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Yu H, Kou Q, Yuan H, Qi Y, Li Q, Li L, Zhao G, Wang G, Li S, Qu J, Chen H, Zhao M, Wang Q, Li S, Chen K, Lu C, Xiao H, Lin P, Li K. Alkannin triggered apoptosis and ferroptosis in gastric cancer by suppressing lipid metabolism mediated by the c-Fos/SREBF1 axis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 140:156604. [PMID: 40049103 DOI: 10.1016/j.phymed.2025.156604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 02/19/2025] [Accepted: 03/02/2025] [Indexed: 03/17/2025]
Abstract
BACKGROUND Gastric cancer (GC), one of the most common malignancies with high mortality worldwide, currently requires beneficial therapeutic strategies. Alkannin is the primary active component of Lithospermum erythrorhizon and has been shown to have potential anticancer effects on a variety of cancers. However, the specific effects and molecular mechanisms of alkannin against GC remain unknown. PURPOSE This study aimed to explore the detailed role and downstream effectors of alkannin in the treatment of GC. METHODS The functions of alkannin on the proliferation, migration and invasion of GC cells were measured via CCK-8, EdU, colony formation, LDH release, flow cytometry, wound healing, and Transwell assays. BODIPY-C11 staining, determination of cellular ferrous iron, MDA and GSH levels, and western blotting were used to evaluate alkannin-induced ferroptosis. Transcriptome sequencing was analyzed to identify differentially expressed genes. Nile red staining and cholesterol and triglyceride assays were utilized to examine changes in lipid metabolism. Transcriptional regulation was determined by real-time PCR, dual-luciferase reporter and chromatin immunoprecipitation assays. Finally, a xenograft animal model was employed to assess tumor growth in vivo. RESULTS Alkannin inhibited growth and motility and simultaneously triggered apoptotic and ferroptotic cell death in GC cells. Transcriptome sequencing analysis revealed that alkannin treatment downregulated c-Fos expression. The overexpression of c-Fos conferred the GC cells to tolerate alkannin in vitro and in vivo. Moreover, we confirmed that c-Fos activated SREBF1 transcription by directly binding to TPA-responsive elements within the SREBF1 promoter, leading to increased expression of lipid biosynthesis-related genes, which counteracted ferroptosis through the maintenance of cellular lipid homeostasis. CONCLUSION Our present study provides the first evidence that alkannin induces both apoptosis and ferroptosis in GC cells and reveals a novel mechanism by which alkannin restrains c-Fos-dependent SREBF1 transcriptional activation, leading to lipid metabolism and redox homeostasis disorders. Our findings highlight that alkannin is an available and promising natural product for the avoidance of drug resistance and the clinical treatment of GC.
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Affiliation(s)
- Huayang Yu
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, PR China
| | - Qiming Kou
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, PR China
| | - Hang Yuan
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, PR China
| | - Yanyu Qi
- Department of Oncology, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Sichuan Chengdu 610404, PR China
| | - Qin Li
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, PR China
| | - Liang Li
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, PR China
| | - Gang Zhao
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, PR China
| | - Guanru Wang
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, PR China
| | - Siqi Li
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, PR China
| | - Jie Qu
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, PR China
| | - Hongbai Chen
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, PR China
| | - Minghui Zhao
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, PR China
| | - Qijing Wang
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, PR China
| | - Shan Li
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, PR China
| | - Kang Chen
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, PR China
| | - Chenghong Lu
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, PR China
| | - Hengyi Xiao
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, PR China.
| | - Ping Lin
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, PR China.
| | - Kai Li
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center and Lab of Experimental Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, PR China.
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Luo HL, Luo HL. Analysis of the effect of multi-channel continuous nursing intervention on patients post-radical gastrectomy. World J Gastrointest Surg 2025; 17:100848. [DOI: 10.4240/wjgs.v17.i4.100848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 02/08/2025] [Accepted: 03/10/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Radical gastrectomy (RGE) for gastric carcinoma (GC) has exerted definite therapeutic efficacy in treating patients with GC. However, a notable risk of postoperative complications (POCs) persists among middle-aged and elderly patients with compromised physiological functions. Hence, developing and implementing reliable nursing interventions to optimize the comprehensive management of these patients is deemed imperative.
AIM To analyze the association of multi-channel continuous nursing intervention with POCs, negative emotions (NEs), and quality of life (QoL) of patients undergoing RGE for GC.
METHODS This retrospective study selected 99 patients who underwent RGE for GC in our hospital from May 2020 to May 2023. Participants were categorized into the control (n = 49 cases) and research groups (n = 50 cases) receiving routine and multi-channel continuous nursing care, respectively. Comparative analysis involved data on postoperative rehabilitation (time to first anal exhaust, oral feeding and ambulation, and hospital stay), complications (nausea and vomiting, delayed gastric emptying, and abdominal distension), NEs [Self-rating Anxiety (SAS)/Depression Scale (SDS)], treatment compliance, self-efficacy, and QoL [World Health Organization QoL Brief Version (WHOQOL-BREF)].
RESULTS Compared to the control group, the research group demonstrated earlier first postoperative anal exhaust, oral feeding, and ambulation, shorter hospital stay, lower POC rate, and more reduced SAS and SDS scores postintervention, which was significantly lower than the baseline. The treatment compliance scores were significantly higher in the research group than in the control group in terms of medication adherence, daily exercise, reasonable diet, and regular review. Further, the research group demonstrated increased self-efficacy scores in terms of positive attitude, self-stress relief, and self-decision-making, as well as the overall score postintervention, which were higher than the control group. Moreover, the research group reported notably higher WHOQOL-BREF scores in domains such as physiology, psychology, social relations, and environment.
CONCLUSION Multi-channel continuous nursing intervention prevents POCs in patients undergoing RGE for GC as well as significantly alleviates patients’ NEs and boosts their QoL.
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Affiliation(s)
- Huan-Li Luo
- Department of Nursing, Henan Vocational College of Nursing, Anyang 455000, Henan Province, China
| | - Huan-Ling Luo
- Department of International Education, Henan Vocational College of Nursing, Anyang 455000, Henan Province, China
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Meng FD, Jia SM, Ma YB, Du YH, Liu WJ, Yang Y, Yuan L, Nan Y. Identification of key hub genes associated with anti-gastric cancer effects of lotus plumule based on machine learning algorithms. World J Gastrointest Oncol 2025; 17:103048. [DOI: 10.4251/wjgo.v17.i4.103048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 12/11/2024] [Accepted: 01/16/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Lotus plumule and its active components have demonstrated inhibitory effects on gastric cancer (GC). However, the molecular mechanism of lotus plumule against GC remains unclear and requires further investigation.
AIM To identify the key hub genes associated with the anti-GC effects of lotus plumule.
METHODS This study investigated the potential targets of traditional Chinese medicine for inhibiting GC using weighted gene co-expression network analysis and bioinformatics. Initially, the active components and targets of the lotus plumule and the differentially expressed genes associated with GC were identified. Subsequently, a protein-protein interaction network was constructed to elucidate the interactions between drug targets and disease-related genes, facilitating the identification of hub genes within the network. The clinical significance of these hub genes was evaluated, and their upstream transcription factors and downstream targets were identified. The binding ability of a hub gene with its downstream targets was verified using molecular docking technology. Finally, molecular docking was performed to evaluate the binding affinity between the active ingredients of lotus plumule and the hub gene.
RESULTS This study identified 26 genes closely associated with GC. Machine learning analysis and external validation narrowed the list to four genes: Aldo-keto reductase family 1 member B10, fructose-bisphosphatase 1, protein arginine methyltransferase 1, and carbonic anhydrase 9. These genes indicated a strong correlation with anti-GC activity.
CONCLUSION Lotus plumule exhibits anti-GC effects. This study identified four hub genes with potential as novel targets for diagnosing and treating GC, providing innovative perspectives for its clinical management.
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Affiliation(s)
- Fan-Di Meng
- Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Shu-Min Jia
- Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yu-Bin Ma
- Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yu-Hua Du
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Wen-Jing Liu
- Key Laboratory of Hui Ethnic Medicine Modernization of Ministry of Education, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yi Yang
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Ling Yuan
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yi Nan
- Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
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Ding Y, Yu Y. Therapeutic potential of flavonoids in gastrointestinal cancer: Focus on signaling pathways and improvement strategies (Review). Mol Med Rep 2025; 31:109. [PMID: 40017144 PMCID: PMC11884236 DOI: 10.3892/mmr.2025.13474] [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: 09/18/2024] [Accepted: 01/30/2025] [Indexed: 03/01/2025] Open
Abstract
Flavonoids are a group of polyphenolic compounds distributed in vegetables, fruits and other plants, which have considerable antioxidant, anti‑tumor and anti‑inflammatory activities. Several types of gastrointestinal (GI) cancer are the most common malignant tumors in the world. A large number of studies have shown that flavonoids have inhibitory effects on cancer, and they are recognized as a class of potential anti‑tumor drugs. Therefore, the present review investigated the molecular mechanisms of flavonoids in the treatment of different types of GI cancer and summarized the drug delivery systems commonly used to improve their bioavailability. First, the classification of flavonoids and the therapeutic effects of various flavonoids on human diseases were briefly introduced. Then, to clarify the mechanism of action of flavonoids on different types of GI cancer in the human body, the metabolic process of flavonoids in the human body and the associated signaling pathways causing five common types of GI cancer were discussed, as well as the corresponding therapeutic targets of flavonoids. Finally, in clinical settings, flavonoids have poor water solubility, low permeability and inferior stability, which lead to low absorption efficiency in vivo. Therefore, the three most widely used drug delivery systems were summarized. Suggestions for improving the bioavailability of flavonoids and the focus of the next stage of research were also put forward.
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Affiliation(s)
- Ye Ding
- Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Yong Yu
- Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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Hou R, Wu X, Wang C, Fan H, Zhang Y, Wu H, Wang H, Ding J, Jiang H, Xu J. Tumor‑associated neutrophils: Critical regulators in cancer progression and therapeutic resistance (Review). Int J Oncol 2025; 66:28. [PMID: 40017131 PMCID: PMC11900975 DOI: 10.3892/ijo.2025.5734] [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: 11/21/2024] [Accepted: 02/11/2025] [Indexed: 03/01/2025] Open
Abstract
Cancer is the second leading cause of death among humans worldwide. Despite remarkable improvements in cancer therapies, drug resistance remains a significant challenge. The tumor microenvironment (TME) is intimately associated with therapeutic resistance. Tumor‑associated neutrophils (TANs) are a crucial component of the TME, which, along with other immune cells, play a role in tumorigenesis, development and metastasis. In the current review, the roles of TANs in the TME, as well as the mechanisms of neutrophil‑mediated resistance to cancer therapy, including immunotherapy, chemotherapy, radiotherapy and targeted therapy, were summarized. Furthermore, strategies for neutrophil therapy were discussed and TANs were explored as potential targets for cancer treatment. In conclusion, the need to explore the precise roles, recruitment pathways and mechanisms of action of TANs was highlighted for the purpose of developing therapies that precisely target TANs and reverse drug resistance.
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Affiliation(s)
- Rui Hou
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Nanjing 214023, P.R. China
| | - Xi Wu
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Nanjing 214023, P.R. China
| | - Cenzhu Wang
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Nanjing 214023, P.R. China
| | - Hanfang Fan
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Nanjing 214023, P.R. China
| | - Yuhan Zhang
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Nanjing 214023, P.R. China
| | - Hanchi Wu
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Nanjing 214023, P.R. China
| | - Huiyu Wang
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Nanjing 214023, P.R. China
| | - Junli Ding
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Nanjing 214023, P.R. China
| | - Huning Jiang
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Nanjing 214023, P.R. China
| | - Junying Xu
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Nanjing 214023, P.R. China
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Wu Z, Wang X, Shi S, Kong D, Ren C, Bian L, Gu Y, An F, Zhan Q, Yan C, Hu C, Chen Y, Jiang R, Chen J. Heterogeneity of T cells regulates tumor immunity mediated by Helicobacter pylori infection in gastric cancer. BMC Cancer 2025; 25:567. [PMID: 40155861 PMCID: PMC11954285 DOI: 10.1186/s12885-025-13957-9] [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: 11/19/2024] [Accepted: 03/17/2025] [Indexed: 04/01/2025] Open
Abstract
The impact of Helicobacter pylori (H. pylori) status on gastric cancer survival remains unclear. In this study, we conducted a prognostic analysis of 488 gastric cancer patients and performed single-cell RNA sequencing (scRNA-seq) on 18,717 T cells from six tumor samples with varying H. pylori statuses. Our findings revealed that gastric cancer patients with H. pylori infection had significantly longer survival times compared to those with negative H. pylori status. After unsupervised re-clustering of T cells based on scRNA-seq data, we identified ten CD4+ and twelve CD8+ clusters. Among them, four CD8+ T cell clusters exhibited distinct distributions based on H. pylori infection status. One cluster, marked by CXCL13, showed high levels of IFNG and GZMB in H. pylori-infected patients, while another cluster, which expressed immune suppression related genes like AREG and PTGER2, was predominantly comprised of cells from non-infected patients. High PTGER2 expression was significantly associated with worse prognosis in patients with high CD8 expression. These insights advance our understanding of H. pylori's influence on T cell responses in gastric cancer, aiding in treatment and prognostic strategies.
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Affiliation(s)
- Zhisheng Wu
- School of Chemistry and Chemical Engineering, Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Medical School, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, China
| | - Xinya Wang
- Wuxi People's Hospital, Wuxi People's Hospital of Nanjing Medical University, Wuxi Medical Center, Wuxi, China
- Department of Immunology, Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
| | - Shujing Shi
- Department of Rehabilitation, School of Sport and Health, Nanjing Sport Institute, Nanjing, China
| | - Deyuan Kong
- Department of Immunology, Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
| | - Chuanli Ren
- Department of Laboratory Medicine, Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Lijun Bian
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yuanliang Gu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Fangmei An
- Wuxi People's Hospital, Wuxi People's Hospital of Nanjing Medical University, Wuxi Medical Center, Wuxi, China
- Department of Gastroenterology, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Qiang Zhan
- Wuxi People's Hospital, Wuxi People's Hospital of Nanjing Medical University, Wuxi Medical Center, Wuxi, China
- Department of Gastroenterology, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Caiwang Yan
- Wuxi People's Hospital, Wuxi People's Hospital of Nanjing Medical University, Wuxi Medical Center, Wuxi, China
- Department of Immunology, Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Chupeng Hu
- Department of Immunology, Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China.
| | - Yun Chen
- School of Chemistry and Chemical Engineering, Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Medical School, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, China.
- Wuxi People's Hospital, Wuxi People's Hospital of Nanjing Medical University, Wuxi Medical Center, Wuxi, China.
