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Subsomwong P, Asano K, Akada J, Matsumoto T, Nakane A, Yamaoka Y. Proteomic Profiling of Extracellular Vesicles Reveals Potential Biomarkers for Helicobacter pylori Infection and Gastric Cancer. Helicobacter 2025; 30:e70022. [PMID: 40033163 PMCID: PMC11876490 DOI: 10.1111/hel.70022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 02/04/2025] [Accepted: 02/13/2025] [Indexed: 03/05/2025]
Abstract
BACKGROUND Helicobacter pylori (H. pylori) has been identified as a type I carcinogen and contributes to a high rate of gastric cancer (GC), especially in Eastern Asia. Extracellular vesicles (EVs) have the potential to be used to detect various cancer types and diseases. However, the protein markers in EVs for the prognosis of H. pylori infection and GC are unknown. We aim to identify the proteins within EVs derived from a gastric epithelial cell line (AGS) infected with H. pylori by using LC-MS/MS. MATERIALS AND METHODS EVs were isolated from AGS cells infected with high- and low-virulence H. pylori (strains TN2wt and Tx30a) by ultracentrifugation. Proteins within these EVs were identified and analyzed for potential marker candidates through bioinformatics. Proteins in H. pylori-derived EVs (HpEVs) from bacterial culture supernatant and HpEVs derived from H. pylori-infected AGS cells were elucidated. RESULTS Differentially expressed proteins by proteomic analysis in AGSEVs-Tx30a vs. AGSEVs-noninfected (NI) and AGSEVs-TN2wt vs. AGSEVs-NI were 107 and 55 proteins, respectively. Bioinformatics of these proteomes revealed that essential proteins for H. pylori survival and pathogenicity including outer membrane proteins, metabolism-related, host cell infection-related, and virulence-related proteins were observed in HpEVs. Interestingly, EVs derived from AGS cells infected with H. pylori TN2wt significantly contained multiple proteins related to GC (ATP6V0A1, GAPDH, HINT1, LYZ, and RBX1). CONCLUSION This study provides a comprehensive protein profile of EVs from H. pylori-infected AGS cells and HpEVs, which could serve as liquid-based biomarkers in the future for screening H. pylori infection, especially GC-related.
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Affiliation(s)
- Phawinee Subsomwong
- Department of Microbiology and ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
- Department of Environmental and Preventive Medicine, Faculty of MedicineOita UniversityYufuJapan
| | - Krisana Asano
- Department of Microbiology and ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Junko Akada
- Department of Environmental and Preventive Medicine, Faculty of MedicineOita UniversityYufuJapan
| | - Takashi Matsumoto
- Department of Environmental and Preventive Medicine, Faculty of MedicineOita UniversityYufuJapan
- Research Center for Global and Local Infectious DiseasesOita UniversityYufuJapan
| | - Akio Nakane
- Department of Microbiology and ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
- Department of Biopolymer and Health ScienceHirosaki University Graduate School of MedicineHirosakiJapan
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Faculty of MedicineOita UniversityYufuJapan
- Research Center for Global and Local Infectious DiseasesOita UniversityYufuJapan
- Department of Medicine, Gastroenterology and Hepatology SectionBaylor College of MedicineHoustonTexasUSA
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Yuan J, Lu J, Zhu J, Chen F, Zeng Z, Yan J, Li Q, Zhou R, Tong Q. LncRNA FIRRE drives gastric cancer progression via ZFP64-mediated TUBB3 promoter activation. Cancer Lett 2024; 611:217398. [PMID: 39706253 DOI: 10.1016/j.canlet.2024.217398] [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: 06/05/2024] [Revised: 12/10/2024] [Accepted: 12/14/2024] [Indexed: 12/23/2024]
Abstract
Gastric cancer is a common global malignancy that requires detailed study of its development mechanisms. Although LncRNA FIRRE is known to play a crucial role in the progression and treatment resistance of several cancers, its effect on gastric cancer is not well understood. This study confirms the impact of FIRRE on the malignant behavior of gastric cancer. Using RNA-sequencing, dual luciferase reporter assay, RIP and CHIP, we identified transcription factors and target genes linked to FIRRE. Elevated FIRRE expression in gastric cancer correlates with worse patient prognosis and promotes gastric cancer proliferation, migration, and invasion both in vitro and in vivo. FIRRE regulates the TUBB3 gene, facilitating gastric cancer progression by activating the TUBB3 promoter in vitro. ZFP64 is the transcription factor for TUBB3, activating its promoter and binding specifically with FIRRE. Reducing ZFP64 disrupts FIRRE's positive regulation of TUBB3 in vitro and in vivo. This study shows FIRRE promotes gastric cancer progression by binding to ZFP64 and activating the TUBB3 promoter.
