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Albano F, Severini FL, Calice G, Zoppoli P, Falco G, Notarangelo T. The role of the tumor microenvironment and inflammatory pathways in driving drug resistance in gastric cancer: A systematic review and meta-analysis. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167821. [PMID: 40203956 DOI: 10.1016/j.bbadis.2025.167821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 03/14/2025] [Accepted: 03/26/2025] [Indexed: 04/11/2025]
Abstract
Tumor microenvironment (TME) plays a pivotal role in progression and low responsiveness to chemotherapy of gastric cancer (GC). The cascade of events that culminate with a sustained and chronic activation of inflammatory pathways underlies gastric tumorigenesis. Infiltrating immune cells enrolling in crosstalk with cancer cells that regulate inflammatory and immune status, generating an immunosuppressive TME that influences the response to therapy. Here we discuss the role of TME and the activation of inflammatory pathways to comprehend strategies to improve drug response. Furthermore, we provides systematic insight the role of TME cytotypes and related signatures reinforcing the critical roles of TAMs and Tregs, in promoting GC chemoresistance and tumor progression.
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Affiliation(s)
- Francesco Albano
- Department of Biology, University of Naples Federico II, Naples, Italy
| | - Francesca Lospinoso Severini
- Laboratory of Preclinical and Translational Research, IRCCS CROB Centro di Riferimento Oncologico della Basilicata, PZ, Rionero in Vulture, Italy
| | - Giovanni Calice
- Laboratory of Preclinical and Translational Research, IRCCS CROB Centro di Riferimento Oncologico della Basilicata, PZ, Rionero in Vulture, Italy
| | - Pietro Zoppoli
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Geppino Falco
- Department of Biology, University of Naples Federico II, Naples, Italy; Biogem, Istituto di Biologia e Genetica Molecolare, AV, Ariano Irpino, Italy
| | - Tiziana Notarangelo
- Laboratory of Preclinical and Translational Research, IRCCS CROB Centro di Riferimento Oncologico della Basilicata, PZ, Rionero in Vulture, Italy.
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Wei J, Qin Y, Zhang L, Gong X. Combined protein and transcriptomics identifies DCTPP1 as a putative biomarkers for predicting immunotherapy responsiveness in gastric cancer patients. Anticancer Drugs 2025; 36:415-426. [PMID: 39908235 DOI: 10.1097/cad.0000000000001704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2025]
Abstract
This study aimed to screen the changes after overexpression of dCTP pyrophosphatase 1 (DCTPP1) in human gastric adenocarcinoma cells (AGS) cells by proteome and transcriptome sequencing. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed to explore the functional significance of the differentially expressed DCTPP1 in gastric cancer (GC). Cell Counting Kit-8 (CCK-8) assay was used to detect the proliferation of cells. Western blot was used to detect the expression of proteins. A total of 28 genes that were significantly associated with DCTPP1 overexpression and had prognostic value were screened by Cox regression analysis. The results of gene set enrichment analysis showed that the genomes of patients with subtype A exhibited significant enrichment in pathways such as DNA repair, pyrimidine synthesis, and glucose metabolism. The tumor immune dysfunction and exclusion and The Cancer Immunome Atlas databases showed that patients with type A GC were better candidates for immunotherapy than patients with type B GC. Furthermore, the CCK-8 assay indicated significantly enhanced proliferative activity after overexpressing DCTPP1 in AGS cells, corroborating the findings from the bioinformatic analysis. The data suggest a potential association between DCTPP1 expression and both the prognosis of GC patients and the efficacy of immunotherapy. These findings offer valuable insights for the potential optimization of therapeutic strategies in gastric cancer.
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Affiliation(s)
- Jun Wei
- Department of Gastroenterology, General Practice, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical University
| | | | - Luwen Zhang
- School of Clinic Medicine, Bengbu Medical University, Bengbu, Anhui Province, China
| | - Xiaobing Gong
- Department of Gastroenterology, General Practice, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province
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Mo W, Deng L, Cheng Y, Ge S, Wang J. IGFBP7 regulates cell proliferation and migration through JAK/STAT pathway in gastric cancer and is regulated by DNA and RNA methylation. J Cell Mol Med 2024; 28:e70080. [PMID: 39351597 PMCID: PMC11443158 DOI: 10.1111/jcmm.70080] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 06/06/2024] [Accepted: 08/22/2024] [Indexed: 10/04/2024] Open
Abstract
New biomarkers for early diagnosis of gastric cancer (GC), the second leading cause of cancer-related death, are urgently needed. IGFBP7, known to play various roles in multiple tumours, is complexly regulated across diverse cancer types, as evidenced by our pancancer analysis. Bioinformatics analysis revealed that IGFBP7 expression was related to patient prognosis, tumour clinicopathological characteristics, tumour stemness, microsatellite instability and immune cell infiltration, as well as the expression of oncogenes and immune checkpoints. GSEA links IGFBP7 to several cancer-related pathways. IGFBP7 deficiency inhibited GC cell proliferation and migration in vitro. Furthermore, an in vivo nude mouse model revealed that IGFBP7 downregulation suppressed the tumorigenesis of GC cells. Western blotting analysis showed that the JAK1/2-specific inhibitor ruxolitinib could rescue alterations induced by IGFBP7 overexpression in GC cells. Additionally, our bioinformatics analysis and in vitro assays suggested that IGFBP7 is regulated by DNA methylation at the genetic level and that the RNA m6A demethylase FTO modulates it at the posttranscriptional level. This study emphasizes the clinical relevance of IGFBP7 in GC and its influence on cell proliferation and migration via the JAK/STAT signalling pathway. This study also highlights the regulation of IGFBP7 in GC by DNA and m6A RNA methylation.
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Affiliation(s)
- Weilie Mo
- Department of General SurgeryChangzhou No.7 People's HospitalChangzhouChina
- Department of General SurgeryChangzhou Geriatric Hospital affiliated to Soochow UniversityChangzhouChina
| | - Lijian Deng
- Department of OncologyChangzhou No.7 People's HospitalChangzhouChina
- Department of OncologyChangzhou Geriatric Hospital affiliated to Soochow UniversityChangzhouChina
| | - Yun Cheng
- Department of General SurgeryChangzhou No.7 People's HospitalChangzhouChina
- Department of General SurgeryChangzhou Geriatric Hospital affiliated to Soochow UniversityChangzhouChina
| | - Sen Ge
- Department of General SurgeryChangzhou No.7 People's HospitalChangzhouChina
- Department of General SurgeryChangzhou Geriatric Hospital affiliated to Soochow UniversityChangzhouChina
| | - Jin Wang
- School of Public HealthSuzhou Medical College of Soochow UniversitySuzhouChina
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Li W, Wan L, Zhang J. Cost-effectiveness of tislelizumab plus chemotherapy vs chemotherapy as first-line treatment of PD-L1 positive advanced gastric or gastroesophageal junction adenocarcinoma from a Chinese perspective. Expert Rev Gastroenterol Hepatol 2024; 18:293-301. [PMID: 38923910 DOI: 10.1080/17474124.2024.2373730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 06/25/2024] [Indexed: 06/28/2024]
Abstract
BACKGROUND This work was designed to assess the cost-effectiveness of front-line tislelizumab plus chemotherapy (TIS+Chemo) in advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC) with positive expression of programmed cell death ligand 1 (PD-L1) from the perspective of Chinese healthcare system. RESEARCH DESIGN AND METHODS A 10-year partitioned survival model was undertaken utilizing clinical data from RATIONALE 305. Costs and utilities were both discounted at an annual rate of 5%. The primary outcome was incremental cost-effectiveness ratios (ICERs) and calculated as the cost per quality-adjusted life years (QALYs). The willingness-to-pay (WTP) threshold was set as $18,625/QALY. Only direct medical costs were considered. Sensitivity analyses and subgroup analyses were performed to evaluate the robustness of the model. RESULTS In the base-case analysis, the incremental cost and effectiveness associated with TIS+Chemo vs Chemo was 7,361 and 0.38 QALYs, respectively, leading to an ICER of 19,371/QALY. At the WTP threshold of $18,625/QALY, the TIS+Chemo was not a cost-effective first-line treatment option. The model outcomes were robust. CONCLUSIONS TIS+Chemo did not provide a cost-effective approach for PD-L1 positive advanced GC/GEJC in China setting. However, TIS+Chemo might be cost-effective in provinces with higher WTP threshold. CLINICAL TRIAL REGISTRATION RATIONALE 305, www.clinicaltrials.gov, identifier is NCT03777657.
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Affiliation(s)
- Wei Li
- Department of Pharmacy, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Hubei, Wuhan, China
| | - Li Wan
- Department of Pharmacy, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Hubei, Wuhan, China
| | - Jiangyan Zhang
- Department of Pharmacy, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Hubei, Wuhan, China
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Wen W, Ertas YN, Erdem A, Zhang Y. Dysregulation of autophagy in gastric carcinoma: Pathways to tumor progression and resistance to therapy. Cancer Lett 2024; 591:216857. [PMID: 38583648 DOI: 10.1016/j.canlet.2024.216857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 03/22/2024] [Accepted: 04/02/2024] [Indexed: 04/09/2024]
Abstract
The considerable death rates and lack of symptoms in early stages of gastric cancer (GC) make it a major health problem worldwide. One of the most prominent risk factors is infection with Helicobacter pylori. Many biological processes, including those linked with cell death, are disrupted in GC. The cellular "self-digestion" mechanism necessary for regular balance maintenance, autophagy, is at the center of this disturbance. Misregulation of autophagy, however, plays a role in the development of GC. In this review, we will examine how autophagy interacts with other cell death processes, such as apoptosis and ferroptosis, and how it affects the progression of GC. In addition to wonderful its role in the epithelial-mesenchymal transition, it is engaged in GC metastasis. The role of autophagy in GC in promoting drug resistance stands out. There is growing interest in modulating autophagy for GC treatment, with research focusing on natural compounds, small-molecule inhibitors, and nanoparticles. These approaches could lead to breakthroughs in GC therapy, offering new hope in the fight against this challenging disease.
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Affiliation(s)
- Wen Wen
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, China
| | - Yavuz Nuri Ertas
- Department of Biomedical Engineering, Erciyes University, Kayseri, Turkey; ERNAM-Nanotechnology Research and Application Center, Erciyes University, Kayseri, Turkey.
| | - Ahmet Erdem
- Institute for Quantitative Health Science and Engineering (IQ), Department of Biomedical Engineering, College of Engineering and Human Medicine, Michigan State University, East Lansing, MI, 48824, USA; Department of Biomedical Engineering, Kocaeli University, Umuttepe Campus, Kocaeli, 41001 Turkey.
| | - Yao Zhang
- Department of Gynaecology, Shengjing Hospital of China Medical University, Shenyang, China.
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Li F, Yu J, Pan T, Feng H, Li J, Yu B, Fan Z, Sang Q, Chen M, Zang M, Hou J, Wu X, Yu Y, Li Y, Yan C, Zhu Z, Su L, Liu B. BPTF Drives Gastric Cancer Resistance to EGFR Inhibitor by Epigenetically Regulating the C-MYC/PLCG1/Perk Axis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2303091. [PMID: 37863665 PMCID: PMC10700682 DOI: 10.1002/advs.202303091] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 08/06/2023] [Indexed: 10/22/2023]
Abstract
Erlotinib, an EGFR tyrosine kinase inhibitor, is used for treating patients with cancer exhibiting EGFR overexpression or mutation. However, the response rate of erlotinib is low among patients with gastric cancer (GC). The findings of this study illustrated that the overexpression of bromodomain PHD finger transcription factor (BPTF) is partially responsible for erlotinib resistance in GC, and the combination of the BPTF inhibitor AU-1 with erlotinib synergistically inhibited tumor growth both in vivo and in vitro. AU-1 inhibited the epigenetic function of BPTF and decreased the transcriptional activity of c-MYC on PLCG1 by attenuating chromosome accessibility of the PLCG1 promoter region, thus decreasing the expression of p-PLCG1 and p-Erk and eventually improving the sensitivity of GC cells to erlotinib. In patient-derived xenograft (PDX) models, AU-1 monotherapy exhibited remarkable tumor-inhibiting activity and is synergistic anti-tumor effects when combined with erlotinib. Altogether, the findings illustrate that BPTF affects the responsiveness of GC to erlotinib by epigenetically regulating the c-MYC/PLCG1/pErk axis, and the combination of BPTF inhibitors and erlotinib is a viable therapeutic approach for GC.
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Affiliation(s)
- Fangyuan Li
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Junxian Yu
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Tao Pan
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Haoran Feng
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Jianfang Li
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Beiqin Yu
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Zhiyuan Fan
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Qingqing Sang
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Mengdi Chen
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Mingde Zang
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
- Department of Gastric Cancer SurgeryFudan University Shanghai Cancer CenterDepartment of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Junyi Hou
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Xiongyan Wu
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Yingyan Yu
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Yuan‐Yuan Li
- Shanghai Center for Bioinformation TechnologyShanghai Engineering Research Center of Pharmaceutical Translation & Shanghai Industrial Technology InstituteShanghai202163P. R. China
| | - Chao Yan
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Zhenggang Zhu
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Liping Su
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Bingya Liu
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
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Qiu Z, Qin R, Zhang Z, Zhang T, Zhang Z, Qiao C, Xi Y, Tian G, Wang Y. Expression of p53 as a biomarker in determining response to apatinib for advanced gastric cancer. Front Oncol 2023; 13:1203980. [PMID: 37655112 PMCID: PMC10466417 DOI: 10.3389/fonc.2023.1203980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 07/26/2023] [Indexed: 09/02/2023] Open
Abstract
Background Apatinib has shown outstanding value in the treatment of advanced gastric cancer (AGC). However, no biomarkers are available to select AGC patients who will benefit from apatinib. The aim of the present study was to investigate the association between p53 and Ki67 expression of and the outcome in AGC patients treated with apatinib. Methods From December 2015 to December 2020, 92 AGC patients were enrolled and was retrospectively evaluated. They were given apatinib at a daily dose of 500 or 250 mg every 4 weeks to monitor clinical efficacy and adverse events (AEs). Kaplan-Meier method was used for survival analysis. Expression of p53 and Ki67 was detected by immunohistochemistry (IHC) and correlated with survival. Results Among 92 evaluable patients, the objective response rate (ORR) and disease control rate (DCR) were 17.4% and 79.3%, respectively, and none of them achieved a CR, 16 achieved a PR (17.4%) (95% CI 9.8%-26.1%). Stable disease (SD) was observed in 57.6% of patients (95% CI 49.2%-69.9%) and PD in 21.7% of patients (95% CI 13.6%-31.3%). The median progression free survival (mPFS) was 122.7 ± 8.2 days, and the median overall survival (mOS) was 203.4 ± 11.9 days. P53 expression was observed in 35 patients (38.0%) and high expression of Ki67 was detected in 34 patients (37.0%). There was a statistically significant inverse relationship between p53 and Ki67 expression (P=0.014). Moreover, p53 was significantly correlated with the OS (P=0.018), but Ki67 had no significant influence on OS. Conclusions Apatinib showed promising efficiency and was well tolerated as a second-line treatment for AGC patients. AGC patients with p53-negative were likely to benefit from apatinib treatment; however, the expression of Ki67 proteins has no significant impact on the outcome of AGC patients.