- Department of Immunology, Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
- Research center for clinical oncology, Jiangsu Cancer Hospital, the Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.
| | - Runqiu Jiang
- Jiangsu Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China.
| | - Jinfei Chen
- Department of Oncology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
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Guo Y, Hu Z, Bai L, Tang Y, Hu J, Zhang Q, Liu J, Feng S. Increased glucose utilization is a targetable vulnerability to overcome drug resistance associated with neddylation blockade. Biochem Pharmacol 2025; 236:116905. [PMID: 40158819 DOI: 10.1016/j.bcp.2025.116905] [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: 12/10/2024] [Revised: 03/12/2025] [Accepted: 03/25/2025] [Indexed: 04/02/2025]
Abstract
Gastric cancer, a leading cause of cancer-related mortality, has a median survival of just 15 months in advanced stages and currently lacks effective treatment options. Neddylation blockade is a promising therapeutic strategy, yet its clinical application faces challenge with the emergence of drug resistance. Currently, the underlying mechanisms behind the drug resistance are not fully understood. Our study uncovers the link between MLN4924-induced metabolic reprogramming and its antitumor efficacy in gastric cancer cells. We first demonstrated that MLN4924, a neddylation blocker, has multiple effects on gastric cancer cell growth, notably inducing mitochondrial damage. Untargeted metabolomic analysis revealed that MLN4924 enhances glucose utilization in gastric cancer cells in a concentration-dependent manner. Mechanistically, MLN4924 reduces the neddylation of cullin2, thereby inhibiting the degradation of HIF-1α. This leads to the accumulation of HIF-1α, which upregulates GLUT1 levels and facilitates increased glucose uptake. This metabolic adaptation allows gastric cancer cells to maintain their energy supply despite mitochondrial impairment. Based on the increased glucose dependency following neddylation inhibition by MLN4924, we propose a co-targeting strategy with GLUT1 inhibition, which significantly improves therapeutic efficacy in vitro and in vivo models without safety risks. This dual-targeting approach represents a potent new strategy for gastric cancer treatment.
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Affiliation(s)
- Yueyang Guo
- School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China
| | - Zhuang Hu
- School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China
| | - Linyue Bai
- School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China
| | - Yanjun Tang
- School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China
| | - Jingyi Hu
- School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China
| | - Qianqian Zhang
- School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China
| | - Jiali Liu
- Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
| | - Siqi Feng
- School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China.
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Yang B, Cao HX, He YW, Ouyang JJ, Lv M, Li YX, Lu YD. Increased keratin 80 expression predicts poor prognosis and promotes oxaliplatin resistance in gastric cancer. World J Gastroenterol 2025; 31:103991. [DOI: 10.3748/wjg.v31.i12.103991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 01/26/2025] [Accepted: 02/24/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Keratin 80 (KRT80), a type I intermediate filament protein, is a member of the keratin family with specialized functions in epithelial tissues. While KRT80 has been implicated in both normal physiological processes and various diseases, its role in gastric cancer (GC), particularly its expression and prognostic significance, remains poorly understood. In this study, we investigated the role and underlying molecular mechanisms of KRT80 in oxaliplatin resistance in GC. Our analysis revealed that KRT80 is significantly upregulated in GC tissues and is associated with poor clinical prognosis. The role of KRT80 in GC cell proliferation was assessed through in vitro and in vivo assays.
AIM To explore the expression of KRT80 in GC and its impact on the prognosis of patients.
METHODS KRT80 expression in GC tissues was analyzed using Western blotting, quantitative reverse transcription PCR, multiple immunofluorescence staining, and immunohistochemistry. Survival analysis was conducted using the Kaplan-Meier method with the log-rank test. The role of KRT80 in GC cell proliferation was assessed through in vitro and in vivo assays. Immunoprecipitation and mass spectrometry analyses identified elongation factor 1-alpha 1 (EEF1A1) as a binding protein of KRT80.
RESULTS Integrating our experimental findings with multiple published studies, we found that increased KRT80 expression is associated with poor prognosis in GC and promotes resistance to oxaliplatin. Moreover, we have preliminarily verified the interaction between KRT80 and EEF1A1. Therefore, this study provides a novel perspective on overcoming oxaliplatin resistance in GC.
CONCLUSION Increased KRT80 expression predicts poor prognosis and promotes oxaliplatin resistance in GC, suggesting its potential as a novel prognostic biomarker.
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Affiliation(s)
- Bo Yang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China
| | - Hong-Xia Cao
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, Anhui Province, China
| | - Ya-Wei He
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, Anhui Province, China
| | - Ji-Jie Ouyang
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, Anhui Province, China
| | - Meng Lv
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, Anhui Province, China
| | - Yong-Xiang Li
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China
| | - Yi-Da Lu
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, Anhui Province, China
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9
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Munini M, Fodor M, Corradi A, Frena A. Clinical benefits and controversies of jejunostomy feeding in patients undergoing gastrectomy for gastric cancer. World J Gastrointest Surg 2025; 17:100384. [PMID: 40162383 PMCID: PMC11948112 DOI: 10.4240/wjgs.v17.i3.100384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 01/20/2025] [Accepted: 02/08/2025] [Indexed: 02/24/2025] Open
Abstract
Globally, gastric cancer ranks as the fifth most common malignancy and the third leading cause of cancer-related mortality. Gastrectomy combined with perioperative chemotherapy is currently the standard of care in locally advanced stages, but the completion rate of multimodal approach is influenced also by patient related factors. Malnutrition is a well-known risk factor associated with poor oncological outcomes. Its perioperative supplementation could lead to an improvement of the nutritional status. This article reviews and comments the retrospective study conducted by Jaquet et al, which evaluates the impact of enteral nutrition by jejunostomy feeding in patients undergoing gastrectomy for cancer. The authors included 172 patients, 35% of whom received jejunostomy. Patients with optimized biological nutritional parameters (body mass index, albumin, prealbumin) showed reduced major complications (> III), according to the Dindo-Clavien classification, 0 (0%) vs 8 (4.7%) (P = 0.05). In the era of multimodal treatment, optimization of nutritional and performance status is integral part of the therapeutic strategy.
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Affiliation(s)
- Martino Munini
- Department of General and Pediatric Surgery, Bolzano Central Hospital, Bolzano 39100, Trentino-Alto Adige, Italy
| | - Margot Fodor
- Department of General and Pediatric Surgery, Bolzano Central Hospital, Bolzano 39100, Trentino-Alto Adige, Italy
| | - Alessio Corradi
- Department of General and Pediatric Surgery, Bolzano Central Hospital, Bolzano 39100, Trentino-Alto Adige, Italy
| | - Antonio Frena
- Department of General and Pediatric Surgery, Bolzano Central Hospital, Bolzano 39100, Trentino-Alto Adige, Italy
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10
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Guo X, Wang W, Cheng X, Song Q, Wang X, Wei J, Xu S, Lv X, Ji G. Diagnostic efficacy of an extracellular vesicle-derived lncRNA-based liquid biopsy signature for the early detection of early-onset gastric cancer. Gut 2025:gutjnl-2024-333657. [PMID: 40113244 DOI: 10.1136/gutjnl-2024-333657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Accepted: 02/25/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND Early-onset gastric cancer (EOGC) is a lethal malignancy. It differs from late-onset gastric cancer (LOGC) in clinical and molecular characteristics. The current strategies for EOGC detection have certain limitations in diagnostic performance due to the rising trend in EOGC. OBJECTIVE We developed a liquid biopsy signature for EOGC detection. DESIGN We use a systematic discovery approach by analysing genome-wide transcriptomic profiling data from EOGC (n=43), LOGC (n=31) and age-matched non-disease controls (n=37) tissue samples. An extracellular vesicle-derived long non-coding RNA (EV-lncRNA) signature was identified in blood samples from a training cohort (n=299), and subsequently confirmed by qPCR in two external validation cohorts (n=462 and n=438), a preoperative/postoperative cohort (n=66) and a gastrointestinal tumour cohort (n=225). RESULTS A three EV-lncRNA (NALT1, PTENP1 and HOTTIP) liquid biopsy signature was developed for EOGC detection with an area under the receiver operating characteristic curve (AUROC) of 0.924 (95% CI 0.889 to 0.953). This EV-lncRNA signature provided robust diagnostic performance in two external validation cohorts (Xi'an cohort: AUROC, 0.911; Beijing cohort: AUROC, 0.9323). Furthermore, the EV-lncRNA signature reliably identified resectable stage EOGC patients (stage I/II) and demonstrated better diagnostic performance than traditional GC-related biomarkers in distinguishing early-stage EOGC (stage I) from precancerous lesions. The low levels of this biomarker in postsurgery and other gastrointestinal tumour plasma samples indicated its GC specificity. CONCLUSIONS The newly developed EV-lncRNA signature effectively identified EOGC patients at a resectable stage with enhanced precision, thereby improving the prognosis of patients who would have otherwise missed the curative treatment window.
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Affiliation(s)
- Xin Guo
- Department of General Surgery, Xijing 986th Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
- Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Weidong Wang
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xin Cheng
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Qiying Song
- Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xinxin Wang
- Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jiangpeng Wei
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Shenhui Xu
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xiaohui Lv
- Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Gang Ji
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
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11
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Zhu W, Sun J, Jing F, Xing Y, Luan M, Feng Z, Ma X, Wang Y, Jia Y. GLI2 inhibits cisplatin sensitivity in gastric cancer through DEC1/ZEB1 mediated EMT. Cell Death Dis 2025; 16:204. [PMID: 40133270 PMCID: PMC11937514 DOI: 10.1038/s41419-025-07564-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 02/28/2025] [Accepted: 03/18/2025] [Indexed: 03/27/2025]
Abstract
Cisplatin (CDDP) based chemotherapy has emerged as the predominant therapeutic regimen for patients with advanced gastric cancer (GC). However, its efficacy is dampened by the development of chemoresistance, which results in poor prognosis of patients. GLI2, a key transcription factor in the Hedgehog (Hh) signaling pathway, is regarded as a target for cancer therapy. However, the significance of GLI2 for CDDP resistance in GC has not been well established. Here, we show that GLI2 expression was upregulated in EMT-type GC and associated with poor prognosis. GLI2 promotes proliferation, migration, and CDDP resistance of GC cells by inducing EMT. In terms of mechanism, GLI2 binds to the promoter region of DEC1 and enhances its expression, thereby co-transcriptionally regulating ZEB1 expression. Animal experiments have demonstrated that both GLI2 knockdown and GLI2 inhibitor significantly enhance CDDP sensitivity in GC. Our data not only identify a novel GLI2/DEC1/ZEB1/EMT pathway in GC CDDP resistance but also provide novel strategies to treat GC in the future.
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Affiliation(s)
- Wenshuai Zhu
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China
| | - Jingguo Sun
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China
| | - Fubo Jing
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, People's Republic of China
| | - Yuanxin Xing
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, People's Republic of China
| | - Muhua Luan
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, People's Republic of China
| | - Zhaotian Feng
- Department of Medical Laboratory, Shandong Second Medical University, Weifang, People's Republic of China
| | - Xiaoli Ma
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, People's Republic of China
| | - Yunshan Wang
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China.
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, People's Republic of China.
| | - Yanfei Jia
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China.
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, People's Republic of China.
- Department of Medical Laboratory, Shandong Second Medical University, Weifang, People's Republic of China.
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12
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Xu Y, Qian X, Cai G, Lin Z, Huang W, Wang C, Wu H, Zhang Y, Sun J, Zhang Q. WTX-L/β-arrestin2/LCN2 axis controls vulnerability to ferroptosis in gastric cancer. iScience 2025; 28:111964. [PMID: 40109379 PMCID: PMC11919608 DOI: 10.1016/j.isci.2025.111964] [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: 07/07/2024] [Revised: 10/20/2024] [Accepted: 02/04/2025] [Indexed: 03/22/2025] Open
Abstract
Gastric cancer (GC) is one of the most prevalent and lethal cancers worldwide. Ferroptosis is a form of iron-dependent regulated cell death emerging as a promising strategy for cancer therapy, whereas the regulation mechanism remains unclear. WTX has been recognized as a potential tumor suppressor, but attempts at targeted therapy have not achieved substantial progress. Further research into the structure, function, and mechanisms is urgently needed. Herein, we identified a long isoform of WTX (WTX-L) as a potent ferroptosis effector in GC. Mechanistically, WTX-L competitively interacts with β-arrestin2, disrupting its direct binding to IκBα and subsequently activating the NF-κB/LCN2 pathway. LCN2 further triggers ferroptosis by significantly increasing the labile Fe2+ pool and promoting excessive lipid peroxidation. Blockade of the WTX-L/β-arrestin2/NF-κB/LCN2 axis significantly diminished the activity of ferroptosis inducers (erastin and RSL3) in vivo. Collectively, these findings reveal that targeting the ferroptosis vulnerabilities through WTX-L may represent a promising strategy for GC.
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Affiliation(s)
- Yangwei Xu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
| | - Xuexia Qian
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
- Department of Pathology, Xijing Hospital, Fourth Military Medical University (Air Force Medical University), Xi'an, Shanxi 710032, China
| | - Guixing Cai
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
- Department of Orthopedic Oncology, Guangdong Provincial People's Hospital, Southern Medical University, Guangzhou, Guangdong 510080, China
| | - Zhihao Lin
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
| | - Weiye Huang
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
| | - Chuangyuan Wang
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, China
| | - Hongmei Wu
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
| | - Yiqiong Zhang
- School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510282, China
| | - Jingbo Sun
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
| | - Qingling Zhang
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
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13
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Nanda AK, Walcott A, Goodnough M, Bernardez-Lai S, Villamil S. Synchronous metastatic malignancy of the prostate and stomach: A case report. Int J Surg Case Rep 2025; 129:111179. [PMID: 40147202 DOI: 10.1016/j.ijscr.2025.111179] [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: 01/24/2025] [Revised: 02/21/2025] [Accepted: 03/17/2025] [Indexed: 03/29/2025] Open
Abstract
INTRODUCTION Gastric cancers are silent malignancies that are typically diagnosed at advanced stages. Similarly, patients with prostate cancer can have an asymptomatic presentation despite widespread metastasis. The insidious nature of both malignancies highlights the importance of implementing appropriate screening protocols for early detection, prompt treatment, and better patient outcomes. PRESENTATION A 66-year-old man presented with unintentional weight loss and early satiety for 3 months and was found to have gastric adenocarcinoma after diagnostic testing. Further imaging demonstrated prostate enlargement and diffuse bony involvement, culminating in the diagnosis of a second primary tumor, prostate adenocarcinoma. A workup of gastric adenocarcinoma revealed metastasis to aortic-pulmonary (level 5) lymph nodes. Gastric outlet obstruction was treated with open gastrojejunostomy. Metastatic prostate cancer was treated with hormonal therapy. DISCUSSION Double primary tumors are rare occurrences and patient care should be optimized using an interdisciplinary care team. Treatment aims to mitigate disease progression, and is influenced by tumor type, anatomical location, and criteria for resectability. CONCLUSION Both gastric and prostate cancer pose significant challenges in both diagnosis and treatment, largely due to its often-asymptomatic nature in early stages and the complexity of its progression.
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Affiliation(s)
- Atul K Nanda
- Humboldt Park Health, Chicago, IL 60622, USA; St. George's University School of Medicine, Grenada.