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Affiliation(s)
- Jingwen Yuan
- Department of Gastrointestinal Surgery I Section, Renmin Hospital of Wuhan University, Wuhan, 430060, China; Colorectal Surgery Department, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Jiatong Lu
- Department of Gastrointestinal Surgery I Section, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Jie Zhu
- Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Parasitology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China
| | - Fangfang Chen
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Zhi Zeng
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Junfeng Yan
- Department of Gastrointestinal Surgery I Section, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Qiang Li
- Department of Gastrointestinal Surgery I Section, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Rui Zhou
- Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Parasitology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China.
| | - Qiang Tong
- Department of Gastrointestinal Surgery I Section, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
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3
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Sun J, Rao L, Zhou S, Zeng Y, Sun Y. Unraveling the regulatory cell death pathways in gastric cancer: a multi-omics study. Front Pharmacol 2024; 15:1447970. [PMID: 39314752 PMCID: PMC11417042 DOI: 10.3389/fphar.2024.1447970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 08/26/2024] [Indexed: 09/25/2024] Open
Abstract
Gastric cancer (GC) is a prevalent form of cancer worldwide and has a high death rate, with less than 40% of patients surviving for 5 years. GC demonstrates a vital characteristic of evading regulatory cell death (RCD). However, the extent to which RCD patterns are clinically significant in GC has not been well investigated. The study created a regulatory cell death index (RCDI) signature by employing 101 machine-learning algorithms. These algorithms were based on the expression files of 1292 GC patients from 6 multicenter cohorts. RCDI is a reliable and robust determinant of the likelihood of surviving in general. Furthermore, the precision of RCDI surpasses that of the 20 signatures that have been previously disclosed. The presence of RCDI signature is closely linked to immunological characteristics, such as the infiltration of immune cells, the presence of immunotherapy markers, and the activation of immune-related functions. This suggests that there is a higher level of immune activity in cases with RCDI signature. Collectively, the use of RCDI has the potential to be a strong and encouraging method for enhancing the clinical results of individual individuals with GC.
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Affiliation(s)
- Jiazheng Sun
- Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lixiang Rao
- Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sirui Zhou
- Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yulan Zeng
- Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yalu Sun
- Affiliated Hospital of Jining Medical University, Jining, China
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4
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Bell CJ, Potts KG, Hitt MM, Pink D, Tuszynski JA, Lewis JD. Novel colchicine derivative CR42-24 demonstrates potent anti-tumor activity in urothelial carcinoma. Cancer Lett 2022; 526:168-179. [PMID: 34838691 DOI: 10.1016/j.canlet.2021.11.028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 11/09/2021] [Accepted: 11/23/2021] [Indexed: 01/03/2023]
Abstract
Bladder cancers, and specifically urothelial carcinoma, have few effective treatment options, and tumors typically develop resistance against standard of care chemotherapies leading to significant mortality. The development of alternative therapies with increased selectivity and improved tolerability would significantly impact this patient population. Here, we investigate a novel colchicine derivative, CR42-24, with increased selectivity for the βIII tubulin subtype as a treatment for urothelial carcinoma. βIII tubulin is a promising target due to its low expression in healthy tissues and its clinical association with poor prognosis. This study demonstrated that CR42-24 is selectively cytotoxic to several cancer cell lines at low nanomolar IC50, with high activity in bladder cancer cell lines both in vitro and in vivo. CR42-24 monotherapy in an aggressive urothelial carcinoma xenograft model results in effective control when treated early. We observed significant ablation of large tumors and patient-derived xenografts at low doses with excellent tolerability. CR42-24 was highly synergistic in combination with the standard of care chemotherapies gemcitabine and cisplatin, further increasing its therapeutic potential as a novel treatment for urothelial carcinoma.
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Affiliation(s)
- Clayton J Bell
- Department of Oncology, University of Alberta, Edmonton, Alberta, T6G 2E1, Canada
| | - Kyle G Potts
- Department Microbiology, Immunology & Infectious Diseases, Alberta Children's Hospital Research Institute, T2N-4N1, Canada
| | - Mary M Hitt
- Department of Oncology, University of Alberta, Edmonton, Alberta, T6G 2E1, Canada
| | - Desmond Pink
- Department of Oncology, University of Alberta, Edmonton, Alberta, T6G 2E1, Canada
| | - Jack A Tuszynski
- Department of Oncology, University of Alberta, Edmonton, Alberta, T6G 2E1, Canada
| | - John D Lewis
- Department of Oncology, University of Alberta, Edmonton, Alberta, T6G 2E1, Canada.
