|
1
|
Zhu H, Jiang W, Zhang Q, Yu C. The role of UPK1B in gastric cancer: multi-omics analysis and experimental validation. Discov Oncol 2025; 16:476. [PMID: 40189715 PMCID: PMC11973043 DOI: 10.1007/s12672-025-02263-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 03/28/2025] [Indexed: 04/09/2025] Open
Abstract
BACKGROUND UPK1B has been implicated in various cancers; however, its mechanism of action in gastric cancer remains elusive. METHODS We utilized transcriptional data and clinical information, and mutation profiles from The Cancer Genome Atlas (TCGA) database to analyze UPK1B's expression and clinical relevance. Biological enrichment, immune microenvironment characterization, and drug sensitivity analyses were conducted. Functional assays, including proliferation, migration, invasion, and in vivo metastasis models, were used to validate UPK1B's role in gastric cancer. RESULTS UPK1B was significantly upregulated in gastric cancer and correlated with worse clinical outcomes, including advanced stages and reduced survival rates. Biological enrichment analysis revealed its involvement in cancer-related pathways such as DNA replication and immune regulation. UPK1B was negatively correlated with NK cells and M1 macrophages, indicating its role in immune evasion. Functional experiments demonstrated that knockdown of UPK1B significantly suppressed gastric cancer cell proliferation, invasion, and migration in vitro and reduced pulmonary metastases in vivo. Drug sensitivity analysis suggested that high UPK1B expression was associated with increased sensitivity to lapatinib and resistance to cisplatin. CONCLUSIONS UPK1B promotes tumor progression and modulates the immune microenvironment in gastric cancer, making it a potential therapeutic target for future research and clinical applications.
Collapse
Affiliation(s)
- Haixing Zhu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, People's Republic of China
| | - Wen Jiang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, People's Republic of China
| | - Qian Zhang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, People's Republic of China
| | - Changjun Yu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, People's Republic of China.
| |
Collapse
|
|
2
|
Wang S, Hu W, Xie Y, Wu H, Jia Z, Zhang Z, Zhang X. Functional genetic variants in complement component 7 confer susceptibility to gastric cancer. PeerJ 2022; 10:e12816. [PMID: 35111412 PMCID: PMC8781313 DOI: 10.7717/peerj.12816] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 12/29/2021] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Complement system plays an important role in innate immunity which involved in the changes tumor immune microenvironment by mediating the inflammatory response. This study aims to explore the relationship between complement component 7 (C7) polymorphisms and the risk of gastric cancer (GC). MATERIALS AND METHODS All selected SNPs of C7 were genotyped in 471 patients and 471 controls using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional Logistic regression to analyze the relationship between each genotype and the genetic susceptibility to gastric cancer. The level of C7 expression in GC was analyzed by Gene Expression Profiling Interactive Analysis (GEPIA) and detected by Enzyme Linked Immunosorbent Assay. Kaplan-Meier plotter were used to reveal C7 of prognostic value in GC. We examined SNPs associated with the expression of C7 using the GTEx database. The effect of C7 polymorphisms on the regulatory activity of C7 was detected by luciferase reporter assay. RESULTS Unconditional logistic regression showed that individuals with C7 rs1376178 AA or CA genotype had a higher risk of GC with OR (95% CI) of 2.09 (1.43-3.03) and 1.88 (1.35-2.63), respectively. For C7 rs1061429 C > A polymorphism, AA genotype was associated with the elevated risk for developing gastric cancer (OR = 2.16, 95% CI [1.37-3.38]). In stratified analysis, C7 rs1376178 AA genotype increased the risk of GC among males (OR = 2.88, 95% CI [1.81-4.58]), but not among females (OR = 1.06, 95% CI [0.55-2.06]). Individuals carrying rs1061429 AA significantly increased the risk of gastric cancer among youngers (OR = 2.84, 95% CI [1.39-5.80]) and non-smokers (OR = 2.79, 95% CI [1.63-4.77]). C7 was overexpressed in gastric cancer tissues and serum of cancer patients and was significantly associated with the prognosis. C7 rs1061429 C > A variant contributed to reduced protein level of C7 (P = 0.029), but rs1376178 didn't. Luciferase reporter assay showed that rs1376178C-containing plasmid exhibited 2.86-fold higher luciferase activity than rs1376178 A-containing plasmid (P < 0.001). We also found that rs1061429A allele contributed 1.34-fold increased luciferase activity than rs1061429C allele when co-transfected with miR-591 (P = 0.0012). CONCLUSIONS These findings highlight the role of C7 in the development of gastric cancer.
Collapse
Affiliation(s)
- Siyue Wang
- School of Public Health, North China University of Science and Technology, Tangshan, China,College of Life Science, North China University of Science and Technology, Tangshan, China
| | - Wenqian Hu
- School of Public Health, North China University of Science and Technology, Tangshan, China
| | - Yuning Xie
- School of Public Health, North China University of Science and Technology, Tangshan, China
| | - Hongjiao Wu
- School of Public Health, North China University of Science and Technology, Tangshan, China
| | - Zhenxian Jia
- School of Public Health, North China University of Science and Technology, Tangshan, China
| | - Zhi Zhang
- Affiliated Tangshan Gongren Hospital, North China University of Science and Technology, Tangshan, China
| | - Xuemei Zhang
- School of Public Health, North China University of Science and Technology, Tangshan, China,College of Life Science, North China University of Science and Technology, Tangshan, China
| |
Collapse
|
|
3
|
Fonseca CDAD, Martelli DRB, Maia CMF, Dias VO, Carvalho AA, Júnior HM. Digital biomarker 2D:4D as a predictor of cancer: A systematic review. Early Hum Dev 2022; 164:105521. [PMID: 34922146 DOI: 10.1016/j.earlhumdev.2021.105521] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 11/27/2021] [Accepted: 11/30/2021] [Indexed: 01/05/2023]
Abstract
BACKGROUND The digital ratio between the second and fourth digits of the hands, known as 2D:4D, is sexually dimorphic. It has been suggested that a low 2D:4D indicates high exposure to prenatal testosterone and low estrogen exposure while a high 2D:4D indicates the inverse. The 2D:4D may be predictive of cancer susceptibility, and this may be particularly true in cancers that show differences between sexes in their occurrence. AIM To conduct a systematic review of published epidemiological literature examining the association between 2D:4D and cancer. METHOD This review was carried out according to criteria recommended for the systematic review of Statement PRISMA. We enrolled 25 papers involving eleven cancer topographies with 4,569 cases and 19,416 controls from Europe, America, Asia and Australia. RESULTS We noticed variations and discrepancies in the results of the association between 2D:4D and cancer among the studies, either in those that had evaluated the same or different types of cancer, or in the same or distinct lateralities. However, a high 2D:4D was considered a likely predictor of cancer risk in 11 of 25 studies, a low 2D:4D was suggested as a predictor of risk in eight papers, and five of the twenty-five studies did not demonstrate any association. CONCLUSIONS Although this biomarker has the advantage of being easy to measure, it is noted that its relationship with sex hormone levels at specific stages of life has not yet been well quantified, and it has still been questioned. Hence, it is suggested that those findings from studies involving 2D:4D as a proxy for foetal hormone exposure should be interpreted with caution, as well as those studies which claim its association with cancer. Thus, this review shows the need for a greater number of epidemiological studies using more homogeneous methodology and techniques to better investigate the strength of the findings.
Collapse
Affiliation(s)
- Cláudia de A D Fonseca
- Health Science Program, State University of Montes Claros, Unimontes, Minas Gerais, Brazil; Medicine School, State University of Montes Claros, Montes Claros, Minas Gerais, Brazil.
| | - Daniella R B Martelli
- Dental School, State University of Montes Claros, Montes Claros, Minas Gerais, Brazil
| | - Célia M F Maia
- Health Science Program, State University of Montes Claros, Unimontes, Minas Gerais, Brazil
| | - Verônica O Dias
- Dental School, State University of Montes Claros, Montes Claros, Minas Gerais, Brazil
| | - Adriana A Carvalho
- Health Science Program, State University of Montes Claros, Unimontes, Minas Gerais, Brazil; Medicine School, State University of Montes Claros, Montes Claros, Minas Gerais, Brazil
| | - Hercílio Martelli Júnior
- Health Science Program, State University of Montes Claros, Unimontes, Minas Gerais, Brazil; Dental School, State University of Montes Claros, Montes Claros, Minas Gerais, Brazil; Center for Rehabilitation of Craniofacial Anomalies, University of José Rosario Vellano, Alfenas, Minas Gerais, Brazil
| |
Collapse
|
|
4
|
Soliman SE, Elabd NS, El-Kousy SM, Awad MF. Down regulation of miR-30a-5p and miR-182-5p in gastric cancer: Clinical impact and survival analysis. Biochem Biophys Rep 2021; 27:101079. [PMID: 34355069 PMCID: PMC8321916 DOI: 10.1016/j.bbrep.2021.101079] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 07/10/2021] [Accepted: 07/12/2021] [Indexed: 01/17/2023] Open
Abstract
Background and aim Gastric Cancer (GC) is a leading cause of morbidity and mortality worldwide, particularly in developing nations, only a few suitable gastric cancer serum biomarkers with acceptable sensitivity and specificity exist. This work aims to highlight and uncover miR-30a-5p and miR-182-5p's diagnostic roles regarding gastric cancer and their roles in predicting prognosis. Methods 148 patients participated in this study. Groups I, II, and III had 47 patients with GC, 54 patients with benign gastric lesions, and 47 apparently healthy subjects of coincided age and gender as controls, respectively. All participants were clinically evaluated and subjected to CBC, serum CEA, and CA19-9 by ELISA, and real-time PCR tests of miR-30a-5p and miR-182-5p. Results MiR30a-5p and miR-182-5p were down regulated in gastric cancer patients in Group I more than Groups II and III (P < 0.001). ROC curve analysis revealed that miR30a-5p had better AUC, sensitivity, and specificity (0.961%, 93.62%, and 90.74%respectively). When miR-182-5p was gathered with CEA and CA19-9, specificity raised to 98.15% and PPV to 97.6%. Lower miR-30a-5p levels are linked with the presence of distant metastases, advanced TNM stage, and degree of pathological differentiation of tumors in GC patients (p = 0.034, 0.019, 0.049) respectively. According to the multivariate analysis, miR30a-5p expression level could be an independent predictor of GC. Conclusion Our results exhibited that miRNAs, miR-30a-5p and miR182-5p, gene expression have a diagnostic power and can identify patients with GC. MiR-30a-5p displayed the highest diagnostic specificity and sensitivity. Besides other known tumor markers, they could offer simple noninvasive biomarkers that predict gastric cancer.
Collapse
Affiliation(s)
- Shimaa E Soliman
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Menoufia University, Egypt
| | - Naglaa S Elabd
- Tropical Medicine Department, Faculty of Medicine - Menoufia University, Egypt
| | - Salah M El-Kousy
- Department of Organic Chemistry, Faculty of Science - Menoufia University, Egypt
| | - Mohamed F Awad
- Chemist at Faculty of Science - Menoufia University, Egypt Organic Chemistry, Egypt
| |
Collapse
|
|
5
|
Yang Z, OuYang X, Zheng L, Dai L, Luo W. Long intergenic noncoding RNA00265 promotes proliferation of gastric cancer via the microRNA-144-3p/Chromobox 4 axis. Bioengineered 2021; 12:1012-1025. [PMID: 33464142 PMCID: PMC8291797 DOI: 10.1080/21655979.2021.1876320] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The expression and biological function of long intergenic noncoding RNA00265 (LINC00265) in gastric cancer (GC) have not yet been explored. This study aimed to detect LINC00265 expression in GC tissues and cell lines, investigate its roles in the proliferation of GC cells in vitro, and elucidate the regulatory mechanisms of LINC00265 action. It was found that LINC00265 expression was significantly upregulated in GC tissue samples and cell lines compared with their normal counterparts. Additionally, LINC00265 knockdown could inhibit GC cell proliferation in vitro. Further investigation revealed that LINC00265 acted as a competing endogenous RNA for microRNA-144-3p (miR-144-3p) and inhibition of miR-144-3p markedly counteracted LINC00265 knockdown-meditated suppression on GC cell proliferation. Additionally, Chromobox 4 (CBX4) was upregulated in GC and silencing CBX4 could reduce GC cell proliferation. Then, CBX4 mRNA was demonstrated to be a direct target of miR-144-3p in GC cells and LINC00265/miR-144-3p axis could regulate CBX4 expression. Taken together, LINC00265 may promote GC cell proliferation via the miR-144-3p/CBX4 axis.
Collapse
Affiliation(s)
- Zengxi Yang
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Xi OuYang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Liang Zheng
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Lizhen Dai
- Department of Obstetrics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wenjuan Luo
- Department of Ophthalmology, Lanzhou University Second Hospital, Lanzhou, China
| |
Collapse
|
|
6
|
Zamani SA, McClain KM, Graubard BI, Liao LM, Abnet CC, Cook MB, Petrick JL. Dietary Polyunsaturated Fat Intake in Relation to Head and Neck, Esophageal, and Gastric Cancer Incidence in the National Institutes of Health-AARP Diet and Health Study. Am J Epidemiol 2020; 189:1096-1113. [PMID: 32141493 DOI: 10.1093/aje/kwaa024] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Revised: 03/12/2020] [Accepted: 02/19/2020] [Indexed: 12/13/2022] Open
Abstract
Recent epidemiologic studies have examined the association of fish consumption with upper gastrointestinal cancer risk, but the associations with n-3 and n-6 polyunsaturated fatty acid (PUFA) subtypes remain unclear. Using the National Institutes of Health-AARP Diet and Health Study (United States, 1995-2011), we prospectively investigated the associations of PUFA subtypes, ratios, and fish with the incidence of head and neck cancer (HNC; n = 2,453), esophageal adenocarcinoma (EA; n = 855), esophageal squamous cell carcinoma (n = 267), and gastric cancer (cardia: n = 603; noncardia: n = 631) among 468,952 participants (median follow-up, 15.5 years). A food frequency questionnaire assessed diet. Multivariable-adjusted hazard ratios were estimated using Cox proportional hazards regression. A Benjamini-Hochberg (BH) procedure was used for false-discovery control. Long-chain n-3 PUFAs were associated with a 20% decreased HNC and EA risk (for HNC, quintile5 vs. 1 hazard ratio = 0.81, 95% confidence interval: 0.71, 0.92, and BH-adjusted Ptrend = 0.001; and for EA, quintile5 vs. 1 hazard ratio = 0.79, 95% confidence interval: 0.64, 0.98, and BH-adjusted Ptrend = 0.1). Similar associations were observed for nonfried fish but only for high intake. Further, the ratio of long-chain n-3:n-6 was associated with a decreased HNC and EA risk. No consistent associations were observed for gastric cancer. Our results indicate that dietary long-chain n-3 PUFA and nonfried fish intake are associated with lower HNC and EA risk.