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14
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Yang D, Zhang X, Hu Z, Sun Q, Fu H, Yao J, Zheng B, Zhang X, Wang W. Organoid-based single cell sequencing revealed the lineage evolution during docetaxel treatment in gastric cancer. Cancer Lett 2025; 619:217617. [PMID: 40118243 DOI: 10.1016/j.canlet.2025.217617] [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: 01/31/2025] [Revised: 03/03/2025] [Accepted: 03/06/2025] [Indexed: 03/23/2025]
Abstract
Docetaxel resistance in gastric cancer poses a major therapeutic challenge. In this study, we established docetaxel-sensitive and -resistant gastric cancer organoids and performed single-cell RNA sequencing to identify cellular and molecular alterations. We observed significant shifts in cell populations, with increased secretory, immune-chemotactic, and transitional gastric cancer cells in the resistant group. Key resistance-related genes, including FOS, IFI27, and PTTG1IP, were upregulated in resistant organoids and gastric cancer patients. A pseudo-time trajectory analysis revealed that resistant cells predominantly occupied terminal differentiation stages. Knocking down FOS, IFI27, and PTTG1IP enhanced docetaxel sensitivity in both cell lines and organoids, regulating ROS production, autophagy, and apoptosis. In vivo, silencing these genes reduced tumor growth in response to docetaxel. These findings suggest that targeting FOS, IFI27, and PTTG1IP could overcome resistance and improve treatment outcomes for gastric cancer patients.
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Affiliation(s)
- Dejun Yang
- Department of Gastrointestinal Surgery, Second Affiliated Hospital (Changzheng Hospital) of Naval Medical University, Huangpu District, No. 415 Fengyang Road, Shanghai, 200003, China.
| | - Xin Zhang
- Department of Gastrointestinal Surgery, First Affiliated Hospital (Changhai Hospital) of Naval Medical University, Yangpu District, No. 168 Changhai Road, Shanghai, 200433, China
| | - Zunqi Hu
- Department of Gastrointestinal Surgery, Second Affiliated Hospital (Changzheng Hospital) of Naval Medical University, Huangpu District, No. 415 Fengyang Road, Shanghai, 200003, China
| | - Qiang Sun
- Department of Gastrointestinal Surgery, Second Affiliated Hospital (Changzheng Hospital) of Naval Medical University, Huangpu District, No. 415 Fengyang Road, Shanghai, 200003, China
| | - Hongbing Fu
- Department of Gastrointestinal Surgery, Second Affiliated Hospital (Changzheng Hospital) of Naval Medical University, Huangpu District, No. 415 Fengyang Road, Shanghai, 200003, China
| | - Jun Yao
- Department of Gastrointestinal Surgery, Second Affiliated Hospital (Changzheng Hospital) of Naval Medical University, Huangpu District, No. 415 Fengyang Road, Shanghai, 200003, China
| | - Binbin Zheng
- Department of Gastrointestinal Surgery, Second Affiliated Hospital (Changzheng Hospital) of Naval Medical University, Huangpu District, No. 415 Fengyang Road, Shanghai, 200003, China
| | - Xin Zhang
- Department of Gastrointestinal Surgery, Second Affiliated Hospital (Changzheng Hospital) of Naval Medical University, Huangpu District, No. 415 Fengyang Road, Shanghai, 200003, China.
| | - Weijun Wang
- Department of Gastrointestinal Surgery, Second Affiliated Hospital (Changzheng Hospital) of Naval Medical University, Huangpu District, No. 415 Fengyang Road, Shanghai, 200003, China.
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15
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Chen P, Chen Z, Sui W, Han W. Recent advances in the mechanisms of PD-L1 expression in gastric cancer: a review. Biol Res 2025; 58:16. [PMID: 40091086 PMCID: PMC11912799 DOI: 10.1186/s40659-025-00597-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 03/07/2025] [Indexed: 03/19/2025] Open
Abstract
In the progression of gastric cancer (GC), various cell types in the tumor microenvironment (TME) exhibit upregulated expression of programmed death ligand 1 (PD-L1), leading to impaired T-cell function and evasion of immune surveillance. Infection with H. pylori and EBV leads to increased PD-L1 expression in various cell types within TME, resulting in immune suppression and facilitating immune escape of GC cells. In the TME, mesenchymal stem cells (MSCs), M1-like tumor-associated macrophages (MI-like TAM), and myeloid-derived suppressor cells (MDSCs) contribute to the upregulation of PD-L1 expression in GC cells. Conversely, mast cells, M2-like tumor-associated macrophages (M2-like TAM), and tumor-associated neutrophils (TANs) exhibit elevated levels of PD-L1 expression in response to the influence of GC cells. Together, these factors collectively contribute to the upregulation of PD-L1 expression in GC. This review aims to provide a comprehensive summary of the cellular expression patterns of PD-L1 in GC and the underlying molecular mechanisms. Understanding the complex regulatory pathways governing PD-L1 expression may offer novel insights for the development of effective immunotherapeutic interventions.
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Affiliation(s)
- Peifeng Chen
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Avenue, Shushan District, Hefei, Anhui Province, 230022, China
| | - Zhangming Chen
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Avenue, Shushan District, Hefei, Anhui Province, 230022, China
| | - Wannian Sui
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Avenue, Shushan District, Hefei, Anhui Province, 230022, China
| | - Wenxiu Han
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Avenue, Shushan District, Hefei, Anhui Province, 230022, China.
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16
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Gemmell JS, Lucke-Wold B. Traditional Chinese medicine and modern technology: Network pharmacology and omics sequencing in gastric cancer. World J Gastrointest Oncol 2025; 17:102077. [PMID: 40092959 PMCID: PMC11866215 DOI: 10.4251/wjgo.v17.i3.102077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 12/10/2024] [Accepted: 01/02/2025] [Indexed: 02/14/2025] Open
Abstract
In this editorial, we comment on the article by Micucci et al published in the recent issue. We focus on the heterogenous nature of gastric cancer (GC) and the potential benefits of integrating traditional Chinese medicine (TCM) with the modern technology of network pharmacology (NP) and omics sequencing. GC is a heterogenous disease, as it incorporates several biochemical pathways that contribute to pathogenesis. TCM acknowledges the multifactorial, heterogenous nature of disease and utilizes an integrative approach to medicine. NP, a modern philosophy within drug development, integrates traditional knowledge of nutraceuticals and modern technologies to address the complex interactions of pathways within the body. Omics technologies, which is at the core of precision medicine, has allowed for this newfound principle of drug development. Metabolic pathways are better distinguished, leading to more targeted drug development. However, the use of omics technology needs to be employed to better characterize the subtypes of GC. This will allow TCM's use of nutraceuticals in the application of NP to better target metabolic pathways that may aid in the prevention of GC as well as enhance treatment.
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Affiliation(s)
| | - Brandon Lucke-Wold
- Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL 32608, United States
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17
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Ji X, Wang G, Pan D, Xu S, Lei X. Efficacy and safety of pembrolizumab in advanced gastric and gastroesophageal junction cancer: a systematic review and meta-analysis. BMC Gastroenterol 2025; 25:173. [PMID: 40087572 PMCID: PMC11908035 DOI: 10.1186/s12876-025-03754-w] [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: 11/26/2024] [Accepted: 03/03/2025] [Indexed: 03/17/2025] Open
Abstract
BACKGROUND Pembrolizumab, a PD-1 inhibitor, has shown potential for treating advanced gastric and gastroesophageal junction (GEJ) cancer. This meta-analysis evaluates its efficacy and safety, alone or combined with chemotherapy, in this population. METHODS A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines. Databases including PubMed, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science were searched up to October 31, 2024. Twelve studies comprising 4,069 patients were included. The primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes included objective response rate (ORR), adverse events (AEs), and grade ≥ 3 AEs. Effect sizes were calculated using mean differences (MDs) and odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS Pembrolizumab combined with chemotherapy significantly improved OS (MD = 1.92 months; 95% CI: 0.94 to 2.91) and ORR (MD = 11.05%; 95% CI: 6.29 to 15.82) compared to chemotherapy alone. Pembrolizumab monotherapy did not show a significant effect on OS (MD = 0.24 months; 95% CI: -1.15 to 1.63) and was associated with a significant reduction in PFS (MD = -2.28 months; 95% CI: -2.85 to -1.71) compared to chemotherapy alone. For safety, pembrolizumab monotherapy significantly reduced the risk of AEs (OR = 0.68; 95% CI: 0.57 to 0.81) and grade ≥ 3 AEs (OR = 0.39; 95% CI: 0.30 to 0.51) compared to chemotherapy. Pembrolizumab combined with chemotherapy did not significantly alter the risk of AEs (OR = 1.01; 95% CI: 0.90 to 1.13) or grade ≥ 3 AEs (OR = 1.12; 95% CI: 0.99 to 1.27) compared to chemotherapy alone. CONCLUSION Pembrolizumab combined with chemotherapy improves survival and response rates with a manageable safety profile in advanced gastric and GEJ cancers. Monotherapy shows limited efficacy, highlighting the need for combination strategies and patient selection.
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Affiliation(s)
- Xiaoying Ji
- Department of Pharmacy, Yiwu Central Hospital, Yiwu, Zhejiang, 322000, China
| | - Guoping Wang
- Department of Pharmacy, Yiwu Central Hospital, Yiwu, Zhejiang, 322000, China
| | - Dandan Pan
- Department of Pharmacy, Yiwu Central Hospital, Yiwu, Zhejiang, 322000, China
| | - Shanxia Xu
- Quzhou Zhong Da Lang Yuan Nursing Home, Quzhou, Zhejiang, 324000, China
| | - Xinming Lei
- The Quzhou Afliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, Zhejiang, 324000, China.
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18
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Yang S, Liu H, Zheng Y, Chu H, Lu Z, Yuan J, Xu S. The Role of PLIN3 in Prognosis and Tumor-Associated Macrophage Infiltration: A Pan-Cancer Analysis. J Inflamm Res 2025; 18:3757-3777. [PMID: 40098998 PMCID: PMC11913039 DOI: 10.2147/jir.s509245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 03/04/2025] [Indexed: 03/19/2025] Open
Abstract
Background Nucleolar and spindle-associated protein 1 (PLIN3), a member of the perilipin family, plays a critical role in lipid droplet dynamics and is implicated in promoting tumor progression across several cancers. However, its influence on the tumor immune microenvironment and its potential as a prognostic indicator regarding immunotherapy responses have yet to be systematically evaluated. This study leverages data retrieved from multiple databases to address these questions. Methods PLIN3 mRNA and protein expressions were analyzed across a diverse range of normal and cancerous tissues, utilizing data retrieved from multiple databases. The potential of PLIN3 as a diagnostic and prognostic biomarker in cancers was assessed. Advanced computational algorithms were employed to examine the impact of PLIN3 on immune cell infiltration. The association between PLIN3 expression and the presence of M2 macrophages was validated through analyses incorporating bulk and single-cell transcriptomics, spatial transcriptomics, and multicolor fluorescence staining techniques. Furthermore, the effects of PLIN3 on tumor malignancy and growth were investigated in vitro in lung adenocarcinoma (LUAD) cells. Potential compounds targeting PLIN3 were identified using the Connectivity Map (cMap) web tool, and their efficacy was further assessed through molecular docking. Results PLIN3 was predominantly upregulated in various cancers, correlating with adverse prognostic outcomes. A strong positive association was observed between PLIN3 levels and M2 macrophage infiltration in several cancer types, establishing it as a potential pan-cancer marker for M2 macrophage presence. This was confirmed by integrative multi-omics analysis and multiple fluorescence staining. Additionally, PLIN3 knockdown in LUAD cells diminished their malignant traits, resulting in decreased proliferation and migration. In LUAD, clofibrate was identified as a potential inhibitor of PLIN3's pro-oncogenic functions. Conclusion PLIN3 may serve as a potential biomarker and oncogene, particularly in LUAD. It plays a key role in mediating M2 macrophage infiltration in various cancers and presents a promising immunotherapeutic target.
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Affiliation(s)
- Shaohua Yang
- Department of General Surgery, Foshan Clinical Medical School, Guangzhou University of Chinese Medicine, Foshan, Guangdong, People’s Republic of China
- Department of General Surgery, Foshan Fosun Chancheng Hospital, Foshan, Guangdong, People’s Republic of China
- Institute of Gastroenterology, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China
| | - Hejie Liu
- Department of Thoracic Surgery, Jiangmen Central Hospital, Jiangmen, Guangdong, People’s Republic of China
| | - Youbin Zheng
- Department of Radiology, Jiangmen Wuyi Hospital of Traditional Chinese Medicine, Jiangmen, Guangdong, People’s Republic of China
| | - Hongyu Chu
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
| | - Zhuming Lu
- Department of Thoracic Surgery, Jiangmen Central Hospital, Jiangmen, Guangdong, People’s Republic of China
| | - Jie Yuan
- Department of General Surgery, Foshan Clinical Medical School, Guangzhou University of Chinese Medicine, Foshan, Guangdong, People’s Republic of China
- Department of General Surgery, Foshan Fosun Chancheng Hospital, Foshan, Guangdong, People’s Republic of China
| | - Shengshan Xu
- Department of Thoracic Surgery, Jiangmen Central Hospital, Jiangmen, Guangdong, People’s Republic of China
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Li N, Zhang Y, Zhang Q, Jin H, Han M, Guo J, Zhang Y. Machine learning reveals glycolytic key gene in gastric cancer prognosis. Sci Rep 2025; 15:8688. [PMID: 40082583 PMCID: PMC11906761 DOI: 10.1038/s41598-025-93512-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 03/07/2025] [Indexed: 03/16/2025] Open
Abstract
Glycolysis is recognized as a central metabolic pathway in the neoplastic evolution of gastric cancer, exerting profound effects on the tumor microenvironment and the neoplastic growth trajectory. However, the identification of key glycolytic genes that significantly affect gastric cancer prognosis remains underexplored. In this work, five machine-learning algorithms were used to elucidate the intimate association between the glycolysis-associated gene phosphofructokinase fructose-bisphosphate 3 (PFKFB3) and the prognosis of gastric cancer patients. Validation across multiple independent datasets confirmed the prognostic significance of PFKFB3. Further, we delved into the functional implications of PFKFB3 in modulating immune responses and biological processes within gastric cancer patients, as well as its broader relevance across multiple cancer types. Results underscore the potential of PFKFB3 as a prognostic biomarker and therapeutic target in gastric cancer. Our project can be found at https://github.com/PiPiNam/ML-GCP .
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Affiliation(s)
- Nan Li
- China Academy of Electronics and Information Technology, National Engineering Research Center for Public Safety Risk Perception and Control by Big Data (RPP), Beijing, China
| | - Yuzhe Zhang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China
| | - Qianyue Zhang
- China Academy of Electronics and Information Technology, National Engineering Research Center for Public Safety Risk Perception and Control by Big Data (RPP), Beijing, China
| | - Hao Jin
- China Academy of Electronics and Information Technology, National Engineering Research Center for Public Safety Risk Perception and Control by Big Data (RPP), Beijing, China
| | - Mengfei Han
- China Academy of Electronics and Information Technology, National Engineering Research Center for Public Safety Risk Perception and Control by Big Data (RPP), Beijing, China
| | - Junhan Guo
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ye Zhang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China.