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Liu J, Geng Z, Zhang Y, Alharbi SA, Shi Y. Sesquiterpenoid bilobalide inhibits gastric carcinoma cell growth and induces apoptosis both in vitro and in vivo models. J Biochem Mol Toxicol 2021; 35:e22723. [PMID: 33511709 DOI: 10.1002/jbt.22723] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 10/15/2020] [Accepted: 11/26/2020] [Indexed: 12/15/2022]
Abstract
Gastric carcinoma is one of the most aggressive types of cancer that ranks fifth among all cancer incidences and third in cancer mortality. As it exhibits a prolonged asymptomatic condition and high recurrence rate, it is a great challenge to treat gastric cancer. Traditional medicine that utilizes herbal phytochemicals to treat various diseases is a potent alternative for current allopathic treatment. Hence, we evaluated the potency of a phytochemical bilobalide for treating gastric cancer in in vitro and in vivo models. Bilobalide, a sesquiterpenoid, is present in the Ginkgo biloba plant that belongs to the family of Ginkgoaceae. The cytotoxicity effect of bilobalide was evaluated in both gastric cancer (AGS) cells and normal gastric epithelial cells. Apoptosis-inducing property of bilobalide against the AGS cell line was analyzed with different fluorescent staining techniques and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and cell cycle analysis was carried out by flow cytometry. The in vivo studies were assessed with N-methyl-N-nitrosourea (MNU)-induced gastric cancer in rats. Serum-specific gastric markers were quantified and histopathological analysis of stomach tissue was performed. The expression of target-signaling molecules was analyzed by a reverse-transcription polymerase chain reaction. The in vitro results proved that bilobalide effectively suppressed the AGS cell growth and induced cell death by nuclear damage and apoptosis induction. The bilobalide treatment effectively arrested the cell cycle of AGS cells via inhibiting the PI3K-signaling pathway. Our in vivo results also confirmed that the bilobalide persuasively inhibited the MNU-induced gastric carcinoma via inhibiting the thioredoxin-fold family proteins and inflammatory markers' expression. Overall, our results authentically prove that bilobalide possesses therapeutic potency to cure gastric carcinoma.
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Affiliation(s)
- Jinglei Liu
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China
| | - Zhen Geng
- Department of Gastrointestinal Surgery, Binzhou People's Hospital, Binzhou, Shandong Province, China
| | - Yingying Zhang
- Department of Oncology, Binzhou People's Hospital, Binzhou, Shandong Province, China
| | - Sulaiman Ali Alharbi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Yulong Shi
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China
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Influence of paclitaxel therapy on expression of ßIII-Tubulin and Carbonic anhydrase IX proteins in chemically-induced rat mammary tumors. Biologia (Bratisl) 2020. [DOI: 10.2478/s11756-020-00496-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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7
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Zhang Y, Yuan Z, Shen R, Jiang Y, Xu W, Gu M, Gu X. Identification of biomarkers predicting the chemotherapeutic outcomes of capecitabine and oxaliplatin in patients with gastric cancer. Oncol Lett 2020; 20:290. [PMID: 33029206 PMCID: PMC7530885 DOI: 10.3892/ol.2020.12153] [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: 04/13/2020] [Accepted: 08/20/2020] [Indexed: 12/18/2022] Open
Abstract
The capecitabine and oxaliplatin (CapeOX) regimen is a commonly used adjuvant chemotherapeutic regimen for gastric cancer (GC). However, some patients exhibit a poor chemotherapy response due to genetic differences among individuals. Therefore, finding an effective sensitization strategy for CapeOX is important in the treatment of GC. The present study aimed to investigate the predictive biomarkers of the CapeOX chemotherapeutic outcomes for patients with GC. A total of 30 differentially expressed genes (DEGs) were identified using the gene expression profiles from The Cancer Genome Atlas capecitabine and oxaliplatin treatment GC cases and seven key DEGs [uroplakin-1b (UPK1B), fatty acid-binding protein, heart (FABP3), cystatin-M, caspase-5 (CASP5), corticosteroid 11-β-dehydrogenase isozyme 2, cytochrome P450 4X1 (CYP4X1) and epidermal growth factor receptor kinase substrate 8-like protein 3] were associated with survival. Gene validation was performed in clinical samples divided into recurrence and nonrecurrence groups. Patients with high or low expression of UPK1B, FABP3, CASP5 and CYP4X1 had markedly different overall survival rates. A model was established and the area under the curve of the receiver operating characteristic reached 0.875 (0.793–0.957), indicating that the model had good sensitivity and specificity.