Collapse
|
|
7
|
Xu X, Wang Q, Cao H, Gao Z, Qian G, Lu Q, Wu Y. Prognostic value of serum alpha-fetoprotein levels in patients with gastric cancer: a meta-analysis. J Int Med Res 2020; 48:300060519899780. [PMID: 32228092 PMCID: PMC7133086 DOI: 10.1177/0300060519899780] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background Methods Results Conclusions
Collapse
Affiliation(s)
- Xiang Xu
- Department of General Surgery, The Third Affiliated Hospital of Soochow University and The First People's Hospital of Changzhou, Changzhou, Jiangsu, China
| | - Qing Wang
- Department of General Surgery, The Third Affiliated Hospital of Soochow University and The First People's Hospital of Changzhou, Changzhou, Jiangsu, China
| | - Huihua Cao
- Department of General Surgery, The Third Affiliated Hospital of Soochow University and The First People's Hospital of Changzhou, Changzhou, Jiangsu, China
| | - Zhenyan Gao
- Department of General Surgery, The Third Affiliated Hospital of Soochow University and The First People's Hospital of Changzhou, Changzhou, Jiangsu, China
| | - Guangyang Qian
- Department of General Surgery, The Third Affiliated Hospital of Soochow University and The First People's Hospital of Changzhou, Changzhou, Jiangsu, China
| | - Qicheng Lu
- Department of General Surgery, The Third Affiliated Hospital of Soochow University and The First People's Hospital of Changzhou, Changzhou, Jiangsu, China
| | - Yugang Wu
- Department of General Surgery, The Third Affiliated Hospital of Soochow University and The First People's Hospital of Changzhou, Changzhou, Jiangsu, China
| |
Collapse
|
|
8
|
Yuan K, Ye J, Liu Z, Ren Y, He W, Xu J, He Y, Yuan Y. Complement C3 overexpression activates JAK2/STAT3 pathway and correlates with gastric cancer progression. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:9. [PMID: 31928530 PMCID: PMC6956509 DOI: 10.1186/s13046-019-1514-3] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 12/22/2019] [Indexed: 12/21/2022]
Abstract
Background Localized C3 deposition is a well-known factor of inflammation. However, its role in oncoprogression of gastric cancer (GC) remains obscured. This study aims to explore the prognostic value of C3 deposition and to elucidate the mechanism of C3-related oncoprogression for GC. Methods From August to December 2013, 106 GC patients were prospectively included. The regional expression of C3 and other effectors in gastric tissues were detected by WB, IHC, qRT-PCR and other tests. The correlation of localized C3 deposition and oncologic outcomes was determined by 5-year survival significance. Human GC and normal epithelial cell lines were employed to detect a relationship between C3 and STAT3 signaling pathway in vitro experiments. Results C3 and C3a expression were markedly enhanced in GC tissues at both mRNA and protein levels compared with those in paired nontumorous tissues. According to IHC C3 score, 65 (61.3%) and 41 (38.7%) patients had high and low C3 deposition, respectively. C3 deposition was negatively correlated with plasma levels of C3 and C3a (both P < 0.001) and positively correlated with pathological T and TNM stages (both P < 0.001). High C3 deposition was identified as an independent prognostic factor of poor 5-year overall survival (P = 0.045). In vitro C3 administration remarkably enhanced p-JAK2/p-STAT3 expression in GC cell lines but caused a reduction of such activation when pre-incubated with a C3 blocker. Importantly, C3 failed to activate such signaling in cells pre-treated with a JAK2 inhibitor. Conclusions Localized C3 deposition in the tumor microenvironment is a relevant immune signature for predicting prognosis of GC. It may aberrantly activate JAK2/STAT3 pathway allowing oncoprogression. Trial registration ClinicalTrials.gov, NCT02425930, Registered 1st August 2013.
Collapse
Affiliation(s)
- Kaitao Yuan
- Center of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.,Center of Gastric cancer, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Jinning Ye
- Center of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.,Center of Gastric cancer, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Zhenguo Liu
- Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Yufeng Ren
- Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Weiling He
- Center of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China. .,Center of Gastric cancer, Sun Yat-sen University, Guangzhou, People's Republic of China.
| | - Jianbo Xu
- Center of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China. .,Center of Gastric cancer, Sun Yat-sen University, Guangzhou, People's Republic of China.
| | - Yulong He
- Center of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China. .,Center of Gastric cancer, Sun Yat-sen University, Guangzhou, People's Republic of China.
| | - Yujie Yuan
- Center of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China. .,Center of Gastric cancer, Sun Yat-sen University, Guangzhou, People's Republic of China.
| |
Collapse
|
|
9
|
Song H, Wang T, Tian L, Bai S, Chen L, Zuo Y, Xue Y. Macrophages on the Peritoneum are involved in Gastric Cancer Peritoneal Metastasis. J Cancer 2019; 10:5377-5387. [PMID: 31632482 PMCID: PMC6775704 DOI: 10.7150/jca.31787] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Accepted: 07/23/2019] [Indexed: 02/07/2023] Open
Abstract
Tumor-associated macrophages (TAM) have been shown to support tumor growth and progression by various mechanisms. However, the roles of TAM in gastric cancer (GC) peritoneal metastasis remain elusive. To explore the roles of macrophages in the process of GC peritoneal metastasis, we performed the present study. Samples from the primary GC tumor beds, surgical margins, peritoneal metastatic lesions and surrounding tissue, and the Pouch of Douglas, were collected, fixed by formalin, and embedded with paraffin. Immunohistochemistry staining for macrophages markers was performed. The peritoneal lavage was obtained from a fraction of patients to analyze the ratios of epidermal growth factor (EGF)- and vascular endothelial growth factor (VEGF)-secreting macrophages in the peritoneal cavity. GC patients with peritoneal metastasis had increased levels of macrophages and alternatively activated macrophages in the peritoneum compared to those without dissemination. Patients bearing more macrophages in the peritoneum had a poorer prognosis. GC patients bearing peritoneal metastasis harbored an increased level of angiogenesis. Macrophages in the peritoneal cavity were a source of EGF and VEGF. Macrophages in the peritoneum of GC patients play a supportive role for peritoneal metastasis by producing EGF and VEGF. Macrophages in the peritoneum might be a therapeutic target in the future.
Collapse
Affiliation(s)
- Hongjiang Song
- Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China
| | - Tie Wang
- Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China
| | - Lining Tian
- Department of Medical Education, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Shuping Bai
- Department of Internal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China
| | - Li Chen
- Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China
| | - Yanjiao Zuo
- Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China
| | - Yingwei Xue
- Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China
| |
Collapse
|
|
10
|
Lu J, Li X, Tu K, Guan Y, Fung KP, Liu F. Verticillin A suppresses HGF-induced migration and invasion via repression of the c-Met/FAK/Src pathway in human gastric and cervical cancer cells. Onco Targets Ther 2019; 12:5823-5833. [PMID: 31440058 PMCID: PMC6668566 DOI: 10.2147/ott.s208683] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 06/12/2019] [Indexed: 01/06/2023] Open
Abstract
Background and purpose: Verticillin A is a fungal epipolythiodioxopiperazine (ETP) metabolite that was isolated from Amanita flavorubescens Alk infected by Verticillium sp. It was previously proven to possess potent anti-tumor cell growth activity, and we have recently determined that verticillin A is a selective inhibitor of H3K9me3-specific histone methyltransferase. The objective of this study was to find out whether verticillin A is an effective agent for suppression of gastric and cervical tumor progression. Materials and methods: Wound healing and transwell assays was performed to evaluate the effect of verticillin A on hepatocyte growth factor (HGF)-induced AGS and HeLa cells migration and invasion in vitro. Western blot was used to detect signaling proteins verticillin A affected. Results: We determined that verticillin A effectively suppressed hepatocyte growth factor (HGF)-induced AGS and HeLa cells migration and invasion in vitro. At the molecular level, we demonstrated that verticillin A inhibited HGF-induced c-Met phosphorylation and repressed the expression of total c-Met protein in AGS and HeLa cells, resulting from reduced expression of fatty acid synthase. In addition, verticillin A could suppress c-Met downstream FAK/Src signaling pathways by impairing c-Met phosphorylation induced by HGF. Conclusion: Our study demonstrated verticillin A inhibits the migration ability of human gastric cancer (AGS) cells and cervical cancer (HeLa) cells by targeting c-Met and its downstream FAK/Src signaling pathways, and suggested that verticillin A acts as a novel HGF/c-Met inhibitor by reducing expression of this receptor.
Collapse
Affiliation(s)
- Jingxin Lu
- Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Hangzhou310058, People’s Republic of China
- Joint Centre of Zhejiang University and the Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Hangzhou, People’s Republic of China
| | - Xia Li
- Joint Centre of Zhejiang University and the Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Hangzhou, People’s Republic of China
- Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou 310022, People’s Republic of China
| | - Kai Tu
- Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Hangzhou310058, People’s Republic of China
- Joint Centre of Zhejiang University and the Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Hangzhou, People’s Republic of China
| | - Yuelin Guan
- Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Hangzhou310058, People’s Republic of China
- Joint Centre of Zhejiang University and the Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Hangzhou, People’s Republic of China
| | - Kwok-Pui Fung
- Joint Centre of Zhejiang University and the Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Hangzhou, People’s Republic of China
- School of Biomedical Sciences (SBS), The Chinese University of Hong Kong, Shatin, Hong Kong SAR, People’s Republic of China
| | - Feiyan Liu
- Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Hangzhou310058, People’s Republic of China
- Joint Centre of Zhejiang University and the Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Hangzhou, People’s Republic of China
| |
Collapse
|
|
11
|
Yu H, Xu N, Li ZK, Xia H, Ren HT, Li N, Wei JB, Bao HZ. Association of ABO Blood Groups and Risk of Gastric Cancer. Scand J Surg 2019; 109:309-313. [PMID: 31282314 DOI: 10.1177/1457496919863886] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
OBJECTIVE This study sought to investigate the relationship between ABO blood groups and the risk of gastric cancer as well as clinical pathological parameters and prognosis. METHODS Gastric cancer patient data were collected from January 1995 to January 2012 at Jilin Cancer Hospital, and the blood group information of the blood donors at Jilin City Blood Center was recorded. The relationships between ABO blood group and both clinicopathological parameters and the risk of gastric cancer were analyzed retrospectively. The impact of ABO blood type on the 5-year survival rate of patients with gastric cancer was evaluated through outpatient and telephone interviews. RESULTS (1) Compared with the healthy population, the frequency distribution of gastric cancer patients with the A blood group was significantly increased (χ2 = 4.708, P = 0.000), whereas the frequency distribution of gastric cancer patients with the AB blood group was significantly decreased (χ2 = 9.630, P = 0.002). However, there was no significant difference in the distributions of the B blood group and O blood group (P > 0.05). (2) The risk of gastric cancer in people with the A blood group was higher, whereas the risk of gastric cancer in people with the AB blood group was lower. There was no significant difference in the risk of gastric cancer between type B and type O patients (P > 0.05). (3) The ABO blood group was not related to pathological factors, including the size of the gastric tumor or the T stage or N stage of the disease (P > 0.05). (4) Univariate analysis results showed that the degree of differentiation, tumor size, T stage, lymph node metastasis, and type O blood were factors affecting the 5-year survival rate of gastric cancer patients (P < 0.05). Multivariate analysis results showed that tumor size, T stage, lymph node metastasis, and O blood group were independent prognostic factors. The 5-year survival rate for gastric cancer was significantly better in patients with type O blood (hazard ratio = 0.97, 95% confidence interval = 1.67-3.92). CONCLUSION (1) The risk of gastric cancer was higher in patients with the A blood group and lower in those with the AB blood group. (2) The ABO blood group showed no significant effect on the clinicopathological parameters of gastric cancer. (3) The O blood group may be a prognostic factor for gastric cancer patients.