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20
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Liao Y, Chen X, Xu H, Zhi Y, Zhuo X, Yu J, Zhao L. N6-methyladenosine RNA modified BAIAP2L2 facilitates extracellular vesicles-mediated chemoresistance transmission in gastric cancer. J Transl Med 2025; 23:320. [PMID: 40082986 PMCID: PMC11905699 DOI: 10.1186/s12967-025-06340-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 03/01/2025] [Indexed: 03/16/2025] Open
Abstract
BACKGROUND Extracellular vesicles (EVs) produced in the tumor microenvironment in response to chemotherapy promote chemotherapy-resistant phenotypes. However, the role of EVs proteins induced by gastric cancer (GC) cell chemotherapy in regulating chemotherapy resistance remains unclear. METHODS Immunohistochemistry was used to verify the relationship between brain-specific angiogenesis inhibitor 1-associated protein-2-like protein 2 (BAIAP2L2) expression and chemotherapy resistance in advanced GC. The relationship between BAIAP2L2 and chemotherapy resistance was verified using a subcutaneous tumor model in nude mice. Transmission electron microscopy, nanoparticle tracking analysis, and western blotting were performed to detect purified EVs. Tandem mass tag (TMT) analysis was used to detect differential labels. The interaction between YTH domain-containing family protein1 (YTHDF1) and BAIAP2L2 in GC cells was confirmed by RIP-qPCR analysis using a YTHDF1-specific antibody. RESULTS We found that BAIAP2L2 was associated with chemotherapy resistance to GC in clinical samples and was increased in chemotherapy-resistant GC cells. Mechanistically, BAIAP2L2 promotes the transfer of chemotherapy resistance from resistant GC cells to sensitive cells through EVs proteins, such as ANXA4. Furthermore, ANXA4 promoted platinum-based chemical resistance in GC by mediating autophagy. Interestingly, YTHDF1 facilitates the translation of BAIAP2L2 and ANXA4 through m6A modifications. CONCLUSIONS Our findings reveal the key role of BAIAP2L2 as a potential prognostic marker and therapeutic target for chemotherapy resistance in GC.
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Affiliation(s)
- Yuhan Liao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Pathology &, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xinhua Chen
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hao Xu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Pathology &, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yunfei Zhi
- Department of Gastroenterology, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
| | - Xinghua Zhuo
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Pathology &, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Jiang Yu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Liang Zhao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
- Department of Pathology &, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
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21
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Dai L, Yin J, Xin X, Yao C, Tang Y, Xia X, Chen Y, Lai S, Lu G, Huang J, Zhang P, Li J, Chen X, Zhong X. An interpretable machine learning model based on computed tomography radiomics for predicting programmed death ligand 1 expression status in gastric cancer. Cancer Imaging 2025; 25:31. [PMID: 40075494 PMCID: PMC11905525 DOI: 10.1186/s40644-025-00855-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 03/02/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Programmed death ligand 1 (PD-L1) expression status, closely related to immunotherapy outcomes, is a reliable biomarker for screening patients who may benefit from immunotherapy. Here, we developed and validated an interpretable machine learning (ML) model based on contrast-enhanced computed tomography (CECT) radiomics for preoperatively predicting PD-L1 expression status in patients with gastric cancer (GC). METHODS We retrospectively recruited 285 GC patients who underwent CECT and PD-L1 detection from two medical centers. A PD-L1 combined positive score (CPS) of ≥ 5 was considered to indicate a high PD-L1 expression status. Patients from center 1 were divided into training (n = 143) and validation sets (n = 62), and patients from center 2 were considered a test set (n = 80). Radiomics features were extracted from venous-phase CT images. After feature reduction and selection, 11 ML algorithms were employed to develop predictive models, and their performance in predicting PD-L1 expression status was evaluated using areas under receiver operating characteristic curves (AUCs). SHapley Additive exPlanations (SHAP) were used to interpret the optimal model and visualize the decision-making process for a single individual. RESULTS Nine features significantly associated with PD-L1 expression status were ultimately selected to construct the predictive model. The light gradient-boosting machine (LGBM) model demonstrated the best performance for PD-L1 high expression status prediction in the training, validation, and test sets, with AUCs of 0.841(95% CI: 0.773, 0.908), 0.834 (95% CI:0.729, 0.939), and 0.822 (95% CI: 0.718, 0.926), respectively. The SHAP summary and bar plots illustrated that a feature's value affected the feature's impact attributed to the model. The SHAP waterfall plots were used to visualize the decision-making process for a single individual. CONCLUSION Our CT radiomics-based LGBM model may aid in preoperatively predicting PD-L1 expression status in GC patients, and the SHAP method may improve the interpretability of this model.
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Affiliation(s)
- Lihuan Dai
- Department of Medical Imaging, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China
| | - Jinxue Yin
- Department of Medical Imaging, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China
| | - Xin Xin
- Department of Medical Imaging, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China
| | - Chun Yao
- Department of Radiology, Meizhou People's Hospital, Mei Zhou, 514031, China
| | - Yongfang Tang
- Department of Medical Imaging, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China
| | - Xiaohong Xia
- Department of Pathology, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China
| | - Yuanlin Chen
- Department of Pathology, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China
| | - Shuying Lai
- Department of Radiology, Meizhou People's Hospital, Mei Zhou, 514031, China
| | - Guoliang Lu
- Department of Medical Imaging, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China
| | - Jie Huang
- Department of Medical Imaging, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China
| | - Purong Zhang
- Department of Medical Imaging, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China
| | - Jiansheng Li
- Department of Medical Imaging, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China.
| | - Xiangguang Chen
- Department of Radiology, Meizhou People's Hospital, Mei Zhou, 514031, China.
| | - Xi Zhong
- Department of Medical Imaging, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China.
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22
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Yang S, Jiang Y, Yang Z. Hypoxia-associated genes as predictors of outcomes in gastric cancer: a genomic approach. Front Immunol 2025; 16:1553477. [PMID: 40129974 PMCID: PMC11931070 DOI: 10.3389/fimmu.2025.1553477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 02/21/2025] [Indexed: 03/26/2025] Open
Abstract
Objective To investigate the effects of hypoxia-related genes in stomach adenocarcinoma (STAD) and construct an excellent prognostic model. Methods RNA expression data and clinical details were retrieved from the TCGA and GEO database dataset. scRNA-seq analysis was conducted on primary gastric cancer samples from GSE183904. Cellular hypoxia status was predicted using the CHPF software. WGCNA and GO-BP/KEGG enrichment of module genes analyses were performed to identify gene modules associated with hypoxia and biological pathway enrichment. A prognostic model was developed employing the LassoCox algorithm. GES-1, AGS, BGC823, and MGC803 cell lines were obtained for qRT-PCR analysis to identify the expression of model genes. Results Single-cell atlas within STAD delineated that most of neoplastic cells, fibroblasts, endothelial cells, and myeloid cells were hypoxic. Further analysis of neoplastic cell subpopulations identified four hypoxic subpopulations (H1-H4) and four non-hypoxic subpopulations (N1-N4), with H1 subpopulation had the highest degree of hypoxia. The prognostic model constructed by five H1-specific transcription factors EHF, EIF1AD, GLA, KEAPI, and MAGED2, was demonstrated efficacy in predicting overall survival (OS), with significantly worse OS in high-risk patients. qRT-PCR analysis determined the higher expression level of five H1-specific transcription factors in gastric cancer cell lines than that in normal gastric epithelial cell line. Conclusion Hypoxia exerts a profound influence on STAD due to the overexpression of hypoxic cellular subpopulations-specific transcription factors EHF, EIF1AD, GLA, KEAPI, and MAGED2. The novel prognostic model developed by these hypoxia-associated genes presents a novel approach to risk stratification, exhibiting an excellent prognostic value for STAD patients.
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Affiliation(s)
- Shuo Yang
- Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, China
- NHC Key Laboratory of Congenital Malformation, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yuhao Jiang
- Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhonghua Yang
- Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, China
- NHC Key Laboratory of Congenital Malformation, Shengjing Hospital of China Medical University, Shenyang, China
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23
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Mitea G, Iancu IM, Schröder V, Roșca AC, Iancu V, Crețu RM, Mireșan H. Therapeutic Potential of Prunus Species in Gastrointestinal Oncology. Cancers (Basel) 2025; 17:938. [PMID: 40149274 PMCID: PMC11940452 DOI: 10.3390/cancers17060938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 03/01/2025] [Accepted: 03/06/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Gastrointestinal tract cancers represent a significant worldwide health concern, accounting for almost one-third of cancer-related deaths. The existing chemotherapy drugs used in gastrointestinal cancers are ineffective, so prognosis is poor, recurrence and metastasis rates are high, and survival time remains short, necessitating the development of novel antitumor drugs that exhibit low toxicity and less potential for the development of drug resistance. This challenge is considerable, but evidence from the past decades supports the medicinal properties and functionalities of bioactive compounds such as flavonoids and acid phenolics with anticancer activities. Our purpose was to find data on the relationship between gastrointestinal cancer and bioactive compounds from Prunus species, focusing on their molecular mechanisms of action. RESULTS Studies highlight the potential of bioactive compounds from Prunus species to modulate the cancer cell signaling pathways involved in gastrointestinal tumorigenesis. CONCLUSIONS The studies reviewed suggest that polyphenols from Prunus species exhibit promising gastrointestinal anticancer activities and could represent an adjunctive therapeutic strategy in cancer treatment. Further studies are necessary to validate these compounds' therapeutic potential and their feasibility as cost-effective treatments for cancer.
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Affiliation(s)
- Gabriela Mitea
- Department of Pharmacology, Faculty of Pharmacy, Ovidius University of Constanta, 900470 Constanta, Romania;
| | - Irina Mihaela Iancu
- Department of Toxicology, Faculty of Pharmacy, Ovidius University of Constanta, 900470 Constanta, Romania;
| | - Verginica Schröder
- Department of Cellular and Molecular Biology, Faculty of Pharmacy, Ovidius University of Constanta, 900470 Constanta, Romania
| | - Adrian Cosmin Roșca
- Department of Analysis and Quality Control of Drugs, Faculty of Pharmacy, Ovidius University of Constanta, 900470 Constanta, Romania;
| | - Valeriu Iancu
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Ovidius University of Constanta, 900470 Constanta, Romania;
| | - Ruxandra-Mihaela Crețu
- National Institute of Research and Development for Biological Sciences, “Stejarul” Biological Research Centre, 060031 Bucharest, Romania;
| | - Horațiu Mireșan
- Department of Toxicology, Faculty of Pharmacy, Ovidius University of Constanta, 900470 Constanta, Romania;
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24
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Zhao X, Zhang H, Liu Y, Li L, Wei H. Study on the metastatic mechanism of LINC00115 in adenocarcinoma of the Esophagogastric junction. Hum Mol Genet 2025; 34:492-511. [PMID: 39807637 DOI: 10.1093/hmg/ddae193] [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: 06/15/2024] [Revised: 10/16/2024] [Accepted: 12/16/2024] [Indexed: 01/16/2025] Open
Abstract
Adenocarcinoma of the esophagogastric junction (AEG) is a common and deadly cancer, and an in-depth investigation of its molecular mechanisms of metastasis is crucial for discovering new therapeutic targets. This study explores the role of the long non-coding RNA (lncRNA) LINC00115 in AEG metastasis and its underlying mechanisms. Through the analysis of 108 pairs of AEG cancer tissues and matched adjacent tissues, we found a significant upregulation of LINC00115 in AEG tissues, closely associated with TNM staging and lymph node metastasis. Utilizing cell counting kit-8 (CCK-8) assays, colony formation experiments, wound healing assays, flow cytometry for apoptosis and cell cycle analysis, and Transwell assays, we have confirmed that LINC00115 significantly promotes proliferation, migration, and invasion of AEG cells in vitro. Animal experiments further validate the role of LINC00115 in promoting tumor growth and metastasis in vivo. Additionally, our nuclear-cytoplasmic fractionation experiments and RNA fluorescence in situ hybridization (FISH) reveal that LINC00115, along with its interacting protein KH-Type splicing regulatory protein (KHSRP), predominantly localizes to the cell nucleus. By conducting RNA pull-down assays and mass spectrometry (MS) analysis, we have identified a direct interaction between LINC00115 and KHSRP protein and further determined their binding sites through catRAPID and ENCORI databases. This study provides evidence of LINC00115 as a novel biomarker and potential therapeutic target for AEG and offers a fresh perspective on understanding the molecular mechanisms of AEG metastasis.
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Affiliation(s)
- Xia Zhao
- Department of Gastroenterology, Huaihe Hospital of Henan University, No. 8, Baobei Road, Gulou District, Kaifeng City, Henan Province, China
| | - Haifeng Zhang
- Department of Thoracic Surgery, Huaihe Hospital of Henan University, No. 8, Baobei Road, Gulou District, Kaifeng City, Henan Province, China
| | | | - Li Li
- Department of Thoracic Surgery, Huaihe Hospital of Henan University, No. 8, Baobei Road, Gulou District, Kaifeng City, Henan Province, China
- Department of Thoracic Surgery, Huaihe Hospital of Henan University/Henan University School of Nursing and Health, No. 8, Baobei Road, Gulou District, Kaifeng City, Henan Province, China
| | - Haitao Wei
- Department of Thoracic Surgery, Huaihe Hospital of Henan University, No. 8, Baobei Road, Gulou District, Kaifeng City, Henan Province, China
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25
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Cheng CY, Chen YL, Ho H, Huang CY, Chu SE, Liang YJ. Prognostic Significance of DNAJB4 Expression in Gastric Cancer: Correlation with CD31, Caspase-3, and Tumor Progression. Diagnostics (Basel) 2025; 15:652. [PMID: 40149995 PMCID: PMC11941126 DOI: 10.3390/diagnostics15060652] [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: 10/10/2024] [Revised: 02/28/2025] [Accepted: 03/03/2025] [Indexed: 03/29/2025] Open
Abstract
Background/Objectives: Gastric cancer is one of the most common and lethal cancers worldwide, with particularly high incidence and mortality rates in East Asia and Europe. DNAJB4 has been shown to have prognostic implications in other cancer types; however, its expression patterns and role in gastric cancer have not been extensively studied. This study aimed to analyze DNAJB4 expression in gastric cancer and explore its association with clinical characteristics, molecular markers, and patient outcomes. Methods: We selected suitable tumor samples from 189 gastric cancer patients who had not undergone chemotherapy or radiotherapy, with 188 patients ultimately included in the analysis. Tissue microarray and immunohistochemistry were used to evaluate DNAJB4 expression, and the samples were divided into high- and low-expression groups based on the H-score. Multivariate logistic regression and survival analysis were conducted to identify influencing factors. Results: High DNAJB4 expression was significantly correlated with increased CD31 levels but was inversely associated with advanced cancer stages. Subgroup analysis revealed that in patients with advanced gastric cancer, high DNAJB4 expression was associated with increased caspase-3 levels and with elevated CD31 and decreased E-cadherin levels. Conclusions: High DNAJB4 expression was associated with both angiogenesis and apoptosis, indicating its complex role in gastric cancer progression. Although DNAJB4 promoted angiogenesis by increasing CD31 levels, it may also enhance apoptosis in tumor cells through caspase-3-induced apoptosis.
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Affiliation(s)
- Chiao-Yin Cheng
- Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, New Taipei 242062, Taiwan; (C.-Y.C.); (C.-Y.H.)
- Department of Emergency Medicine, Far Eastern Memorial Hospital, New Taipei 220216, Taiwan; (H.H.); (S.-E.C.)
| | - Yen-Lin Chen
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114201, Taiwan;
| | - Hua Ho
- Department of Emergency Medicine, Far Eastern Memorial Hospital, New Taipei 220216, Taiwan; (H.H.); (S.-E.C.)
| | - Chun-Yen Huang
- Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, New Taipei 242062, Taiwan; (C.-Y.C.); (C.-Y.H.)
- Department of Emergency Medicine, Far Eastern Memorial Hospital, New Taipei 220216, Taiwan; (H.H.); (S.-E.C.)
| | - Sheng-En Chu
- Department of Emergency Medicine, Far Eastern Memorial Hospital, New Taipei 220216, Taiwan; (H.H.); (S.-E.C.)