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Affiliation(s)
- Yan Zhang
- Department of Gastrointestinal Surgery, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Gusu, Suzhou, Jiangsu 215000, P.R. China
| | - Zhen Yuan
- Department of Gastrointestinal Surgery, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Gusu, Suzhou, Jiangsu 215000, P.R. China
| | - Renbin Shen
- Department of Gastrointestinal Surgery, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Gusu, Suzhou, Jiangsu 215000, P.R. China
| | - Yannan Jiang
- Department of Gastrointestinal Surgery, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Gusu, Suzhou, Jiangsu 215000, P.R. China
| | - Wei Xu
- Department of Gastrointestinal Surgery, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Gusu, Suzhou, Jiangsu 215000, P.R. China
| | - Menghui Gu
- Department of Gastrointestinal Surgery, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Gusu, Suzhou, Jiangsu 215000, P.R. China
| | - Xinhua Gu
- Department of Gastrointestinal Surgery, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Gusu, Suzhou, Jiangsu 215000, P.R. China
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8
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Sinomenine sensitizes human gastric cancer cells to cisplatin through negative regulation of PI3K/AKT/Wnt signaling pathway. Anticancer Drugs 2020; 30:983-990. [PMID: 31609766 PMCID: PMC6824511 DOI: 10.1097/cad.0000000000000834] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Sinomenine (SIN) has been reported its antitumor effects on various types of human cancers, but there is no available information regarding the antitumor effects of SIN and cisplatin on gastric cancer. Here, we examined the antitumor effects of SIN combined with cisplatin on gastric cancer cells as well as the underlying biological mechanisms. CCK-8 assay and Calcusyn 2.0 software analysis, Hoechst 33258 staining and flow cytometry, transwell assay showed that SIN and cisplatin synergistically inhibited growth, induced apoptosis, and suppressed invasion than did either drug alone in gastric cancer cells. Interestingly, no change in the AKT level was found, whereas SIN and cisplatin led to a dramatic decrease in p-AKT level compared with either alone treatment. SIN and cisplatin further decreased the Bcl-2, procaspase-3, and β-catenin, but increased Bax, cleaved dcaspase 3, MMP9, and MMP2 in combined group than in either alone group. Immunofluorescence staining showed again a significant decrease in nucleus β-catenin was found in combined group. These data suggested that SIN sensitizes human gastric cancer cells to cisplatin through negative regulation of PI3K/AKT/Wnt signaling pathway. In conclusion, SIN and cisplatin exerted synergistic antitumor effects in gastric cancer cells and might constitute a promising therapeutic approach for gastric cancer.
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Refolo MG, Lotesoriere C, Lolli IR, Messa C, D'Alessandro R. Molecular mechanisms of synergistic action of Ramucirumab and Paclitaxel in Gastric Cancers cell lines. Sci Rep 2020; 10:7162. [PMID: 32346056 PMCID: PMC7188894 DOI: 10.1038/s41598-020-64195-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Accepted: 04/05/2020] [Indexed: 12/15/2022] Open
Abstract
Ramucirumab is approved both as monotherapy and in combination with Paclitaxel for advanced gastric cancer in patients with disease progression after chemotherapy. In tumor cells, the VEGFA-VEGFR2 binding activates autocrine survival and migration signaling in angiogenesis independent manner. The present in vitro study investigated the effects of single and combined treatments with Ramucirumab and Paclitaxel on cell growth and migration highlighting the mechanisms underlying the interaction between the two drugs in gastric cancer cells. Cell growth and motility were investigated in human gastric cancer cell lines characterized by different tumorigenicity. The inhibitory effect on cell growth exerted by both drugs was potentiated by their combination and was synergistic. Ramucirumab was able to enhance the inhibitory effect exerted by Paclitaxel on cell cycle progression. A synergistic action was also observed in the expression of proteins crucial for cell motility, microtubule organization and epithelial-mesenchymal transition. Furthermore, synergistic inhibition of VEGFR2 expression was obtained by the drug combination. These findings highlighted the importance of the combined treatment to strongly inhibit all the main molecules of both PI3K/Akt/mTOR and MAPK pathways thus preventing possible reactivations due to cross-talk phenomena. The combined treatment with Ramucirumab seems to be a promising option to overcome the Paclitaxel resistance.
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Affiliation(s)
- Maria Grazia Refolo
- Laboratory of Cellular and Molecular Biology, Department of Clinical Pathology, National Institute of Gastroenterology, "Saverio de Bellis" Research Hospital, Castellana Grotte (BARI), 70013, Italy
| | - Claudio Lotesoriere
- Medical Oncology Unit, National Institute of Gastroenterology, "Saverio de Bellis" Research Hospital, Castellana Grotte (BARI), 70013, Italy
| | - Ivan Roberto Lolli
- Medical Oncology Unit, National Institute of Gastroenterology, "Saverio de Bellis" Research Hospital, Castellana Grotte (BARI), 70013, Italy
| | - Caterina Messa
- Laboratory of Cellular and Molecular Biology, Department of Clinical Pathology, National Institute of Gastroenterology, "Saverio de Bellis" Research Hospital, Castellana Grotte (BARI), 70013, Italy.
| | - Rosalba D'Alessandro
- Laboratory of Cellular and Molecular Biology, Department of Clinical Pathology, National Institute of Gastroenterology, "Saverio de Bellis" Research Hospital, Castellana Grotte (BARI), 70013, Italy.