Collapse
Affiliation(s)
- Hao Yu
- Department of Hematology, Jilin Cancer Hospital, Changchun, China
| | - Na Xu
- Department of Hematology, Jilin Cancer Hospital, Changchun, China
| | - Zhong-Kun Li
- Department of Hematology, Jilin Cancer Hospital, Changchun, China
| | - Hong Xia
- Department of Hematology, Jilin Cancer Hospital, Changchun, China
| | - Hong-Tao Ren
- Department of Hematology, Jilin Cancer Hospital, Changchun, China
| | - Na Li
- Department of Hematology, Jilin Cancer Hospital, Changchun, China
| | - Jan-Biao Wei
- Department of Hematology, Jilin Cancer Hospital, Changchun, China
| | - Hui-Zheng Bao
- Department of Hematology, Jilin Cancer Hospital, Changchun, China
| |
Collapse
|
|
12
|
Mohammadi A, Mansoori B, Savadi P, Khaze V, Minouei M, McMillan NAJ, Hallaj-Nezhadi S, Baradaran B. Targeting of high mobility group A2 by small interfering RNA-loaded nanoliposome-induced apoptosis and migration inhibition in gastrointestinal cancer cells. J Cell Biochem 2018; 120:9203-9212. [PMID: 30507008 DOI: 10.1002/jcb.28196] [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] [Received: 06/14/2018] [Accepted: 11/08/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Considering the complex nature of gastrointestinal cancer, different methods including surgery, radiotherapy, and chemotherapy are considered for the treatment. Novel strategies including silencing of oncogenes using safe delivery systems could be considered as a novel approach in colorectal cancer treatment. The aim of this study was to investigate the silencing effect of high mobility group A2 (HMGA2) small interfering RNA (siRNA)-loaded nanoliposomes on gastrointestinal cancers. METHODS The siRNA-lipoplexes were prepared using dioleoyl trimethylammonium propane (DOTAP)/cholesterol (Chol)/1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) through the freeze-drying of a monophase solution method. The size, polydispersity index (PDI), and zeta-potential of nanoliposomes were determined using Zetasizer analyzer. The morphology of the nanoliposomes was determined by transmission electron microscopy (TEM). The agarose gel-retardation assay was carried out to confirm the loading of siRNAs into liposome. The silencing of the HMGA2 in cancer cells was evaluated by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The effect of liposomes on cell cytotoxicity was studied by MTT assay. The inhibitory effect of siRNA-loaded liposomes was evaluated by a wound-healing assay. The apoptosis induction was investigated via the annexin V/propidium iodide assay. RESULTS The size, PDI, and zeta-potential of the prepared liposomes were found to be 350 nm, 0.67, and 86.3 mV, respectively. They were spherical in shape and could efficiently associate with siRNA. The results of gene silencing showed that the optimum condition of HMGA2 silencing was 80 pmol HMGA2 and 24 hours after treatment in each cancer cell lines. MTT assays indicated that silencing of HMGA2 in optimal condition could reduce the viability of the cancer cells more than 60% in the three cell lines. The result of the apoptosis assay showed more than 50% of the cell deaths related to the apoptosis in all three cell lines. The gene expression evaluation confirmed that apoptosis was induced via the intrinsic pathway inducing both caspase-3 and -9 expressions. Also, the reduction in Bcl2 expression confirmed the activation apoptosis pathway in the treated cancer cells. The wound-healing assay showed the suppression of cancer cell migration after treatment with the prepared nanoliposomes. CONCLUSION The results of this study showed the HMGA2 siRNA-loaded nanoliposomes could be effective in the treatment of gastrointestinal cancers.
Collapse
Affiliation(s)
- Ali Mohammadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Pouria Savadi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahid Khaze
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahsa Minouei
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nigel A J McMillan
- School of Medical Sciences and Menzies Health Institute Queensland, Griffith University, Southport, Australia
| | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
13
|
Retroperitoneal fibrosis secondary to non-urology carcinomas: a clinical and outcome analysis of 97 cases. Clin Transl Oncol 2018; 21:373-379. [DOI: 10.1007/s12094-018-1936-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 08/11/2018] [Indexed: 11/26/2022]
|
|
14
|
Fashoyin-Aje L, Donoghue M, Chen H, He K, Veeraraghavan J, Goldberg KB, Keegan P, McKee AE, Pazdur R. FDA Approval Summary: Pembrolizumab for Recurrent Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma Expressing PD-L1. Oncologist 2018; 24:103-109. [PMID: 30120163 PMCID: PMC6324629 DOI: 10.1634/theoncologist.2018-0221] [Citation(s) in RCA: 172] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 05/31/2018] [Indexed: 02/06/2023] Open
Abstract
This report presents evidence for FDA approval of pembrolizumab for the treatment of adult and pediatric patients with either unresectable or metastatic, microsatellite instability‐high (MSI‐H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment, and who have no satisfactory alternative treatment options, or who have metastatic, MSI‐H or dMMR colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. On September 22, 2017, the U.S. Food and Drug Administration (FDA) granted accelerated approval for pembrolizumab (Keytruda, Merck & Co., Inc., Whitehouse Station, NJ) for the treatment of patients with recurrent, locally advanced or metastatic, gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after two or more systemic therapies, including fluoropyrimidine‐ and platinum‐containing chemotherapy and, if appropriate, HER2/neu‐targeted therapy, and whose tumors express programmed death‐ligand 1 (PD‐L1), as determined by an FDA‐approved test. Approval was based on demonstration of durable overall response rate (ORR) in a multicenter, open‐label, multicohort trial (KEYNOTE‐059/Cohort 1) that enrolled 259 patients with locally advanced or metastatic gastric or GEJ adenocarcinoma. Among the 55% (n = 143) of patients whose tumors expressed PD‐L1 based on a combined positive score ≥1 and either were microsatellite stable or had undetermined microsatellite instability or mismatch repair status, the confirmed ORR as determined by blinded independent central review was 13.3% (95% CI, 8.2–20.0); 1.4% had complete responses. Response durations ranged from 2.8+ to 19.4+ months; 11 patients (58%) had response durations of 6 months or longer, and 5 patients (26%) had response durations of 12 months or longer. The most common (≥20%) adverse reactions of pembrolizumab observed in KEYNOTE‐059/Cohort 1 were fatigue, decreased appetite, nausea, and constipation. The most frequent (≥2%) serious adverse drug reactions were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. Pembrolizumab was approved concurrently with the PD‐L1 immunohistochemistry 22C3 pharmDx test (Dako, Agilent, Santa Clara, CA) for selection of patients with gastric cancer for treatment with pembrolizumab based on PD‐L1 tumor expression. Implications for Practice. This report presents key information on the basis for Food and Drug Administration approval of pembrolizumab for the treatment of patients with locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD‐L1. The report discusses the basis for limiting the indication to patients with PD‐L1‐expressing tumors and the basis for recommending that PD‐L1 status be assessed using a fresh tumor specimen if PD‐L1 expression is not detected in an archival gastric or GEJ cancer specimen.
Collapse
Affiliation(s)
- Lola Fashoyin-Aje
- Office of Hematology and Oncology Products, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Martha Donoghue
- Office of Hematology and Oncology Products, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Huanyu Chen
- Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Kun He
- Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Janaki Veeraraghavan
- Office of In Vitro Diagnostics and Radiological Health, Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Kirsten B Goldberg
- Office of Hematology and Oncology Products, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Patricia Keegan
- Office of Hematology and Oncology Products, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Amy E McKee
- Office of Hematology and Oncology Products, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
- Oncology Center of Excellence, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Richard Pazdur
- Office of Hematology and Oncology Products, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
- Oncology Center of Excellence, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| |
Collapse
|
|
15
|
Peng J. si-TP73-AS1 suppressed proliferation and increased the chemotherapeutic response of GC cells to cisplatin. Oncol Lett 2018; 16:3706-3714. [PMID: 30127981 PMCID: PMC6096144 DOI: 10.3892/ol.2018.9107] [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: 07/29/2017] [Accepted: 04/16/2018] [Indexed: 12/20/2022] Open
Abstract
Previous studies have revealed that long noncoding RNAs (lncRNAs) function as crucial regulators in various biological processes, including tumorigenesis. Although the expression of lncRNA TP73-antisense RNA1 (AS1) has been identified in hepatocellular carcinoma and glioma, the biological function of TP73-AS1 in gastric cancer (GC) remains unclear. Thus, the present study employed a comprehensive analysis on the function of lncRNA TP73-AS1 in GC. The aim of the present study was to determine the clinical significance and biological function of TP73-AS1 in human GC tissues and cells. Additionally, the expression of TP73-AS1 was increased in GC tissues and cell lines and increased expression level of TP73-AS1 was associated with poor prognosis in patients with GC. Functional assays revealed that silencing of TP73-AS1 may suppress cell proliferation and enhance the chemotherapeutic response of GC cells to cisplatin through targeting the high mobility group 1/receptor for advanced glycation endproducts signaling pathway. Collectively, the results of the present study demonstrated that TP73-AS1 may be a novel lncRNA for the clinical prognosis of GC and a potential therapeutic target for the treatment of GC.
Collapse
Affiliation(s)
- Jianjun Peng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| |
Collapse
|
|
16
|
The Combination of Seven Preoperative Markers for Predicting Patients with Gastric Cancer to Be Either Stage IV or Non-Stage IV. Gastroenterol Res Pract 2018; 2018:3450981. [PMID: 29967637 PMCID: PMC6008646 DOI: 10.1155/2018/3450981] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 05/09/2018] [Accepted: 05/16/2018] [Indexed: 02/06/2023] Open
Abstract
To assess whether preoperative markers could predict the stage of patients with gastric cancer. We analyzed retrospectively the preoperative indicators between stage IV and non-stage IV gastric cancer at the Gastrointestinal Surgery of Nanjing Drum Tower Hospital. A total of 500 patients with gastric cancer were screened. Of all the variables, alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 125, carbohydrate antigen (CA) 199, carbohydrate antigen (CA) 724, carbohydrate antigen (CA) 242, thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time (APTT), blood platelet count (PLT), white blood cell (WBC) count, C-reactive protein (CRP), neutrophil count (NC), lymphocyte count (LC), neutrophil-lymphocyte ratio (NLR), hemoglobin (HB), aspartate aminotransferase (AST), and ascites were found to have statistical differences between the two groups. Then, Stepwise Discriminant Analysis was conducted to establish a prediction model including 7 indexes (CA724, CA242, TT, PLT, CRP, AST, and ascites). According to the model, 90.6% of original grouped cases were correctly classified and 90.6% of cross-validated grouped cases were correctly classified. We built a discriminant including CA724, CA242, TT, PLT, CRP, AST, and ascites for predicting patients with gastric cancer to be either stage IV or non-stage IV. According to this discriminant, 90.6% of patients could be correctly predicted.
Collapse
|
|
17
|
Li D, Chen Y, Mei H, Jiao W, Song H, Ye L, Fang E, Wang X, Yang F, Huang K, Zheng L, Tong Q. Ets-1 promoter-associated noncoding RNA regulates the NONO/ERG/Ets-1 axis to drive gastric cancer progression. Oncogene 2018; 37:4871-4886. [PMID: 29773901 PMCID: PMC6117270 DOI: 10.1038/s41388-018-0302-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 03/20/2018] [Accepted: 04/16/2018] [Indexed: 01/12/2023]
Abstract
Emerging studies have indicated the essential functions of long noncoding RNAs (lncRNAs) during cancer progression. However, whether lncRNAs contribute to the upregulation of v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets-1), an established oncogenic protein facilitating tumor invasion and metastasis, in gastric cancer remains elusive. Herein, we identified Ets-1 promoter-associated noncoding RNA (pancEts-1) as a novel lncRNA associated with the gastric cancer progression via mining of publicly available datasets and rapid amplification of cDNA ends. RNA pull-down, RNA immunoprecipitation, in vitro binding, and RNA electrophoretic mobility shift assays indicated the binding of pancEts-1 to non-POU domain containing octamer binding (NONO) protein. Mechanistically, pancEts-1 facilitated the physical interaction between NONO and Ets related gene (ERG), resulting in increased ERG transactivation and transcription of Ets-1 associated with gastric cancer progression. In addition, pancEts-1 facilitated the growth and aggressiveness of gastric cancer cells via interacting with NONO. In gastric cancer tissues, pancEts-1, NONO, and ERG were upregulated and significantly correlated with Ets-1 levels. High levels of pancEts-1, NONO, ERG, or Ets-1 were respectively associated with poor survival of gastric cancer patients, whereas simultaneous expression of all of them (HR = 3.012, P = 0.105) was not an independent prognostic factor for predicting clinical outcome. Overall, these results demonstrate that lncRNA pancEts-1 exhibits oncogenic properties that drive the progression of gastric cancer via regulating the NONO/ERG/Ets-1 axis.
Collapse
Affiliation(s)
- Dan Li
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, 430022, Wuhan, Hubei Province, China
| | - Yajun Chen
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, 430022, Wuhan, Hubei Province, China
| | - Hong Mei
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, 430022, Wuhan, Hubei Province, China
| | - Wanju Jiao
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, 430022, Wuhan, Hubei Province, China
| | - Huajie Song
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, 430022, Wuhan, Hubei Province, China
| | - Lin Ye
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, 430022, Wuhan, Hubei Province, China
| | - Erhu Fang
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, 430022, Wuhan, Hubei Province, China
| | - Xiaojing Wang
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, 430022, Wuhan, Hubei Province, China
| | - Feng Yang
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, 430022, Wuhan, Hubei Province, China
| | - Kai Huang
- Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, 430022, Wuhan, Hubei Province, China
| | - Liduan Zheng
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, 430022, Wuhan, Hubei Province, China. .,Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, 430022, Wuhan, Hubei Province, China.
| | - Qiangsong Tong
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, 430022, Wuhan, Hubei Province, China. .,Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, 430022, Wuhan, Hubei Province, China.
| |
Collapse
|
|
18
|
Yu Y, Yu X, Liu H, Song Q, Yang Y. miR‑494 inhibits cancer‑initiating cell phenotypes and reverses resistance to lapatinib by downregulating FGFR2 in HER2‑positive gastric cancer. Int J Mol Med 2018; 42:998-1007. [PMID: 29786108 DOI: 10.3892/ijmm.2018.3680] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 01/11/2018] [Indexed: 12/11/2022] Open
Abstract
In gastric cancer, >15% of cases are associated with the amplification of human epidermal growth factor receptor 2 (HER2), which leads to poor clinical outcomes. Lapatinib, a potent ATP‑competitive inhibitor, is a small, orally active molecule, which inhibits the tyrosine kinases of HER2 and epidermal growth factor receptor type 1. The activation of receptor tyrosine kinases can contribute to lapatinib resistance in HER2‑positive gastric cancer. The aim of the present study was to explore the effects of miR‑494 and FGFR2 in regulation of cancer‑initiating cell phenotypes and therapeutic efficiency of lapatinib in HER2‑positive gastric cancer. Western blot analysis was used to identify that the expression of fibroblast growth factor receptor 2 (FGFR2), a receptor tyrosine kinase, was upregulated in gastric cancer tissues. Formation of cancer initiating cells (CICs) and resistance to lapatinib were determined using sphere growth assay and MTT assay, respectively. The overexpression of FGFR2 promoted the generation of cancer‑initiating cells (CICs) and resistance to lapatinib in HER2‑positive gastric cancer YCC1 cells. In addition, it was observed that overexpression of microRNA (miR)‑494 downregulated the protein expression of FGFR2, inhibited the formation of CICs and reversed lapatinib resistance in YCC1‑F cells (HER2‑positive, FGFR2 overexpressing and lapatinib‑resistant gastric cancer cells). Therefore, it was concluded that miR‑494 inhibited the CIC phenotype and reversed resistance to lapatinib by inhibiting FGFR2 in HER2‑positive gastric cancer.