- Department of Emergency Medicine, National Taiwan University Hospital, Yun-Lin Branch, Douliu City 640203, Taiwan
| | - Yao-Jen Liang
- Graduate Institute of Applied Science and Engineering, Fu-Jen Catholic University, New Taipei 242062, Taiwan; (C.-Y.C.); (C.-Y.H.)
- Department and Institute of Life Science, Fu-Jen Catholic University, New Taipei 242062, Taiwan
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Chen X, He Z, Zhao C, Wu K, Zhu Q, Fu Y, Pan Y, Fan Y, Yang S, Zeng Y, Luo S, Liu L, Du F, Zhou X. Construction and validation of a nomogram based on the log odds of positive lymph nodes to predict the prognosis of T1 gastric cancer. Sci Rep 2025; 15:7788. [PMID: 40044765 PMCID: PMC11882822 DOI: 10.1038/s41598-025-91265-9] [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] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 02/19/2025] [Indexed: 03/09/2025] Open
Abstract
In patients with gastric cancer (GC), metastatic progression through the lymphatic, haematogenous, peritoneal, and ovarian routes is the ultimate cause of death. We developed a nomogram to estimate cancer-specific survival (CSS) in patients with T1 gastric cancer based on log odds of positive lymph nodes (LODDS). A total of 2,221 patients from the Surveillance, Epidemiology, and End Results (SEER) database were split into training and internal validation cohorts, while an external validation cohort included 165 patients from our hospital. Multivariate Cox regression analysis revealed that age, sex, tumour size, LODDS score, and M stage were independent prognostic factors for CSS. The LODDS outperformed the N stage and positive lymph node (PLN) count in terms of predictive ability and is recognised as an independent prognostic factor for nomogram construction. In the training and internal and external validation sets, the 1-year AUCs of the columniogram were 0.732, 0.672, and 0.719, respectively. The 3-year AUCs were 0.705, 0.692, and 0.638, respectively. The 5-year AUCs were 0.726, 0.698, and 0.713, respectively, indicating good predictive power. The calibration curve revealed that the predicted survival rate was consistent with the actual survival rate in the three groups. The ROC and DCA demonstrated that the nomogram has more potential in predicting prognosis than the existing AJCC staging system. We constructed and validated a novel nomogram leveraging LODDS, which effectively estimates the CSS at 1, 3, and 5 years for individuals with gastric cancer.
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Affiliation(s)
- Xiaqin Chen
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Zhijie He
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Caiqing Zhao
- The Third Clinical Medical College of Nanchang University, Nanchang, China
| | - Kaini Wu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Qi Zhu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yunfeng Fu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yating Pan
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yuanping Fan
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Sicheng Yang
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yonghua Zeng
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Shicheng Luo
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Lihua Liu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Fan Du
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
- Postdoctoral Innovation Practice Base, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, People's Republic of China.
| | - Xiaodong Zhou
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
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Carpio AR, Talubo ND, Tsai PW, Chen BY, Tayo LL. Berries as Nature's Therapeutics: Exploring the Potential of Vaccinium Metabolites in Gastric Cancer Treatment Through Computational Insights. Life (Basel) 2025; 15:406. [PMID: 40141751 PMCID: PMC11944152 DOI: 10.3390/life15030406] [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: 01/20/2025] [Revised: 03/02/2025] [Accepted: 03/03/2025] [Indexed: 03/28/2025] Open
Abstract
Berries from the Vaccinium genus, known for their rich array of bioactive metabolites, are recognized for their antioxidant, anti-inflammatory, and anticancer properties. These compounds, including anthocyanins, flavonoids, and phenolic acids, have attracted significant attention for their potential health benefits, particularly in cancer prevention and treatment. Gastric cancer (GC), a leading cause of cancer-related deaths worldwide, remains challenging to treat, especially in its advanced stages. This study investigates the therapeutic potential of Vaccinium species in GC treatment using computational methods. RNA sequencing revealed upregulated genes associated with GC, while network pharmacology and molecular docking approaches identified strong interactions between cyanidin 3-O-glucoside (C3G), a key bioactive metabolite. Furthermore, molecular dynamics simulations of the HSP90AA1-C3G complex demonstrated stable binding and structural integrity, suggesting that C3G may inhibit HSP90AA1, a protein involved in cancer progression. These findings highlight the therapeutic potential of Vaccinium metabolites, offering a novel approach to GC treatment by targeting key molecular pathways. This research provides valuable insights into the role of berries as natural therapeutics, supporting their integration into future gastric cancer treatment strategies.
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Affiliation(s)
- Angelica Rachel Carpio
- School of Chemical, Biological, and Materials Engineering and Sciences, School of Graduate Studies, Mapúa University, Manila 1002, Philippines; (A.R.C.); (N.D.T.)
| | - Nicholas Dale Talubo
- School of Chemical, Biological, and Materials Engineering and Sciences, School of Graduate Studies, Mapúa University, Manila 1002, Philippines; (A.R.C.); (N.D.T.)
| | - Po-Wei Tsai
- Department of Food Science, National Taiwan Ocean University, Keelung 202, Taiwan;
| | - Bor-Yann Chen
- Department of Chemical and Materials Engineering, National I-Lan University, I-Lan 260, Taiwan
| | - Lemmuel L. Tayo
- Department of Biology, School of Health Sciences, Mapúa University, Makati 1200, Philippines
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Y M, L D. Gastric cancer peritoneal metastasis: a bibliometric study from 2000 to 2024 using VOSviewer software. Front Oncol 2025; 15:1489043. [PMID: 40104504 PMCID: PMC11913700 DOI: 10.3389/fonc.2025.1489043] [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: 08/31/2024] [Accepted: 02/13/2025] [Indexed: 03/20/2025] Open
Abstract
Background Gastric cancer remains a prevalent malignancy worldwide, with peritoneal metastasis being the predominant form of recurrence and metastasis, which are clear predictors of prognosis. The aim of this comprehensive bibliometric analysis was to assess the current status of the research landscape and to identify impending trends in gastric cancer peritoneal metastasis (GCPM). Methods Relevant studies of GCPM were retrieved from the Web of Science Core Collection database. Qualified articles were screened based on the inclusion and exclusion criteria for further analysis. The selected publications were then subjected to bibliometric analysis utilizing VOSviewer software. Results In total, 1,100 publications were included for analysis. The results revealed a consistent upward trend in the number of publications annually from 2000 to 2024, with an anticipated continuation of this growth in future research. The National Cancer Center Japan, emerged as the institution with the most publications and Professor Kodera and Annals of Surgical Oncology were identified as the most influential author and journal, respectively, in the domain of GCPM. In terms of international collaborations, the USA, Japan, and France were the most engaged countries. Yonemura was recognized as the most frequently cited author. Gastrectomy, systemic chemotherapy, and intraperitoneal therapy are the current research hotspots within this domain. Conclusion Research related to GCPM had rapidly increased over the past two decades. These findings identify the most influential countries, institutions, authors, journals, and academic collaboration networks, while also clarifying hotspots and future trends in GCPM research.
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Affiliation(s)
- Manting Y
- College of Integrative Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Dongfang L
- Hunan Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
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Yu Y, Liu D, Xie J, Feng Z, Huang X, Li H, Xie Y, Zhou X. Clinical significance and immune landscape analyses of the coagulation-related gene signatures in gastric cancer. J Cancer 2025; 16:1971-1986. [PMID: 40092689 PMCID: PMC11905418 DOI: 10.7150/jca.104221] [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: 09/26/2024] [Accepted: 12/16/2024] [Indexed: 03/19/2025] Open
Abstract
Gastric cancer (GC) is one of the most common types of clinically malignant tumors and a global health challenge due to its high mortality and poor prognosis. The coagulation cascade is closely related to GC and plays a key role in the tumor immune microenvironment. However, the specific mechanisms by which coagulation-related genes involved in the occurrence and development of GC remains unclear. The data of GC patients and coagulation-related genes were obtained from the TCGA and the GSEA databases, respectively. After univariate Cox regression analysis, the non-negative matrix factorization method was used to identify coagulation-related molecular subtypes. GC patients were categorized into high-risk and low-risk score groups based on median risk scores, which included six genes (PCDHAC1, HABP2, GPC3, GFRA1, F5, and DKK1). There was a significant difference in survival between the two groups, and the predictive abilities for 1-, 3-, and 5-year survival were valid. Here, we demonstrated that coagulation-related gene signatures are valuable in predicting the survival of GC patients. Besides, the high- and low-risk grouping also better reflects the status of tumor mutation burden and the characteristics of tumor immune infiltration in GC, which provides a theoretical basis for individualized chemotherapy and immunotherapy for GC patients.
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Affiliation(s)
| | | | | | | | | | | | - Yong Xie
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Province, China
| | - Xiaojiang Zhou
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Province, China
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Wang J, Zhou M, Zhou Q, Sun G, Zhang Y, Tao F, Ye M. Beta-sitosterol regulates PTGS1 to inhibit gastric cancer cell proliferation and angiogenesis. Prostaglandins Other Lipid Mediat 2025; 177:106964. [PMID: 39863019 DOI: 10.1016/j.prostaglandins.2025.106964] [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: 11/04/2024] [Revised: 01/13/2025] [Accepted: 01/21/2025] [Indexed: 01/27/2025]
Abstract
BACKGROUND Gastric cancer (GC) is the third leading culprit of cancer-related deaths around the world. Beta-sitosterol (BS) is an important phytosterol that has been proven to have anti-proliferative effects on GC and other tumors. However, mechanisms and targets of BS in cancer are rarely explored. METHODS In this investigation, the targets of BS in the treatment of GC were analyzed by network pharmacology. Molecular docking and cellular thermal shift assay were introduced to validate the binding relationship between BS and PTGS1. The impacts of BS on GC cell viability, half maximal inhibitory concentration, proliferation ability, apoptosis level, and angiogenesis ability were detected by using Cell Counting Kit-8, clone formation assay, flow cytometry, and angiogenesis experiment, respectively. In addition, the expression levels of angiogenic factors (VEGF, FGF, PAI-1) were detected by using western blot. RESULTS In this project, through cell experiments, PTGS1 was identified as a protein that directly binds to BS. In vitro cell experiments revealed that BS promoted apoptosis and inhibited GC cell proliferation and angiogenesis. Importantly, treatment with BS attenuated the promoting influence of PTGS1 overexpression on GC cell proliferation and angiogenesis. CONCLUSION This investigation highlighted PTGS1 as the target of BS in GC cells. BS can regulate PTGS1 to inhibit GC cell proliferation and angiogenesis, providing new evidence for the potential use of BS as a therapeutic agent for GC.
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Affiliation(s)
- Jindao Wang
- Department of Endoscopy Center, Shaoxing People's Hospital, Shaoxing 312000, China
| | - Minghui Zhou
- Department of Gastrointestinal Surgery, Shaoxing People's Hospital, Shaoxing 312000, China
| | - Qiuli Zhou
- Department of Gastrointestinal Surgery, Shaoxing People's Hospital, Shaoxing 312000, China
| | - Guangyang Sun
- Department of Gastrointestinal Surgery, Shaoxing People's Hospital, Shaoxing 312000, China
| | - Yu Zhang
- Department of Gastrointestinal Surgery, Shaoxing People's Hospital, Shaoxing 312000, China
| | - Feng Tao
- Department of Gastrointestinal Surgery, Shaoxing People's Hospital, Shaoxing 312000, China
| | - Minfeng Ye
- Department of Gastrointestinal Surgery, Shaoxing People's Hospital, Shaoxing 312000, China.
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Zhong B, Du J, Liu F, Sun S. The Role of Yes-Associated Protein in Inflammatory Diseases and Cancer. MedComm (Beijing) 2025; 6:e70128. [PMID: 40066231 PMCID: PMC11892025 DOI: 10.1002/mco2.70128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 02/02/2025] [Accepted: 02/11/2025] [Indexed: 03/17/2025] Open
Abstract
Yes-associated protein (YAP) plays a central role in the Hippo pathway, primarily governing cell proliferation, differentiation, and apoptosis. Its significance extends to tumorigenesis and inflammatory conditions, impacting disease initiation and progression. Given the increasing relevance of YAP in inflammatory disorders and cancer, this study aims to elucidate its pathological regulatory functions in these contexts. Specifically, we aim to investigate the involvement and molecular mechanisms of YAP in various inflammatory diseases and cancers. We particularly focus on how YAP activation, whether through Hippo-dependent or independent pathways, triggers the release of inflammation and inflammatory mediators in respiratory, cardiovascular, and digestive inflammatory conditions. In cancer, YAP not only promotes tumor cell proliferation and differentiation but also modulates the tumor immune microenvironment, thereby fostering tumor metastasis and progression. Additionally, we provide an overview of current YAP-targeted therapies. By emphasizing YAP's role in inflammatory diseases and cancer, this study aims to enhance our understanding of the protein's pivotal involvement in disease processes, elucidate the intricate pathological mechanisms of related diseases, and contribute to future drug development strategies targeting YAP.
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Affiliation(s)
- Bing Zhong
- Department of Otolaryngology‐Head and Neck SurgeryWest China HospitalSichuan UniversityChengduSichuanChina
| | - Jintao Du
- Department of Otolaryngology‐Head and Neck SurgeryWest China HospitalSichuan UniversityChengduSichuanChina
| | - Feng Liu
- Department of Otolaryngology‐Head and Neck SurgeryWest China HospitalSichuan UniversityChengduSichuanChina
| | - Silu Sun
- State Key Laboratory of Oral DiseasesNational Clinical Research Center for Oral DiseasesChinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and ManagementWest China Hospital of StomatologySichuan UniversityChengduSichuanChina
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Liao Y, Chen X, Hu S, Chen B, Zhuo X, Xu H, Wu X, Zeng X, Zeng H, Zhang D, Zhi Y, Zhao L. Artificial Intelligence for Predicting HER2 Status of Gastric Cancer Based on Whole-Slide Histopathology Images: A Retrospective Multicenter Study. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2408451. [PMID: 39792693 PMCID: PMC11904990 DOI: 10.1002/advs.202408451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 12/15/2024] [Indexed: 01/12/2025]
Abstract
Human epidermal growth factor receptor 2 (HER2) positive gastric cancer (GC) shows a robust response to the combined therapy based HER2-targeted therapy. The application of these therapies is highly dependent on the evaluation of tumor HER2 status. However, there are many risks and challenges in HER2 assessment in GC. Therefore, an economically viable and readily available instrument is requisite for distinguishing HER2 status among patients diagnosed with GC. The study has innovatively developed a deep learning model, HER2Net, which can predict the HER2 status by quantitatively calculating the proportion of HER2 high-expression regions. The HER2Net is trained on an internal training set derived from 531 hematoxylin & eosin (H&E) whole slide images (WSI) of 520 patients. Subsequently, the performance of HER2Net is validated on an internal test set from 115 H&E WSI of 111 patients and an external multi-center test set from 102 H&E WSI of 101 patients. The HER2Net achieves an accuracy of 0.9043 on the internal test set, and an accuracy of 0.8922 on an external test set from multiple institutes. This discovery indicates that the HER2Net can potentially offer a novel methodology for the identification of HER2-positive GC.