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Dual PI3K/mTOR inhibitor BEZ235 as a promising therapeutic strategy against paclitaxel-resistant gastric cancer via targeting PI3K/Akt/mTOR pathway. Cell Death Dis 2018; 9:123. [PMID: 29374144 PMCID: PMC5833539 DOI: 10.1038/s41419-017-0132-2] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Revised: 09/28/2017] [Accepted: 11/08/2017] [Indexed: 02/07/2023]
Abstract
Paclitaxel (PTX) is widely used in the front-line chemotherapy for gastric cancer (GC), but resistance limits its use. Due to the lack of proper models, mechanisms underlying PTX resistance in GC were not well studied. Using established PTX-resistant GC cell sublines HGC-27R, we for the first time integrated biological traits and molecular mechanisms of PTX resistance in GC. Data revealed that PTX-resistant GC cells were characterized by microtubular disorders, an EMT phenotype, reduced responses to antimitotic drugs, and resistance to apoptosis (marked by upregulated β-tubulin III, vimentin, attenuated changes in G2/M molecules or pro-apoptotic factors in response to antimitotic drugs or apoptotic inducers, respectively). Activation of the phosphoinositide 3-kinase, the serine/threonine kinase Akt and mammalian target of rapamycin (PI3K/Akt/mTOR) and mitogen-activated protein kinase (MAPK) pathways were also observed, which might be the reason for above phenotypic alternations. In vitro data suggested that targeting these pathways were sufficient to elicit antitumor responses in PTX-resistant GC, in which the dual PI3K/mTOR inhibitor BEZ235 displayed higher therapeutic efficiency than the mTOR inhibitor everolimus or the MEK inhibitor AZD6244. Antitumor effects of BEZ235 were also confirmed in mice bearing HGC-27R tumors. Thus, these data suggest that PI3K/Akt/mTOR and MAPK pathway inhibition, especially PI3K/mTOR dual blockade, might be a promising therapeutic strategy against PTX-resistant GC.
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Cao Y, Zhang G, Wang P, Zhou J, Gan W, Song Y, Huang L, Zhang Y, Luo G, Gong J, Zhang L. Clinical significance of UGT1A1 polymorphism and expression of ERCC1, BRCA1, TYMS, RRM1, TUBB3, STMN1 and TOP2A in gastric cancer. BMC Gastroenterol 2017; 17:2. [PMID: 28056823 PMCID: PMC5217235 DOI: 10.1186/s12876-016-0561-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Accepted: 12/16/2016] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Individualized therapeutic regimen is a recently intensively pursued approach for targeting diseases, in which the search for biomarkers was considered the first and most important. Thus, the goal of this study was to investigate whether the UGT1A1, ERCC1, BRCA1, TYMS, RRM1, TUBB3, STMN1 and TOP2A genes are underlying biomarkers for gastric cancer, which, to our knowledge, has not been performed. METHODS Ninety-eight tissue specimens were collected from gastric cancer patients between May 2012 and March 2015. A multiplex branched DNA liquidchip technology was used for measuring the mRNA expressions of ERCC1, BRCA1, TYMS, RRM1, TUBB3, STMN1 and TOP2A. Direct sequencing was performed for determination of UGT1A1 polymorphisms. Furthermore, correlations between gene expressions, polymorphisms and clinicopathological characteristics were investigated. RESULTS The expressions of TYMS, TUBB3 and STMN1 were significantly associated with the clinicopathological characteristics of age, gender and family history of gastric cancer, but not with differentiation, growth patterns, metastasis and TNM staging in patients with gastric cancer. No clinical characteristics were correlated with the expressions of ERCC1, BRCA1, RRM1 and TOP2A. Additionally, patients carrying G allele at -211 of UGT1A1 were predisposed to developing tubular adenocarcinoma, while individuals carrying 6TAA or G allele respectively at *28 or -3156 of UGT1A1 tended to have a local invasion. CONCLUSIONS The UGT1A1 polymorphism may be useful to screen the risk population of gastric cancer, while TYMS, TUBB3 and STMN1 may be potential biomarkers for prognosis and chemotherapy guidance.