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Affiliation(s)
- Zhiyuan Qiu
- Department of Oncology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Rong Qin
- Department of Oncology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Ziyi Zhang
- Department of Oncology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Ting Zhang
- Department of Oncology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Zhao Zhang
- Department of Oncology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Chunyue Qiao
- Department of Oncology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yan Xi
- Department of Geriatrics, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Guangyu Tian
- Department of Oncology, Jiangdu People’s Hospital Affiliated to Medical College of Yangzhou University, Yangzhou, Jiangsu, China
| | - Yan Wang
- Department of Oncology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
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Marilina S, Adriana M, Anna S, Roberto AD, Nicolás M, Jesús QM, Javier B, Carolina R, Josefina S, Gerardo RG, Ivan S, Gerard U, Xavier BC. Comparative analysis of systemic oncological treatments and best supportive care for advanced gastresophageal cancer: A comprehensive scoping review and evidence map. J Evid Based Med 2023; 16:216-236. [PMID: 37303304 DOI: 10.1111/jebm.12539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 05/30/2023] [Indexed: 06/13/2023]
Abstract
OBJECTIVE To identify, describe, and organize the available evidence regarding systemic oncological treatments compared to best supportive care (BSC) for advanced gastresophageal cancer. METHODS We conducted a thorough search across MEDLINE (PubMed), EMbase (Ovid), The Cochrane Library, Epistemonikos, PROSPERO, and Clinicaltrials.gov. Our inclusion criteria encompassed systematic reviews, randomized controlled trials, quasi-experimental and observational studies involving patients with advanced esophageal or gastric cancer receiving chemotherapy, immunotherapy or biological/targeted therapy compared to BSC. The outcomes included survival, quality of life, functional status, toxicity, and quality of end-of-life care. RESULTS We included and mapped 72 studies, comprising SRs, experimental and observational designs, 12 on esophageal cancer, 51 on gastric cancer, and 10 both locations. Most compared schemes including chemotherapy (47 studies), but did not report therapeutic lines. Moreover, BSC as a control arm was poorly defined, including integral support and placebo. Data favor the use of systemic oncological treatments in survival outcomes and BSC in toxicity. Data for outcomes including quality of life, functional status, and quality of end-of-life care were limited. We found sundry evidence gaps specifically in assessing new treatments such as immunotherapy and important outcomes such as functional status, symptoms control, hospital admissions, and the quality of end-life care for all the treatments. CONCLUSIONS There are important evidence gaps regarding new for patients with advanced gastresophageal cancer and the effect of systemic oncological treatments on important patient-centered outcomes beyond survival. Future research should clearly describe the population included, specifying previous treatments and considering therapeutic, and consider all patient-centered outcomes. Otherwise, it will be complex to apply research results into practice.
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Affiliation(s)
- Santero Marilina
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Meade Adriana
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Selva Anna
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- Clinical Epidemiology and Cancer Screening, Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT_CERCA). Univesitat Autònoma de Barcelona., Sabadell, Spain
| | - Acosta-Dighero Roberto
- Faculty of Medicine, Department of Physical Therapy, University of Chile, Santiago, Chile
| | - Meza Nicolás
- Interdisciplinary Centre for Health Studies (CIESAL), Universidad de Valparaíso, Viña del Mar, Chile
| | - Quintana Maria Jesús
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), CIBER, Barcelona, Spain
- Department of Paediatrics, Obstetrics and Gynaecology and Preventive Medicine and Public Health, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Bracchiglione Javier
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- Interdisciplinary Centre for Health Studies (CIESAL), Universidad de Valparaíso, Viña del Mar, Chile
| | - Requeijo Carolina
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Salazar Josefina
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | | | - Solà Ivan
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), CIBER, Barcelona, Spain
| | - Urrútia Gerard
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), CIBER, Barcelona, Spain
| | - Bonfill Cosp Xavier
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), CIBER, Barcelona, Spain
- Department of Paediatrics, Obstetrics and Gynaecology and Preventive Medicine and Public Health, Universitat Autònoma de Barcelona, Barcelona, Spain
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Comprehensive Evaluation of Serum tRF-17-WS7K092 as a Promising Biomarker for the Diagnosis of Gastric Cancer. JOURNAL OF ONCOLOGY 2022; 2022:8438726. [PMID: 36245992 PMCID: PMC9553536 DOI: 10.1155/2022/8438726] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 09/09/2022] [Indexed: 11/18/2022]
Abstract
Background Gastric cancer (GC) is a malignant tumor of the gastrointestinal system. Since the early symptoms of GC are not obvious and lack efficient diagnostic markers, it is urgent to find new diagnostic markers with good sensitivity and specificity. tRNA-derived small RNAs (tsRNAs) are an emerging class of small noncoding RNAs with good abundance in body fluids. We aim to find new tsRNAs as biomarkers for GC diagnosis. Methods High-throughput sequencing was used to identify differentially expressed tsRNAs in GC tissues, and quantitative real-time PCR was used to detect the expression level of tRF-17-WS7K092. Agarose gel electrophoresis and Sanger sequencing were performed to verify the characteristics of tRF-17-WS7K092. The diagnostic efficacy of tRF-17-WS7K092 was analyzed by the receiver operating characteristic curve. Results In this study, the expression levels of tRF-17-WS7K092 were significantly increased in GC tissues, cells, and serum. After GC surgery, the expression level of serum tRF-17-WS7K092 decreased, and its high expression was associated with low survival rates. In addition, the expression level of serum tRF-17-WS7K092 was correlated with the T stage, TNM stage, lymph node metastasis, and nerve/vascular invasion and could distinguish GC patients from gastritis patients and healthy donors as well. Conclusions The expression of serum tRF-17-WS7K092 was significantly increased in GC and decreased after GC surgery, suggesting that serum tRF-17-WS7K092 may serve as a promising biomarker for the diagnostic and prognostic monitoring of GC.
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Wang Z, Chen Y, Li X, Zhang Y, Zhao X, Zhou H, Lu X, Zhao L, Yuan Q, Shi Y, Zhao J, Dong Z, Jiang Y, Liu K. Tegaserod Maleate Suppresses the Growth of Gastric Cancer In Vivo and In Vitro by Targeting MEK1/2. Cancers (Basel) 2022; 14:cancers14153592. [PMID: 35892850 PMCID: PMC9332868 DOI: 10.3390/cancers14153592] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/14/2022] [Accepted: 07/16/2022] [Indexed: 11/16/2022] Open
Abstract
Gastric cancer (GC) ranks fifth in global incidence and fourth in mortality. The current treatments for GC include surgery, chemotherapy and radiotherapy. Although treatment strategies for GC have been improved over the last decade, the overall five-year survival rate remains less than 30%. Therefore, there is an urgent need to find novel therapeutic or preventive strategies to increase GC patient survival rates. In the current study, we found that tegaserod maleate, an FDA-approved drug, inhibited the proliferation of gastric cancer cells, bound to MEK1/2 and suppressed MEK1/2 kinase activity. Moreover, tegaserod maleate inhibited the progress of gastric cancer by depending on MEK1/2. Notably, we found that tegaserod maleate suppressed tumor growth in the patient-derived gastric xenograft (PDX) model. We further compared the effect between tegaserod maleate and trametinib, which is a clinical MEK1/2 inhibitor, and confirmed that tegaserod maleate has the same effect as trametinib in inhibiting the growth of GC. Our findings suggest that tegaserod maleate inhibited GC proliferation by targeting MEK1/2.
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Affiliation(s)
- Zitong Wang
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (Z.W.); (Y.C.); (X.L.); (Y.Z.); (X.Z.); (H.Z.); (X.L.); (L.Z.); (Q.Y.); (Y.S.); (J.Z.); (Z.D.)
| | - Yingying Chen
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (Z.W.); (Y.C.); (X.L.); (Y.Z.); (X.Z.); (H.Z.); (X.L.); (L.Z.); (Q.Y.); (Y.S.); (J.Z.); (Z.D.)
| | - Xiaoyu Li
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (Z.W.); (Y.C.); (X.L.); (Y.Z.); (X.Z.); (H.Z.); (X.L.); (L.Z.); (Q.Y.); (Y.S.); (J.Z.); (Z.D.)
| | - Yuhan Zhang
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (Z.W.); (Y.C.); (X.L.); (Y.Z.); (X.Z.); (H.Z.); (X.L.); (L.Z.); (Q.Y.); (Y.S.); (J.Z.); (Z.D.)
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450001, China
| | - Xiaokun Zhao
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (Z.W.); (Y.C.); (X.L.); (Y.Z.); (X.Z.); (H.Z.); (X.L.); (L.Z.); (Q.Y.); (Y.S.); (J.Z.); (Z.D.)
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450001, China
| | - Hao Zhou
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (Z.W.); (Y.C.); (X.L.); (Y.Z.); (X.Z.); (H.Z.); (X.L.); (L.Z.); (Q.Y.); (Y.S.); (J.Z.); (Z.D.)
| | - Xuebo Lu
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (Z.W.); (Y.C.); (X.L.); (Y.Z.); (X.Z.); (H.Z.); (X.L.); (L.Z.); (Q.Y.); (Y.S.); (J.Z.); (Z.D.)
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450001, China
| | - Lili Zhao
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (Z.W.); (Y.C.); (X.L.); (Y.Z.); (X.Z.); (H.Z.); (X.L.); (L.Z.); (Q.Y.); (Y.S.); (J.Z.); (Z.D.)
| | - Qiang Yuan
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (Z.W.); (Y.C.); (X.L.); (Y.Z.); (X.Z.); (H.Z.); (X.L.); (L.Z.); (Q.Y.); (Y.S.); (J.Z.); (Z.D.)
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450001, China
| | - Yunshu Shi
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (Z.W.); (Y.C.); (X.L.); (Y.Z.); (X.Z.); (H.Z.); (X.L.); (L.Z.); (Q.Y.); (Y.S.); (J.Z.); (Z.D.)
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450001, China
| | - Jimin Zhao
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (Z.W.); (Y.C.); (X.L.); (Y.Z.); (X.Z.); (H.Z.); (X.L.); (L.Z.); (Q.Y.); (Y.S.); (J.Z.); (Z.D.)
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou 450001, China
- Basic Medicine Research Center, Zhengzhou University, Zhengzhou 450001, China
| | - Ziming Dong
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (Z.W.); (Y.C.); (X.L.); (Y.Z.); (X.Z.); (H.Z.); (X.L.); (L.Z.); (Q.Y.); (Y.S.); (J.Z.); (Z.D.)
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou 450001, China
- Basic Medicine Research Center, Zhengzhou University, Zhengzhou 450001, China
| | - Yanan Jiang
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (Z.W.); (Y.C.); (X.L.); (Y.Z.); (X.Z.); (H.Z.); (X.L.); (L.Z.); (Q.Y.); (Y.S.); (J.Z.); (Z.D.)
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450001, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou 450001, China
- Basic Medicine Research Center, Zhengzhou University, Zhengzhou 450001, China
- Correspondence: (Y.J.); (K.L.)
| | - Kangdong Liu
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; (Z.W.); (Y.C.); (X.L.); (Y.Z.); (X.Z.); (H.Z.); (X.L.); (L.Z.); (Q.Y.); (Y.S.); (J.Z.); (Z.D.)
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450001, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou 450001, China
- Basic Medicine Research Center, Zhengzhou University, Zhengzhou 450001, China
- Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou 450001, China
- Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou 450001, China
- Correspondence: (Y.J.); (K.L.)
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11
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Xu D, Guo J, Xu H. High Expression of UPK3A Promotes the Progression of Gastric Cancer Cells by Inactivating p53 Pathway. Anal Cell Pathol (Amst) 2022; 2022:6897561. [PMID: 35774082 PMCID: PMC9239834 DOI: 10.1155/2022/6897561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 05/13/2022] [Accepted: 05/31/2022] [Indexed: 12/24/2022] Open
Abstract
Background Gastric cancer is a common gastrointestinal tract cancer and is a considerable health burden worldwide. TCGA analysis found Uroplakin 3A (UPK3A) was upregulated in gastric cancer tissues. Our study was designed to investigate the underlying mechanism of Uroplakin 3A (UPK3A) in gastric cancer. Methods Data from TCGA database were used to assess the expression, and Kaplan-Meier plotter analysis was used to assess the prognosis value of UPK3A. Furthermore, there are effects of UPK3A silencing on the activity, proliferation, migration, and invasion of human gastric cancer cells (SNU-216 and HGC-27) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing, and Transwell assays. In addition, the expression of UPK3A, p53, KLF4, ZMAT3, MDM2, and SP1 was detected by qRT-PCR and Western blot assay. Results UPK3A was markedly upregulated in gastric cancer tissues compared to that in normal tissues, and patients with high UPK3A level showed poor prognosis. UPK3A was highly expressed in human gastric cancer cell lines compared to that in a normal human gastric epithelial cell line. Silencing of UPK3A inhibited the proliferation, migration, and invasion of gastric cancer cells. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that UPK3A was involved in the p53 signaling pathway. UPK3A suppressed the activation of p53 signaling pathway, and treatment with Pifithrin-α (an inhibitor of the p53 signaling pathway) or silencing of p53 significantly reversed the effect of UPK3A silencing on the expression of p53, KLF4, ZMAT3, MDM2, and SP1. Conclusion Our findings showed that UPK3A promotes the progression of gastric cancer by regulating the p53 signaling pathway and could be a potential therapeutic target for gastric cancer.
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Affiliation(s)
- Deliang Xu
- Department of Gastroenterology, Zaozhuang Municipal Hospital, Zaozhuang, Shandong 277100, China
| | - Jing Guo
- Department of Gastroenterology, Zaozhuang Municipal Hospital, Zaozhuang, Shandong 277100, China
| | - Hongwei Xu
- Department of Gastroenterology, Shandong Provincial Hospital, Jinan, Shandong 250000, China
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12
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YILDIRIM S, BULUT G. Metastatik mide kanserinde karsinoembriyonik antijen (cea) prediktif midir? EGE TIP DERGISI 2022. [DOI: 10.19161/etd.1086149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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13
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meta.shrinkage: An R Package for Meta-Analyses for Simultaneously Estimating Individual Means. ALGORITHMS 2022. [DOI: 10.3390/a15010026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Meta-analysis is an indispensable tool for synthesizing statistical results obtained from individual studies. Recently, non-Bayesian estimators for individual means were proposed by applying three methods: the James–Stein (JS) shrinkage estimator, isotonic regression estimator, and pretest (PT) estimator. In order to make these methods available to users, we develop a new R package meta.shrinkage. Our package can compute seven estimators (named JS, JS+, RML, RJS, RJS+, PT, and GPT). We introduce this R package along with the usage of the R functions and the “average-min-max” steps for the pool-adjacent violators algorithm. We conduct Monte Carlo simulations to validate the proposed R package to ensure that the package can work properly in a variety of scenarios. We also analyze a data example to show the ability of the R package.