Collapse
Affiliation(s)
- Yanxia Yu
- Cancer Treatment Research Center, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Xuejuan Yu
- Cancer Treatment Research Center, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Hong Liu
- Cancer Treatment Research Center, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Qingxun Song
- Cancer Treatment Research Center, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Yongmei Yang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| |
Collapse
|
|
19
|
Mariani L, Miceli R, Lusa L, Di Bartolomeo M, Bozzetti F. A Modified Prognostic Score for Patients with Curatively Resected Gastric Cancer. TUMORI JOURNAL 2018; 91:221-6. [PMID: 16206644 DOI: 10.1177/030089160509100302] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Aims and background Gastric cancer is the second leading cause of cancer death worldwide; the risk of dying depends on several patient and disease characteristics. An existing prognostic score predicts survival in gastric cancer patients undergoing curative resection based on patient age, tumor site, extent of wall invasion and nodal status, categorized as simply as negative or positive. Methods Our aim was to modify the original prognostic score by incorporating information on nodal stage according to the latest TNM classification (number of involved nodes), based on a retrospective series of 610 chemotherapy-naïve gastric cancer patients recruited to a surgical clinical trial. We then tested the modified score on an independent series of 136 gastric cancer patients. Results Nodal stage added significant prognostic information to the nodal status classification (P <0.001), and was therefore included in the modified score. With the latter, we were able to identify three risk groups with overall five-year survival varying from more than 70% to less than 30%. The prognostic performance of the modified score was better than that achieved with the AJCC-UICC TNM staging. Conclusions The modified score, based on established prognostic factors, is proposed as a simple tool for prognostic grouping of gastric cancer patients undergoing curative surgery.
Collapse
Affiliation(s)
- Luigi Mariani
- Medical Statistics and Biometry Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano.
| | | | | | | | | |
Collapse
|
|
20
|
Bai F, Jiu M, You Y, Feng Y, Xin R, Liu X, Mo L, Nie Y. miR‑29a‑3p represses proliferation and metastasis of gastric cancer cells via attenuating HAS3 levels. Mol Med Rep 2018; 17:8145-8152. [PMID: 29693123 PMCID: PMC5983988 DOI: 10.3892/mmr.2018.8896] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 04/03/2018] [Indexed: 12/30/2022] Open
Abstract
MicroRNA-29a (miR-29a) has recently been in the spotlight as a tumor suppressor whose encoding gene is frequently suppressed in cancers. The aim of the present study was to investigate the biological functions and underlying molecular mechanism by which miR-29a-3p suppresses gastric cancer peritoneum metastasis. Cell proliferation, colony-forming, wound healing and Transwell migration assays were performed in the present study. MiR-29a-3p expression was markedly decreased in gastric cancer cell lines with stronger metastatic potential. Silencing miR-29a-3p expression promoted gastric cancer cell proliferation, colony-forming, migration and invasion. By contrast, overexpression of miR-29a-3p inhibited these biological phenotypes. In addition, it was revealed that miR-29a-3p functioned through downregulating hyaluronan synthase 3 expression. Collectively, dysregulated miR-29a-3p expression in gastric cancer cells was associated with malignant properties primarily relevant to migration and metastasis. The results suggest that miR-29a-3p may be a potential therapeutic target for gastric cancer.
Collapse
Affiliation(s)
- Feihu Bai
- Department of Gastroenterology, Ningxia Hui Autonomous Region People's Hospital, Yinchuan, Ningxia Hui Autonomous Region 750021, P.R. China
| | - Mengna Jiu
- Department of Gastroenterology, Ankang Central Hospital, Ankang, Shanxi 725000, P.R. China
| | - Yanjie You
- Department of Gastroenterology, Ningxia Hui Autonomous Region People's Hospital, Yinchuan, Ningxia Hui Autonomous Region 750021, P.R. China
| | - Yaning Feng
- Department of Gastroenterology, Ningxia Hui Autonomous Region People's Hospital, Yinchuan, Ningxia Hui Autonomous Region 750021, P.R. China
| | - Ruijuan Xin
- Department of Gastroenterology, Ningxia Hui Autonomous Region People's Hospital, Yinchuan, Ningxia Hui Autonomous Region 750021, P.R. China
| | - Xiaogang Liu
- Department of Basic Medicine, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Lirong Mo
- Department of Basic Medicine, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Yongzhan Nie
- Department of Gasteroenterology, Xijing Hospital of Digestive Diseases, State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xi'an, Shanxi 710000, P.R. China
| |
Collapse
|
|
21
|
Gao P, Wang S, Jing F, Zhan J, Wang Y. microRNA-203 suppresses invasion of gastric cancer cells by targeting ERK1/2/Slug/ E-cadherin signaling. Cancer Biomark 2018; 19:11-20. [PMID: 28269747 DOI: 10.3233/cbm-160167] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS Growing evidence suggests that microRNA plays an essential role in the development and metastasis of many tumors, including gastric cancer (GC). Expression of microRNA-203 (miR-203) has been reported to decrease in GC. In addition, overexpression of miR-203 inhibits grow of GC cells in vitro and in vivo. However, whether miR-203 affects cell migration and invasion of GC remains unclear. This study aimed to reveal the role of miR-203 on migration and invasion of GC, and its potential mechanisms. METHODS Synthetic pre-miR-203 (miR-203), anti-miR-203 and scrambled negative control RNAs was transfected into the gastric cancer SGC7901 cells to generate miR-203 or anti-miR-203-transfected stable clones. The roles of miR-203 on cell invasion and motility were then analyzed by Transwell migration assay and Wound healing assay in vitro. Using siRNA to targeting ERK1/2, Slug, and E-cadherin or Slug cDNA transfection (to increase Slug expression) to examine the miR-203 signaling pathway. We also examined the efficacies of miR-203 or anti-miR-203 on peritoneal metastasis of SGC7901 cells in the nude mouse model. RESULTS Overexpression of miR-203 inhibits SGC7901 cell invasion and motility, followed by decreased phospho-ERK1/2 (pERK1/2) and Slug expression, as well as increased E-cadherin expression. Re-expression of Slug in miR-203/SGC7901cells decreased E-cadherin expression and restored the invasive phenotypes. Targeting E-cadherin in miR-203/SGC7901cells also restored the invasive phenotypes. Inhibition of miR-203 promotes SGC7901 cell invasion and motility, followed by increased phospho-ERK1/2 (pERK1/2) and Slug expression, as well as decreased E-cadherin expression. Targeting ERK1/2 or Slug in anti-miR-203/SGC7901cells increased E-cadherin expression and reversed the invasive phenotypes. In addition, targeting ERK1/2 decreased Slug and increased the E-cadherin expression. Significantly, we found that miR-203 could exert marked inhibition of the peritoneal metastasis of SGC7901 in nude mice in vivo. Targeting miR-203 could exert marked promotion of the peritoneal metastasis of SGC7901 in nude mice in vivo. CONCLUSIONS miR-203/ERK1/2/Slug/E-cadherin signaling pathway plays an essential role on SGC7901 cell invasion and motility. miR-203 can be novel modalities to prevent peritoneal metastasis of invasive cancers such as gastric cancer.
Collapse
Affiliation(s)
- Peng Gao
- Department of Emergency Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Shijie Wang
- Department of Gastroenterology, People's Hospital of Juxian, Rizhao, Shandong, China
| | - Fuchun Jing
- Department of General Surgery, The Second Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Jiang Zhan
- Department of General Surgery, The Second Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Yunhui Wang
- Department of General Surgery, The Second Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| |
Collapse
|
|
22
|
Li X, Zhong X, Pan X, Ji Y. Tumor-Suppressive MicroRNA-708 Targets Notch1 to Suppress Cell Proliferation and Invasion in Gastric Cancer. Oncol Res 2018; 26:1317-1326. [PMID: 29444743 PMCID: PMC7844794 DOI: 10.3727/096504018x15179680859017] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Growing evidence has demonstrated that numerous microRNAs (miRNAs) may participate in the regulation of gastric carcinogenesis and progression. This phenomenon suggests that gastric cancer-related miRNAs can be identified as effective therapeutic targets for this disease. miRNA-708 (miR-708) has recently been reported to be aberrantly expressed in several types of cancer and contribute to carcinogenesis and progression. However, the expression level, biological roles, and underlying mechanisms of miR-708 in gastric cancer are poorly understood. Here we found that miR-708 was downregulated in gastric cancer tissues and cell lines. Downregulated miR-708 expression was significantly associated with lymphatic metastasis, invasive depth, and TNM stage. Further investigation indicated that ectopic expression of miR-708 prohibited cell proliferation and invasion in gastric cancer. Bioinformatics analysis showed that Notch1 was a potential target of miR-708. Notch1 was further confirmed as a direct target gene of miR-708 in gastric cancer by dual-luciferase reporter assay, reverse transcription quantitative polymerase chain reaction, and Western blot analysis. Furthermore, an inverse association was found between miR-708 and Notch1 mRNA levels in gastric cancer tissues. In addition, restored Notch1 expression rescued the inhibitory effects on gastric cancer cell proliferation and invasion induced by miR-708 overexpression. Our findings highlight the tumor-suppressive roles of miR-708 in gastric cancer and suggest that miR-708 may be investigated as a novel target for gastric cancer treatment.
Collapse
Affiliation(s)
- Xuyan Li
- Clinical Laboratory Central, Huizhou Central People's Hospital, Guangdong, P.R. China
| | - Xuanfang Zhong
- Department of Digestion, Huizhou Central People's Hospital, Guangdong, P.R. China
| | - Xiuhua Pan
- Department of Radiotherapy, Huizhou Central People's Hospital, Guangdong, P.R. China
| | - Yan Ji
- Department of Prenatal Diagnosis, Huizhou Central People's Hospital, Guangdong, P.R. China
| |
Collapse
|
|
23
|
Chen X, Huang Z, Chen R. Microrna-136 promotes proliferation and invasion ingastric cancer cells through Pten/Akt/P-Akt signaling pathway. Oncol Lett 2018. [PMID: 29541241 DOI: 10.3892/ol.2018.7848] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer is the fourth most common cancer and the second most frequent cause of cancer-associated mortality in the world. Previous studies have revealed that expression levels of microRNAs (miRNAs) are associated with the initiation and progression of several types of cancer, including gastric cancer. Previous studies have demonstrated that the abnormal expression of miRNA-136 may serve a function in the progression of several types of human cancer. However, the expression pattern of miR-136, its functions and underlying molecular mechanisms in gastric cancer remain unresolved. In the present study, it was revealed that the expression of miR-136 was aberrantly up regulated in gastric cancer tissues and cell lines. The suppression of miR-136 was able to inhibit proliferation and invasion in gastric cancer cell lines. Furthermore, phosphatase and tensin homolog (PTEN) was identified as a direct target gene of miR-136 in gastric cancer. PTEN was under expressed in gastric cancer tissues compared with non-tumor gastric tissues, and PTEN expression was negatively correlated with miR-136 expression. Furthermore, PTEN overexpression mimics the effects of miR-136 knockdown on gastric cancer cells. Additionally, miR-136 under expression decreased phospho-(p) AKT expression, but did not affect AKT expression in gastric cancer cells. In conclusion, the data of the present study suggest that miR-136 acts as an oncogene in gastric cancer via regulation of the PTEN/AKT/p-AKT signaling pathway and may potentially serve as a novel therapeutic target for the treatment of gastric cancer.
Collapse
Affiliation(s)
- Xuyan Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Zhiming Huang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Renpin Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| |
Collapse
|
|
24
|
miRNA-337-3p inhibits gastric cancer progression through repressing myeloid zinc finger 1-facilitated expression of matrix metalloproteinase 14. Oncotarget 2018; 7:40314-40328. [PMID: 27259238 PMCID: PMC5130010 DOI: 10.18632/oncotarget.9739] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2016] [Accepted: 05/13/2016] [Indexed: 11/25/2022] Open
Abstract
Matrix metalloproteinase 14 (MMP-14), a membrane-anchored MMP that promotes the tumorigenesis and aggressiveness, is highly expressed in gastric cancer. However, the transcriptional regulators of MMP-14 expression in gastric cancer still remain largely unknown. In this study, through mining computational algorithm programs and chromatin immunoprecipitation datasets, we identified adjacent binding sites of myeloid zinc finger 1 (MZF1) and miRNA-337-3p (miR-337-3p) within the MMP-14 promoter. We demonstrated that MZF1 directly bound to the MMP-14 promoter to facilitate its nascent transcription and expression in gastric cancer cell lines. In contrast, endogenous miR-337-3p suppressed the MMP-14 expression through recognizing its binding site within MMP-14 promoter. Mechanistically, miR-337-3p repressed the binding of MZF1 to MMP-14 promoter via recruiting Argonaute 2 and inducing repressive chromatin remodeling. Gain- and loss-of-function studies demonstrated that miR-337-3p suppressed the growth, invasion, metastasis, and angiogenesis of gastric cancer cells in vitro and in vivo through repressing MZF1-facilitated MMP-14 expression. In clinical specimens and cell lines of gastric cancer, MZF1 was highly expressed and positively correlated with MMP-14 expression. Meanwhile, miR-337-3p was under-expressed and inversely correlated with MMP-14 levels. miR-337-3p was an independent prognostic factor for favorable outcome of gastric cancer, and patients with high MZF1 or MMP-14 expression had lower survival probability. Taken together, these data indicate that miR-337-3p directly binds to the MMP-14 promoter to repress MZF1-facilitatd MMP-14 expression, thus suppressing the progression of gastric cancer.