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Affiliation(s)
- Yongkuan Cao
- Department of Gastrointestinal Surgery, Center of General Surgery of P.L.A., Chengdu Army General Hospital, No.270 Rongdu avenue, Chengdu, 610083, Sichuan Province, China.
| | - Guohu Zhang
- Department of Gastrointestinal Surgery, Center of General Surgery of P.L.A., Chengdu Army General Hospital, No.270 Rongdu avenue, Chengdu, 610083, Sichuan Province, China
| | - Peihong Wang
- Department of Gastrointestinal Surgery, Center of General Surgery of P.L.A., Chengdu Army General Hospital, No.270 Rongdu avenue, Chengdu, 610083, Sichuan Province, China
| | - Jun Zhou
- Department of Gastrointestinal Surgery, Center of General Surgery of P.L.A., Chengdu Army General Hospital, No.270 Rongdu avenue, Chengdu, 610083, Sichuan Province, China
| | - Wei Gan
- Department of Gastrointestinal Surgery, Center of General Surgery of P.L.A., Chengdu Army General Hospital, No.270 Rongdu avenue, Chengdu, 610083, Sichuan Province, China
| | - Yaning Song
- Department of Gastrointestinal Surgery, Center of General Surgery of P.L.A., Chengdu Army General Hospital, No.270 Rongdu avenue, Chengdu, 610083, Sichuan Province, China
| | - Ling Huang
- Department of Gastrointestinal Surgery, Center of General Surgery of P.L.A., Chengdu Army General Hospital, No.270 Rongdu avenue, Chengdu, 610083, Sichuan Province, China
| | - Ya Zhang
- Department of Gastrointestinal Surgery, Center of General Surgery of P.L.A., Chengdu Army General Hospital, No.270 Rongdu avenue, Chengdu, 610083, Sichuan Province, China
| | - Guode Luo
- Department of Gastrointestinal Surgery, Center of General Surgery of P.L.A., Chengdu Army General Hospital, No.270 Rongdu avenue, Chengdu, 610083, Sichuan Province, China
| | - Jiaqing Gong
- Department of Gastrointestinal Surgery, Center of General Surgery of P.L.A., Chengdu Army General Hospital, No.270 Rongdu avenue, Chengdu, 610083, Sichuan Province, China
| | - Lin Zhang
- Department of Gastrointestinal Surgery, Center of General Surgery of P.L.A., Chengdu Army General Hospital, No.270 Rongdu avenue, Chengdu, 610083, Sichuan Province, China
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Abstract
The development of drug resistance has largely limited the clinical outcome of anti-cancer treatment. Recent work has highlighted the involvement of non-coding RNAs, microRNAs (miRNAs), in cancer development. The present study aimed to investigate the role of miR-21 in the development of drug resistance to paclitaxel in gastric cancer cells. Our study found that the expression of miR-21 upregulated in the paclitaxel resistant cell line SGC7901/paclitaxel compared to its parental line SGC7901. Moreover, over-expression of miR-21 significantly decreased antiproliferative effects and apoptosis induced by paclitaxel, while knockdown of miR-21 dramatically increased antiproliferative effects and apoptosis induction by paclitaxel. Moreover, our results demonstrated that miR-21 may modulate the sensitivity to PTX, at least in part, by regulating the expression of P-glycoprotein.
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13
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Yang Z, Dai H, Lv D, Feng AL, Shu W, Han J. Clinical observation of gene expression-guided chemoradiation therapy for nonsurgical esophageal squamous cell carcinoma patients: a retrospective analysis of 36 cases. Onco Targets Ther 2016; 9:4561-8. [PMID: 27524911 PMCID: PMC4966573 DOI: 10.2147/ott.s105221] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Objective To make an informed choice of chemotherapy drugs according to the oncogene mRNA expression and to explore whether it could increase the survival rate of patients. Patients and methods The study retrospectively analyzed 36 cases of nonsurgical esophageal squamous cell carcinoma patients treated at the Center for Oncology of Shandong Provincial Hospital from December 1, 2010, to November 1, 2013. Intensity-modulated radiation therapy was used for the treatment with a conventional radiotherapy dose of 60–66 Gy. Chemotherapy started 1–5 weeks after radiation therapy. The selection of the chemotherapy drug was based on the mRNA expression levels of excision repair cross-complementation 1, thymidylate synthetase, ribonucleotide reductase M1, and β-tubulin isotype III. The objective response rate, progression-free survival, and overall survival were observed. Results The reason for poor prognosis of patients with high expression of excision repair cross-complementation 1 was unknown. No correlation was observed between patient survival and expression of thymidylate synthetase, ribonucleotide reductase M1, and β-tubulin isotype III. Complete response, partial response, stable disease, and progressive disease were observed in 25, five, three, and three patients, respectively. The objective response rate was 83.3%. The 1-year, 2-year, and 3-year progression-free survival rates were 79.8%, 58.9%, and 54.4%, respectively. The 1-year, 2-year, and 3-year overall survival rates were 83.3%, 68.1%, and 58.4%, respectively. Conclusion Selecting the chemotherapy drug according to the oncogene expression, combined with radiation therapy, could increase the 3-year survival rate in nonsurgical esophageal squamous cell carcinoma patients. Such conclusion needs to be further confirmed using a larger sample size.