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14
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Tsai MM, Lin HC, Yu MC, Lin WJ, Chu MY, Tsai CC, Cheng CY. Anticancer Effects of Helminthostachys zeylanica Ethyl acetate Extracts on Human Gastric Cancer Cells through Downregulation of the TNF-α-activated COX-2-cPLA2-PGE 2 Pathway. J Cancer 2021; 12:7052-7068. [PMID: 34729107 PMCID: PMC8558661 DOI: 10.7150/jca.64638] [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: 07/06/2021] [Accepted: 09/24/2021] [Indexed: 12/13/2022] Open
Abstract
Background: Gastric cancer (GC) is the second most prevalent cancer worldwide and the eighth most common cause of tumor-related death in Taiwan. Helminthostachys zeylanica, a flavonoid compound, has anti-inflammatory, immunomodulatory, and anticancer effects. We examined whether an extract of H. zeylanica (E1 and E2) has potential as a treatment for GC. Methods: We investigated the effects (pro-apoptosis, pro-autophagy, and antiproliferation ability) of H. zeylanica-E2 on cell viability in healthy gastric epithelial (GES-1) and GC cells (AGS and BGC823). H. zeylanica-E2 was toxic to GC cells but had little or no toxicity to normal cells. Results: In this study, H. zeylanica-E2 induced apoptosis through caspase 3/7, Bcl-2, Bax, cyclooxygenase-2 (COX-2), and cleaved poly (ADP-ribose) polymerase pathways in GC cells. In addition, it increased autophagy by stimulating autophagy-related protein (ATG)5, ATG7, LC3-I/LC3-II, and inhibiting COX-2 activity in GC cells. We also found that H. zeylanica-E2 exhibited antiproliferation ability through cell cycle arrest in G0/G1 and G2/M and suppressed the migration of GC cells. The anticancer effects of H. zeylanica-E2 in GC cells might be mediated partly through inhibition of tumor necrosis factor-α (TNF-α)-activated proinflammatory cytosolic phospholipase A2 (cPLA2)-COX-2-prostaglandin E2 (PGE2) pathway. Conclusions: Our results suggest that H. zeylanica-E2 has potential as a novel adjunctive agent for the treatment of GC.
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Affiliation(s)
- Ming-Ming Tsai
- Department of Nursing, Division of Basic Medical Sciences, Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan and Department of General Surgery, Chang Gung Memorial Hospital at Chiayi, Chiayi, Taiwan
| | - Horng-Chyuan Lin
- Department of Thoracic Medicine, Chang Gung Memorial Hospital at Linkou and College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ming-Chin Yu
- Department of Surgery, New Taipei Municipal TuCheng Hospital, Chang Gung Memorial Hospital at Linkou, and College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wan-Jung Lin
- Graduate Institute of Health Industry Technology, Research Center for Chinese Herbal Medicine and Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan
| | - Mei-Yi Chu
- Graduate Institute of Health Industry Technology, Research Center for Chinese Herbal Medicine and Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan
| | - Ching-Ching Tsai
- Department of Nursing, College of Nursing, Chang Gung University of Science and Technology, and Department of Cardiology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Ching-Yi Cheng
- Graduate Institute of Health Industry Technology, Research Center for Chinese Herbal Medicine and Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.,Department of Pulmonary Infection and Immunology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
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15
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A Meta-Analysis for Simultaneously Estimating Individual Means with Shrinkage, Isotonic Regression and Pretests. AXIOMS 2021. [DOI: 10.3390/axioms10040267] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Meta-analyses combine the estimators of individual means to estimate the common mean of a population. However, the common mean could be undefined or uninformative in some scenarios where individual means are “ordered” or “sparse”. Hence, assessments of individual means become relevant, rather than the common mean. In this article, we propose simultaneous estimation of individual means using the James–Stein shrinkage estimators, which improve upon individual studies’ estimators. We also propose isotonic regression estimators for ordered means, and pretest estimators for sparse means. We provide theoretical explanations and simulation results demonstrating the superiority of the proposed estimators over the individual studies’ estimators. The proposed methods are illustrated by two datasets: one comes from gastric cancer patients and the other from COVID-19 patients.
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16
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Emura T, Sofeu CL, Rondeau V. Conditional copula models for correlated survival endpoints: Individual patient data meta-analysis of randomized controlled trials. Stat Methods Med Res 2021; 30:2634-2650. [PMID: 34632882 DOI: 10.1177/09622802211046390] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Correlations among survival endpoints are important for exploring surrogate endpoints of the true endpoint. With a valid surrogate endpoint tightly correlated with the true endpoint, the efficacy of a new drug/treatment can be measurable on it. However, the existing methods for measuring correlation between two endpoints impose an invalid assumption: correlation structure is constant across different treatment arms. In this article, we reconsider the definition of Kendall's concordance measure (tau) in the context of individual patient data meta-analyses of randomized controlled trials. According to our new definition of Kendall's tau, its value depends on the treatment arms. We then suggest extending the existing copula (and frailty) models so that their Kendall's tau can vary across treatment arms. Our newly proposed model, a joint frailty-conditional copula model, is the implementation of the new definition of Kendall's tau in meta-analyses. In order to facilitate our approach, we develop an original R function condCox.reg(.) and make it available in the R package joint.Cox (https://CRAN.R-project.org/package=joint.Cox). We apply the proposed method to a gastric cancer dataset (3288 patients in 14 randomized trials from the GASTRIC group). This data analysis concludes that Kendall's tau has different values between the surgical treatment arm and the adjuvant chemotherapy arm (p-value<0.001), whereas disease-free survival remains a valid surrogate at individual level for overall survival in these trials.
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Affiliation(s)
| | | | - Virginie Rondeau
- INSERM U1219 (Biostatistic), Université Bordeaux Segalen, France
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17
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Burzykowski T. Semi-parametric accelerated failure-time model: A useful alternative to the proportional-hazards model in cancer clinical trials. Pharm Stat 2021; 21:292-308. [PMID: 34553482 DOI: 10.1002/pst.2169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 07/14/2021] [Accepted: 08/25/2021] [Indexed: 11/11/2022]
Abstract
The accelerated failure-time (AFT) model has been long recognized as a useful alternative to the proportional-hazards (PH) model. Semi-parametric AFT model has been known since 1981. Its use has been hampered by the difficulty in solving the estimating equations for the model's coefficients. In recent years, however, important developments have taken place regarding the methods of solving the equations. In this article, we briefly review the developments, focusing mainly on rank-based estimation. We conduct a simulation study that directly focuses on the applicability of the model in the context of (cancer) clinical trials. We also investigate the robustness of the AFT model to the omission of covariates. Finally, we conduct a meta-analysis of multiple clinical trials in gastric cancer to illustrate the benefits of the use of the model in practice.
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Affiliation(s)
- Tomasz Burzykowski
- Data Science Institute, Hasselt University, Hasselt, Belgium.,International Drug Development Institute, Louvain-la-Neuve, Belgium.,Department of Statistics and Medical Informatics, Medical University of Bialystok, Białystok, Poland
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18
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Almeida GM, Pereira C, Park JH, Lemos C, Campelos S, Gullo I, Martins D, Gonçalves G, Leitão D, Neto JL, André A, Borges C, Almeida D, Lee HJ, Kong SH, Kim WH, Carneiro F, Almeida R, Yang HK, Oliveira C. CD44v6 High Membranous Expression Is a Predictive Marker of Therapy Response in Gastric Cancer Patients. Biomedicines 2021; 9:biomedicines9091249. [PMID: 34572441 PMCID: PMC8465138 DOI: 10.3390/biomedicines9091249] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/06/2021] [Accepted: 09/08/2021] [Indexed: 01/27/2023] Open
Abstract
In gastric cancer (GC), biomarkers that define prognosis and predict treatment response remain scarce. We hypothesized that the extent of CD44v6 membranous tumor expression could predict prognosis and therapy response in GC patients. Two GC surgical cohorts, from Portugal and South Korea (n = 964), were characterized for the extension of CD44v6 membranous immuno-expression, clinicopathological features, patient survival, and therapy response. The value of CD44v6 expression in predicting response to treatment and its impact on prognosis was determined. High CD44v6 expression was associated with invasive features (perineural invasion and depth of invasion) in both cohorts and with worse survival in the Portuguese GC cohort (HR 1.461; 95% confidence interval 1.002–2.131). Patients with high CD44v6 tumor expression benefited from conventional chemotherapy in addition to surgery (p < 0.05), particularly those with heterogeneous CD44v6-positive and -negative populations (CD44v6_3+) (p < 0.007 and p < 0.009). Our study is the first to identify CD44v6 high membranous expression as a potential predictive marker of response to conventional treatment, but it does not clarify CD44v6 prognostic value in GC. Importantly, our data support selection of GC patients with high CD44v6-expressing tumors for conventional chemotherapy in addition to surgery. These findings will allow better stratification of GC patients for treatment, potentially improving their overall survival.
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Affiliation(s)
- Gabriela M Almeida
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (G.M.A.); (C.P.); (C.L.); (S.C.); (I.G.); (D.M.); (A.A.); (F.C.); (R.A.)
- Ipatimup—Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal;
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal;
| | - Carla Pereira
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (G.M.A.); (C.P.); (C.L.); (S.C.); (I.G.); (D.M.); (A.A.); (F.C.); (R.A.)
- Ipatimup—Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal;
- Doctoral Programme in Biomedicine, Faculty of Medicine of the University of Porto, 4200-319 Porto, Portugal
| | - Ji-Hyeon Park
- Department of Surgery, Seoul National University Hospital, Seoul 03080, Korea; (J.-H.P.); (H.-J.L.); (S.-H.K.); (H.-K.Y.)
| | - Carolina Lemos
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (G.M.A.); (C.P.); (C.L.); (S.C.); (I.G.); (D.M.); (A.A.); (F.C.); (R.A.)
- UnIGENe, IBMC—Institute for Molecular and Cell Biology, 4200-135 Porto, Portugal
- ICBAS—Instituto Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal
| | - Sofia Campelos
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (G.M.A.); (C.P.); (C.L.); (S.C.); (I.G.); (D.M.); (A.A.); (F.C.); (R.A.)
- Department of Pathology, Ipatimup Diagnostics, Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal
| | - Irene Gullo
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (G.M.A.); (C.P.); (C.L.); (S.C.); (I.G.); (D.M.); (A.A.); (F.C.); (R.A.)
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal;
- Department of Pathology, Centro Hospitalar Universitário de São João, 4200-319 Porto, Portugal
| | - Diana Martins
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (G.M.A.); (C.P.); (C.L.); (S.C.); (I.G.); (D.M.); (A.A.); (F.C.); (R.A.)
- Ipatimup—Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal;
- Department of Biomedical Laboratory Sciences, ESTeSC—Coimbra Health School, Polytechnic Institute of Coimbra, 3046-854 Coimbra, Portugal
| | - Gilza Gonçalves
- Ipatimup—Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal;
| | - Dina Leitão
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal;
- Department of Pathology, Centro Hospitalar Universitário de São João, 4200-319 Porto, Portugal
| | - João Luís Neto
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal;
| | - Ana André
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (G.M.A.); (C.P.); (C.L.); (S.C.); (I.G.); (D.M.); (A.A.); (F.C.); (R.A.)
- Ipatimup—Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal;
| | - Clara Borges
- Medical Oncology Department, Centro Hospitalar Universitário de São João, 4200-319 Porto, Portugal; (C.B.); (D.A.)
| | - Daniela Almeida
- Medical Oncology Department, Centro Hospitalar Universitário de São João, 4200-319 Porto, Portugal; (C.B.); (D.A.)
| | - Hyuk-Joon Lee
- Department of Surgery, Seoul National University Hospital, Seoul 03080, Korea; (J.-H.P.); (H.-J.L.); (S.-H.K.); (H.-K.Y.)
- Cancer Research Institute, Seoul National University, Seoul 03080, Korea
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Seong-Ho Kong
- Department of Surgery, Seoul National University Hospital, Seoul 03080, Korea; (J.-H.P.); (H.-J.L.); (S.-H.K.); (H.-K.Y.)
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Woo Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea;
| | - Fátima Carneiro
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (G.M.A.); (C.P.); (C.L.); (S.C.); (I.G.); (D.M.); (A.A.); (F.C.); (R.A.)
- Ipatimup—Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal;
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal;
- Department of Pathology, Centro Hospitalar Universitário de São João, 4200-319 Porto, Portugal
| | - Raquel Almeida
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (G.M.A.); (C.P.); (C.L.); (S.C.); (I.G.); (D.M.); (A.A.); (F.C.); (R.A.)
- Ipatimup—Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal;
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal;
- Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
| | - Han-Kwang Yang
- Department of Surgery, Seoul National University Hospital, Seoul 03080, Korea; (J.-H.P.); (H.-J.L.); (S.-H.K.); (H.-K.Y.)
- Cancer Research Institute, Seoul National University, Seoul 03080, Korea
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Carla Oliveira
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (G.M.A.); (C.P.); (C.L.); (S.C.); (I.G.); (D.M.); (A.A.); (F.C.); (R.A.)
- Ipatimup—Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal;
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal;
- Correspondence: ; Tel.: +351-220-408-800
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Chen Y, Chen N, Xu J, Wang X, Wei X, Tang C, Duanmu Z, Shi J. Apatinib inhibits the proliferation of gastric cancer cells via the AKT/GSK signaling pathway in vivo. Aging (Albany NY) 2021; 13:20738-20747. [PMID: 34453028 PMCID: PMC8436942 DOI: 10.18632/aging.203458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 08/14/2021] [Indexed: 12/03/2022]
Abstract
Gastric cancer (GC) is the third leading cause of cancer-associated mortality globally. Although the diagnosis and therapeutic strategies for GC have improved, the prognosis for advanced gastric cancer (AGC) remains poor. Hence, the present study sought to design a zebrafish model established by microinjecting human MGC-803 GC cell line for studying personalized molecular-targeted cancer therapy. Apatinib, a novel molecular-targeted agent, was evaluated for its in vivo efficacy through a comparison among the control groups (no treatment) and subject groups (treatment). Newly formed vessel length and tumor volume were measured in all of the groups for further study. The length of newly formed vessels was obviously shortened after apatinib treatment in the zebrafish model established in this study. Meanwhile, apatinib exhibited the best antitumor growth effect with dose and time dependence by suppressing AKT/GSK3α/β signaling, which may be the mechanism underlying the profound antitumor clinical effect of apatinib. The data indicated that apatinib therapy exerts an anti-angiogenesis effect and it can be recommended as a proper antitumor growth therapy for GC patients. Additionally, zebrafish models could be designed as a potential practical tool to explore new anti-GC cancer drugs.