Collapse
|
|
25
|
Chiappini PBO, de Medeiros IUD, Lima LGC, Fregnani JH, Nonogaki S, da Costa WL, Coimbra FJF, Silva MJDBE, de Mello CAL, Pinto CAL, Begnami MD. Prognostic implications of phosphatidylinositol 3-kinase/AKT signaling pathway activation in gastric carcinomas. Arch Med Sci 2017; 13:1262-1268. [PMID: 29181056 PMCID: PMC5701681 DOI: 10.5114/aoms.2016.60394] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Accepted: 01/20/2016] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway plays a critical role in carcinogenesis and resistance to anticancer drugs. In this study, gastric carcinomas (GC) were investigated and statistical analyses were performed concerning the correlation between the clinicopathological features and activation of the PI3K/AKT pathway. MATERIAL AND METHODS Immunohistochemistry for p-AKT, p-mTOR and PTEN was performed in 239 GC and 200 non-neoplastic gastric tissues. The clinicopathological parameters were recorded from the medical charts. Statistical significance was defined by a p-value < 0.05. RESULTS High p-AKT expression was observed in 10% of the normal gastric tissue and in 90% of GC, and it was significantly associated with tumor size (p < 0.001), T3/T4 tumors (p < 0.001), and presence of metastases (p = 0.02). Similarly, p-mTOR positivity was found in GC cells, but not in the normal gastric mucosa, and was correlated with perineural invasion (p = 0.02) and T3/T4 tumors (p = 0.03). On the other hand, PTEN expression was weak and focal in the tumor cells, while in the normal gastric tissue this staining was strong and diffuse. Importantly, the expression of p-mTOR and PTEN was associated with overall survival. CONCLUSIONS The results of the present study, characterized by the loss of PTEN expression and higher expression of p-AKT and p-mTOR in the majority of tumor cells, apparently are implicated in the carcinogenesis and progression of GC. The identification of p-mTOR and PTEN expression as prognostic factors corroborates the identification and use of potential target drugs that could be more efficient for the treatment of these patients.
Collapse
|
|
26
|
Sun L, Subar AF, Bosire C, Dawsey SM, Kahle LL, Zimmerman TP, Abnet CC, Heller R, Graubard BI, Cook MB, Petrick JL. Dietary Flavonoid Intake Reduces the Risk of Head and Neck but Not Esophageal or Gastric Cancer in US Men and Women. J Nutr 2017; 147:1729-1738. [PMID: 28724656 PMCID: PMC5572494 DOI: 10.3945/jn.117.251579] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 04/02/2017] [Accepted: 06/14/2017] [Indexed: 01/28/2023] Open
Abstract
Background: Flavonoids are bioactive polyphenolic compounds found in fruits, vegetables, and beverages of plant origin. Previous studies have shown that flavonoid intake reduces the risk of certain cancers; however, few studies to date have examined associations of flavonoids with upper gastrointestinal cancers or used prospective cohorts.Objective: Our study examined the association between intake of flavonoids (anthocyanidins, flavan-3-ols, flavanones, flavones, flavonols, and isoflavones) and risk of head and neck, esophageal, and gastric cancers.Methods: The NIH-AARP Diet and Health Study is a prospective cohort study that consists of 469,008 participants. Over a mean 12-y follow-up, 2453 head and neck (including 1078 oral cavity, 424 pharyngeal, and 817 laryngeal), 1165 esophageal (890 adenocarcinoma and 275 squamous cell carcinoma), and 1297 gastric (625 cardia and 672 noncardia) cancer cases were identified. We used Cox proportional hazards regression models to estimate HRs and CIs for the associations between flavonoid intake assessed at study baseline and cancer outcomes. For 56 hypotheses examined, P-trend values were adjusted using the Benjamini-Hochberg (BH) procedure for false discovery rate control.Results: The highest quintile of total flavonoid intake was associated with a 24% lower risk of head and neck cancer (HR: 0.76; 95% CI: 0.66, 0.86; BH-adjusted 95% CI: 0.63, 0.91; P-trend = 0.02) compared with the lowest quintile. Notably, anthocyanidins were associated with a 28% lower risk of head and neck cancer (HR: 0.72; 95% CI: 0.62, 0.82; BH-adjusted 95% CI: 0.59, 0.87; P-trend = 0.0005), and flavanones were associated with a 22% lower risk of head and neck cancer (HR: 0.78; 95% CI: 0.68, 0.89; BH-adjusted 95% CI: 0.64, 0.94; P-trend: 0.02). No associations between flavonoid intake and risk of esophageal or gastric cancers were found.Conclusions: Our results indicate that flavonoid intake is associated with lower head and neck cancer risk. These associations suggest a protective effect of dietary flavonoids on head and neck cancer risk, and thus potential as a risk reduction strategy.
Collapse
Affiliation(s)
- Lucy Sun
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA;,Divisions of Cancer Epidemiology and Genetics and
| | - Amy F Subar
- Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD
| | | | | | | | | | | | - Ruth Heller
- Divisions of Cancer Epidemiology and Genetics and,Department of Statistics and Operations Research, Tel Aviv University, Tel Aviv-Yafo, Israel
| | | | | | | |
Collapse
|
|
27
|
miRNA-584-3p inhibits gastric cancer progression by repressing Yin Yang 1- facilitated MMP-14 expression. Sci Rep 2017; 7:8967. [PMID: 28827574 PMCID: PMC5566321 DOI: 10.1038/s41598-017-09271-5] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 07/21/2017] [Indexed: 12/31/2022] Open
Abstract
Recent evidence shows the emerging roles of promoter-targeting endogenous microRNAs (miRNAs) in regulating gene transcription. However, miRNAs affecting the transcription of matrix metalloproteinase 14 (MMP-14) in gastric cancer remain unknown. Herein, through integrative mining of public datasets, we identified the adjacent targeting sites of Yin Yang 1 (YY1) and miRNA-584-3p (miR-584-3p) within MMP-14 promoter. We demonstrated that YY1 directly targeted the MMP-14 promoter to facilitate its expression in gastric cancer cells. In contrast, miR-584-3p recognized its complementary site within MMP-14 promoter to suppress its expression. Mechanistically, miR-584-3p interacted with Argonaute 2 to recruit enhancer of zeste homolog 2 and euchromatic histone lysine methyltransferase 2, resulting in enrichment of repressive epigenetic markers and decreased binding of YY1 to MMP-14 promoter. miR-584-3p inhibited the in vitro and in vivo tumorigenesis and aggressiveness of gastric cancer cells through repressing YY1-facilitated MMP-14 expression. In clinical gastric cancer tissues, the expression of YY1 and miR-584-3p was positively or negatively correlated with MMP-14 levels. In addition, miR-584-3p and YY1 were independent prognostic factors associated with favorable and unfavorable outcome of gastric cancer patients, respectively. These data demonstrate that miR-584-3p directly targets the MMP-14 promoter to repress YY1-facilitated MMP-14 expression and inhibits the progression of gastric cancer.
Collapse
|
|
28
|
Chung HW, Lim JB. High-mobility group box-1 contributes tumor angiogenesis under interleukin-8 mediation during gastric cancer progression. Cancer Sci 2017; 108:1594-1601. [PMID: 28574630 PMCID: PMC5543560 DOI: 10.1111/cas.13288] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 05/26/2017] [Accepted: 05/30/2017] [Indexed: 12/12/2022] Open
Abstract
Many soluble factors are involved in tumor angiogenesis. Thus, it is valuable to identify novel soluble factors for effective control of tumor angiogenesis in gastric cancer (GC). We investigated the role of extracellular high‐mobility group box‐1 (HMGB1) and its associated soluble factors in the tumor angiogenesis of GC. Clinically, we measured serum levels of HMGB1 and GC‐associated cytokines/chemokines using GC serum samples (n = 120), and calculated microvessel density (MVD) by CD34 immunostaining using human GC tissues (n = 27). Then we analyzed the correlation of serum HMGB1 levels with MVD or that with cytokine/chemokine levels by linear regression. As in vitro angiogenesis assay for HMGB1, HUVEC migration and capillary tube formation assay were carried out using different histological types of human GC cells (N87 and KATOIII). CD34‐positive microvessels were detected from early GC, but MVD increased according to GC stages, and were closely correlated with serum HMGB1 levels (R = 0.608, P = 0.01). The HUVECs cultured in conditioned media derived from rhHMGB1‐treated or HMGB1‐TF GC cells showed remarkably enhanced migration and tube formation activities. These effects were abrogated by anti‐HMGB1 antibody or HMGB1 siRNA in both N87 and KATOIII cells (all P < 0.05). Among tested cytokines/chemokines, interleukin‐8 (IL‐8) was the most remarkable cytokine correlated with serum HMGB1 (P < 0.001), and enhanced HUVEC migration and tube formation activities by rhHMGB1 or HMGB1‐TF were significantly reversed by IL‐8 inhibition. These results indicate overexpressed HMGB1 contributes to tumor angiogenesis through IL‐8 mediation, and combined targeting of HMGB1 and IL‐8 can control tumor angiogenesis in GC.
Collapse
Affiliation(s)
| | - Jong-Baeck Lim
- Department of Laboratory Medicine, Seoul, Korea.,Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea
| |
Collapse
|
|
29
|
miR-182-5p improves the viability, mitosis, migration, and invasion ability of human gastric cancer cells by down-regulating RAB27A. Biosci Rep 2017; 37:BSR20170136. [PMID: 28546229 PMCID: PMC6434084 DOI: 10.1042/bsr20170136] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 05/22/2017] [Accepted: 05/25/2017] [Indexed: 12/27/2022] Open
Abstract
We investigated the effect of miR-182-5p on the viability, proliferation, invasion, and migration ability of human gastric cells by regulating the expression of RAB27A. Real-time PCR assay was used to detect the expression of miR-182-5 and RAB27A in human gastric carcinoma tissues, para-carcinoma tissues, and different cell lines. Western blotting was also used to determine the RAB27A expression in both tissues and cell lines. We chose the HGC-27 cell line as experiment subject as it demonstrated the highest miR-182-5p level. HGC-27 cells were transfected with different vectors and the cell viability, mitosis, invasion, and migration ability were measured through MTT assay, flow cytometry (FCM) analysis, Transwell assay, and wound healing assay. In comparison with the normal tissues, miR-182-5p is expressed at a higher level in gastric cancer (GC) tissues, while RAB27A is expressed at a lower level in cancerous tissues. The down-regulation of miR-182-5p and up-regulation of RAB27A can significantly decrease the viability, migration, invasion, and mitosis of HGC-27 cells. The target relationship between miR-182-5p and RAb27A was confirmed through a dual-luciferase reporter gene assay and Western blot assay. miR-182-5p enhances the viability, mitosis, migration, and invasion of human GC cells by down-regulating RAB27A.
Collapse
|
|
30
|
Li Y, Hu X, Ding D, Zou Y, Xu Y, Wang X, Zhang Y, Chen L, Chen Z, Tan W. In situ targeted MRI detection of Helicobacter pylori with stable magnetic graphitic nanocapsules. Nat Commun 2017. [PMID: 28643777 PMCID: PMC5501158 DOI: 10.1038/ncomms15653] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Helicobacter pylori infection is implicated in the aetiology of many diseases. Despite numerous studies, a painless, fast and direct method for the in situ detection of H. pylori remains a challenge, mainly due to the strong acidic/enzymatic environment of the gastric mucosa. Herein, we report the use of stable magnetic graphitic nanocapsules (MGNs), for in situ targeted magnetic resonance imaging (MRI) detection of H. pylori. Several layers of graphene as the shell effectively protect the magnetic core from corrosion while retaining the superior contrast effect for MRI in the gastric environment. Boronic-polyethylene glycol molecules were synthesized and modified on the MGN surface for targeted MRI detection. In a mouse model of H. pylori-induced infection, H. pylori was specifically detected through both T2-weighted MR imaging and Raman gastric mucosa imaging using functionalized MGNs. These results indicated that enhancement of MRI using MGNs may be a promising diagnostic and bioimaging platform for very harsh conditions.
Collapse
Affiliation(s)
- Yunjie Li
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Hunan University, Changsha 410082, China
| | - Xiaoxiao Hu
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Hunan University, Changsha 410082, China
| | - Ding Ding
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Hunan University, Changsha 410082, China
| | - Yuxiu Zou
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Hunan University, Changsha 410082, China
| | - Yiting Xu
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Hunan University, Changsha 410082, China
| | - Xuewei Wang
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Hunan University, Changsha 410082, China
| | - Yin Zhang
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Hunan University, Changsha 410082, China
| | - Long Chen
- Faculty of Science and Technology, University of Macau, Av. da Universidade, Taipa 999078, Macau
| | - Zhuo Chen
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Hunan University, Changsha 410082, China
| | - Weihong Tan
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Hunan University, Changsha 410082, China.,Department of Chemistry and Department of Physiology and Functional Genomics, Center for Research at Bio/nano Interface, Shands Cancer Center, UF Genetics Institute and McKnight Brain Institute, University of Florida, Gainesville, Florida 32611-7200, USA
| |
Collapse
|
|
31
|
Decreased digit ratio (2D:4D) and gastric cancer in Chinese men. Early Hum Dev 2016; 103:109-112. [PMID: 27565127 DOI: 10.1016/j.earlhumdev.2016.08.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Revised: 07/27/2016] [Accepted: 08/09/2016] [Indexed: 12/26/2022]
Abstract
BACKGROUND The development of finger length is influenced by the level of hormones during pregnancy in the womb. The relative length of 2nd to 4th digit (2D:4D) is considered as a putative marker for prenatal hormone exposure and may represent an individual susceptibility to certain diseases, particularly those hormone-related cancers (e.g., gastric cancer). AIMS The aim of this study is to investigate whether there is a possible relationship between 2D:4D ratio and gastric cancer (GCA) in Chinese men. METHODS 94 male patients with GCA and 91 controls were chosen to participate in this study. Photographs of both hands were collected and then the lengths of second and fourth digits of both hands were measured. Left hand, right hand, mean hand, and right minus left hand (∆R-L) 2D:4D ratios were analyzed and compared. RESULTS In GCA group, 2D:4D ratios were significantly lower (right hand: p<0.01; left hand, mean hand: p<0.001) than controls. No association was observed between 2D:4D ratio and tumor staging (neither in tumor size (T) nor in lymph node involvement (N) or distant metastases (M)). There was also no correlation between 2D:4D ratio and age of onset. CONCLUSIONS Decreased 2D:4D ratio may be an indicator for forecasting the susceptibility to develop GCA.