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Affiliation(s)
- Yuhan Liao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Xinhua Chen
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Shupeng Hu
- School of Computer Science, University of Manchester, Manchester, M13 9PL, UK
| | - Bing Chen
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Xinghua Zhuo
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Hao Xu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Xiaojin Wu
- Department of Pathology, Shunde Hospital of Southern Medical University (The First People's Hospital of Shunde), Foshan, Guangdong, 528399, China
| | - Xiaofeng Zeng
- Department of Pathology, Shunde Hospital of Southern Medical University (The First People's Hospital of Shunde), Foshan, Guangdong, 528399, China
| | - Huimin Zeng
- Department of Pathology, Shunde Hospital of Southern Medical University (The First People's Hospital of Shunde), Foshan, Guangdong, 528399, China
| | - Donghui Zhang
- Department of Pathology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, China
| | - Yunfei Zhi
- Department of Gastroenterology, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, 100730, China
| | - Liang Zhao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
- Department of Pathology, Shunde Hospital of Southern Medical University (The First People's Hospital of Shunde), Foshan, Guangdong, 528399, China
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Raimondi A, Lonardi S, Murgioni S, Cardellino GG, Tamberi S, Strippoli A, Palermo F, De Manzoni G, Bencivenga M, Bittoni A, Chiodoni C, Lorenzini D, Todoerti K, Manca P, Sangaletti S, Prisciandaro M, Randon G, Nichetti F, Bergamo F, Brich S, Belfiore A, Bertolotti A, Stetco D, Guidi A, Torelli T, Vingiani A, Joshi RP, Khoshdeli M, Beaubier N, Stumpe MC, Nappo F, Leone AG, Pircher CC, Leoncini G, Sabella G, Airo' Farulla L, Alessi A, Morano F, Martinetti A, Niger M, Fassan M, Di Maio M, Kaneva K, Milione M, Nimeiri H, Sposito C, Agnelli L, Mazzaferro V, Di Bartolomeo M, Pietrantonio F. Tremelimumab and durvalumab as neoadjuvant or non-operative management strategy of patients with microsatellite instability-high resectable gastric or gastroesophageal junction adenocarcinoma: the INFINITY study by GONO. Ann Oncol 2025; 36:285-296. [PMID: 39637944 DOI: 10.1016/j.annonc.2024.11.016] [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: 10/15/2024] [Revised: 11/22/2024] [Accepted: 11/27/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND In resectable gastric/gastroesophageal junction adenocarcinoma, microsatellite instability-high (MSI-H) confers improved survival, but limited benefit from chemotherapy. Immunotherapy may eliminate the need for chemotherapy or surgery. PATIENTS AND METHODS INFINITY is a multicenter, multicohort phase II trial (NCT04817826) investigating in cohort 1 the activity and safety of tremelimumab + durvalumab (T300/D) as neoadjuvant treatment of mismatch repair deficient/MSI-H, resectable gastric/gastroesophageal junction adenocarcinoma. Primary endpoint was pathologic complete response (pCR) rate; Secondary endpoints: progression-free survival (PFS), overall survival (OS), quality of life, and translational analyses. In cohort 2, the activity and safety of T300/D was explored as definitive treatment in patients achieving clinical complete response (cCR). Primary endpoint was 2-year cCR rate, and secondary endpoints were PFS, OS, quality of life, gastrectomy-free survival and translational analyses. RESULTS In cohort 1, 18 patients were recruited and 15 evaluable. pCR and major pathologic response-pCR were 60% and 80%, respectively. Since pCR rate in T4 tumors was 17%, this subgroup of patients was excluded from enrollment in cohort 2. At 28.1 months median follow-up, 24-month gastric cancer-specific PFS and OS rates were 85% and 92%, respectively. In cohort 2, 18 patients were enrolled and 17 assessable, and 13 had cCR and started non-operative management. At 11.5 months median follow-up, one patient had local regrowth and underwent salvage surgery; 12-month gastrectomy-free survival was 64.2%. CONCLUSIONS The INFINITY study provided promising activity results of a chemo-free T300/D combination regimen as preoperative treatment in mismatch repair deficient/MSI gastric/gastroesophageal junction adenocarcinoma and the first available feasibility results of a non-operative management strategy in this disease setting, worthy of further validation in larger cohorts.
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Affiliation(s)
- A Raimondi
- Department of Medical Oncology, Istituto Nazionale Tumori IRCCS Milan, Milan, USA
| | - S Lonardi
- Medical Oncology 3, Veneto Institute of Oncology IOV - IRCCS, Padua, USA
| | - S Murgioni
- Medical Oncology 1, Veneto Institute of Oncology IOV - IRCCS, Padua, USA
| | - G G Cardellino
- Department of Oncology, Presidio Ospedaliero "Santa Maria della Misericordia"-ASUFC, Udine, USA
| | - S Tamberi
- Oncology Unit, Ravenna Hospital, AUSL Romagna, Ravenna, USA
| | - A Strippoli
- Medical Oncology Unit, Policlinico Universitario A. Gemelli, Rome, USA
| | - F Palermo
- Department of Medical Oncology, Istituto Nazionale Tumori IRCCS Milan, Milan, USA
| | - G De Manzoni
- Department of Surgery, Azienda Ospedaliero Universitaria Integrata di Verona-Borgo Trento, Verona, USA
| | - M Bencivenga
- Department of Surgery, Azienda Ospedaliero Universitaria Integrata di Verona-Borgo Trento, Verona, USA
| | - A Bittoni
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, USA
| | - C Chiodoni
- Molecular Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, USA
| | - D Lorenzini
- Department of Diagnostic Innovation, Istituto Nazionale Tumori IRCCS, Milan, USA
| | - K Todoerti
- Department of Diagnostic Innovation, Istituto Nazionale Tumori IRCCS, Milan, USA
| | - P Manca
- Department of Medical Oncology, Istituto Nazionale Tumori IRCCS Milan, Milan, USA
| | - S Sangaletti
- Molecular Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, USA
| | - M Prisciandaro
- Department of Medical Oncology, Istituto Nazionale Tumori IRCCS Milan, Milan, USA
| | - G Randon
- Department of Medical Oncology, Istituto Nazionale Tumori IRCCS Milan, Milan, USA
| | - F Nichetti
- Department of Medical Oncology, Istituto Nazionale Tumori IRCCS Milan, Milan, USA
| | - F Bergamo
- Medical Oncology 1, Veneto Institute of Oncology IOV - IRCCS, Padua, USA
| | - S Brich
- Department of Diagnostic Innovation, Istituto Nazionale Tumori IRCCS, Milan, USA
| | - A Belfiore
- Department of Diagnostic Innovation, Istituto Nazionale Tumori IRCCS, Milan, USA
| | - A Bertolotti
- Department of Diagnostic Innovation, Istituto Nazionale Tumori IRCCS, Milan, USA
| | - D Stetco
- Department of Diagnostic Innovation, Istituto Nazionale Tumori IRCCS, Milan, USA
| | - A Guidi
- Department of Diagnostic Innovation, Istituto Nazionale Tumori IRCCS, Milan, USA
| | - T Torelli
- Department of Diagnostic Innovation, Istituto Nazionale Tumori IRCCS, Milan, USA
| | - A Vingiani
- Department of Diagnostic Innovation, Istituto Nazionale Tumori IRCCS, Milan, USA
| | | | | | | | | | - F Nappo
- Medical Oncology 1, Veneto Institute of Oncology IOV - IRCCS, Padua, USA
| | - A G Leone
- Department of Medical Oncology, Istituto Nazionale Tumori IRCCS Milan, Milan, USA
| | - C C Pircher
- Department of Medical Oncology, Istituto Nazionale Tumori IRCCS Milan, Milan, USA
| | - G Leoncini
- Department of Diagnostic Innovation, Istituto Nazionale Tumori IRCCS, Milan, USA
| | - G Sabella
- Department of Diagnostic Innovation, Istituto Nazionale Tumori IRCCS, Milan, USA
| | - L Airo' Farulla
- Division of Nuclear Medicine, Istituto Nazionale Tumori IRCCS Milan, Milan, Italy
| | - A Alessi
- Division of Nuclear Medicine, Istituto Nazionale Tumori IRCCS Milan, Milan, Italy
| | - F Morano
- Department of Medical Oncology, Istituto Nazionale Tumori IRCCS Milan, Milan, USA
| | - A Martinetti
- Department of Medical Oncology, Istituto Nazionale Tumori IRCCS Milan, Milan, USA
| | - M Niger
- Department of Medical Oncology, Istituto Nazionale Tumori IRCCS Milan, Milan, USA
| | - M Fassan
- School of Medicine and Surgery, University of Padua, Padua, Italy
| | - M Di Maio
- Department of Oncology, University of Turin, at Le Molinette Hospital, Turin, Italy
| | | | - M Milione
- Department of Diagnostic Innovation, Istituto Nazionale Tumori IRCCS, Milan, USA
| | | | - C Sposito
- Department of Oncology, University of Milan and G.I. Surgery, Istituto Nazionale Tumori IRCCS Milan, Milan, Italy
| | - L Agnelli
- Department of Medical Oncology, Istituto Nazionale Tumori IRCCS Milan, Milan, USA; Department of Diagnostic Innovation, Istituto Nazionale Tumori IRCCS, Milan, USA
| | - V Mazzaferro
- Department of Oncology, University of Milan and G.I. Surgery, Istituto Nazionale Tumori IRCCS Milan, Milan, Italy
| | - M Di Bartolomeo
- Department of Medical Oncology, Istituto Nazionale Tumori IRCCS Milan, Milan, USA
| | - F Pietrantonio
- Department of Medical Oncology, Istituto Nazionale Tumori IRCCS Milan, Milan, USA.
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Cai X, Li X, Zhang M, Dong Z, Weng Y, Yu W. RBM15 promotes lipogenesis and malignancy in gastric cancer by regulating N6-Methyladenosine modification of ACLY mRNA in an IGF2BP2-dependent manner. Biochim Biophys Acta Mol Cell Biol Lipids 2025; 1870:159580. [PMID: 39549859 DOI: 10.1016/j.bbalip.2024.159580] [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: 10/08/2024] [Revised: 10/29/2024] [Accepted: 11/13/2024] [Indexed: 11/18/2024]
Abstract
N6-methyladenosine (m6A) and lipid metabolism reprogramming play pivotal roles in cancer development. Nevertheless, the precise functions of m6A methyltransferase RNA Binding Motif Protein 15 (RBM15) and its interactions with ATP Citrate Lyase (ACLY) in gastric cancer (GC) have not been fully elucidated. In this study, we comprehensively investigate the biological roles and potential mechanisms of RBM15 and ACLY in GC. We employed a combination of fundamental experiments and bioinformatics analyses to unravel the enigmatic roles of RBM15 and ACLY. The expression of RBM15 was evaluated. The biological roles of RBM15 in GC cells were investigated through in vitro and in vivo studies. ACLY was selected as the candidate target of RBM15. Subsequently, to decipher the underlying mechanisms of the RBM15/ACLY axis, we conducted a series of experiments including methylated RNA immunoprecipitation qPCR, dual-luciferase reporter assays, and RNA immunoprecipitation qPCR. We observed a conspicuous upregulation of RBM15 in GC, and its heightened expression was associated with an unfavorable prognosis. Functionally, RBM15 fostered the proliferation and invasiveness of GC cells both in vitro and in vivo. Mechanistically, ACLY emerged as the downstream target of RBM15 and it was validated as an oncogene in GC cells. RBM15 mediated the activation of ACLY by regulating m6A modification in an IGF2BP2-dependent manner, thereby driving lipogenesis and exacerbating the malignant characteristics in GC. The activation of ACLY, facilitated by RBM15/IGF2BP2-mediated m6A modification, drives lipogenesis and promotes the progression of GC.
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Affiliation(s)
- Xianlei Cai
- Department of Gastrointestinal Surgery, The Lihuili Affiliated Hospital, Ningbo University, Ningbo, Zhejiang 315000, China.
| | - Xueying Li
- Department of Gastroenterology, The First Affiliated Hospital, Ningbo University, Ningbo, Zhejiang 315000, China
| | - Miaozun Zhang
- Department of Gastrointestinal Surgery, The Lihuili Affiliated Hospital, Ningbo University, Ningbo, Zhejiang 315000, China
| | - Zhebin Dong
- Department of Gastrointestinal Surgery, The Lihuili Affiliated Hospital, Ningbo University, Ningbo, Zhejiang 315000, China
| | - Yihui Weng
- Department of Gastrointestinal Surgery, The Lihuili Affiliated Hospital, Ningbo University, Ningbo, Zhejiang 315000, China
| | - Weiming Yu
- Department of Gastrointestinal Surgery, The Lihuili Affiliated Hospital, Ningbo University, Ningbo, Zhejiang 315000, China.
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Wei R, Song J, Liu C, Zhao Z, Liu X, Yamamoto M, Tsukamoto T, Nomura S, Liu F, Wang Y, Liu X. FAP upregulates PD-L1 expression in cancer-associated fibroblasts to exacerbate T cells dysfunction and suppress anti-tumor immunity. Cancer Lett 2025; 612:217475. [PMID: 39828123 DOI: 10.1016/j.canlet.2025.217475] [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: 07/16/2024] [Revised: 01/13/2025] [Accepted: 01/17/2025] [Indexed: 01/22/2025]
Abstract
FAP-positive cancer-associated fibroblasts (CAFs), recognized as a critical subset of CAFs, have been implicated in fostering an immunosuppressive tumor microenvironment in various cancers. However, their potential mechanisms of immunosuppression, particularly in modulating T cells, remain elusive. In this study, multiple internal cohorts consisting of 328 patients as well as 5 external cohorts were integrated to delineate the association between unfavorable prognosis or therapeutic resistance and FAP+ CAFs in gastric cancer patients. Subsequently, using in vivo mice models and in vitro co-culture system, we found that elevated infiltration levels of FAP+ CAF exacerbated immunosuppression in the tumor microenvironment by facilitating CD8+ T cells dysfunction. Mechanistically, FAP impeded the degradation of STAT1 protein in CAFs, thereby sustaining PD-L1 transcription and fostering T cell exhaustion. Treatment with PD-L1 neutralizing antibodies effectively attenuated FAP-mediated immunosuppression, restoring anti-tumor immunity of T cells. Overall, our findings underscore the vital role of FAP+ CAFs in directly suppressing T cell-mediated anti-tumor immunity via PD-L1 upregulation, paving the way for the development of FAP-targeted therapies in clinical settings.
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Affiliation(s)
- Rongyuan Wei
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Junquan Song
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chenchen Liu
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Zhenxiong Zhao
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Xuanjun Liu
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Masami Yamamoto
- Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Tetsuya Tsukamoto
- Department of Diagnostic Pathology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Sachiyo Nomura
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Fenglin Liu
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China.
| | - Yanong Wang
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China.
| | - Xiaowen Liu
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China.