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Affiliation(s)
- Zhe Yang
- Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China
| | - Honghai Dai
- Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China
| | - Dongxiao Lv
- Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China
| | - A Lei Feng
- Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China
| | - Weibin Shu
- Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China
| | - Junqing Han
- Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China
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Matboli M, El-Nakeep S, Hossam N, Habieb A, Azazy AEM, Ebrahim AE, Nagy Z, Abdel-Rahman O. Exploring the role of molecular biomarkers as a potential weapon against gastric cancer: A review of the literature. World J Gastroenterol 2016; 22:5896-5908. [PMID: 27468184 PMCID: PMC4948264 DOI: 10.3748/wjg.v22.i26.5896] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 05/25/2016] [Accepted: 06/13/2016] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is a global health problem and a major cause of cancer-related death with high recurrence rates ranging from 25% to 40% for GC patients staging II-IV. Unfortunately, while the majority of GC patients usually present with advanced tumor stage; there is still limited evidence-based therapeutic options. Current approach to GC management consists mainly of; endoscopy followed by, gastrectomy and chemotherapy or chemo-radiotherapy. Recent studies in GC have confirmed that it is a heterogeneous disease. Many molecular characterization studies have been performed in GC. Recent discoveries of the molecular pathways underlying the disease have opened the door to more personalized treatment and better predictable outcome. The identification of molecular markers is a useful tool for clinical managementin GC patients, assisting in diagnosis, evaluation of response to treatment and development of novel therapeutic modalities. While chemotherapeutic agents have certain physiological effects on the tumor cells, the prediction of the response is different from one type of tumor to the other. The specificity of molecular biomarkers is a principal feature driving their application in anticancer therapies. Here we are trying to focus on the role of molecular pathways of GC and well-established molecular markers that can guide the therapeutic management.
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Hesperetin Induces the Apoptosis of Gastric Cancer Cells via Activating Mitochondrial Pathway by Increasing Reactive Oxygen Species. Dig Dis Sci 2015; 60:2985-95. [PMID: 25972151 DOI: 10.1007/s10620-015-3696-7] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 04/29/2015] [Indexed: 01/19/2023]
Abstract
BACKGROUND Hesperetin, has been shown to exert biological activities on various types of human cancers. However, few related studies on gastric cancer are available. AIM In this study, we sought to investigate the effect of hesperetin on gastric cancer and clarify its specific mechanism. MATERIALS AND METHODS Cell Counting Kit-8, 2',7'-dichlorofluorescin diacetate, JC-1, Hoechst 33258 staining, and western bolt were used to detect cell viability, levels of intracellular reactive oxygen species (ROS), changes in mitochondrial membrane potential (△ψ m), cell apoptosis, and expressions of mitochondrial pathway proteins, respectively. Meanwhile, xenograft tumor models in nude mice were made to evaluate the effect of hesperetin on gastric cancer in vivo. RESULTS Compared with the control group, the proliferation of gastric cancer cells in hesperetin groups was significantly inhibited (P < 0.05), and dose- and time-dependent effects were observed. Pretreatment with H2O2 (1 mM) or N-acetyl-L-cysteine (5 mM) enhanced or attenuated the hesperetin-induced inhibition of cell viability (P < 0.05). Percentages of apoptotic cells, levels of intracellular ROS, and △ψ m varied with the dose and treatment time of hesperetin (P < 0.05), and hesperetin caused an increase in the levels of AIF, Apaf-1, Cyt C, caspase-3, caspase-9, and Bax and a decrease in Bcl-2 levels (P < 0.05). Meanwhile, hesperetin significantly inhibited the growth of xenograft tumors (P < 0.05). CONCLUSION Our study suggests that hesperetin could inhibit the proliferation and induce the apoptosis of gastric cancer cells via activating the mitochondrial pathway by increasing the ROS.
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Kanda M, Kodera Y. Recent advances in the molecular diagnostics of gastric cancer. World J Gastroenterol 2015; 21:9838-9852. [PMID: 26379391 PMCID: PMC4566379 DOI: 10.3748/wjg.v21.i34.9838] [Citation(s) in RCA: 92] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2015] [Revised: 06/15/2015] [Accepted: 08/25/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is the third most common cause of cancer-related death in the world, representing a major global health issue. Although the incidence of GC is declining, the outcomes for GC patients remain dismal because of the lack of effective biomarkers to detect early GC and predict both recurrence and chemosensitivity. Current tumor markers for GC, including serum carcinoembryonic antigen and carbohydrate antigen 19-9, are not ideal due to their relatively low sensitivity and specificity. Recent improvements in molecular techniques are better able to identify aberrant expression of GC-related molecules, including oncogenes, tumor suppressor genes, microRNAs and long non-coding RNAs, and DNA methylation, as novel molecular markers, although the molecular pathogenesis of GC is complicated by tumor heterogeneity. Detection of genetic and epigenetic alterations from gastric tissue or blood samples has diagnostic value in the management of GC. There are high expectations for molecular markers that can be used as new screening tools for early detection of GC as well as for patient stratification towards personalized treatment of GC through prediction of prognosis and drug-sensitivity. In this review, the studies of potential molecular biomarkers for GC that have been reported in the publicly available literature between 2012 and 2015 are reviewed and summarized, and certain highlighted papers are examined.