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Affiliation(s)
- Yi Chen
- Department of Oncology, Nanjing Pukou Central Hospital, Pukou Branch Hospital of Jiangsu Province Hospital, Nanjing 210000, China
| | - Nan Chen
- Department of Outpatient, General Hospital of Eastern Theater Command, PLA, Nanjing 210002, China
| | - Jin Xu
- Department of Thyroid and Mammary Gland Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing 210000, China
| | - Xindong Wang
- Department of Oncology, Medical School, Southeast University, Nanjing 210009, China
| | - Xiaowei Wei
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210000, China
| | - Cuiju Tang
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210000, China
| | - Zhong Duanmu
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210000, China
| | - Junfeng Shi
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210000, China
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20
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Qin S, Ji J, Xu RH, Wang W, Tang Y, Bi F, Li J, Wang K, Xu JM, Fan Q, Su W, Shen L. Treatment Patterns and Outcomes in Chinese Patients with Gastric Cancer by HER2 Status: A Noninterventional Registry Study (EVIDENCE). Oncologist 2021; 26:e1567-e1580. [PMID: 34003545 DOI: 10.1002/onco.13826] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 12/21/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Real-world safety and effectiveness data for trastuzumab plus chemotherapy treatment of patients with HER2-positive metastatic gastric cancer (mGC) in China are lacking. PATIENTS AND METHODS EVIDENCE was a prospective, multicenter, noninterventional registry study evaluating the safety and effectiveness of trastuzumab in five cohorts of Chinese patients with gastric cancer, stratified by HER2 status and trastuzumab treatment. Effectiveness was analyzed for cohorts I (HER2-positive, trastuzumab treated), II (HER2-positive, trastuzumab untreated), and IV (HER2-negative, trastuzumab untreated); trastuzumab-related adverse events (AEs) were analyzed for cohort I. RESULTS Cohorts I, II, and IV included 174, 113, and 422 patients, respectively. Most patients received first-line chemotherapy (87.6%). Median overall survival (OS1) for first-line treatment was 22.3, 17.2, and 17.4 months in cohorts I, II, and IV, respectively. After excluding patients who had surgery, respective median OS1 was 19.9, 15.3, and 12.9 months. Respective first-line progression-free survival (PFS1) was 8.2, 6.9, and 6.2 months; and respective first-line response rates (RR) were 51.7%, 18.4%, and 32.8%. Cohort I was significantly favored over cohort II for propensity score-matched first-line median OS1 (hazard ratio [HR], 0.61), PFS1 (HR, 0.64), and RR (odds ratio, 4.93). Trastuzumab-related AEs, grade 3-5 AEs, serious AEs, and AEs with a fatal outcome occurred in 23.6%, 3.4%, 2.3%, and 0.6% of cohort I patients, respectively. CONCLUSION Safety profiles were consistent with those known for trastuzumab and chemotherapy; trastuzumab treatment improved outcomes. Our study provides real-world data supporting first-line trastuzumab plus chemotherapy in Chinese patients with HER2-positive mGC. IMPLICATIONS FOR PRACTICE This prospective, noninterventional registry study aimed to provide safety and effectiveness data for the use of trastuzumab in combination with chemotherapy in Chinese patients with HER2-positive metastatic gastric cancer (mGC) from the real-world clinical setting. Trastuzumab plus first-line chemotherapy was shown to be safe and to improve outcomes when compared with patients treated with chemotherapy alone. Trastuzumab was effective within a range of treatment regimens; subgroup analysis showed that trastuzumab paired most effectively with the XELOX regimen. This study provides real-world clinical safety and effectiveness data supporting the use of trastuzumab in the treatment of Chinese patients with HER2-positive mGC.
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Affiliation(s)
- Shukui Qin
- Nanjing Bayi Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People's Republic of China
| | - Jiafu Ji
- Peking University Cancer Hospital and Institute, Beijing, People's Republic of China
| | - Rui-Hua Xu
- Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China
| | - Wei Wang
- The First People's Hospital of Foshan, Foshan, Guangdong, People's Republic of China
| | - Yong Tang
- Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People's Republic of China
| | - Feng Bi
- West China Hospital of Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Jin Li
- Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - Kang Wang
- Sichuan Provincial People's Hospital, Chengdu, Sichuan, People's Republic of China
| | - Jian-Ming Xu
- Chinese People's Liberation Army 307 Hospital, Beijing, People's Republic of China
| | - Qingxia Fan
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Wuyun Su
- Affiliated Hospital, Inner Mongolia Medical College, Hohhot, Inner Mongolia, People's Republic of China
| | - Lin Shen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, People's Republic of China
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21
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Joshi SS, Badgwell BD. Current treatment and recent progress in gastric cancer. CA Cancer J Clin 2021; 71:264-279. [PMID: 33592120 PMCID: PMC9927927 DOI: 10.3322/caac.21657] [Citation(s) in RCA: 1041] [Impact Index Per Article: 260.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 12/08/2020] [Accepted: 12/09/2020] [Indexed: 12/15/2022] Open
Abstract
Gastric cancer is not a top-10 malignancy in the United States but represents one of the most common causes of cancer death worldwide. Biological differences between tumors from Eastern and Western countries add to the complexity of identifying standard-of-care therapy based on international trials. Systemic chemotherapy, radiotherapy, surgery, immunotherapy, and targeted therapy all have proven efficacy in gastric adenocarcinoma; therefore, multidisciplinary treatment is paramount to treatment selection. Triplet chemotherapy for resectable gastric cancer is now accepted and could represent a plateau of standard cytotoxic chemotherapy for localized disease. Classification of gastric cancer based on molecular subtypes is providing an opportunity for personalized therapy. Biomarkers, in particular microsatellite instability (MSI), programmed cell death ligand 1 (PD-L1), human epidermal growth factor receptor 2 (HER2), tumor mutation burden, and Epstein-Barr virus, are increasingly driving systemic therapy approaches and allowing for the identification of populations most likely to benefit from immunotherapy and targeted therapy. Significant research opportunities remain for the less differentiated histologic subtypes of gastric adenocarcinoma and those without markers of immunotherapy activity.
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Affiliation(s)
- Smita S Joshi
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Brian D Badgwell
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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22
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Chamseddine AN, Oba K, Buyse M, Boku N, Bouché O, Satar T, Auperin A, Paoletti X. Impact of follow-up on generalized pairwise comparisons for estimating the irinotecan benefit in advanced/metastatic gastric cancer. Contemp Clin Trials 2021; 105:106400. [PMID: 33866004 DOI: 10.1016/j.cct.2021.106400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 04/07/2021] [Accepted: 04/08/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND AND OBJECTIVES The net treatment effect (∆) is a new method to assess the treatment benefit that combines multiple time-to-event, binary and continuous endpoints according to a pre-specified sequence. It represents the net probability for a random patient treated in the experimental arm to have a better overall outcome than a random patient from the control arm does. We aimed at characterizing the impact of follow-up on ∆ estimated from both time-to-event and binary toxicity endpoints, in randomized controlled trials (RCTs) of irinotecan-based regimen in advanced/metastatic gastric cancer (AGC). STUDY DESIGN Three RCTs are reanalysed. The net treatment effect using from one to three outcomes (i.e. overall survival, time to progression and toxicity in this order) and the hazard ratio (HR) were estimated after various cut-off dates and compared to the values obtained after complete follow-up were reported. RESULTS In all three RCTs (897 patients), the irinotecan-based regimen was superior to the non-irinotecan containing regimen in terms of HR and ∆. This superiority was lower when the net treatment effect also accounted for toxicity. The HR was slightly less influenced by an incomplete follow-up than ∆ was, but correction proposed by Péron to account for censored observations showed quite robust results. CONCLUSIONS The net treatment effect using Péron's correction can be used in case of interim analyses or high censoring rates. In addition to relative measures such as the hazard ratio, it provides a simple mean to evaluate the net treatment effect with and without toxicity outcomes.
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Affiliation(s)
- Ali N Chamseddine
- OncoStat CESP, INSERM, Université Paris-Saclay, Équipe Labellisée Ligue Contre le Cancer, Villejuif, France; Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France
| | - Koji Oba
- Department of Biostatistics, The University of Tokyo, Tokyo, Japan
| | - Marc Buyse
- International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium & Interuniversity Institute for Biostatistics and Statistical Bioinformatics (I-BioStat), University of Hasselt, Hasselt, Belgium
| | - Narikazu Boku
- Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Olivier Bouché
- Fédération Francophone de Cancérologie Digestive (FFCD), Department of Digestive Oncology, CHU Reims, Reims, France
| | - Tuvana Satar
- Service de Biostatistique et dEpidémiologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Anne Auperin
- OncoStat CESP, INSERM, Université Paris-Saclay, Équipe Labellisée Ligue Contre le Cancer, Villejuif, France; Service de Biostatistique et dEpidémiologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Xavier Paoletti
- Université de Versailles-St Quentin, France; Institut Curie & INSERM U900, Biostatistics for Precision Medicine (STAMPM), Saint-Cloud, France; Université Paris Saclay, France.
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23
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Chen XJ, Chen GM, Wei YC, Yu H, Wang XC, Zhao ZK, Luo TQ, Nie RC, Zhou ZW. Palliative Gastrectomy versus Gastrojejunostomy for advanced Gastric cancer with outlet obstruction: a propensity score matching analysis. BMC Cancer 2021; 21:188. [PMID: 33622258 PMCID: PMC7903659 DOI: 10.1186/s12885-021-07904-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 02/08/2021] [Indexed: 12/27/2022] Open
Abstract
Background Gastric outlet obstruction (GOO) is a late complication of advanced gastric cancer, and it is controversial how to select the therapeutic strategies: gastrojejunostomy and palliative gastrectomy? Therefore, this study was to compare the surgical and survival outcomes of gastrojejunostomy and palliative gastrectomy. Methods In total, 199 gastric cancer patients with outlet obstruction treated by surgery between January 2000 and December 2015 at Sun Yat-sen University Cancer Center were retrospectively reviewed. Patients were divided into gastrojejunostomy group and palliative gastrectomy group. Propensity score matching (PSM) was performed to balance the selection bias. Results After 1:1 PSM, a total of 104 patients were included for final analysis. The median overall survival (OS) times in the gastrojejunostomy group and palliative gastrectomy group were 8.50 and 11.87 months, respectively (P = 0.243). The postoperative complication rates in the gastrojejunostomy group and palliative gastrectomy group were 19.23% (10/52) and 17.31% (9/52), respectively (P = 0.800), and no treatment-related death was observed. Multivariate analysis showed that periton0eal seeding (P = 0.014) and chemotherapy (P < 0.001) were independent prognostic factors. Among them, peritoneal seeding was a risk factor and postoperative chemotherapy was a protective factor. Conclusions Our results indicated that although the surgical complications of palliative gastrectomy were manageable, it showed no survival benefit. Therefore, relieving obstruction symptom, improving patients’ quality of life and creating better conditions for chemotherapy appear to be the main therapeutic strategies for advanced gastric cancer with GOO.
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Affiliation(s)
- Xiao-Jiang Chen
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou, 510060, Guangdong, China
| | - Guo-Ming Chen
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou, 510060, Guangdong, China
| | - Yi-Cheng Wei
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou, 510060, Guangdong, China
| | - Hong Yu
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou, 510060, Guangdong, China
| | - Xi-Cheng Wang
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou, 510060, Guangdong, China
| | - Zhou-Kai Zhao
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou, 510060, Guangdong, China
| | - Tian-Qi Luo
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou, 510060, Guangdong, China
| | - Run-Cong Nie
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou, 510060, Guangdong, China.
| | - Zhi-Wei Zhou
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, No.651 Dongfeng Road East, Guangzhou, 510060, Guangdong, China.
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Cao CQ, Chang L, Wu Q. Circulating methylated Septin 9 and ring finger protein 180 for noninvasive diagnosis of early gastric cancer. Transl Cancer Res 2020; 9:7012-7021. [PMID: 35117307 PMCID: PMC8799148 DOI: 10.21037/tcr-20-1330] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 09/28/2020] [Indexed: 12/14/2022]
Abstract
Background Gastric cancer (GC) has a poor prognosis due to patients often being diagnosed at an advanced stage, when metastasis has already occurred. To improve the 5-year survival rate and reduce the number of cancer-related deaths in patients with GC, noninvasive methods for early detection need to be developed. This study aimed to evaluate the value of circulating methylated Septin 9 (SEPT9) and ring finger protein 180 (RNF180) for the early diagnosis of GC. Methods Seventy-four patients with early GC, 99 patients with benign gastric diseases (BGD) (inflammation, polyps, intestinal metaplasia, ulcers, and erosion), and 57 cases with no evidence of disease (NED) were enrolled. Methylated SEPT9 and RNF180 in circulating cell-free DNA in blood samples from each group were detected, and the positivity rates were calculated. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), confidence interval (CI), and area under the curve (AUC) were determined for methylated SEPT9 and RNF180 in relation to early GC. Results As a diagnostic target, methylated SEPT9 had a sensitivity of 28.3% (95% CI: 18.5–40.0%), specificity of 94.2% (95% CI: 89.3–97.3%), and AUC value of 0.616 (95% CI: 52.0–71.1%). Methylated RNF180 had a sensitivity of 32.4% (95% CI: 22.0–44.3%), specificity of 89.7% (95% CI: 83.9–94.0%), and AUC value of 0.636 (95% CI: 54.2–73.0%). A combination of the two yielded a sensitivity of 40.5% (95% CI: 29.3–52.6%), specificity of 85.3% (95% CI: 78.7–90.4%), and AUC value of 0.65 (95% CI: 55.7–74.4%). Conclusions Methylated SEPT9 and RNF180 could be used as diagnostic biomarkers for early gastric cancer (EGC).
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Affiliation(s)
- Chang-Qi Cao
- Department of Endoscopy Center, Peking University Cancer Hospital & Institute, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Beijing, China
| | - Lin Chang
- Department of Endoscopy Center, Peking University Cancer Hospital & Institute, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Beijing, China
| | - Qi Wu
- Department of Endoscopy Center, Peking University Cancer Hospital & Institute, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Beijing, China
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Lv GB, Wang TT, Zhu HL, Wang HK, Sun W, Zhao LF. Vortioxetine induces apoptosis and autophagy of gastric cancer AGS cells via the PI3K/AKT pathway. FEBS Open Bio 2020; 10:2157-2165. [PMID: 32750222 PMCID: PMC7530385 DOI: 10.1002/2211-5463.12944] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 05/24/2020] [Accepted: 06/05/2020] [Indexed: 12/24/2022] Open
Abstract
Vortioxetine is a potent antagonist of the 5‐hydroxytryptamine receptor and serotonin transporter and has been reported to function as an antidepressant in the treatment of major depressive disorder. However, its antitumor effects remain unclear. Here, we examined whether vortioxetine affects the characteristics of GC cells. Cell viability was measured by a colony formation assay and, in addition, cell invasion, migration and apoptosis assays were performed with a transwell assay and a flow cytometry assay. Protein levels were measured by western blotting. We found that vortioxetine inhibited the proliferation, invasion and migration abilities of AGS cells. Additionally, vortioxetine could induce apoptosis and autophagy by increasing the levels of Bax, active caspase‐3/‐9, Beclin‐1 and light chain 3, as well as by downregulating Bcl‐2 and P62. Further investigations indicated that vortioxetine regulated apoptosis and autophagy via activation of the phosphoinositide 3‐kinase/AKT pathway. Taken together, our data suggest that vortioxetine has cytotoxic effects against GC AGS cells as a result of inhibiting proliferation, invasion and migration, as well as by inducing apoptosis and autophagy through the phosphoinositide 3‐kinase/AKT pathway.