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Fan H, Ren C, Feng Y, Zhu L, Yu A, Guan T. A Systematic Review of the Phytochemical Profile and Potential Medicinal Functions of Codonopsis pilosula in Cancer. Food Sci Nutr 2025; 13:e70054. [PMID: 40008240 PMCID: PMC11848418 DOI: 10.1002/fsn3.70054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 01/25/2025] [Accepted: 02/04/2025] [Indexed: 02/27/2025] Open
Abstract
As a valuable medicine and food homology plant suitable for people of all ages, Codonopsis pilosula has been used for dietary nourishment and medicinal purposes with high acceptance for a long history. Interest in the potential anticancer functions of C. pilosula has increased due to its numerous chemical constituents with diverse structures and extensive pharmacological activities. With the growing interest, C. pilosula-based antitumor traditional Chinese medicine (TCM) formulations are also considered as vital intervention strategy for cancer, which exhibit prospective antitumor potential with multiple targets, multiple signaling pathways, and less side effects in both experimental and epidemiological studies. However, the prospective molecular mechanisms and newly emerging research methods in cancer auxiliary regulation require further elaboration. Consequently, this review systematically presents the latest research progress and future prospect of C. pilosula and highlights current gaps in knowledge, which facilitate the great rejuvenation of C. pilosula for the long-term therapy use of tumor. Remarkably, with the gathering of the findings of biological evaluation, combinations with network computing approaches, such as network pharmacology, molecular docking, and quantum-chemical calculations, this review is expected to provide theoretical support and open further research perspectives on C. pilosula in biological function and potential clinical efficacy.
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Affiliation(s)
- Haoran Fan
- College of Tourism and Culinary ScienceYangzhou UniversityYangzhouJiangsuChina
| | - Chenxi Ren
- School of Food Science and EngineeringYangzhou UniversityYangzhouJiangsuChina
| | - Yining Feng
- School of Food Science and EngineeringYangzhou UniversityYangzhouJiangsuChina
| | - Lingyi Zhu
- Jiangsu Vocational College of TourismYangzhouChina
| | - Aobo Yu
- The Second Norman Bethune Hospital of Jilin UniversityChangchunChina
| | - Tianzhu Guan
- School of Food Science and EngineeringYangzhou UniversityYangzhouJiangsuChina
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Hu C, Xu J, Zhang Y, Zhang R, Pan S, Chen J, Wang Y, Zhao Q, Wang Y, Zhu W, Cao M, Zhang S, Zu D, Xu Z, Jing J, Cheng X. Inhibition of glutathione peroxidase 4 suppresses gastric cancer peritoneal metastasis via regulation of RCC2 homeostasis. Redox Biol 2025; 80:103519. [PMID: 39908861 PMCID: PMC11847474 DOI: 10.1016/j.redox.2025.103519] [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: 01/12/2025] [Accepted: 01/24/2025] [Indexed: 02/07/2025] Open
Abstract
Gastric cancer (GC) is one of the most lethal malignancies due to high metastatic rate, making the identification of new therapeutic targets critical for developing effective anti-GC treatments. Glutathione peroxidase 4 (GPx4), a key regulator of ferroptosis and redox homeostasis, contributes to progression and influences patient survival. However, the molecular mechanism by which GPx4 drives GC progression has not been fully illuminated. In this study, we found that GPx4 was overexpressed and negatively associated with poor prognosis and distant metastasis, as confirmed by single-cell RNA sequencing (scRNA-seq) and validation with retrospective clinical samples. GPx4 knockdown suppressed GC invasion, migration and peritoneal metastasis in vitro and in vivo. Proteomic analysis revealed that GPx4 expression regulated the Homeostasis of RCC2, an oncogene link to epithelial-mesenchymal transition (EMT). Furthermore, we demonstrated that the reactive oxygen species (ROS) accumulation induced by GPx4 inhibition or knockdown activated aurora A phosphorylation, leading to RCC2 ubiquitination and degradation, thereby suppressing peritoneal metastasis in GC. We also identified that the Thr418 phosphorylation site is crucial for RCC2 ubiquitination at the K377, initiating its degradation in response to ROS. In conclusion, our results indicate that GPx4 acts as an oncogene in GC, and that suppressing GPx4 prevents GC progression and metastasis by promoting ROS-induced RCC2 ubiquitination and degradation.
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Affiliation(s)
- Can Hu
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China
| | - Jingli Xu
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China
| | - Yanqiang Zhang
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China
| | - Ruolan Zhang
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China
| | - Siwei Pan
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China
| | - Jiahui Chen
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China
| | - Yan Wang
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Qianyu Zhao
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China
| | - Yuqi Wang
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China
| | - Weiwei Zhu
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China
| | - Mengxuan Cao
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China
| | - Shengjie Zhang
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China
| | - Dan Zu
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China
| | - Zhiyuan Xu
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China
| | - Ji Jing
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Xiangdong Cheng
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China
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Liu Y, Bian B, Chen S, Zhou B, Zhang P, Shen L, Chen H. Identification and Validation of Four Serum Biomarkers With Optimal Diagnostic and Prognostic Potential for Gastric Cancer Based on Machine Learning Algorithms. Cancer Med 2025; 14:e70659. [PMID: 40084401 PMCID: PMC11907202 DOI: 10.1002/cam4.70659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 01/20/2025] [Accepted: 01/26/2025] [Indexed: 03/16/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) is considered a highly heterogeneous disease, and currently, a comprehensive approach encompassing molecular data from various biological levels is lacking. METHODS This study conducted different analyses, including the identification of differentially expressed genes (DEGs), weighted correlation networks (WGCNA), single-cell RNA sequencing (scRNA-seq), mRNA expression-based stemness index (mRNAsi), and multiCox analysis, utilizing data from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Subsequently, the machine learning algorithms including least absolute shrinkage and selection operator (LASSO) regression and random forest (RF), combined with multiCox analysis were exploited to identify hub genes. These findings were then validated through the receiver operating characteristic (ROC) curve and Kaplan-Meier analysis, and were experimentally confirmed in GC samples by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). RESULTS Integrated analysis of TCGA and GEO databases, coupled with LASSO regression and RF algorithms, allowed us to identify 18 hub genes encoding differentially expressed secreted proteins in GC. The results of RT-PCR and bioinformatics analysis revealed four promising biomarkers with optimal diagnostic and prognostic potential. ROC analysis and Kaplan-Meier curves highlighted CHI3L1, FCGBP, VSIG2, and TFF2 as promising biomarkers for GC, offering superior modeling accuracy. These findings were further confirmed by RT-PCR and ELISA, affirming the clinical utility of these four biomarkers. Additionally, CIBERSORT analysis indicated a potential correlation between the four biomarkers and the infiltration of B memory cells and Treg cells. CONCLUSION This study unveiled four promising biomarkers present in the serum of patients with GC, which could serve as powerful indicators of GC and provide valuable insights for further research into GC pathogenesis.
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Affiliation(s)
- Yi Liu
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Artificial Intelligence Medicine, Shanghai Academy of Experimental Medicine, Shanghai, China
| | - Bingxian Bian
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shiyu Chen
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bingqian Zhou
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Peng Zhang
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lisong Shen
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Artificial Intelligence Medicine, Shanghai Academy of Experimental Medicine, Shanghai, China
- Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Chen
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Artificial Intelligence Medicine, Shanghai Academy of Experimental Medicine, Shanghai, China
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Zhang X, Yu X, Shen Q, Jiang X, Zhou Y, Xue Q, Cao G. The role of TMSB15A in gastric cancer progression and its prognostic significance. J Gastrointest Oncol 2025; 16:27-40. [PMID: 40115917 PMCID: PMC11921194 DOI: 10.21037/jgo-2025-64] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 02/16/2025] [Indexed: 03/23/2025] Open
Abstract
Background Human thymosin β15 (TMSB15A) has been found to have protumorigenic effects in various malignant tumors, yet its function in gastric cancer (GC) remains unclear. This study investigated the value and function of TMSB15A in the diagnosis and tumorigenesis of GC, respectively. Methods Expression data for TMSB15A in GC tissues were analyzed using The Cancer Genome Atlas (TCGA). We evaluated the prognostic significance of TMSB15A through Kaplan-Meier survival analysis, time-dependent receiver operating characteristic (ROC) curves, and Cox regression models. Gene set enrichment analysis (GSEA) was performed to identify pathways associated with TMSB15A. In vitro assays assessed the effects of TMSB15A knockdown on GC cell proliferation, migration, and invasion. Results TMSB15A was significantly overexpressed in GC tissues compared to normal tissues (P<0.05). ROC analysis showed high diagnostic accuracy for TMSB15A (area under the curve =0.851, 95% confidence interval: 0.786-0.905, P<0.05). Kaplan-Meier survival analysis revealed that high TMSB15A expression was associated with poor overall survival, disease-specific survival, and progression-free survival. TMSB15A levels were correlated with advanced tumor stages (P<0.05), lymph node metastasis (P<0.01), and perineural invasion (P<0.05). GSEA showed significant enrichment of TMSB15A in inflammatory and oncogenic pathways, including interleukin-6 (IL-6)/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), transforming growth factor β (TGF-β), and Hedgehog. Functional assays demonstrated that TMSB15A knockdown significantly reduced GC cell proliferation, migration, and invasion, suggesting that TMSB15A contributes to GC tumorigenesis and metastasis. Conclusions TMSB15A could serve as a prospective therapeutic target for GC due to its involvement in disease progression and metastasis.
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Affiliation(s)
- Xiaolei Zhang
- Department of General Surgery, Nantong Tumor Hospital and Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Xiang Yu
- Department of General Surgery, Nantong Tumor Hospital and Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Qicheng Shen
- Department of General Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Xiaohui Jiang
- Department of General Surgery, Nantong Tumor Hospital and Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Yuan Zhou
- Department of General Surgery, Nantong Tumor Hospital and Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Qiu Xue
- Department of General Surgery, Nantong Tumor Hospital and Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Guangxin Cao
- Department of General Surgery, Nantong Tumor Hospital and Affiliated Tumor Hospital of Nantong University, Nantong, China
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40
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Wang N, Zeng X, Xu M, Shi Y, Zhang J, Ling Z, Xie X, Qin T, Huang H, Yang J, Ma T, He L. Design, Synthesis, and Mechanism Study of Novel BMX Inhibitors Based on the Core of 1,3,5-Triazin-2-Amine for the Treatment of Gastric Carcinoma. J Med Chem 2025; 68:4196-4216. [PMID: 39953991 DOI: 10.1021/acs.jmedchem.4c01947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2025]
Abstract
BMX, a member of the Tec family of kinases, plays a pivotal role in the occurrence and progression of cancers and multiple chronic inflammations. However, there are rarely BMX inhibitors reported, and the signaling pathways mediated by BMX are still poorly understood. In this study, a series of novel BMX inhibitors bearing the core of 1,3,5-triazin-2-amine were designed and synthesized by structural modifications from the lead compound B1c. Among them, compound B6a irreversibly and selectively inhibited BMX (IC50 = 12 nM) and displayed good antiproliferative activities in various cancer cell lines. A mechanism study in gastric carcinoma HGC-27 and MGC-803 cells revealed that B6a promoted cell cycle arrest and apoptosis, triggered protective autophagy, and suppressed the BMX/AKT/mTOR pathway. Notably, although B6a's bioavailability was extremely low, it still exhibited excellent antitumor potency in the HGC-27 xenograft model with high safety, demonstrating that B6a was a promising BMX inhibitor and worth further exploration.
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Affiliation(s)
- Nan Wang
- School of Pharmaceutical Sciences & Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Pingyuan Laboratory, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Xianxia Zeng
- Pharmaceutical College, Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Mengyang Xu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, China
| | - Yamin Shi
- Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Jie Zhang
- Pharmaceutical College, Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Zhen Ling
- Pharmaceutical College, Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Xin Xie
- Pharmaceutical College, Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Tingsheng Qin
- Pharmaceutical College, Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Huaizheng Huang
- Pharmaceutical College, Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Jie Yang
- Pharmaceutical College, Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Ting Ma
- School of Pharmaceutical Sciences & Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Pingyuan Laboratory, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Linhong He
- Pharmaceutical College, Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Guangxi Medical University, Nanning, Guangxi 530021, China
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Semenova Y, Kerimkulov A, Uskenbayev T, Zharlyganova D, Shatkovskaya O, Sarina T, Manatova A, Yessenbayeva G, Adylkhanov T. Chemotherapy Options for Locally Advanced Gastric Cancer: A Review. Cancers (Basel) 2025; 17:809. [PMID: 40075656 PMCID: PMC11899121 DOI: 10.3390/cancers17050809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 02/20/2025] [Accepted: 02/24/2025] [Indexed: 03/14/2025] Open
Abstract
Cancers represent a significant global health burden, affecting millions of individuals each year [...].
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Affiliation(s)
- Yuliya Semenova
- Department of Surgery, School of Medicine, Nazarbayev University, Astana 010000, Kazakhstan;
| | - Altay Kerimkulov
- Department of Multidisciplinary Surgery, National Research Oncology Center, Astana 020000, Kazakhstan; (A.K.); (T.U.); (T.S.); (T.A.)
| | - Talgat Uskenbayev
- Department of Multidisciplinary Surgery, National Research Oncology Center, Astana 020000, Kazakhstan; (A.K.); (T.U.); (T.S.); (T.A.)
| | - Dinara Zharlyganova
- Department of Scientific Management, National Research Oncology Center, Astana 020000, Kazakhstan; (D.Z.); (G.Y.)
| | - Oxana Shatkovskaya
- Board for Strategic Development, Scientific and Educational Activities, National Research Oncology Center, Astana 020000, Kazakhstan;
| | - Tomiris Sarina
- Department of Multidisciplinary Surgery, National Research Oncology Center, Astana 020000, Kazakhstan; (A.K.); (T.U.); (T.S.); (T.A.)
| | - Almira Manatova
- Department of Scientific Management, National Research Oncology Center, Astana 020000, Kazakhstan; (D.Z.); (G.Y.)
| | - Gulfairus Yessenbayeva
- Department of Scientific Management, National Research Oncology Center, Astana 020000, Kazakhstan; (D.Z.); (G.Y.)
| | - Tasbolat Adylkhanov
- Department of Multidisciplinary Surgery, National Research Oncology Center, Astana 020000, Kazakhstan; (A.K.); (T.U.); (T.S.); (T.A.)
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Wu T, Zhou J, He W, Jin L, Li T, Gong T, Liu X. An injectable multimodal thiolated carboxymethyl cellulose hydrogel for advanced gastric cancer treatment. Int J Biol Macromol 2025; 306:141546. [PMID: 40020807 DOI: 10.1016/j.ijbiomac.2025.141546] [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: 09/17/2024] [Revised: 02/14/2025] [Accepted: 02/25/2025] [Indexed: 03/03/2025]
Abstract
Chemotherapy is a standard preoperative treatment for locally advanced resectable gastric cancer (GC). However, its efficacy is often limited by the high intracellular glutathione (GSH) levels in tumor cells, which diminish the effectiveness of chemotherapeutic agents. In this study, we developed a GSH-sensitive injectable hydrogel, T-CMC@Fe3+(5-FU + GOx), incorporating ferric ions (Fe3+), glucose oxidase (GOx), and 5-fluorouracil (5-FU) for advanced GC multimodal treatment. The hydrogel synergistically enhances anti-tumor activity through multiple mechanisms, including chemodynamic therapy, starvation therapy, and chemotherapy. Thiolated carboxymethyl cellulose (T-CMC) was synthesized by grafting L-cysteine onto carboxymethyl cellulose, with successful preparation confirmed by XPS, FTIR, and 13C NMR characterizations. The T-CMC@Fe3+ hydrogel demonstrated responsive degradation of GSH and exhibited favorable biocompatibility in co-culture experiments with GES-1 cells. In vitro analyses revealed that the T-CMC@Fe3+(5-FU + GOx) hydrogel significantly enhanced anti-tumor efficacy compared to chemotherapy alone, reducing cell viability to 12.28 ± 2.88 % after 48 h. In vivo studies using cell-derived and patient-derived xenograft models further confirmed its potent anti-tumor effects, with a marked reduction in tumor volume by 14 days (8.12 ± 4.89 mm3). These findings highlight the potential of the T-CMC@Fe3+(5-FU + GOx) hydrogel as a novel and effective strategy for enhancing GC treatment through its multimodal therapeutic approach.