Collapse
|
|
32
|
Shivappa N, Hébert JR, Ferraroni M, La Vecchia C, Rossi M. Association between Dietary Inflammatory Index and Gastric Cancer Risk in an Italian Case-Control Study. Nutr Cancer 2016; 68:1262-1268. [PMID: 27636679 PMCID: PMC5154551 DOI: 10.1080/01635581.2016.1224367] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND In this study, we explored the association between the dietary inflammatory index (DII) and gastric cancer risk in an Italian case-control study. MATERIALS AND METHODS Cases were 230 patients with incident, histologically confirmed cases of gastric cancer from the Greater Milan area, Northern Italy. Controls were 547 frequency-matched subjects admitted to the same network of hospitals as cases for a wide spectrum of acute, non-neoplastic conditions. The DII was computed using a reproducible and valid 78-item food frequency questionnaire. Odds ratios (ORs) were estimated through logistic regression models conditioned on age and sex and adjusted for recognized confounding factors, including total energy intake. RESULTS Subjects with the most pro-inflammatory diet had a higher risk of gastric cancer compared to subjects with the most anti-inflammatory diet (ORQuartile4vs1 = 2.35, 95% confidence interval, 1.32, 4.20; P-trend = 0.004). CONCLUSION These results indicate that a pro-inflammatory diet, as indicated by higher DII score, was associated with increased risk of gastric cancer.
Collapse
Affiliation(s)
- Nitin Shivappa
- Cancer Prevention and Control Program, University of South Carolina, Columbia, SC 29208, USA
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
- Connecting Health Innovations LLC, Columbia, SC, 29229, USA
| | - James R. Hébert
- Cancer Prevention and Control Program, University of South Carolina, Columbia, SC 29208, USA
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
- Connecting Health Innovations LLC, Columbia, SC, 29229, USA
- Department of Family and Preventive Medicine, University of South Carolina School of Medicine, Columbia, South Carolina, 29208, USA
| | - Monica Ferraroni
- Department of Clinical Sciences and Community Health. Universitá degli Studi di Milano, Milan, Italy
| | - Carlo La Vecchia
- Department of Clinical Sciences and Community Health. Universitá degli Studi di Milano, Milan, Italy
| | - Marta Rossi
- Department of Clinical Sciences and Community Health. Universitá degli Studi di Milano, Milan, Italy
| |
Collapse
|
|
33
|
Li C, Dong J, Han Z, Zhang K. MicroRNA-219-5p Represses the Proliferation, Migration, and Invasion of Gastric Cancer Cells by Targeting the LRH-1/Wnt/β-Catenin Signaling Pathway. Oncol Res 2016; 25:617-627. [PMID: 27983934 PMCID: PMC7841075 DOI: 10.3727/096504016x14768374457986] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
MicroRNAs (miRNAs) are reportedly involved in gastric cancer development and progression. In particular, miR-219-5p has been reported to be a tumor-associated miRNA in human cancer. However, the role of miR-219-5p in gastric cancer remains unclear. In this study, we investigated for the first time the potential role and underlying mechanism of miR-219-5p in the proliferation, migration, and invasion of human gastric cancer cells. miR-219-5p was found to be markedly decreased in gastric cancer tissues and cell lines compared with adjacent tissues and normal gastric epithelial cells. miR-219-5p mimics or anti-miR-219-5p was transfected into gastric cancer cell lines to overexpress or suppress miR-219-5p expression, respectively. Results showed that miR-219-5p overexpression significantly decreased the proliferation, migration, and invasion of gastric cancer cells. Conversely, miR-219-5p suppression demonstrated a completely opposite effect. Bioinformatics and luciferase reporter assays indicated that miR-219-5p targeted the 3′-untranslated region of the liver receptor homolog-1 (LRH-1), a well-characterized oncogene. Furthermore, miR-219-5p inhibited the mRNA and protein levels of LRH-1. LRH-1 mRNA expression was inversely correlated with miR-219-5p expression in gastric cancer tissues. miR-219-5p overexpression significantly decreased the Wnt/β-catenin signaling pathway in gastric cancer cells. Additionally, LRH-1 restoration can markedly reverse miR-219-5p-mediated tumor suppressive effects. Our study suggests that miR-219-5p regulated the proliferation, migration, and invasion of human gastric cancer cells by suppressing LRH-1. miR-219-5p may be a potential target for gastric cancer therapy.
Collapse
Affiliation(s)
- Chunsheng Li
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, P.R. China
| | - Jingrong Dong
- Endoscopic Center, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, P.R. China
| | - Zhenqi Han
- Endoscopic Center, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, P.R. China
| | - Kai Zhang
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, Jilin, P.R. China
| |
Collapse
|
|
34
|
Zheng L, Jiao W, Song H, Qu H, Li D, Mei H, Chen Y, Yang F, Li H, Huang K, Tong Q. miRNA-558 promotes gastric cancer progression through attenuating Smad4-mediated repression of heparanase expression. Cell Death Dis 2016; 7:e2382. [PMID: 27685626 PMCID: PMC5059886 DOI: 10.1038/cddis.2016.293] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 08/20/2016] [Accepted: 08/23/2016] [Indexed: 12/25/2022]
Abstract
Previous studies have indicated that as the only mammalian endo-β-D-glucuronidase, heparanase (HPSE) is up-regulated and associated with poor prognosis in gastric cancer, while the underlying mechanisms still remain to be determined. Herein, through integrative analysis of public datasets, we found microRNA-558 (miR-558) and SMAD family member 4 (Smad4) as the crucial transcription regulators of HPSE expression in gastric cancer, with their adjacent target sites within the promoter of HPSE. We identified that endogenous miR-558 activated the transcription and expression of HPSE in gastric cancer cell lines. In contrast, Smad4 suppressed the nascent transcription and expression of HPSE via directly binding to its promoter. Mechanistically, miR-558 recognized its complementary site within HPSE promoter to decrease the binding of Smad4 in an Argonaute 1-dependent manner. Ectopic expression or knockdown experiments indicated that miR-558 promoted the in vitro and in vivo tumorigenesis and aggressiveness of gastric cancer cell lines via attenuating Smad4-mediated repression of HPSE expression. In clinical gastric cancer specimens, up-regulation of miR-558 and down-regulation of Smad4 were positively correlated with HPSE expression. Kaplan–Meier survival analysis revealed that miR-558 and Smad4 were associated with unfavourable and favourable outcome of gastric cancer patients, respectively. Therefore, these findings demonstrate that miR-558 facilitates the progression of gastric cancer through directly targeting the HPSE promoter to attenuate Smad4-mediated repression of HPSE expression.
Collapse
Affiliation(s)
- Liduan Zheng
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, P. R. China.,Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, P. R. China
| | - Wanju Jiao
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, P. R. China
| | - Huajie Song
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, P. R. China
| | - Hongxia Qu
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, P. R. China
| | - Dan Li
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, P. R. China
| | - Hong Mei
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, P. R. China
| | - Yajun Chen
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, P. R. China
| | - Feng Yang
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, P. R. China
| | - Huanhuan Li
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, P. R. China
| | - Kai Huang
- Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, P. R. China
| | - Qiangsong Tong
- Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, P. R. China.,Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, P. R. China
| |
Collapse
|
|
35
|
Li D, Zhao X, Xiao Y, Mei H, Pu J, Xiang X, Jiao W, Song H, Qu H, Huang K, Zheng L, Tong Q. Intelectin 1 suppresses tumor progression and is associated with improved survival in gastric cancer. Oncotarget 2016; 6:16168-82. [PMID: 25965823 PMCID: PMC4599263 DOI: 10.18632/oncotarget.3753] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Accepted: 04/06/2015] [Indexed: 12/30/2022] Open
Abstract
Recent evidence shows the emerging roles of intelectin 1 (ITLN1), a secretory lectin, in human cancers. Our previous studies have implicated the potential roles of ITLN1 in the aggressiveness of gastric cancer. Herein, we investigated the functions, downstream targets, and clinical significance of ITLN1 in the progression of gastric cancer. We demonstrated that ITLN1 increased the levels of hepatocyte nuclear factor 4 alpha (HNF4α), resulting in suppression of nuclear translocation and transcriptional activity of β-catenin in gastric cancer cells. Mechanistically, ITLN1 attenuated the activity of nuclear factor-kappa B, a transcription factor repressing the HNF4α expression, in gastric cancer cells through inactivating the phosphoinositide 3-kinase/AKT/Ikappa B kinase signaling. Gain- and loss-of-function studies demonstrated that ITLN1 suppressed the growth, invasion, and metastasis of gastric cancer cells in vitro and in vivo. In addition, restoration of HNF4α expression prevented the gastric cancer cells from ITLN1-mediated changes in these biological features. In clinical gastric cancer tissues, HNF4α expression was positively correlated with that of ITLN1. Patients with high ITLN1 or HNF4α expression had greater survival probability. Taken together, these data indicate that ITLN1 suppresses the progression of gastric cancer through up-regulation of HNF4α, and is associated with improved survival in patients with gastric cancer.
Collapse
Affiliation(s)
- Dan Li
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| | - Xiang Zhao
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| | - Yong Xiao
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| | - Hong Mei
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| | - Jiarui Pu
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| | - Xuan Xiang
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| | - Wanju Jiao
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| | - Huajie Song
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| | - Hongxia Qu
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| | - Kai Huang
- Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.,Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| | - Liduan Zheng
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.,Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| | - Qiangsong Tong
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.,Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
| |
Collapse
|
|
36
|
Jiang SB, He XJ, Xia YJ, Hu WJ, Luo JG, Zhang J, Tao HQ. MicroRNA-145-5p inhibits gastric cancer invasiveness through targeting N-cadherin and ZEB2 to suppress epithelial-mesenchymal transition. Onco Targets Ther 2016; 9:2305-15. [PMID: 27143926 PMCID: PMC4846054 DOI: 10.2147/ott.s101853] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
MicroRNA (miR)-145-5p has been reported to function as a suppressor of cancer and plays an important role in cancer invasiveness. Epithelial-mesenchymal transition (EMT) is an important process in cancer invasion and migration. However, the involvement of miR-145-5p in EMT in human gastric cancer (GC) remains unclear. In this study, we aimed to investigate the molecular mechanisms by which miR-145-5p regulates EMT in GC invasiveness. We used quantitative real-time polymerase chain reaction to investigate the miR-145-5p expression level in GC and matched normal tissues. The effects of miR-145-5p on GC cell invasion and migration abilities were evaluated using Transwell models. The relationships among miR-145-5p and zinc-finger E-box binding homeobox 2 (ZEB2), E-cadherin, and N-cadherin were analyzed by quantitative real-time polymerase chain reaction and Western blot analyses. miR-145-5p levels in primary GC tissues obtained from 60 patients were significantly downregulated, compared to those in paired normal tissues. Lauren classification, depth of tumor invasion, lymph node metastasis, lymphatic invasion, and tumor-node-metastasis stage were associated with miR-145-5p expression. miR-145-5p inhibits the expression of the candidate target gene ZEB2 to delay the invasion and migration of GC cells. ZEB2 acts as transcriptional repressor of E-cadherin, while miR-145-5p is known to suppress N-cadherin directly to regulate EMT. Therefore, we concluded that miR-145-5p may target N-cadherin and ZEB2 directly to influence EMT.
Collapse
Affiliation(s)
- Shi-Bin Jiang
- Department of Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China
- Wenzhou Medical University, Wenzhou, People’s Republic of China
| | - Xu-Jun He
- Department of Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, People’s Republic of China
| | - Ying-Jie Xia
- Department of Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, People’s Republic of China
| | - Wei-Jian Hu
- Wenzhou Medical University, Wenzhou, People’s Republic of China
| | - Jun-Gang Luo
- Department of Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China
- Wenzhou Medical University, Wenzhou, People’s Republic of China
| | - Jun Zhang
- Wenzhou Medical University, Wenzhou, People’s Republic of China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, People’s Republic of China
| | - Hou-Quan Tao
- Department of Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China
- Wenzhou Medical University, Wenzhou, People’s Republic of China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, People’s Republic of China
| |
Collapse
|
|
37
|
Yan S, Wang Y, Chen M, Li G, Fan J. Deregulated SLC2A1 Promotes Tumor Cell Proliferation and Metastasis in Gastric Cancer. Int J Mol Sci 2015; 16:16144-57. [PMID: 26193257 PMCID: PMC4519943 DOI: 10.3390/ijms160716144] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2015] [Revised: 07/08/2015] [Accepted: 07/09/2015] [Indexed: 11/29/2022] Open
Abstract
Gastric cancer (GC) is one of the common reasons of cancer-related death with few biomarkers for diagnosis and prognosis. Solute carrier family 2 (facilitated glucose transporter) member 1 protein SLC2A1, also known as glucose transporter type 1 (GLUT1), has been associated with tumor progression, metastasis, and poor prognosis in many human solid tumors. However, little is reported about its clinical significance and biological functions in GC. Here we observed a strong up-regulation of SLC2A1 in patients with GC and found that SLC2A1 was significantly correlated with depth of invasion and clinical stage. Additionally, over-expression of SLC2A1 in GC cells promotes cellular proliferation and metastasis in vitro and enhances tumor growth in vivo as well as enhancement of glucose utilization. Meanwhile, elevated SLC2A1 also contributes to tumor metastasis in vitro. Our results indicate SLC2A1 exhibits a pivotal role in tumor growth, metastasis and glucose metabolism, and also suggest SLC2A1 as a promising target for gastric cancer therapy.
Collapse
Affiliation(s)
- Shiyan Yan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
| | - Yuqin Wang
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
| | - Meimei Chen
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
| | - Guangming Li
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
| | - Jiangao Fan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
| |
Collapse
|
|
38
|
Wang J, Ma R, Sharma A, He M, Xue J, Wu J, Dun B, Li G, Wang X, Ji M, She JX, Tang J. Inflammatory serum proteins are severely altered in metastatic gastric adenocarcinoma patients from the Chinese population. PLoS One 2015; 10:e0123985. [PMID: 25884401 PMCID: PMC4401731 DOI: 10.1371/journal.pone.0123985] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Accepted: 02/25/2015] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Inflammation is one of the major hallmarks of cancer. This study was designed to profile a panel of inflammatory mediators in gastric adenocarcinoma (GA) and to identify their potential differences separately in metastatic and non-metastatic patient subgroups. METHODS Serum samples from 216 GA patients and 333 healthy controls from China were analyzed for six proteins using the Luminex multiplex assay. RESULTS The serum levels for all the six proteins were significantly elevated in metastatic GA compared to non-metastatic GA. Two acute phase proteins (SAA and CRP) and a CXC chemokine (GRO) were significantly elevated in metastatic GA (p <0.01) but smaller changes were observed in non-metastatic GA compared to healthy controls. OPN is moderately increased in non-metastatic GA (2.05-fold) and more severely elevated in metastatic GA (3.34-fold). Surprisingly, soluble VCAM1 and AGP were significantly lower in both non-metastatic and metastatic GA patients compared to controls. Several individual proteins were shown to possess moderate diagnostic value for non-metastatic GA (AUC = 0.786, 0.833, 0.823 for OPN, sVCAM1 and AGP, respectively) and metastatic GA (AUC = 0.931, 0.720, 0.834 and 0.737 for OPN, sVCAM1, SAA and CRP, respectively). However, protein combinations further improve the diagnostic potential for both non-metastatic GA (best AUC = 0.946) and metastatic GA (best AUC = 0.963). The protein combination with best AUC value for both comparisons is OPN+sVCAM1+AGP+SAA. CONCLUSIONS These results suggest that several serum proteins are directly related to the severity of gastric cancer. Overall, stronger associations are observed with metastatic than non-metastatic GA as the protein changes are greater with the metastatic status. A combination of these serum proteins may serve as non-invasive markers to assess the severity status and stage of gastric cancer.