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Affiliation(s)
- Gao-Bo Lv
- Department of Anal-colorectal Surgery, Baoji Municipal Central Hospital, Baoji, China
| | - Ting-Ting Wang
- Department of Administration Center Outpatient, Baoji Municipal Central Hospital, Baoji, China
| | - Hai-Lin Zhu
- Department of Hepatobiliary Pancreatic Surgery, Baoji Municipal Central Hospital, Baoji, China
| | - Hong-Ke Wang
- Department of Gastroenterology, Baoji Municipal Central Hospital, Baoji, China
| | - Wen Sun
- Beijing Splinger Institute of Medicine, Jinan, China
| | - Li-Feng Zhao
- Department of Hepatobiliary Pancreatic Surgery, Baoji Municipal Central Hospital, Baoji, China
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Abstract
OPINION STATEMENT Despite a decreasing incidence in the USA, gastric cancer is highly prevalent worldwide. Furthermore, gastric cancer remains highly lethal with median survival of less than 1 year for metastatic disease. The backbone of therapy against metastatic gastric cancer remains cytotoxic chemotherapy, but recent advances in the molecular understanding of gastric cancer have renewed hope within that targeted agents can be leveraged to improve survival and reduce toxicity. For example, in patients with human epidermal growth factor-2 (HER2)-positive gastric cancer, the addition of trastuzumab to frontline chemotherapy improves survival. In the second line, oncologists can now administer a vascular endothelial growth factor (VEGF) receptor inhibitor, ramucirumab, as a single agent or in combination with chemotherapy, and the immune checkpoint inhibitor pembrolizumab is approved in multiple settings dependent on the Programmed Death Ligand 1 (PD-L1) status. For patients with metastatic disease, our approach to standard of care in the first-line setting is a 5FU/platinum doublet with trastuzumab for HER2-positive tumors. In the second-line setting, most patients receive ramucirumab + paclitaxel, but those that are MSI high receive pembrolizumab. For squamous cell carcinoma of the esophagus with high PD-L1 status (combined positive score (CPS) ≥ 10), we recommend pembrolizumab in the second line. While for PD-L1 ≥ 1% gastroesophageal adenocarcinoma, we do not recommend pembrolizumab before the third-line setting, although this may change in the near future for CPS ≥ 10. The future landscape for targeted therapy in gastric cancer is promising. Numerous clinical trials evaluating the combination immune therapy with molecularly targeted agents are generating much excitement. Moreover, genomic data from The Cancer Center Genome (TCGA) and Asian Cancer Research Group (ACRG) classifications is being used to identify molecular subtypes to enable future clinical trials to include biomarker-enriched patient populations.
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Combination Use of Tegafur and Apatinib as First-Line Therapy in Treatment of Advanced Gastric Cancer: A Single-Blinded Randomized Study. Gastroenterol Res Pract 2020; 2020:3232950. [PMID: 32328095 PMCID: PMC7165347 DOI: 10.1155/2020/3232950] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Accepted: 10/30/2019] [Indexed: 11/24/2022] Open
Abstract
Objective To investigate the efficacy and safety of the combination use of tegafur and apatinib as a first-line therapy strategy in advanced gastric cancer (GC). Methods The present study included a total of 62 advanced GC patients. The patients were randomized into the combined group (treated with both tegafur and apatinib) and the control group (treated with only tegafur). Treatment efficacy, KPS score, nutrition condition, and progression-free survival time (PFS) were recorded. Results Both the response and disease control rates were significantly higher in the combined group. The PFS time was remarkably higher and the KPS score was significantly reduced in the combined group after treatment. After treatment, both groups showed significantly increased nutrition risk, but the rates of patients with nutrition risk or innutrition were remarkably higher in the combined group. The ADR rates were also significantly higher in the combined group. Conclusion The combination use could achieve good efficacy and prolong patients' PFS time; however, apatinib also reduced the patients' quality of life and enhanced the nutrition risk and adverse drug reactions.
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Demirelli B, Babacan NA, Ercelep Ö, Öztürk MA, Kaya S, Tanrıkulu E, Khalil S, Hasanov R, Alan Ö, Telli TA, Koca S, Arıbal ME, Kuzan B, Dane F, Yumuk PF. Modified Glasgow Prognostic Score, Prognostic Nutritional Index and ECOG Performance Score Predicts Survival Better than Sarcopenia, Cachexia and Some Inflammatory Indices in Metastatic Gastric Cancer. Nutr Cancer 2020; 73:230-238. [PMID: 32270713 DOI: 10.1080/01635581.2020.1749290] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Background: Gastric carcinoma (GC) patients usually present with locally advanced or metastatic disease; therefore treatment aim is mainly palliation. In this study our purpose is to analyze the prognostic values of the sarcopenia index (SI), cachexia index (CIn) and other inflammatory indexes (advanced lung cancer inflammation index [ALI], modified Glasgow Prognostic Score [mGPS], prognostic index [PI], prognostic nutritional index [PNI] and neutrophil-to-lymphocyte ratio [NLR]) in metastatic GC patients.Methods: Data from the files of metastatic GC patients, who applied to Medical Oncology outpatient clinic in Marmara University Pendik Education and Research Hospital between January 2011 and June 2016, were retrospectively reviewed. Five hundred seventy patients with gastric cancer were detected. Exclusion criteria were the inability to reach the patient surveys for prognostic index calculations, the presence of additional comorbidities to affect the laboratory parameters, and the absence of metastatic disease. Finally, 87 of these patients were included in this study. For SI calculation L3 level muscle area was measured from patients' computed tomography (CT) by a radiologist. SI reference value was obtained from western-EGWSOP (The European Working Group on Sarcopenia in Older People) and eastern (Harada Y, et al.) sources separately, as Turkey doesn't have a reference value for SI. NLR cutoff value was accepted as the median value of patients' NLR measurements. Statistical analysis was conducted using SPSS. Kaplan-Meier and Cox regression models were used to assess independent prognostic factors. The area under the curve was used to compare the prognostic value of indexes.Results: The median length of follow-up of 87 patients was nine months (1-64 mo,/s), and 78 patients died during follow-up. Fifty-nine patients were male (63%), and the median age was 62 (range, 23-88). According to univariate analysis high mGPS and PI score, PNI level <45, NLR level ≥ 3.41, ALI level <18, CI level under 35, SI (Harada Y, et al) ≤44.5 for males and ≤36.5 for females, ECOG score ≥ 2, weight loss more than 10% during last 6 mo, BMI under 24 were poor prognostic factors. Age, gender, having multiple organ metastasis, history of gastric surgery, positivity C-erb-B2, SI (EGWSOP) ≤52.4 for males, and ≤38.4 for females did not have any impact on survival. According to multivariate analysis, high mGPS (score 2) (HR 2,494, 95% CI 1.25-4 .94, p = 0.02), PNI (score 1) (HR 4.2, 95% CI 1.73-10.1, p < 0.001) and ECOG score (≥2) (HR 1.541, 95% CI 1,089-4,214, p = 0.004) have been found to be independent prognostic factors which are determining the survival. mGPS was found to be more valuable than other indexes for predicting mortality by measuring the AUC with ROC analysis.Conclusions: In our study, mGPS, PNI and ECOG score were independent indicators for shorter survival in metastatic gastric cancer patients. mGPS and PNI, which can be done by using only serum CRP, albumin level and complete blood count, might be inexpensive, practical and beneficial to use in routine clinical practice to determine survival.
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Affiliation(s)
- Bülent Demirelli
- Department of Internal Medicine, Marmara University School of Medicine, Istanbul, Turkey
| | - Nalan Akgül Babacan
- Division of Medical Oncology, Marmara University School of Medicine, Istanbul, Turkey
| | - Özlem Ercelep
- Division of Medical Oncology, Marmara University School of Medicine, Istanbul, Turkey
| | - Mehmet Akif Öztürk
- Division of Medical Oncology, Marmara University School of Medicine, Istanbul, Turkey
| | - Serap Kaya
- Division of Medical Oncology, Marmara University School of Medicine, Istanbul, Turkey
| | - Eda Tanrıkulu
- Division of Medical Oncology, Marmara University School of Medicine, Istanbul, Turkey
| | - Süleyman Khalil
- Division of Medical Oncology, Marmara University School of Medicine, Istanbul, Turkey
| | - Rahib Hasanov
- Division of Medical Oncology, Marmara University School of Medicine, Istanbul, Turkey
| | - Özkan Alan
- Division of Medical Oncology, Marmara University School of Medicine, Istanbul, Turkey
| | - Tuğba Akın Telli
- Division of Medical Oncology, Marmara University School of Medicine, Istanbul, Turkey
| | - Sinan Koca
- Division of Medical Oncology, Marmara University School of Medicine, Istanbul, Turkey
| | - Mustafa Erkin Arıbal
- Department of Radiology, Marmara University School of Medicine, Istanbul, Turkey
| | - Beyza Kuzan
- Department of Radiology, Marmara University School of Medicine, Istanbul, Turkey
| | - Faysal Dane
- Division of Medical Oncology, Marmara University School of Medicine, Istanbul, Turkey
| | - Perran Fulden Yumuk
- Division of Medical Oncology, Marmara University School of Medicine, Istanbul, Turkey
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Zhu Z, Xu J, Li L, Ye W, Xu G, Chen B, Zeng J, Li J, Huang Z. Effect of gastric cancer stem cell on gastric cancer invasion, migration and angiogenesis. Int J Med Sci 2020; 17:2040-2051. [PMID: 32788883 PMCID: PMC7415381 DOI: 10.7150/ijms.46774] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 06/26/2020] [Indexed: 12/16/2022] Open
Abstract
Purpose: Using the gastric cancer cell line SGC7901 and gastric cancer stem cell (CSC-G), we conducted this study to investigate the role of cancer stem cells in invasion, metastasis and tumor angiogenesis. Methods: Stem cell markers (OCT4, SOX2, C-Myc and Klf4) expression was detected by RT-PCR and Western blotting. The proliferation, migration, invasion abilities, L-OHP and 5-FU resistance, angiogenesis were assessed using in vitro spherical clone formation assays, plate cloning experiments, transwell migration, transwell invasion, drug resistance, scratch-wound migration, ring formation assay, and their tumorigenic and ability were assessed using a tumor formation experiment in mice. Results: Compared with the SGC7901, the expression of Oct4, Sox2, Klf4 and CD44 mRNA was significantly higher in CSC-G, the mRNA relative expression of E-cadherin in CSC-G was lower than SGC7901, while the expression of c-Myc did not significantly change. The proliferation, drug resistance, migration, and invasion abilities were significantly higher in CSC-G, and the tumorigenic ability in mice was also significantly higher. Conclusion: The proliferation, drug resistance, migration, invasion, and tumorigenic abilities of CSC-G significantly were higher than SGC7901. CSC-G plays important roles in proliferation, migration, invasion, and tumorigenicity.
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Affiliation(s)
- Zhipeng Zhu
- Department of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen (Fujian 361003), P.R. China
| | - Jiuhua Xu
- Department of clinical medicine, Fujian Medical University, Fuzhou (Fujian 350004), P.R. China
| | - Lulu Li
- Department of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen (Fujian 361003), P.R. China
| | - Weipeng Ye
- Department of clinical medicine, Fujian Medical University, Fuzhou (Fujian 350004), P.R. China
| | - Guoxing Xu
- Endoscopy center, The First Affiliated Hospital of Xiamen University, Xiamen (Fujian 361003), P.R. China
| | - Borong Chen
- Department of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen (Fujian 361003), P.R. China
| | - Junjie Zeng
- Department of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen (Fujian 361003), P.R. China
| | - Jiayi Li
- Department of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen (Fujian 361003), P.R. China
| | - Zhengjie Huang
- Department of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen (Fujian 361003), P.R. China.,Department of clinical medicine, Fujian Medical University, Fuzhou (Fujian 350004), P.R. China
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Yu H, Yang AM, Lu XH, Feng L, Wu X, Cui JF, Cheng JY. Analysis of Long Non-Coding RNA Expression Profile and Functional Study of LOC389332 in Early Gastric Cancer. Med Sci Monit 2019; 25:10114-10121. [PMID: 31884510 PMCID: PMC6948287 DOI: 10.12659/msm.917935] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background Long non-coding RNAs (LncRNAs) could potentially function as diagnostic markers for gastric carcinoma. Nevertheless, the expression profile and biological feature of LncRNAs in early gastric cancer (EGC) remains to be explored. Material/Methods LncRNA expression microarray analysis was performed on 6 paired EGC tissues. One deregulated LncRNA, LOC389332, was validated using a quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assay using independent tissue samples and cell lines. The Cell Counting Kit-8 (CCK-8) assay and wound healing assay were conducted to evaluate its influences on the proliferation and migration of gastric cancer cells. LncRNA expression microarray and gene ontology (GO) analysis were also performed on the LOC389332 knockdown cell line model to explore the molecular feature of LOC389332 in gastric carcinoma. Results The LncRNA expression profiling showed that 72 LncRNAs were significantly differentially expressed in EGC tissues. The results in the validation phase revealed that LOC389332 was remarkably overexpressed in gastric carcinoma tissues, precancerous lesions, and gastric cancer cells. Functional study showed that knockdown of LOC389332 expression could inhibit cell proliferation and migration. LncRNA expression microarray on the LOC389332 knockdown cell line model revealed that 393 mRNAs were differentially expressed. The GO enrichment analysis indicated that the downregulated genes were mainly associated with cell membrane function, signal transmission process, and cell adhesion process. Conclusions The LncRNA expression profile between EGC and gastritis tissues was significantly different. LOC389332 was potential non-coding oncogenes in gastric cancer, and it may perform its function through altering cell membrane function, signal transmission, and cell adhesion.
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Affiliation(s)
- Hang Yu
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China (mainland)
| | - Ai-Ming Yang
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China (mainland)
| | - Xing-Hua Lu
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China (mainland)
| | - Lin Feng
- State Key Laboratory of Molecular Oncology, Cancer Institute Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China (mainland)
| | - Xi Wu
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China (mainland)
| | - Jian-Fang Cui
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China (mainland)
| | - Jie-Yao Cheng
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China (mainland)
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31
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Zhou X, Liu M, Ren Q, Zhu W, Wang Y, Chen H, Chen J. Oral and injectable Marsdenia tenacissima extract (MTE) as adjuvant therapy to chemotherapy for gastric cancer: a systematic review. Altern Ther Health Med 2019; 19:366. [PMID: 31830977 PMCID: PMC6909592 DOI: 10.1186/s12906-019-2779-y] [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: 05/09/2019] [Accepted: 11/28/2019] [Indexed: 12/14/2022]
Abstract
Background Marsdenia tenacissima extract (MTE) is a phytochemical widely used as complementary therapy in cancer care. This systematic review was conducted to investigate the anticancer and detoxification effects of MTE, as an adjuvant therapy to chemotherapy, for treating gastric cancer. Methods Ten databases were searched to identify randomized controlled trials (RCTs) comparing oral or injectable MTE plus chemotherapy versus chemotherapy alone for treating gastric cancer up to May 1, 2019. In meta-analyses, proportional odds ratios (PORs) with 95% confidence intervals (CIs) were pooled for the ordinal outcomes using the generalized linear model, and risk ratios (RRs) with 95% CIs were pooled for dichotomous outcomes using the Mantel-Haenszel method. Results Seventeen RCTs with 1329 individuals were included, with a moderate to high risk of selection and performance bias. Compared to chemotherapy alone, MTE adjuvant therapy significantly improved the response to anticancer treatment (POR 2.01, 95% CI 1.60–2.53) and patients’ performance status (POR 3.15, 95% CI 2.22–4.48) and reduce the incidences of chemotherapy-induced leukopenia (RR 0.66, 95% CI 0.56–0.78), thrombocytopenia (RR 0.64, 95% CI 0.48–0.86), anemia (RR 0.89, 95% CI 0.72–1.10), nausea/vomiting (RR 0.79, 95% CI 0.69–0.91), hepatic injury (RR 0.77, 95% CI 0.61–0.96), and peripheral neurotoxicity (RR 0.77, 95% CI 0.59–1.01). However, MTE did not significantly alleviate anemia, diarrhea, constipation, kidney injury, and oral mucosal lesions after chemotherapy. Incidence of nausea/vomiting was lower in patients receiving oral MTE than those receiving injectable MTE (RR 0.47 vs. 0.82, interaction P = 0.04). Heterogeneity was generally low among these outcomes. Three out of five RCTs that reported survival data supported the effects of MTE for prolonging progression-free and/or overall survival. No studies reported safety outcomes of MTE. Conclusions The current evidence with limitations of risk of selection and performance bias suggests that MTE, as an adjuvant therapy to chemotherapy, is effective for inhibiting cancer growth and reducing incidences of multiple chemotherapy side effects. Oral MTE may be a better choice. Uncertainty remains regarding the effects of MTE on survival endpoints and the subgroup differences between acute and chronic use of MTE and between different chemotherapy regimens.
