs2249825 variant exhibited significantly lower infarct volumes than those with the major CC genotype. These clues may help in the development of optimal personalized therapeutic approaches for IS patients.
Collapse
Affiliation(s)
- You Li
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China.,Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China
| | - Jing Zhu
- Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Linfa Chen
- Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Weidong Hu
- Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Mengxu Wang
- Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Shengnan Li
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Xuefeng Gu
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Hua Tao
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Bin Zhao
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Guoda Ma
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Keshen Li
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China.,Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China
| |
Collapse
|
|
23
|
Yeh CM, Su SC, Lin CW, Yang WE, Chien MH, Reiter RJ, Yang SF. Melatonin as a potential inhibitory agent in head and neck cancer. Oncotarget 2017; 8:90545-90556. [PMID: 29163852 PMCID: PMC5685773 DOI: 10.18632/oncotarget.20079] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 07/26/2017] [Indexed: 12/29/2022] Open
Abstract
Melatonin is a molecule secreted by the pineal gland; it is an important regulator of sleep and circadian rhythms. Through multiple interrelated mechanisms, melatonin exhibits various inhibitory properties at different stages of tumor progression. Many studies have explored the oncostatic effects of melatonin on hormone-dependent tumors. In this review, we highlight recent advances in understanding the effects of melatonin on the development of head and neck cancers, including molecular mechanisms identified through experimental and clinical observations. Because melatonin exerts a wide range of effects, melatonin may influence many mechanisms that influence the development of cancer. These include cell proliferation, apoptosis, angiogenesis, extracellular matrix remodeling through matrix metalloproteinases, and genetic polymorphism. Thus, the evidence discussed in this article will serve as a basis for basic and clinical research to promote the use of melatonin for understanding and controlling the development of head and neck cancers.
Collapse
Affiliation(s)
- Chia-Ming Yeh
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Shih-Chi Su
- Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Chiao-Wen Lin
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan.,Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Wei-En Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Ming-Hsien Chien
- Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan
| | - Russel J Reiter
- Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, USA
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| |
Collapse
|