Collapse
Affiliation(s)
- Jiangnan Wang
- Institute of Translational Medicine, School of Pharmaceutical Sciences, Nanjing University of Technology, Nanjing, Jiangsu Province, China
| | - Rong Ma
- Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Ashok Sharma
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America
| | - Mingfang He
- Institute of Translational Medicine, School of Pharmaceutical Sciences, Nanjing University of Technology, Nanjing, Jiangsu Province, China
| | - Jing Xue
- Institute of Translational Medicine, School of Pharmaceutical Sciences, Nanjing University of Technology, Nanjing, Jiangsu Province, China
- Zhengjiang Jintai Biosciences, Zhengjiang, Jiangsu Province, China
| | - Jianzhong Wu
- Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Boying Dun
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America
| | - Gang Li
- Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America
| | - Xiaoxiao Wang
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America
| | - Minghua Ji
- Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America
| | - Jin-Xiong She
- Institute of Translational Medicine, School of Pharmaceutical Sciences, Nanjing University of Technology, Nanjing, Jiangsu Province, China
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America
| | - Jinhai Tang
- Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| |
Collapse
|
|
39
|
Li R, Yuan W, Mei W, Yang K, Chen Z. MicroRNA 520d-3p inhibits gastric cancer cell proliferation, migration, and invasion by downregulating EphA2 expression. Mol Cell Biochem 2014; 396:295-305. [PMID: 25063221 DOI: 10.1007/s11010-014-2164-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2014] [Accepted: 07/14/2014] [Indexed: 01/01/2023]
Abstract
Aberrant expression of microRNAs (miRNAs) has been shown to play important roles in cancer progression as a result of changes in expression of their target genes. In this study, we investigated the roles of miR-520d-3p on gastric cancer (GC) cell proliferation, migration, and invasion, and confirmed that this miRNA regulates EphA2 expression. The mRNA expression levels of miR-520d-3p and EphA2 in GC tissues and cell lines were evaluated. The clinical and prognostic significance of miR-520d-3p was assessed. The biological function of miR-520d-3p in GC cells was investigated using a methylthiazolyldiphenyl-tetrazolium bromide assay, cell cycle assay, transwell invasion assay, and wound-healing assay. miR-520d-3p expression was down-regulated and inversely correlated with the expression of EphA2 in GC tissues and cell lines. Lower expression of miR-520d-3p was associated with tumor invasion (P = 0.0357), lymph nodes metastasis (P = 0.0272), a higher clinical stage (P = 0.0041), and poorer overall survival (P = 0.0105). Luciferase assays revealed that miR-520d-3p inhibited EphA2 expression by targeting the 3'-untranslated region of EphA2 mRNA. Overexpression of miR-520d-3p dramatically inhibited the proliferation, cell cycle progression, invasion, and migration of GC cells, while down-regulation substantially promoted these properties. Moreover, c-Myc, CyclinD1, and matrix metalloproteinase-9 expression levels were down-regulated in miR-520d-3p mimic-transfected cells and up-regulated in miR-520d-3p inhibitor-transfected cells. Taken together, our data showed that miR-520d-3p appears to contribute to GC progression via the regulation of EphA2 and could serve as a novel prognostic and potential therapeutic marker.
Collapse
Affiliation(s)
- Ruixin Li
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Xiangya Road, Changsha, 410008, Hunan, People's Republic of China
| | | | | | | | | |
Collapse
|
|
40
|
Zhang J, Zhan Z, Wu J, Zhang C, Yang Y, Tong S, Wang R, Yang X, Dong W. Association among lifestyle, clinical examination, polymorphisms in CDH1 gene and Traditional Chinese Medicine syndrome differentiation of gastric cancer. J TRADIT CHIN MED 2014; 33:572-9. [PMID: 24660577 DOI: 10.1016/s0254-6272(14)60023-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To explore the association among life-style, clinical examination, polymorphisms in CDH1 gene and Traditional Chinese Medicine (TCM) syndrome differentiation of gastric cancer (GC). METHODS A hospital-based population of 387 GC patients was investigated in Jiangsu province. Relevant information regarding lifestyle and clinical examination were collected by a standard questionnaire. Four known single nucleotide polymorphisms (SNPs) in CDH1 were investigated by polymerase chain reaction-ligation detection reaction methods. Statistical analysis was conducted by SPSS 16.0 software. RESULTS The results showed that meal duration and the status of glutamic pyruvic transaminase were significantly associated with TCM syndrome differentiation of GC (both P < 0.05). None of the four SNPs in the E-cadherin (CDH1) gene achieved significant differences in their distributions among the nine syndrome types of GC (both P > 0.05). However, significant differences were observed in rs13689 genotype distributions between several pairs of syndrome types of GC, suggesting that rs13689 is correlated with the syndrome differentiation of GC. CONCLUSION Integrated analysis of lifestyle, clinical examination and CDH1 gene polymorphisms can contribute to a better understanding of the GC syndrome types and may improve the efficacy of interventions by stratifying disease according to TCM criteria.
Collapse
|
|
41
|
Thiraworawong T, Spinler JK, Werawatganon D, Klaikeaw N, Venable SF, Versalovic J, Tumwasorn S. Anti-inflammatory properties of gastric-derived Lactobacillus plantarum XB7 in the context of Helicobacter pylori infection. Helicobacter 2014; 19:144-55. [PMID: 24387083 DOI: 10.1111/hel.12105] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Helicobacter pylori colonization of the gastric epithelium induces interleukin-8 (IL-8) production and inflammation leading to host cell damage. We searched for gastric-derived Lactobacillus with the ability to suppress H. pylori-induced inflammation. MATERIALS AND METHODS Conditioned media from gastric-derived Lactobacillus spp. were tested for the ability to suppress H. pylori-induced IL-8 production in AGS gastric epithelial cells. IL-8 protein and mRNA levels were measured by ELISA and qPCR, respectively. The changes on host cell signaling pathway were analyzed by Western blotting and the anti-inflammatory effect was tested in a Sprague-Dawley rat model. RESULTS Conditioned media from L. salivarius B101, L. rhamnosus B103, and L. plantarum XB7 suppressed IL-8 production and IL-8 mRNA expression in H. pylori-induced AGS cells without inhibiting H. pylori growth. Conditioned media from LS-B101, LR-B103, and LP-XB7 suppressed the activation of NF-κB in AGS cells, while strain LP-XB7 also suppressed c-Jun activation. The anti-inflammatory effect of LP-XB7 was further assessed in vivo using a H. pylori-infected Sprague-Dawley rat model. Strain LP-XB7 contributed to a delay in the detection and colonization of H. pylori in rat stomachs, attenuated gastric inflammation, and ameliorated gastric histopathology. Additionally, the administration of LP-XB7 correlated with the suppression of TNF-α and CINC-1 in sera, and suppression of CINC-1 in the gastric mucosa of H. pylori-infected rats. CONCLUSIONS These results suggest that L. plantarum XB7 produces secreted factors capable of modulating inflammation during H. pylori infection, and this probiotic Lactobacillus strain shows promise as an adjunctive therapy for treating H. pylori-associated disease.
Collapse
Affiliation(s)
- Thien Thiraworawong
- Interdisciplinary Program of Medical Microbiology, Graduate School, Chulalongkorn University, Bangkok, 10330, Thailand
| | | | | | | | | | | | | |
Collapse
|
|
42
|
Chung HW, Lim JB. Role of the tumor microenvironment in the pathogenesis of gastric carcinoma. World J Gastroenterol 2014; 20:1667-1680. [PMID: 24587646 PMCID: PMC3930967 DOI: 10.3748/wjg.v20.i7.1667] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 11/22/2013] [Accepted: 12/06/2013] [Indexed: 02/06/2023] Open
Abstract
Gastric carcinoma (GC) is the 4th most prevalent cancer and has the 2nd highest cancer-related mortality rate worldwide. Despite the incidence of GC has decreased over the past few decades, it is still a serious health problem. Chronic inflammatory status of the stomach, caused by the infection of Helicobacter pylori (H. pylori) and through the production of inflammatory mediators within the parenchyma is suspected to play an important role in the initiation and progression of GC. In this review, the correlation between chronic inflammation and H. pylori infection as an important factor for the development of GC will be discussed. Major components, including tumor-associated macrophages, lymphocytes, cancer-associated fibroblasts, angiogenic factors, cytokines, and chemokines of GC microenvironment and their mechanism of action on signaling pathways will also be discussed. Increasing our understanding of how the components of the tumor microenviroment interact with GC cells and the signaling pathways involved could help identify new therapeutic and chemopreventive targets.
Collapse
|
|
43
|
Takabayashi K, Kashiwagi K, Kawata T, Sato T, Matsuoka K, Hisamatsu T, Takaishi H, Hibi T, Ogata H, Yahagi N, Kitagawa Y, Shigematsu N, Kanai T. Continuous low-dose irradiation by I-125 seeds induces apoptosis of gastric cancer cells regardless of histological origin. Cancer Biol Ther 2013; 15:81-8. [PMID: 24149371 DOI: 10.4161/cbt.26610] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The efficacy of conventional radiation therapy for gastric cancer is controversial. In this study, we evaluated the in vitro and in vivo effects of continuous low-dose-rate irradiation by I-125 seeds on different histological types of gastric cancer cell lines. Three human gastric cancer cell lines (MKN74, MKN45, and NUGC4) were treated with or without continuous low-dose irradiation by I-125 seeds in vitro and in vivo. Cell viability, apoptosis, caspase-3 assay, and cell-cycle distribution were examined in vitro. Body weight and tumor volumes of BALB/c nude mice bearing MKN74, MKN45, and NUGC4 gastric cancer xenografts were measured, and in vivo cell proliferation and apoptosis assays were performed by Ki67 and TUNEL staining, respectively. Continuous low-dose-rate irradiation by I-125 seeds reduced cell viability and induced cell apoptosis through the activation of caspase-3, and led to the accumulation of cells in the G 2/M phase in vitro. It also suppressed the growth of gastric cancer xenografts in nude mice, while inhibiting cell proliferation and inducing apoptosis as demonstrated by Ki67 and TUNEL staining. Therefore, our data suggest that continuous low-dose-rate irradiation by I-125 seeds could be a promising new option for gastric cancer treatment, regardless of histological origin.
Collapse
Affiliation(s)
- Kaoru Takabayashi
- Division of Gastroenterology and Hepatology; Department of Internal Medicine; School of Medicine; Keio University; Tokyo, Japan
| | - Kazuhiro Kashiwagi
- Center for Diagnostic and Therapeutic Endoscopy; School of Medicine; Keio University; Tokyo, Japan
| | - Tetsuya Kawata
- Department of Radiology; School of Medicine; Keio University; Tokyo, Japan
| | - Toshiro Sato
- Division of Gastroenterology and Hepatology; Department of Internal Medicine; School of Medicine; Keio University; Tokyo, Japan
| | - Katsuyoshi Matsuoka
- Division of Gastroenterology and Hepatology; Department of Internal Medicine; School of Medicine; Keio University; Tokyo, Japan
| | - Tadakazu Hisamatsu
- Division of Gastroenterology and Hepatology; Department of Internal Medicine; School of Medicine; Keio University; Tokyo, Japan
| | | | - Toshifumi Hibi
- Division of Gastroenterology and Hepatology; Department of Internal Medicine; School of Medicine; Keio University; Tokyo, Japan
| | - Haruhiko Ogata
- Center for Diagnostic and Therapeutic Endoscopy; School of Medicine; Keio University; Tokyo, Japan
| | - Naohisa Yahagi
- Division of Research and Development for Minimally Invasive Treatment; Cancer Center; School of Medicine; Keio University; Tokyo, Japan
| | - Yuko Kitagawa
- Department of Surgery; School of Medicine; Keio University; Tokyo, Japan
| | - Naoyuki Shigematsu
- Department of Radiology; School of Medicine; Keio University; Tokyo, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology; Department of Internal Medicine; School of Medicine; Keio University; Tokyo, Japan
| |
Collapse
|
|
44
|
Yoshida T, Kato J, Inoue I, Yoshimura N, Deguchi H, Mukoubayashi C, Oka M, Watanabe M, Enomoto S, Niwa T, Maekita T, Iguchi M, Tamai H, Utsunomiya H, Yamamichi N, Fujishiro M, Iwane M, Takeshita T, Ushijima T, Ichinose M. Cancer development based on chronic active gastritis and resulting gastric atrophy as assessed by serum levels of pepsinogen and Helicobacter pylori antibody titer. Int J Cancer 2013; 134:1445-57. [PMID: 24009139 DOI: 10.1002/ijc.28470] [Citation(s) in RCA: 115] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2013] [Accepted: 08/22/2013] [Indexed: 12/11/2022]
Abstract
Our study investigated the relationship between gastric cancer development and activity of Helicobacter pylori-associated chronic gastritis or the resulting chronic atrophic gastritis (CAG). A cohort of 4,655 healthy asymptomatic subjects, in whom serum pepsinogen (PG) and H. pylori antibody titer had been measured to assess the activity and stage of H. pylori-associated chronic gastritis, was followed for up to 16 years, and cancer development was investigated. In subjects with a serologically diagnosed healthy stomach (H. pylori-negative/CAG-negative), cancer incidence rate was low, at 16/100,000 person-years. With the establishment of H. pylori infection and progression of chronic gastritis, significant stepwise cancer risk elevations were seen from CAG-free subjects (H. pylori-positive/CAG-negative) [hazard ratio (HR) = 8.9, 95% confidence interval (CI) = 2.7-54.7] to subjects with CAG (H. pylori-positive/CAG-positive) (HR = 17.7, 95% CI = 5.4-108.6) and finally to subjects with metaplastic gastritis (H. pylori-negative/CAG-positive) (HR = 69.7, 95% CI = 13.6-502.9). In H. pylori-infected CAG-free subjects, significantly elevated cancer risk was observed in the subgroup with active inflammation-based high PG II level or potent immune response-based high H. pylori antibody titer; the former was associated with a particularly high risk of diffuse-type cancer, and both subgroups showed high cancer incidence rates of around 250/100,000 person-years, comparable to that in subjects with CAG. No such risk elevation was observed in H. pylori-infected subjects with CAG. These results clearly indicate that gastric cancer develops mainly from the gastritis-atrophy-metaplasia-cancer sequence and partly from active inflammation-based direct carcinogenesis, and that serum levels of PG and H. pylori antibody titer provide indices of cancer development in H. pylori-infected subjects.