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Abstract
As one of the most serious cancers, gastric cancer (GC) represents the third leading cause of malignancy-related deaths. G9a is a histone lysine methyltransferase and has been reported to be involved in the progression of some human cancers. In the present study, we aimed to explore the expression patterns and clinical value of G9a in GC patients.The expression of G9a in 142 paired GC tissues and adjacent non-cancerous tissues (no less than 5 cm from tumor edge) was examined with quantitative real-time polymerase chain reaction (qRT-PCR). To estimate the association of G9a expression with clinical characteristics of GC patients, Chi-square test and t test were conducted. Kaplan-Meier survival and multivariate Cox regression analyses were performed to explore the prognostic value of G9a in GC.Upregulated expression of G9a was found in GC tissues compared with noncancerous tissues (P < .001). Elevated G9a expression was significantly correlated with patients' lymph node metastasis (P = .007) and TNM stage (P < .001). Kaplan-Meier survival curves demonstrated that patients with high G9a expression had shorter survival time than those with low expression (log-rank test, P < .05), reaching a median OS of 24 months. According to the results of Cox regression, G9a could be considered as an independent prognostic biomarker in patients with GC (HR = 3.912, 95% CI = 2.213-6.915, P < .001). Additionally, the diagnosis cut-off value of G9a in GC patients was 1.515.Taken together, G9a expression was upregulated in GC tissues and could be an effective prognostic biomarker for GC.
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Shang H, Cao Z, Zhao J, Guan J, Liu J, Peng J, Chen Y, Joseph Sferra T, Sankararaman S, Lin J. Babao Dan induces gastric cancer cell apoptosis via regulating MAPK and NF-κB signaling pathways. J Int Med Res 2019; 47:5106-5119. [PMID: 31456462 PMCID: PMC6833375 DOI: 10.1177/0300060519867502] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 07/12/2019] [Indexed: 01/24/2023] Open
Abstract
OBJECTIVE The objective was to further investigate apoptosis induction by Babao Dan (BBD), which supports its anti-tumor mechanisms, using two human gastric cancer cell lines (AGS and MGC80-3). METHODS After treatment with various BBD concentrations, cell viability and cytotoxic effects were investigated using methyl thiazolyl tetrazolium (MTT) and lactate dehydrogenase (LDH) assays, respectively. The following indicators of cell apoptosis were evaluated: Annexin V-APC staining, caspase-3/-8/-9 activation, and mitochondrial membrane potential loss. Apoptosis-related protein levels (including Bcl-2-associated X protein [Bax], B-cell CLL/lymphoma 2 [Bcl-2], factor associated suicide [Fas], and Fas ligand [FasL]) were determined by western blot. The following multi-pathway factors were also assessed: p-ERK1/2, p-JNK, p-p38, and p-NF-κB. RESULTS The MTT and LDH assays both demonstrated increased BBD cytotoxicity. BBD induced cell apoptosis by stimulating caspase-3/-8/-9 activity and destroying the mitochondrial membrane potential. BBD also regulated key factor expression levels including Bcl-2, Bax, Fas, and FasL and down-regulated protein phosphorylation via the MAPK and NF-κB pathway. CONCLUSIONS The possible anti-tumor mechanism is that BBD induces apoptosis via the MAPK and NF-κB signaling pathways.
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Affiliation(s)
- Haixia Shang
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
| | - Zhiyun Cao
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Key Laboratory of Integrative Medicine on Geriatric, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
| | - Jinyan Zhao
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Key Laboratory of Integrative Medicine on Geriatric, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
| | - Jianhua Guan
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
| | - Jianxin Liu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
| | - Jun Peng
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Key Laboratory of Integrative Medicine on Geriatric, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
| | - Youqin Chen
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Children’s Hospital, Cleveland, OH, USA
| | - Thomas Joseph Sferra
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Children’s Hospital, Cleveland, OH, USA
| | - Senthilkumar Sankararaman
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Children’s Hospital, Cleveland, OH, USA
| | - Jiumao Lin
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
- Fujian Key Laboratory of Integrative Medicine on Geriatric, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
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Hsieh HL, Tsai MM. Tumor progression-dependent angiogenesis in gastric cancer and its potential application. World J Gastrointest Oncol 2019; 11:686-704. [PMID: 31558974 PMCID: PMC6755109 DOI: 10.4251/wjgo.v11.i9.686] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 07/05/2019] [Accepted: 08/19/2019] [Indexed: 02/05/2023] Open
Abstract
Despite improvements in the early diagnosis, prognosis and therapeutic strategies for gastric cancer (GC), human GC remains one of the most frequently diagnosed malignant tumors in the world, and the survival rate of GC patients remains very poor. Thus, a suitable therapeutic strategy for GC is important for prolonging survival. Both tumor cells themselves and the tumor microenvironment play an important role in tumorigenesis, including angiogenesis, inflammation, immunosuppression and metastasis. Importantly, these cells contribute to gastric carcinogenesis by altering the angiogenic phenotype switch. The development, relapse and spreading of tumors depend on new vessels that provide the nutrition, growth factors and oxygen required for continuous tumor growth. Therefore, a state of tumor dormancy could be induced by blocking tumor-associated angiogenesis. Recently, several antiangiogenic agents have been identified, and their potential for the clinical management of GC has been tested. Here, we provide an up-to-date summary of angiogenesis and the angiogenic factors associated with tumor progression in GC. We also review antiangiogenic agents with a focus on the anti-vascular endothelial growth factor receptor (VEGFR)-mediated pathway for endothelial cell growth and their angiogenesis ability in GC. However, most antiangiogenic agents have reported no benefit to overall survival (OS) compared to chemotherapy alone in local or advanced GC. In phase III clinical trials, only ramucirumab (anti-VEGFR blocker) and apatinib (VEGFR-TKI blocker) have reported an improved median overall response rate and prolonged OS and progression-free survival outcomes as a 2nd-line agent combined with chemotherapy treatment in advanced GC. By providing insights into the molecular mechanisms of angiogenesis associated with tumor progression in GC, this review will hopefully aid the optimization of antiangiogenesis strategies for GC therapy in combination with chemotherapy and adjuvant treatment.
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Affiliation(s)
- Hsi-Lung Hsieh
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
- Department of Neurology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Ming-Ming Tsai
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
- Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan
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Ni F, Tang H, Wang C, Wang Z, Yu F, Chen B, Sun L. Berzosertib (VE-822) inhibits gastric cancer cell proliferation via base excision repair system. Cancer Manag Res 2019; 11:8391-8405. [PMID: 31571995 PMCID: PMC6750847 DOI: 10.2147/cmar.s217375] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 09/03/2019] [Indexed: 12/15/2022] Open
Abstract
Background Current investigations suggest that the Base Excision Repair (BER) system may change DNA repair capacity and affect clinical gastric cancer progression such as overall survival. However, the prognostic value of BER system members in gastric cancer remains unclear. Methods We explored the prognostic correlation between 7 individual BER genes, including uracil-DNA glycosylase (UNG), Single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1), Methyl-CpG binding domain 4 (MBD4), thymine DNA glycosylase (TDG), 8-oxoguanine DNA glycosylase (OGG1), MutY DNA glycosylase (MUTYH) and Nei like DNA glycosylase 1 (NEIL1), expression and overall survival (OS) in different clinical data, such as Lauren classification, pathological stages, human epidermal growth factor receptor-2 (HER2) expression status, treatment strategy, gender and differentiation degree in gastric cancer patients, using Kaplan-Meier plotter (KM plotter) online database. Based on the bioinformatics analysis, we utilized Berzosertib (VE-822) to inhibit DNA damage repair in cancer cells compared to solvent control group via real-time cellular analysis (RTCA), flow cytometry, colony formation and migration assay. Finally, we utilized reverse transcription-polymerase chain reaction (RT-PCR) to confirm the expression of BER members between normal and two gastric cancer cells or solvent and VE-822 treated groups. Results Our work revealed that high UNG mRNA expression was correlated with high overall survival probability; however, high SMUG1, MBD4, TDG, OGG1, MUTYH and NEIL1 mRNA expression showed relatively low overall survival probability in all GC patients. Additionally, UNG was associated with high overall survival probability in intestinal and diffuse types, but SMUG1 and NEIL1 showed opposite results. Further, VE-822 pharmacological experiment suggested that inhibition of DNA damage repair suppressed gastric cancer cells’ proliferation and migration ability via inducing apoptosis. Further, real-time polymerase chain reaction results proposed the inhibition of gastric cancer cells by VE-822 may be through UNG, MUTYH and OGG-1 of BER system. Conclusion We comprehensively analyze the prognostic value of the BER system (UNG, SMUG1, MBD4, TDG, OGG1, MUTYH and NEIL1) based on bioinformatics analysis and experimental confirmation. BER members are associated with distinctive prognostic significance and maybe new valuable prognostic indicators in gastric cancer.
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Affiliation(s)
- Fubiao Ni
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Hengjie Tang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Cheng Wang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Zixiang Wang
- First College of Clinical Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Fangyi Yu
- First College of Clinical Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Bicheng Chen
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Linxiao Sun
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
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Li W, Chen Y, Sun X, Yang J, Zhang DY, Wang D, Suo J. Protein expression profiles and clinicopathologic characteristics associate with gastric cancer survival. Biol Res 2019; 52:42. [PMID: 31399040 PMCID: PMC6689162 DOI: 10.1186/s40659-019-0249-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 08/01/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Prognosis remains one of most crucial determinants of gastric cancer (GC) treatment, but current methods do not predict prognosis accurately. Identification of additional biomarkers is urgently required to identify patients at risk of poor prognoses. METHODS Tissue microarrays were used to measure expression of nine GC-associated proteins in GC tissue and normal gastric tissue samples. Hierarchical cluster analysis of microarray data and feature selection for factors associated with survival were performed. Based on these data, prognostic scoring models were established to predict clinical outcomes. Finally, ingenuity pathway analysis (IPA) was used to identify a biological GC network. RESULTS Eight proteins were upregulated in GC tissues versus normal gastric tissues. Hierarchical cluster analysis and feature selection showed that overall survival was worse in cyclin dependent kinase (CDK)2, Akt1, X-linked inhibitor of apoptosis protein (XIAP), Notch4, and phosphorylated (p)-protein kinase C (PKC) α/β2 immunopositive patients than in patients that were immunonegative for these proteins. Risk score models based on these five proteins and clinicopathological characteristics were established to determine prognoses of GC patients. These proteins were found to be involved in cancer related-signaling pathways and upstream regulators were identified. CONCLUSION This study identified proteins that can be used as clinical biomarkers and established a risk score model based on these proteins and clinicopathological characteristics to assess GC prognosis.
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Affiliation(s)
- Wei Li
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, China.,Jilin Province Key Laboratory of Bioinformatics for Gastrointestinal Tumor, Changchun, Jilin, China
| | - Yan Chen
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Xuan Sun
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Jupeng Yang
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - David Y Zhang
- Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA
| | - Daguang Wang
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, China.
| | - Jian Suo
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, China. .,Jilin Province Key Laboratory of Bioinformatics for Gastrointestinal Tumor, Changchun, Jilin, China.
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Belhechmi S, Michiels S, Paoletti X, Rotolo F. An alternative trial-level measure for evaluating failure-time surrogate endpoints based on prediction error. Contemp Clin Trials Commun 2019; 15:100402. [PMID: 31338479 PMCID: PMC6627581 DOI: 10.1016/j.conctc.2019.100402] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 06/13/2019] [Accepted: 06/24/2019] [Indexed: 11/24/2022] Open
Abstract
To validate a failure-time surrogate for an established failure-time clinical endpoint such as overall survival, the meta-analytic approach is commonly used. The standard correlation approach considers two levels: the individual level, with Kendall's τ measuring the rank correlation between the endpoints, and the trial level, with the coefficient of determination R2 measuring the correlation between the treatment effects on the surrogate and on the final endpoint. However, the estimation of R2 is not robust with respect to the estimation error of the trial-specific treatment effects. The alternative proposed in this article uses a prediction error based on a measure of the weighted difference between the observed treatment effect on the final endpoint and a model-based predicted effect. The measures can be estimated by cross-validation within the meta-analytic setting or external validation on a set of trials. Several distances are presented, with varying weights, based on the standard error of the observed treatment effect and of its predicted value. A simulation study was conducted under different scenarios, varying the number and the size of the trials, Kendall's τ and R2. These measures have been applied to individual patient data from a meta-analysis of trials in advanced/recurrent gastric cancer (20 randomized trials of chemotherapy, 4069 patients). The distance-based measures appeared to be robust with respect to different values of simulation parameters in several scenarios (such as Kendall's τ, size and number of clinical trials). The absolute prediction error can be an alternative to the trial-level R2 for evaluation of candidate time-to-event surrogates.
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Affiliation(s)
- Shaima Belhechmi
- Université Paris-Saclay, Univ. Paris-Sud, UVSQ, CESP, INSERM, U1018 ONCOSTAT, F-94805, Villejuif, France.,Gustave Roussy, Service de biostatistique et d'épidémiologie, F-94805, Villejuif, France
| | - Stefan Michiels
- Université Paris-Saclay, Univ. Paris-Sud, UVSQ, CESP, INSERM, U1018 ONCOSTAT, F-94805, Villejuif, France.,Gustave Roussy, Service de biostatistique et d'épidémiologie, F-94805, Villejuif, France
| | - Xavier Paoletti
- Université Paris-Saclay, Univ. Paris-Sud, UVSQ, CESP, INSERM, U1018 ONCOSTAT, F-94805, Villejuif, France.,Gustave Roussy, Service de biostatistique et d'épidémiologie, F-94805, Villejuif, France
| | - Federico Rotolo
- Innate Pharma, Biostatistics and Data Management Unit, F-13009, Marseille, France
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Kim J, Bae DH, Kim JH, Song KS, Kim YS, Kim SY. HOXC10 overexpression promotes cell proliferation and migration in gastric cancer. Oncol Rep 2019; 42:202-212. [PMID: 31115563 PMCID: PMC6549078 DOI: 10.3892/or.2019.7164] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 05/14/2019] [Indexed: 12/24/2022] Open
Abstract
Homeodomain‑containing gene 10 (HOXC10) is a member of the homeobox transcription factors that plays an important role in the development of multicellular organisms. HOXC10 is overexpressed in a variety of human cancers, and recent studies have revealed that HOXC10 is upregulated in gastric cancer as well. However, its mechanism of action is not fully understood, thus, the role of HOXC10 was investigated in the present study in human gastric cancer. First, HOXC10 expression was revealed to be significantly increased in gastric cancer tissues compared to normal tissues (TCGA dataset), and HOXC10 upregulation was associated with decreased recurrence‑free survival in gastric cancer patients in a public gene expression dataset. HOXC10 promoted cell proliferation and metastasis in two gastric cancer cell lines (AGS and MKN74). Analyzing TCGA 450K DNA methylation dataset, it was revealed that HOXC10 CpG sites were hypomethylated in gastric cancer tissues. Bisulfite sequencing revealed that CpG sites in the HOXC10 first intronic region were hypomethylated in three gastric cancer tissues, and HOXC10 expression was increased in gastric cancer cell lines (AGS and SNU620) in response to 5‑azacytidine treatment. By RNA‑sequencing of AGS cells with ectopic HOXC10 expression, it was revealed that many genes were upregulated by HOXC10 overexpression. Among them, CST1 was predicted to be a HOXC10 direct target gene via prediction of HOXC10 binding sites from the JASPAR database. A chromatin immunoprecipitation assay revealed that HOXC10 directly bound to CST1 promoter regions. The present study proposes HOXC10 is a potential prognostic marker or therapeutic target in human gastric cancer.