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He Q, Gao J, Ge S, Wang T, Li Y, Peng Z, Li Y, Shen L. Axitinib alone or in combination with chemotherapeutic drugs exerts potent antitumor activity against human gastric cancer cells in vitro and in vivo. J Cancer Res Clin Oncol 2014; 140:1575-83. [PMID: 24804814 DOI: 10.1007/s00432-014-1693-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Accepted: 04/22/2014] [Indexed: 11/24/2022]
Abstract
OBJECTIVE As the new oral selective VEGFR tyrosine kinase inhibitor, axitinib (AG-013736) exerts powerful antitumor activity in multiple solid tumors, while its' effect was unclear in gastric cancer. We aimed to investigate the antitumor activity of axitinib alone or combined with chemotherapeutic drugs against human gastric cancer cells in vitro and in vivo. METHODS The IC50 values of drugs were determined by MTS assay. The median effect of Chou-Talalay was used to assess the synergistic effect of two drugs. Flow cytometry was employed to analyze cell cycle and cell apoptosis. Cell senescence and microvessel density were evaluated by SA-β-gal staining and CD34 staining, respectively. BGC-823-derived xenografts in nude mice were established to investigate the effects of drugs in vivo. RESULTS Axitinib alone could inhibit cell proliferation and retard tumor growth through inducing cell cycle arrest at G2/M phase, cell senescence, cell apoptosis, and antiangiogenesis in vitro and in vivo. Axitinib combined with 5-fluorouracil (5-FU) had synergistic inhibitory effect compared to axitinib or 5-FU alone. However, the highest inhibitory effect was found between axitinib and cisplatin (inhibitory ratio >80 % compared to control), which was significantly higher than any single drug (inhibitory ratio for single 5-FU, cisplatin, and axitinib >10, >40, and >40 %, respectively, compared to control) or axitinib combined with 5-FU (inhibitory ratio >50 % compared to control). CONCLUSION We highlighted for the first time that axitinib alone or in combination with 5-fluorouracil or cisplatin has potent antitumor activity against human gastric cancer in vitro and in vivo, which provided solid evidence for future clinical trial.
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Affiliation(s)
- Qiong He
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
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Quantification of α-tubulin isotypes by sandwich ELISA with signal amplification through biotinyl-tyramide or immuno-PCR. J Immunol Methods 2013; 395:63-70. [DOI: 10.1016/j.jim.2013.07.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 07/02/2013] [Accepted: 07/02/2013] [Indexed: 11/17/2022]
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Karki R, Mariani M, Andreoli M, He S, Scambia G, Shahabi S, Ferlini C. βIII-Tubulin: biomarker of taxane resistance or drug target? Expert Opin Ther Targets 2013; 17:461-72. [PMID: 23379899 DOI: 10.1517/14728222.2013.766170] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION βIII-Tubulin (TUBB3) is predominantly expressed in neurons of the central and peripheral nervous systems, while in normal non-neoplastic tissues it is barely detectable. By contrast, this cytoskeletal protein is abundant in a wide range of tumors. βIII-Tubulin is linked to dynamic instability of microtubules (MTs), weakening the effects of agents interfering with MT polymerization. Based on this principle, early studies introduced the classical theory linking βIII-tubulin with a mechanism of counteracting taxane activity and accordingly, prompted its investigation as a predictive biomarker of taxane resistance. AREAS COVERED We reviewed 59 translational studies, including cohorts from lung, ovarian, breast, gastric, colorectal and various miscellaneous cancers subject to different chemotherapy regimens. EXPERT OPINION βIII-Tubulin functions more as a prognostic factor than as a predictor of response to chemotherapy. We believe this view can be explained by βIII-tubulin's association with prosurvival pathways in the early steps of the metastatic process. Its prognostic response increases if combined with additional biomarkers that regulate its expression, since βIII-tubulin can be expressed in conditions, such as estrogen exposure, unrelated to survival mechanisms and without any predictive activity. Additional avenues for therapeutic intervention could emerge if drugs are designed to directly target βIII-tubulin and its mechanism of regulation.
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Affiliation(s)
- Roshan Karki
- Reproductive Tumor Biology Research, Department of Obstetrics and Gynecology, Danbury Hospital, Biomedical Laboratory, Danbury, CT 06810, USA
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