Collapse
Affiliation(s)
- Takeichi Yoshida
- Second Department of Internal Medicine, School of Medicine, Wakayama Medical University, Wakayama City, Wakayama, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Jeon C, Chang SC, Mu L, Zhao J, Rao JY, Lu QY, Zhang ZF. Genetic variants of peroxisome proliferator-activated receptor δ are associated with gastric cancer. Dig Dis Sci 2013; 58:2881-6. [PMID: 23907334 PMCID: PMC3783538 DOI: 10.1007/s10620-013-2770-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2013] [Accepted: 06/20/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND Peroxisome proliferator-activated receptors (PPAR) are implicated in pathogenesis of insulin resistance and cancers of the digestive system. AIM We investigated the associations of single nucleotide polymorphisms (SNPs) of PPAR δ and γ with gastric cancer and explored interactions with risk factors of gastric cancer. METHODS We conducted our analysis in a case-control study of 196 gastric cancer patients and 397 controls residing in the Taixing region of Jiangsu, China. Six SNPs in the PPARδ (rs2076167, rs3734254) and PPARγ genes (rs10865710, rs1801282, rs3856806, rs13306747) were genotyped. We employed logistic regression to evaluate the association between each genotype and gastric cancer and tested for gene-environment interaction with Helicobacter pylori (H. pylori) infection, smoking status, and meat and salt intake. RESULTS We found that the G/G variant rs2076167, in tight linkage disequilibrium with rs3734254 (R (2) = 0.97), was associated with increased risk of gastric cancer in a recessive model (OR 2.20, 95 % CI 1.12, 4.32). The association between G/G variant of rs2016167 and gastric cancer was particularly strong among those with higher salt intake (OR 5.11, 95 % CI 1.11, 23.5), but did not vary by H. pylori infection or smoking status. CONCLUSION We found that genetic variants of PPARδ were associated with gastric cancer. If the association is confirmed in larger studies, it may implicate a role for PPARδ activators, such as insulin-sensitizing agents, in prevention of gastric cancer.
Collapse
Affiliation(s)
- Christie Jeon
- Center for Cancer Prevention and Control Research, Fielding School of Public Health, University of California Los Angeles, 650 Charles E Young Drive South, A2-125 CHS, Los Angeles, CA 90095, USA
| | - Shen-Chih Chang
- Department of Epidemiology, Fielding School of Public Health, University of California Los Angeles, 650 Charles E Young Drive South, 73-271 CHS, Los Angeles, CA 90095, USA
| | - Lina Mu
- Department of Social and Preventive Medicine, School of Public Health and Health Professions, University at Buffalo, SUNY, 273A Farber Hall, Buffalo, NY 14214, USA
| | - Jinkou Zhao
- Department of Non-communicable Chronic Disease Control, Jiangsu Provincial Center for Disease Control and Prevention, Jiangsu Rd. Nanjing, Jiangsu, PR China 210009
| | - Jian-Yu Rao
- Center for Cancer Prevention and Control Research, Fielding School of Public Health, University of California Los Angeles, 650 Charles E Young Drive South, A2-125 CHS, Los Angeles, CA 90095, USA,Departments of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Ave 13-188 CHS, Los Angeles, CA 90095, USA
| | - Qing-Yi Lu
- Center for Human Nutrition, David Geffen School of Medicine, University of California Los Angeles, 900 Veteran Ave., 14-165, Los Angeles, CA 90095, USA
| | - Zuo-Feng Zhang
- Center for Cancer Prevention and Control Research, Fielding School of Public Health, University of California Los Angeles, 650 Charles E Young Drive South, A2-125 CHS, Los Angeles, CA 90095, USA,Department of Epidemiology, Fielding School of Public Health, University of California Los Angeles, 650 Charles E Young Drive South, 73-271 CHS, Los Angeles, CA 90095, USA
| |
Collapse
|
|
46
|
Wang Q, Chen Y, Zhang Y, Xu W, He H, Li X, Cui H. Quantitative assessment of the influence of glutathione S-transferase T1 null variant on gastric cancer risk. Tumour Biol 2013; 35:849-58. [PMID: 23979980 DOI: 10.1007/s13277-013-1118-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Accepted: 08/14/2013] [Indexed: 12/26/2022] Open
Abstract
Glutathione S-transferase T1 (GSTT1) catalyzes reactions between glutathione and lipophilic compounds with electrophilic centers, leading to neutralization of toxic compounds, xenobiotics, and products of oxidative stress. In the past decade, a number of case-control studies have been carried out to investigate the relationship between the GSTT1 null polymorphism and gastric cancer (GC), but the results have been inconclusive. To investigate this inconsistency, we performed a meta-analysis of 46 studies involving a total of 9012 GC cases and 14,215 controls for null variant of the GSTT1 gene to evaluate the effect of GSTT1 on genetic susceptibility for GC. Potential sources of heterogeneity including ethnicity, source of control, and sample size were also assessed. Overall, significantly increased GC risk was associated with GSTT1 null polymorphism with OR of 1.20 (95% CI, 1.10-1.32; P < 0.05). In the subgroup analysis by ethnicity, significantly increased risks were found in East Asians and Indians, while no significant associations were found among Caucasian, and Middle Eastern and African populations. By pooling data from 19 studies that considered combinations of GSTT1 and GSTM1 genotypes, a statistically significant increased risk for GC (OR = 2.04, 95% CI, 1.49-2.64; P < 0.05) was detected for individuals with dual deletion in both genes compared with positive genotypes. In addition, we found that cigarette smoking and alcohol drinking may modified the association of GSTT1 null genotypes with the risk of GC. In conclusion, this meta-analysis suggests that GSTT1 null polymorphism is associated with elevated GC risk, but these associations vary in different ethnic populations.
Collapse
Affiliation(s)
- Qing Wang
- Department of Surgery, Qingpu Branch of Zhongshan Hospital, Fudan University, 1158 East Gongyuan road, Shanghai, 201700, People's Republic of China
| | | | | | | | | | | | | |
Collapse
|
|
47
|
Postoperative nodal status and diffuse-type histology are independent prognostic factors in resectable advanced gastric carcinomas after preoperative chemotherapy. Am J Surg Pathol 2013; 37:1022-9. [PMID: 23715160 DOI: 10.1097/pas.0b013e31828778fd] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Surgical resection of primary gastric lesions after neoadjuvant or palliative chemotherapy is performed for curative or palliative purpose in locally advanced (LA) or initially metastatic (IM) gastric cancer. We investigated which histomorphologic features were associated with patient prognosis. We examined 143 patients (57 LA and 86 IM) who underwent gastrectomy after chemotherapy between 2000 and 2009. The tumor regression grade (TRG)-determined by examining the residual neoplastic cells and background stromal changes-was evaluated. Progression-free (PFS) and overall survival (OS) were evaluated according to pretherapeutic and posttherapeutic clinicopathologic factors using univariate and multivariate analyses. Because both the LA and the IM groups showed similar trends of PFS and OS according to TRG, the 2 groups were analyzed together. Patients with TRG1 (no residual primary tumor) showed a superior PFS and OS than the remaining TRGs. We defined pathologic complete regression (pCR) as TRG1 with negative lymph nodes (LN) and the others as non-pCR. Sixteen patients (11.1%) had pCR with better PFS (P=0.007) and OS (P=0.006). Initial disease status (LA or IM) remained as independent prognostic factors for PFS (P=0.021) but not for OS (P=0.109). The postoperative negative LN status correlated with good outcome and postoperative diffuse-type histology correlated with poor outcome after multivariate analysis. This study showed that pCR, but not partial regression, provides meaningful prognostic information in gastrectomy after chemotherapy. In addition, postoperative LN positivity and diffuse-type histology were independent poor prognostic factors for PFS and OS.
Collapse
|
|
48
|
Dan Z, Li K, Wang ZH, Xiangba ZX, Gang Z, Chilie WM, Jiang XY, Ba S, Wang J, Ciren ZX, Cidan LZ, De J. Epidemiological features of gastric cancer in a community population in Lhasa. Shijie Huaren Xiaohua Zazhi 2013; 21:2104-2108. [DOI: 10.11569/wcjd.v21.i21.2104] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the epidemiological features of gastric cancer in a community population in Lhasa to provide a theoretical basis for comprehensive prevention and treatment of gastric cancer in the plateau region.
METHODS: This survey was designed to investigate the incidence and prevalence of gastric cancer in a population in Naiqiong community, which is located in Duilongdeqing county, Lhasa. A total of 9423 subjects participated in this survey on 1 July, 2010. All the participants had an age above 35 years. They selectively underwent either sequence mass screening program for gastric cancer for high-risk population or sequence mass screening program for fecal occult blood test by filling out questionnaires. Disease and death registries were conducted.
RESULTS: The rough incidence of gastric cancer was 64.8/100000 (79.1/100000 for males and 52.0/100000 for females), the rough prevalence was 96.7/100000 (123.9/100000 for males and 72.2/100000 for females), and the rough mortality rate was 31.8/100000 (44.8/100000 for males and 20.2/100000 for females).
CONCLUSION: The incidence of gastric cancer in Lhasa community population is significantly higher than national average level. Effective measures catering to epidemiological features in the plateau region should be implemented to prevent and treat gastric cancer.
Collapse
|
|
49
|
Nicolás Hopp R, de Souza Lima NC, Filho JL, Filho MS, Lima CSP, Jorge J. Digit ratio (2D:4D) is associated with gastric cancer. Early Hum Dev 2013; 89:327-9. [PMID: 23218867 DOI: 10.1016/j.earlhumdev.2012.11.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Revised: 10/24/2012] [Accepted: 11/06/2012] [Indexed: 12/21/2022]
Abstract
BACKGROUND Sex steroid exposure during early human development may influence disease susceptibility. Digit ratio (2D:4D) is a putative marker for prenatal hormone exposure and sensitivity, as well as the action of genes closely related to carcinogenesis. Digit ratio could act as a possible marker for cancer predisposition. AIMS The aim of this study is to investigate the possible correlations between right hand, left hand and right minus left (R-L) 2D:4D and gastric cancer (GCA) in men and women and assess the correlations with tumor staging and histological diagnosis. METHODS Digital images of the right and left hand palms of patients diagnosed with GCA (n=57, 42 males, 15 females) and age and sex-matched controls (n=59, 41 males, 18 females) were obtained. Means for 2D:4D were compared. Data were analyzed by repeated-measures one-way ANOVA and Student's t-test for finger measurements and group comparisons and Pearson's and Spearman's tests for correlations with tumor staging (α=0.05). RESULTS GCA group presented significantly higher left 2D:4D, but significantly lower R-L in comparison to healthy controls, particularly so for males. Digit ratio did not correlate to clinical staging or TNM staging. However, low R-L was significantly related to adenocarcinomas. CONCLUSIONS Early developmental conditions, including prenatal testosterone seem to play a role on the malignant transformation of gastric lesions. The 2D:4D pattern found for gastric cancer parallels that earlier described for breast cancer. The findings suggest that 2D:4D could add to the list of etiological factors and be a putative marker for the screening of patients' susceptibility to develop gastric cancer.
Collapse
|
|
50
|
Li B, Zheng P, Zhu Q, Lin J. Accurate preoperative staging of gastric cancer with combined endoscopic ultrasonography and PET-CT. TOHOKU J EXP MED 2013; 228:9-16. [PMID: 22864063 DOI: 10.1620/tjem.228.9] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Accurate staging of gastric cancer is helpful to determine the most appropriate therapy, but no staging modality has been accepted as the standard. Objective is to evaluate the usefulness of endoscopic ultrasonograph (EUS) combined with position emission tomography and computed tomograph (PET-CT) in gastric cancer staging. A total of 124 patients confirmed with gastric cancer were subjected to staging with EUS and PET-CT scanning. The detection rate of primary tumor was 99.2% by combination use of two modalities and 97.6% by EUS alone (p = 0.6219), but the detection rate was 90.3% (112 of 124) by PET-CT alone (compared with the combination, p = 0.0027; compared with EUS alone, p = 0.0299). The locoregional lymph node invasion was identified in 84/124 (67.7%) by combined PET-CT and EUS, which was obviously higher than that with EUS (52.4%) or PET-CT (43.5%) alone (p = 0.0194 and p = 0.0002, respectively). There was no statistical difference in identification of celiac axis lymph node metastasis among three methods, but the combined examination or PET-CT alone was more effective than EUS alone in the detection of distant metastases (all p < 0.01). Furthermore, the combined EUS and PET-CT was more optimal than using EUS or PET-CT alone in the accurate T and N staging and the effect on change of treatment. The present study indicates that the combination of EUS and PET-CT is an ideal modality in the preoperative staging of gastric cancer and it provides beneficial guidance for the treatment of gastric cancer.
Collapse
Affiliation(s)
- Baiwen Li
- Department of Gastroenterology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, PR China.
| | | | | | | |
Collapse
|