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Affiliation(s)
- Jina Kim
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Republic of Korea
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Dong-Hyuck Bae
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Republic of Korea
- Genome Editing Research Center, KRIBB, Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Jong Hwan Kim
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Kyu-Sang Song
- Department of Pathology, College of Medicine, Chungnam National University, Yuseong-gu, Daejeon 35015, Republic of Korea
| | - Yong Sung Kim
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Republic of Korea
- Genome Editing Research Center, KRIBB, Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Seon-Young Kim
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Republic of Korea
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea
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Zoppoli P, Calice G, Laurino S, Ruggieri V, La Rocca F, La Torre G, Ciuffi M, Amendola E, De Vita F, Petrillo A, Napolitano G, Falco G, Russi S. TRPV2 Calcium Channel Gene Expression and Outcomes in Gastric Cancer Patients: A Clinically Relevant Association. J Clin Med 2019; 8:E662. [PMID: 31083561 PMCID: PMC6572141 DOI: 10.3390/jcm8050662] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 05/07/2019] [Accepted: 05/08/2019] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is characterized by poor efficacy and the modest clinical impact of current therapies. Apoptosis evasion represents a causative factor for treatment failure in GC as in other cancers. Since intracellular calcium homeostasis regulation has been found to be associated with apoptosis resistance, the aberrant expression of intracellular calcium regulator genes (CaRGs) could have a prognostic value in GC patients. We analyzed the association of the expression levels of 98 CaRGs with prognosis by the log-rank test in a collection of 1524 GC samples from four gene expression profiling datasets. We also evaluated differential gene expression in comparison with normal stomach tissue, and then we crossed results with tissue microarrays from the Human Protein Atlas. Among the investigated CaRGs, patients with high levels of TRPV2 expression were characterized by a shorter overall survival. TRPV2 expression was found to increase according to tumor stage. Both mRNA and protein levels were significantly higher in tumor than normal stomach samples. TRPV2 was also associated with poor prognosis in the Lauren's intestinal type GC and in patients treated with adjuvant therapy. Overall, we highlighted the relevance of TRPV2 not only as a prognostic biomarker but also as a potential therapeutic target to improve GC treatment efficacy.
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Affiliation(s)
- Pietro Zoppoli
- Laboratory of Preclinical and Translational Research, IRCCS-Referral Cancer Center of Basilicata (CROB), 85028 Rionero in Vulture (PZ), Italy.
| | - Giovanni Calice
- Laboratory of Preclinical and Translational Research, IRCCS-Referral Cancer Center of Basilicata (CROB), 85028 Rionero in Vulture (PZ), Italy.
| | - Simona Laurino
- Laboratory of Preclinical and Translational Research, IRCCS-Referral Cancer Center of Basilicata (CROB), 85028 Rionero in Vulture (PZ), Italy.
| | - Vitalba Ruggieri
- Laboratory of Preclinical and Translational Research, IRCCS-Referral Cancer Center of Basilicata (CROB), 85028 Rionero in Vulture (PZ), Italy.
| | - Francesco La Rocca
- Laboratory of Preclinical and Translational Research, IRCCS-Referral Cancer Center of Basilicata (CROB), 85028 Rionero in Vulture (PZ), Italy.
| | - Giuseppe La Torre
- Laboratory of Preclinical and Translational Research, IRCCS-Referral Cancer Center of Basilicata (CROB), 85028 Rionero in Vulture (PZ), Italy.
| | - Mario Ciuffi
- Laboratory of Preclinical and Translational Research, IRCCS-Referral Cancer Center of Basilicata (CROB), 85028 Rionero in Vulture (PZ), Italy.
| | - Elena Amendola
- Department of Biology, University of Naples Federico II, 80138 Naples, Italy.
| | - Ferdinando De Vita
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Study of Campania "Luigi Vanvitelli", 80138 Naples, Italy.
| | - Angelica Petrillo
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Study of Campania "Luigi Vanvitelli", 80138 Naples, Italy.
| | - Giuliana Napolitano
- Department of Biology, University of Naples Federico II, 80138 Naples, Italy.
| | - Geppino Falco
- Department of Biology, University of Naples Federico II, 80138 Naples, Italy.
- Biogem, Istituto di Biologia e Genetica Molecolare, Via Camporeale, 83031 Ariano Irpino (AV), Italy.
| | - Sabino Russi
- Laboratory of Preclinical and Translational Research, IRCCS-Referral Cancer Center of Basilicata (CROB), 85028 Rionero in Vulture (PZ), Italy.
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LncRNA PVT1 Mediates Antiapoptosis and 5-Fluorouracil Resistance via Increasing Bcl2 Expression in Gastric Cancer. JOURNAL OF ONCOLOGY 2019; 2019:9325407. [PMID: 31205469 PMCID: PMC6530232 DOI: 10.1155/2019/9325407] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 01/31/2019] [Accepted: 02/18/2019] [Indexed: 12/25/2022]
Abstract
Purpose Plasmacytoma variant translocation 1 (PVT1) is a long noncoding RNA encoded by the human PVT1 gene, which has been verified to mediate tumorigenesis in gastric cancer. However, the underlying molecular mechanisms of PVT1 in gastric cancer (GC) remain largely unknown. Methods The tumorigenic ability of PVT1 was verified by subcutaneous and orthotopic mouse models. Flow cytometry assay and TdT-mediated dUTP Nick-End Labeling staining were conducted to explore the effects of PVT1 on gastric cancer cell apoptosis. We investigated the relative gene and protein that are involved in apoptosis in real-time PCR and western blot assay. The resistance to 5- Fluorouracil (5-Fu) caused by PVT1 was evaluated using cell viability assay. Then, to confirm the effects of PVT1 on 5-Fu resistance, we conducted the Kaplan-Meier analysis based on three public databases. Results We confirmed that PVT1 can promote the progression of gastric cancer. PVT1 inhibited the apoptosis of GC cells, which may account for its promotion on GC. We confirmed that PVT1 can regulate the expression of Bcl2 and enhance drug-resistance of gastric cancer to 5-Fu. Kaplan-Meier analysis showed that patients with high PVT1 expression do not experience survival related benefits from 5-Fu based chemotherapy; instead, therapy containing no 5-Fu chemotherapy can improve the first progression survival and overall survival of high PVT1 expression GC patients significantly. Conclusion Our results showed that PVT1 can inhibit the apoptosis and enhance the 5-Fu resistance of gastric cancer through the activation of Bcl2. PVT1 has the potential to serve as an indicator to predict 5-Fu treatment resistance.
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Prognostic values of signal transducers activators of transcription in gastric cancer. Biosci Rep 2019; 39:BSR20181695. [PMID: 30944204 PMCID: PMC6488950 DOI: 10.1042/bsr20181695] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Revised: 03/06/2019] [Accepted: 04/01/2019] [Indexed: 02/07/2023] Open
Abstract
The signal transducers and activators of transcription genes family (STATs) have been well studied as prognostic predictors for various solid tumors, but their prognostic values in gastric cancer (GC) patients have not been fully elucidated. The 'Kaplan-Meier plotter' and multiple public available databases were used for the characterization of the prognostic roles of STATs family in GC. The results indicated that high mRNA expression of all individual STATs, except STAT3 and STAT6, were significantly associated with favorable overall survival (OS) in GC. Moreover, the prognostic values of STATs were further characterized in subtypes, including HER2 status, Lauren's classification, differentiation, and clinical stages. Moreover, the prognostic value of STATs signature was also characterized. Low risk group displayed a significantly favorable OS than high risk (HR: 1.71; 95% CI: 1.09-2.66, P=0.0184). In addition, STATs showed distinct expression between GC and normal groups. Meanwhile, comparable high correlation between STATs and tumor immune infiltrating cells (TIICs) was also observed. STAT4 displayed highest correlation with dendritic cells (correlation = 0.716, P=1.63e-59) and CD8+ T cells (correlation = 0.697, P=5.02e-55). In conclusion, our results suggest that all individual STATs, except STAT3 and STAT6, may act as prognostic markers in GC.
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Jeung Y, Lee K, Lee HJ, Kim E, Son MJ, Ahn J, Kim H, Kim W, Lee H, Kim JM, Chung K. Cationic amino acid transporter PQLC2 is a potential therapeutic target in gastric cancer. Cancer Sci 2019; 110:1453-1463. [PMID: 30729615 PMCID: PMC6447956 DOI: 10.1111/cas.13966] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 01/25/2019] [Accepted: 02/05/2019] [Indexed: 12/11/2022] Open
Abstract
Tumor cells overexpress amino acid transporters to meet the increased demand for amino acids. PQ loop repeat-containing (PQLC)2 is a cationic amino acid transporter that might be involved in cancer progression. Here, we show that upregulation of PQLC2 is critical to gastric cancer (GC) development in vitro and in vivo. Both PQLC2 mRNA and protein were overexpressed in GC tissues, especially of the diffuse type. Overexpression of PQLC2 promoted cell growth, anchorage independence, and tumor formation in nude mice. This was due to activation of MEK/ERK1/2 and PI3K/AKT signaling. Conversely, PQLC2 knockdown caused growth arrest and cell death of cancer cells and suppressed tumor growth in a mouse xenograft model. These results suggest that targeting PQLC2 is an effective strategy for GC treatment.
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Affiliation(s)
- Yun‐Ji Jeung
- Biomedical Translational Research CenterKRIBBDaejeonKorea
- Department of Pathology and Medical ScienceChungnam National University College of MedicineDaejeonKorea
| | - Kyeong Lee
- College of PharmacyDongguk University‐SeoulGoyangKorea
| | - Hyo Jin Lee
- Department of Internal MedicineChungnam National University College of MedicineDaejeonKorea
| | - Eunah Kim
- Stem Cell Convergence Research CenterKRIBBDaejeonKorea
| | - Myung Jin Son
- Stem Cell Convergence Research CenterKRIBBDaejeonKorea
- Department of Functional GenomicsKRIBB School of BioscienceKorea University of Science and Technology (UST)DaejeonKorea
| | - Jiwon Ahn
- Biomedical Translational Research CenterKRIBBDaejeonKorea
| | - Han‐Gyeul Kim
- Biomedical Translational Research CenterKRIBBDaejeonKorea
- Department of Functional GenomicsKRIBB School of BioscienceKorea University of Science and Technology (UST)DaejeonKorea
| | - Wantae Kim
- Biomedical Translational Research CenterKRIBBDaejeonKorea
| | - Ho‐Joon Lee
- Stem Cell Convergence Research CenterKRIBBDaejeonKorea
| | - Jin Man Kim
- Department of Internal MedicineChungnam National University College of MedicineDaejeonKorea
| | - Kyung‐Sook Chung
- Biomedical Translational Research CenterKRIBBDaejeonKorea
- Stem Cell Convergence Research CenterKRIBBDaejeonKorea
- Department of Functional GenomicsKRIBB School of BioscienceKorea University of Science and Technology (UST)DaejeonKorea
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Barati N, Momtazi-Borojeni AA, Majeed M, Sahebkar A. Potential therapeutic effects of curcumin in gastric cancer. J Cell Physiol 2019; 234:2317-2328. [PMID: 30191991 DOI: 10.1002/jcp.27229] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 07/16/2018] [Indexed: 12/12/2022]
Abstract
Despite recent advancements in understanding of the biology of gastric cancer, treatment of patients with advanced gastric cancer remains a major problem. Among different type of phytochemicals, curcumin, a welltable -known phytochemical, has been shown to be a promising cancer chemopreventive agent. Pharmacokinetics, safety, and efficacy of curcumin have been evaluated in several clinical trials against numerous diseases, and for the treatment of human cancer. In the present review, we have collected in vitro and in vivo investigations and studied the chemosensitizing and anticancer effects of curcumin against the gastric cancer cells. In summary, curcumin has been found to have efficient chemosensitizing effect and also inhibits viability, proliferation, and migration of gastric cancer cells mainly via cell cycle arrest and induction of apoptosis by both mitochondrial-dependent and -independent pathways.
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Affiliation(s)
- Nastaran Barati
- Deputy of Research and Technology, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Amir A Momtazi-Borojeni
- Nanotechnology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Biotechnology, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Irantab
| | | | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Shuto K, Mori M, Kosugi C, Narushima K, Nakabayashi S, Fujisiro T, Sato A, Hayano K, Shimizu H, Koda K. Hepatic blood flow by perfusion computed tomography as an imaging biomarker for patients with gastric cancer. Oncol Lett 2019; 17:3267-3276. [PMID: 30867759 PMCID: PMC6396202 DOI: 10.3892/ol.2019.9969] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 01/17/2019] [Indexed: 11/19/2022] Open
Abstract
Perfusion computed tomography (PCT) is a less invasive imaging modality that provides information about tissue hemodynamics at the capillary level. The present study aimed to investigate the correlation between hepatic perfusion and gastric cancer progression. A total of 136 patients with gastric adenocarcinoma were evaluated in the present study. Prior to initial treatment, liver PCT was performed across the hepatic hilar plane and the hepatic blood flow (HBF) was measured using the dual-input deconvolution method. HBF was compared with clinicopathological factors, patient prognosis and circulating serum proangiogenic cytokines. The median HBF was 217 ml/min/100 g tissue. Patients with high HBF had larger tumors (43 mm vs. 71, P<0.001) and more advanced tumor-node stages (P<0.001 for both). When both patient groups of operable and inoperable were compared by their respective median HBF values, each high-HBF group had a significantly worse prognosis (P=0.002 and P=0.024), notably in the inoperable group, with <1-year survival. In 17 postoperative recurrent patients, the high-HBF at recurrence group also had a significantly worse postrecurrent prognosis (P=0.019). HBF was an independent prognostic factor (hazard ratio, 2.019; P=0.048) and was strongly associated with serum vascular endothelial growth factor level (R=0.607, P<0.001). HBF was significantly correlated with gastric cancer progression, and is an easily measured imaging biomarker reflecting patient survival.
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Affiliation(s)
- Kiyohiko Shuto
- Department of Surgery, Teikyo University Chiba Medical Center, Ichihara, Chiba 299-0111, Japan
| | - Mikito Mori
- Department of Surgery, Teikyo University Chiba Medical Center, Ichihara, Chiba 299-0111, Japan
| | - Chihiro Kosugi
- Department of Surgery, Teikyo University Chiba Medical Center, Ichihara, Chiba 299-0111, Japan
| | - Kazuo Narushima
- Department of Surgery, Teikyo University Chiba Medical Center, Ichihara, Chiba 299-0111, Japan
| | - Satoko Nakabayashi
- Department of Surgery, Teikyo University Chiba Medical Center, Ichihara, Chiba 299-0111, Japan
| | - Takeshi Fujisiro
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Asami Sato
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Koichi Hayano
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Hiroaki Shimizu
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Keiji Koda
- Department of Surgery, Teikyo University Chiba Medical Center, Ichihara, Chiba 299-0111, Japan
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Zhang Y, Liu S, Feng Q, Huang X, Wang X, Peng Y, Zhao Z, Liu Z. Perilaldehyde activates AMP-activated protein kinase to suppress the growth of gastric cancer via induction of autophagy. J Cell Biochem 2019; 120:1716-1725. [PMID: 30378150 DOI: 10.1002/jcb.27491] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 07/18/2018] [Indexed: 01/24/2023]
Abstract
BACKGROUND AND AIM Perillaldehyde (PAH), one of the major oil components in Perilla frutescens, is very critical to health maintenance, for a wide range of human chronic diseases, including cancers. AMP-activated protein kinase (AMPK) has been implicated in the activation of autophagy in distinct tissues. This study was designed to explore whether PAH prevents gastric cancer growth and to investigate the molecular mechanism. METHODS AND RESULTS In cultured mouse gastric cancer cell line MFCs and human gastric cancer cell lines GC9811-P, PAH activated AMPK by increasing the Thr172 phosphorylation and activity in a time-/concentration-dependent manner. Furthermore, incubation of MFCs with PAH also increased autophagy as determined by monodansylcadaverine (MDC) staining, which was reversed by AMPK inhibitor compound C. PAH further decreased MFCs cell survival, which was abolished by compound C or autophagy inhibitor 3-Methyladenine (3-MA). In vivo studies indicated that 4-week administration of PAH (100 mg/kg/day) suppressed the growth of gastric cancer and increased the levels of autophagy-related proteins, including beclin-1, LC3-II, cathepsin, caspase-3, p53, and cathepsin in tumors isolated from the xenograft model of gastric cancer in mice. Moreover, these anticancer effects produced by PAH were abolished by coadministration of compound C or 3-MA in vivo. CONCLUSIONS PAH increases AMPK phosphorylation and activity to induce gastric cancer cell autophagy to inhibit the growth of gastric cancer. In perspective, therapy of PAH should be applied to treat patients with gastric cancer.
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Affiliation(s)
- Yu Zhang
- Department of Gastroenterology and Clinical Nutrition, The First Affiliated Hospital (People's Hospital of Hunan Province), Hunan Normal University, Changsha, Hunan, China
| | - Suosi Liu
- Department of Gastroenterology and Clinical Nutrition, The First Affiliated Hospital (People's Hospital of Hunan Province), Hunan Normal University, Changsha, Hunan, China
| | - Qin Feng
- Department of Gastroenterology and Clinical Nutrition, The First Affiliated Hospital (People's Hospital of Hunan Province), Hunan Normal University, Changsha, Hunan, China
| | - Xiuyun Huang
- Department of Gastroenterology and Clinical Nutrition, The First Affiliated Hospital (People's Hospital of Hunan Province), Hunan Normal University, Changsha, Hunan, China
| | - Xiangyang Wang
- Department of Gastroenterology and Clinical Nutrition, The First Affiliated Hospital (People's Hospital of Hunan Province), Hunan Normal University, Changsha, Hunan, China
| | - Ya Peng
- Department of Gastroenterology and Clinical Nutrition, The First Affiliated Hospital (People's Hospital of Hunan Province), Hunan Normal University, Changsha, Hunan, China
| | - Zhihong Zhao
- Department of Neurology, The First Affiliated Hospital (People's Hospital of Hunan Province), Hunan Normal University, Changsha, Hunan, China
| | - Zhan Liu
- Department of Gastroenterology and Clinical Nutrition, The First Affiliated Hospital (People's Hospital of Hunan Province), Hunan Normal University, Changsha, Hunan, China
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Dang SC, Wang F, Qian XB, Abdul M, Naseer QA, Jin W, Hu R, Gu Q, Gu M. MicroRNA-505 suppresses gastric cancer cell proliferation and invasion by directly targeting Polo-like kinase-1. Onco Targets Ther 2019; 12:795-803. [PMID: 30774367 PMCID: PMC6352865 DOI: 10.2147/ott.s189521] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Purpose The expression of microRNA-505 (miR-505) has been investigated in various cancers; however, its effect and mechanism in relation to gastric cancer (GC) are yet to be determined. Thus, the current evaluation aimed to examine the expression and potential role of miR-505 in GC. Materials and methods Quantitative real-time PCR was carried out to analyze miR-505 expression in GC cells and tissues. We observed that miR-505 is differentially expressed in GC cells following transfection of its mimics or inhibitors. Changes in cell invasion, cell proliferation, and epithelial–mesenchymal transition markers were measured. Results These findings indicated that miR-505 expression is downregulated in both GC cell lines and GC tissues. In addition, knockdown miR-505 induced the invasion and proliferation of GC cells. Transfection of miR-505 mimics led to an elevation in N-cadherin expression but a decrease in E-cadherin expression. Furthermore, we have shown that miR-505 binds to the 3′-UTR region of Polo-like kinase-1. Conclusion Our results indicated that miR-505 suppresses GC cell proliferation and invasion; it may be a valuable candidate gene for seeking therapy strategy for GC.
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Affiliation(s)
- Sheng-Chun Dang
- Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province 212001, People's Republic of China
| | - Fei Wang
- Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province 212001, People's Republic of China
| | - Xiao-Bao Qian
- Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province 212001, People's Republic of China
| | - Malik Abdul
- Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province 212001, People's Republic of China
| | - Qais-Ahmad Naseer
- Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province 212001, People's Republic of China
| | - Wei Jin
- Department of Obstetrics and Gynecology, The Changshu No. 2 People's Hospital, Changshu, Jiangsu Province 215500, People's Republic of China
| | - Rong Hu
- Department of Geriatrics, Zhenjiang First People's Hospital, Jiangsu Province 212001, People's Republic of China
| | - Qian Gu
- Department of Geriatrics, Zhenjiang First People's Hospital, Jiangsu Province 212001, People's Republic of China
| | - Min Gu
- Department of Oncology, Zhenjiang Hospital of Traditional Chinese and Western Medicine, Zhenjiang, Jiangsu 212001, People's Republic of China,
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Prognostic values of E2F mRNA expression in human gastric cancer. Biosci Rep 2018; 38:BSR20181264. [PMID: 30487158 PMCID: PMC6435564 DOI: 10.1042/bsr20181264] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 11/08/2018] [Accepted: 11/26/2018] [Indexed: 12/19/2022] Open
Abstract
Gastric cancer (GC) is the second most frequent cause of cancer-related mortality in the world, with Eastern Asia having the highest incidence rates. E2F is a family of transcription factor proteins that has a variety of functions, which include control of cell cycle, cell differentiation, DNA damage response and cell death. E2F transcription factors are divided into two subfamilies: transcription activators (E2F transcription factors 1 (E2F1), 2 (E2F2) and 3a (E2F3a)) and repressors (E2F3b, E2F transcription factors 4 (E2F4), 5 (E2F5), 6 (E2F6), 7 (E2F7) and 8 (E2F8)). Studies have demonstrated that E2F had prognostic significance in a number of cancers. However, the entirety of the prognostic roles of E2F mRNA expression in GC has not yet been apparently determined. In the present study, the prognostic value of individual family members of E2F mRNA expression for overall survival (OS) was evaluated by using online Kaplan-Meier Plotter (KM Plotter) database. Our result demonstrated that high expressions of three family members of E2F (E2F1, E2F3, E2F4) mRNA were significantly associated with unfavourable OS in all GC patients. However, increased expressions of E2F2, E2F5, E2F6 and E2F7 were significantly associated with favourable OS, especially for higher clinical stages in GC patients. These results provided a better insight into the prognostic functions of E2F mRNA genes in GC. Although the results should be further verified in clinical trials, our findings may be a favourable prognostic predictor for the development of newer therapeutic drugs in the treatment of GC.
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Li L, Li Y, Huang Y, Ouyang Y, Zhu Y, Wang Y, Guo X, Yuan Y, Gong K. Long non-coding RNA MIF-AS1 promotes gastric cancer cell proliferation and reduces apoptosis to upregulate NDUFA4. Cancer Sci 2018; 109:3714-3725. [PMID: 30238562 PMCID: PMC6272088 DOI: 10.1111/cas.13801] [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: 06/23/2018] [Revised: 09/02/2018] [Accepted: 09/16/2018] [Indexed: 12/11/2022] Open
Abstract
Long non‐coding RNA MIF‐AS1 (lncMIF‐AS1) has been found to be upregulated in the tumor tissues of gastric cancer; however, its importance for the progression of gastric cancer remains unknown. Thus, the present study was designed to determine the role of the lncMIF‐AS1‐based signal transduction pathway in mediating the proliferation and apoptosis of gastric cancer cells. Differentially expressed lncRNAs and mRNAs were screened out using microarray analysis, based on the published data (GSE63288), and validated using quantitative RT‐PCR. Target relationships between lncRNA‐micro RNA (miRNA) and miRNA‐mRNA were predicted by bioinformatics analysis and verified by dual‐luciferase reporter assay. Protein expression of NDUFA4, COX6C and COX5B was detected by western blot. Cell proliferation, cell cycle and apoptosis were determined using colony formation assay and flow cytometry analysis. Oxidative phosphorylation in gastric cancer cells was assessed by levels of oxygen consumption and ATP synthase activity. Expression of lncMIF‐AS1 and NDUFA4 were upregulated in gastric cancer tissues and cells as compared with non‐cancerous gastric tissues and cells (P < .05). MiR‐212‐5p was identified as the most important miRNA linker between lncMIF‐AS1 and NDUFA4, which was negatively regulated by lncMIF‐AS1 and its depletion is the main cause of NDUFA4 overexpression (P < .01). The upregulated expression of NDUFA4 then greatly promoted the proliferation and decreased the apoptosis of gastric cancer cells through activation of the oxidative phosphorylation pathway. Taken together, the present study implies that inhibition of lncMIF‐AS1/miR‐212‐5p/NDUFA4 signal transduction may provide a promising therapeutic target for the treatment of gastric cancer.
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Affiliation(s)
- Linhai Li
- Department of General Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Yuejin Li
- Department of General Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Yingguang Huang
- Department of General Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Yiming Ouyang
- Department of General Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Yu Zhu
- Department of General Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Yongzhi Wang
- Department of General Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Xiaodong Guo
- Department of General Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Ying Yuan
- Department of Emergency Internal Medicine, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Kunmei Gong
- Department of General Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
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49
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Li N, Han M, Zhou N, Tang Y, Tang XS. MicroRNA-495 Confers Increased Sensitivity to Chemotherapeutic Agents in Gastric Cancer via the Mammalian Target of Rapamycin (mTOR) Signaling Pathway by Interacting with Human Epidermal Growth Factor Receptor 2 (ERBB2). Med Sci Monit 2018; 24:5960-5972. [PMID: 30147110 PMCID: PMC6122272 DOI: 10.12659/msm.909458] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Accepted: 04/10/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND In recent years, the incidence of gastric cancer (GC) has been increasing worldwide. Emerging evidence shows that microRNAs (miRs) may be involved in the pathogenesis of GC. Thus, this study explored the mediatory role of miR-495 in GC chemosensitivity, and investigated the mechanism by which it affects the biological behaviors of GC cells via the mTOR signaling pathway. MATERIAL AND METHODS After GC and paracancerous tissue collection, the positive rate of ERBB2 and mTOR was evaluated by immunohistochemistry. Subsequently, the expression of miR-495, ERBB2, and mTOR was determined by RT-qPCR and Western blot analysis. Next, the targeting relationship between miR-495 and ERBB2 was confirmed by dual-luciferase reporter gene assay. In addition, chemosensitivity and proliferation were detected by MTT assay and apoptosis was assessed by flow cytometry. RESULTS We found higher positive rates of ERBB2 and mTOR and decreased expression of miR-495 in GC tissues and showed that ERBB2 is the target gene of miR-495. Furthermore, we determined that overexpression of miR-495 and silencing of ERBB2 enhanced GC cell chemosensitivity and apoptosis, but inhibited GC cell proliferation. We also found that the effect of miR-495 inhibition was lost when ERBB2 was suppressed. CONCLUSIONS The key findings of our study demonstrate that the miR-495 exerts promotive effects on GC chemosensitivity via inactivation of the mTOR signaling pathway by suppressing ERBB2. The study provides reliable evidence supporting the use of miR-495 as a novel potential target in the chemotherapy of GC.
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50
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Lang C, Xu M, Zhao Z, Chen J, Zhang L. MicroRNA-96 expression induced by low-dose cisplatin or doxorubicin regulates chemosensitivity, cell death and proliferation in gastric cancer SGC7901 cells by targeting FOXO1. Oncol Lett 2018; 16:4020-4026. [PMID: 30128023 DOI: 10.3892/ol.2018.9122] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 02/15/2018] [Indexed: 02/07/2023] Open
Abstract
MicroRNA-96 (miR-96) is transcriptionally associated with the induction of chemoresistance following chemotherapy by targeting to FOXO1 mRNA at one of two predicted binding sites in its 3'-untranslated region sequence. The upregulation of miR-96 is associated with a high risk of chemoresistance. Nevertheless, the mechanism by which miR-96 is upregulated remains largely undefined. In the present study, the gastric cancer SGC7901 cell line was treated with different doses of the chemotherapeutic agents cisplatin and doxorubicin. miR-96 expression was analyzed by reverse transcription-quantitative polymerase chain reaction at different time points. Western blot and chromatin immunoprecipitation were performed to analyze the expression levels of the target gene. The effects of miR-96 on chemosensitivity were assessed by a carboxyfluorescein succinimidyl ester/propidium iodide labeling assay, and its effects on proliferation were assessed by Cell Counting Kit-8 or EdU staining assays. The results demonstrated that treatment with a low dose of either chemotherapeutic agent induced miR-96 expression. Upregulation of miR-96 caused the post-transcriptional repression of FOXO1 expression. Decreases in FOXO1 protein levels led to a decrease in the transcriptional activity of the cyclin-dependent kinase inhibitor 1A (CDKN1A, also known as p21) promoter region, and thus the expression of p21 was downregulated in a tumor protein p53-independent manner. As a result, induction of miR-96 expression caused chemoresistance and promoted proliferation in SGC7901 cells. Taken together, the results of the present study revealed that treatment with cisplatin or doxorubicin could induce expression of miR-96 at certain doses. Upregulation of miR-96 is partially associated with chemoresistance and miR-96 can also promote cell proliferation by repressing p21.
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Affiliation(s)
- Chunhui Lang
- Department of Nutrition, Food Safety and Toxicology, West China School of Public Health, Sichuan University, Chengdu, Sichuan 610041, P.R. China.,Department of Clinical Nutrition, Chongqing Three Gorges Central Hospital, Wanzhou, Chongqing 404000, P.R. China
| | - Miao Xu
- Department of Nutrition, Food Safety and Toxicology, West China School of Public Health, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Ziyi Zhao
- Central Laboratory, The Teaching Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Jinyao Chen
- Department of Nutrition, Food Safety and Toxicology, West China School of Public Health, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Lishi Zhang
- Department of Nutrition, Food Safety and Toxicology, West China School of Public Health, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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