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Affiliation(s)
- Tao Wu
- College of Medicine and Biological Information Engineering, Northeastern University; Shenyang 110169, China; Department of Biomedical Engineering, Shenyang University of Technology, Shenyang 110870, China; Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, China
| | - Jingqiu Zhou
- College of Medicine and Biological Information Engineering, Northeastern University; Shenyang 110169, China; Department of Biomedical Engineering, Shenyang University of Technology, Shenyang 110870, China; Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, China
| | - Wanli He
- Department of Biomedical Engineering, Shenyang University of Technology, Shenyang 110870, China
| | - Lei Jin
- Department of Biomedical Engineering, Shenyang University of Technology, Shenyang 110870, China
| | - Tenghui Li
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University; Shenyang 110001, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University; Shenyang 110001, China.
| | - Tianxing Gong
- Department of Biomedical Engineering, Shenyang University of Technology, Shenyang 110870, China.
| | - Xu Liu
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, China.
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Zeng X, Zhang Y, Shapaer T, Abudoukelimu A, Zhao Z, Ma B. IGF2BP3 prefers to regulate alternative splicing of genes associated with the progression of gastric cancer in AGS cells. Discov Oncol 2025; 16:235. [PMID: 39998701 PMCID: PMC11861459 DOI: 10.1007/s12672-025-01880-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 02/03/2025] [Indexed: 02/27/2025] Open
Abstract
Gastric cancer (GC) has become the fifth largest malignant tumor in the world, with a mortality rate ranking fourth. IGF2BP3, as a multifunctional RNA binding protein, is involved in regulating alternative splicing (AS) and m6A modification, and plays a carcinogenic role in the development of gastric cancer, while little is known about the impact of IGF2BP3 on alternative splicing in gastric cancer cells and the underlying mechanism. In this study, we overexpressed IGF2BP3 (IGF2BP3-OE) in gastric cancer AGS cells and obtained transcriptome sequencing data (RNA-seq) to explore the effects of IGF2BP3 on gene expression and AS. The RNA binding profile of IGF2BP3 was utilized to identify how IGF2BP3 binds to and modulate expression and AS patterns of target genes. IGF2BP3-OE resulted in 479 differentially expressed genes (DEGs), majority of which were downregulated. We selected 20 DEGs and validated their expression pattern by RT-qPCR experiment, including ZFAS1, DUSP9, GPX3, IDH2, and H19 that were associated with GC development. More importantly, IGF2BP3-OE significantly modulated AS pattern of thousands of genes, which were enriched in mRNA splicing, cell proliferation, and translation pathways. By integrating the RNA binding profile of IGF2BP3, we found IGF2BP3 binding preferred to modulate the splicing pattern of bound genes, and the overlapped genes were also enriched in mRNA splicing pathways. We validated the AS pattern changes of S100A4 and PLK3 by RT-qPCR. IGF2BP3 probably modulate GC development by regulating AS profile in GC cells. In summary, we explored the dysregulated transcriptome profile that IGF2BP3 affects gene expression and alternative splicing by binding to mRNA, and thus plays a role in the development of GC cells. The IGF2BP3 and identified targets has potential value for GC treatment in future.
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Affiliation(s)
- Xiangyue Zeng
- Gastroenterology Department II, The Affiliated Tumor Hospital of Xinjiang Medical University, Ürümqi, 830011, China
| | - Yu Zhang
- Gastroenterology Department II, The Affiliated Tumor Hospital of Xinjiang Medical University, Ürümqi, 830011, China
| | - Tiannake Shapaer
- Gastroenterology Department II, The Affiliated Tumor Hospital of Xinjiang Medical University, Ürümqi, 830011, China
| | - Abulajiang Abudoukelimu
- Gastroenterology Department II, The Affiliated Tumor Hospital of Xinjiang Medical University, Ürümqi, 830011, China
| | - Zeliang Zhao
- Gastroenterology Department II, The Affiliated Tumor Hospital of Xinjiang Medical University, Ürümqi, 830011, China
| | - Binlin Ma
- Breast and Thyroid Surgery Department, The Affiliated Tumor Hospital of Xinjiang Medical University, Ürümqi, 830011, China.
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Rinaldi R, Laurino S, Salvia R, Russi S, De Stefano F, Galasso R, Sgambato A, Scieuzo C, Falco G, Falabella P. Biological Activity of Peptide Fraction Derived from Hermetia illucens L. (Diptera: Stratiomyidae) Larvae Haemolymph on Gastric Cancer Cells. Int J Mol Sci 2025; 26:1885. [PMID: 40076512 PMCID: PMC11899352 DOI: 10.3390/ijms26051885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 02/15/2025] [Accepted: 02/19/2025] [Indexed: 03/14/2025] Open
Abstract
Gastric cancer (GC) is one of the leading causes of cancer-related mortality worldwide, characterised by poor prognosis and limited responsiveness to chemotherapy. There is a need for new and more effective anticancer agents. Antimicrobial peptides (AMPs) represent a promising class of biomolecules for this purpose. Naturally occurring in the innate immune system, these peptides can also exert cytotoxic effects against cancer cells, earning them the designation of "anticancer peptides" (ACPs). They have the potential to be a viable support for current chemotherapy schedules due to their selectivity against cancer cells and minor propensity to induce chemoresistance in cells. Insects are an excellent source of AMPs. Among them, due to its ability to thrive in hostile and microorganism-rich environments, we isolated a peptide fraction from Hermetia illucens L. (Diptera: Stratiomyidae) haemolymph to evaluate a possible anticancer activity. We tested Peptide Fractions (PFs) against AGS and KATO III gastric cancer cell lines. Data obtained indicated that PFs, especially those resulting from Escherichia coli and Micrococcus flavus infection (to boost immune response), were able to inhibit tumour cell growth by inducing apoptosis or cell cycle arrest in a cell line-specific manner. These results support further investigation into the use of antimicrobial peptides produced from insects as possible anticancer agents.
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Affiliation(s)
- Roberta Rinaldi
- Department of Basic and Applied Sciences, University of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy; (R.R.); (R.S.); (F.D.S.)
| | - Simona Laurino
- Centro di Riferimento Oncologico della Basilicata IRCCS (IRCCS-CROB), 85028 Rionero in Vulture, Italy; (S.L.); (S.R.); (R.G.)
| | - Rosanna Salvia
- Department of Basic and Applied Sciences, University of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy; (R.R.); (R.S.); (F.D.S.)
- Spinoff XFlies S.R.L, University of Basilicata, Via Dell’Ateneo Lucano 10, 85100 Potenza, Italy
| | - Sabino Russi
- Centro di Riferimento Oncologico della Basilicata IRCCS (IRCCS-CROB), 85028 Rionero in Vulture, Italy; (S.L.); (S.R.); (R.G.)
| | - Federica De Stefano
- Department of Basic and Applied Sciences, University of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy; (R.R.); (R.S.); (F.D.S.)
| | - Rocco Galasso
- Centro di Riferimento Oncologico della Basilicata IRCCS (IRCCS-CROB), 85028 Rionero in Vulture, Italy; (S.L.); (S.R.); (R.G.)
| | - Alessandro Sgambato
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
- Multiplex Spatial Profiling Facility, Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCS, 00136 Rome, Italy
| | - Carmen Scieuzo
- Department of Basic and Applied Sciences, University of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy; (R.R.); (R.S.); (F.D.S.)
- Spinoff XFlies S.R.L, University of Basilicata, Via Dell’Ateneo Lucano 10, 85100 Potenza, Italy
| | - Geppino Falco
- Department of Biology, University of Naples Federico II, 80126 Naples, Italy;
| | - Patrizia Falabella
- Department of Basic and Applied Sciences, University of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy; (R.R.); (R.S.); (F.D.S.)
- Spinoff XFlies S.R.L, University of Basilicata, Via Dell’Ateneo Lucano 10, 85100 Potenza, Italy
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Hu Y, Du Y, Qiu Z, Mao P, Da M. Identification and validation VAT1 in gastric cancer through bioinformatics and experimental analysis. Int Immunopharmacol 2025; 148:114047. [PMID: 39832459 DOI: 10.1016/j.intimp.2025.114047] [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: 09/15/2024] [Revised: 12/22/2024] [Accepted: 01/06/2025] [Indexed: 01/22/2025]
Abstract
This study investigated the expression pattern of Vesicular Amine Transporter 1 (VAT1) in gastric cancer (GC) and its impact on prognosis, alongside evaluating its potential as a biomarker for immunotherapy and chemotherapy. Analysis of transcriptomic data, supported by experimental validation, revealed that VAT1 is highly expressed in GC and is associated with poor prognosis. Kaplan-Meier and ROC analyses demonstrated VAT1's potential in GC diagnosis, while multivariate analysis confirmed its role as an independent risk factor. Gene set enrichment analysis indicated that VAT1 plays a role in regulating the MAPK signaling pathway and epithelial-mesenchymal transition (EMT) in GC. Immune infiltration analysis showed a positive correlation between VAT1 and immune cells, particularly macrophages, and a negative correlation with chemotherapy sensitivity. In vitro and in vivo experiments further confirmed VAT1's critical role in promoting GC cell proliferation and inhibiting apoptosis. Overall, VAT1 holds significant value not only in GC diagnosis and prognosis but also as a potential target for immunotherapy and overcoming drug resistance.
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Affiliation(s)
- Yongli Hu
- The First Clinical Medical College of Lanzhou University, Lanzhou University, Lanzhou 730000, China; Department of Gastrointestinal Surgery, Affiliated Hospital of Guilin Medical University, Guilin 541001, China.
| | - Yan Du
- The Second Clinical Medical College of Lanzhou University, Lanzhou University, Lanzhou 730000, China.
| | - Zhisheng Qiu
- Department of Oncology Surgery, Gansu Provincial Hospital, Lanzhou 730000, China.
| | - Pengxue Mao
- Department of General Surgery, Minle County People's Hospital, Gansu Province 734500, China.
| | - Mingxu Da
- The First Clinical Medical College of Lanzhou University, Lanzhou University, Lanzhou 730000, China; Department of Oncology Surgery, Gansu Provincial Hospital, Lanzhou 730000, China.
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Yuan YW, Yue ZQ, Zhou Q, Sheng J, Zou YH, Fan LJ, Xu H, Xin L. TFAP4 Regulation of MCM5 Activates the PI3K/AKT Pathway to Promote Invasion and Metastasis of Gastric Cancer. Dig Dis Sci 2025:10.1007/s10620-025-08897-0. [PMID: 39971831 DOI: 10.1007/s10620-025-08897-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 01/27/2025] [Indexed: 02/21/2025]
Abstract
AIMS To investigate the role of transcription factor activating enhancer-binding protein 4 (TFAP4) in gastric cancer (GC) progression and elucidate its mechanism in promoting metastasis and invasion through the PI3K/AKT signaling pathway. METHODS Bioinformatics analysis was performed to assess TFAP4 expression in GC tissues. Clinical specimens were collected and validated for TFAP4 expression. Functional assays were conducted to evaluate the effects of TFAP4 overexpression and inhibition on GC cell proliferation, invasion, and metastasis. In vivo studies with HGC27 cells in BALB/c nude mice were used to assess tumor growth and metastasis. Mechanistic analysis included the measurement of MCM5 expression and activation of the PI3K/AKT signaling pathway, with PI3K inhibitor LY294002 and MCM5 knockdown applied to confirm the pathways involved. RESULTS Elevated TFAP4 expression was observed in GC tissues, and its overexpression promoted GC cell proliferation, invasion, and metastasis. Conversely, TFAP4 inhibition suppressed these behaviors. In vivo studies confirmed that TFAP4 knockdown reduced tumor growth and metastasis in nude mice. Mechanistically, TFAP4 was found to activate MCM5, which in turn facilitated GC cell invasion and metastasis. Furthermore, TFAP4 and MCM5 activated the PI3K/AKT signaling pathway, as evidenced by increased p-PI3K and p-AKT expression. The effects of TFAP4 overexpression were reversed by MCM5 knockdown or treatment with the PI3K inhibitor LY294002. CONCLUSION The TFAP4-MCM5 signaling axis promotes GC progression through the PI3K/AKT pathway, suggesting that targeting this axis could provide a potential therapeutic strategy for managing gastric cancer.
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Affiliation(s)
- Yi-Wu Yuan
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1 Minde Road, Donghu District, Jiangxi, 330006, China
| | - Zhen-Qi Yue
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1 Minde Road, Donghu District, Jiangxi, 330006, China
| | - Qi Zhou
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1 Minde Road, Donghu District, Jiangxi, 330006, China
| | - Jie Sheng
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1 Minde Road, Donghu District, Jiangxi, 330006, China
| | - Yong-Hui Zou
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1 Minde Road, Donghu District, Jiangxi, 330006, China
| | - Luo-Jun Fan
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1 Minde Road, Donghu District, Jiangxi, 330006, China
| | - Hesong Xu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1 Minde Road, Donghu District, Jiangxi, 330006, China
| | - Lin Xin
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1 Minde Road, Donghu District, Jiangxi, 330006, China.
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Serra F, Valerio F, Pedrazzoli P, Viganò J, Caccialanza R, Cicognini D, Pagani A, Corallo S. Real-life effectiveness of FLOT in resectable gastric cancer: existing challenges. Drugs Context 2025; 14:2024-10-7. [PMID: 40017727 PMCID: PMC11867168 DOI: 10.7573/dic.2024-10-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 12/27/2024] [Indexed: 03/01/2025] Open
Abstract
Background Gastric cancer has a high mortality rate. Therapeutic management must be multidisciplinary to offer the patient the best, personalized strategy. Patients and methods We performed an observational study to evaluate the pathological response, survival and nutritional status in patients with resectable gastric cancer and candidates for perioperative chemotherapy with the fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) regimen versus other regimens. The primary endpoints were pathological response rate, care continuity rate and survival outcomes. A total of 96 patients attending the Hospital "Policlinico San Matteo" in Pavia (Italy) between January 2012 and August 2022 were selected for the study. Results Regarding pathological response rates, the best rate (TRG-0) was recorded in the FLOT group with a percentage of 6.2% compared with 4.7% in the NO-FLOT arm (p=0.052). The highest failure rate to complete the post-operative phase was 75% in the NO-FLOT group and only 25% in the FLOT group (p=0.007). Survival outcomes were better in the FLOT group with a median disease-free survival of 30 versus 22.2 months (p=0.586). Conclusions Despite the limitations, the results obtained were consistent with the medical literature and confirmed the effectiveness of the FLOT chemotherapy in real life. Nevertheless, some questions remain: the application in elderly patients, the addition of immunotherapy in patients with microsatellite instability or with high PD-L1 levels, comparison with chemoradiotherapy in junctional cancers and real cure rates. The FLOT regimen has revolutionized the treatment of resectable gastric cancer, but caution is needed before considering it an absolute standard of care.
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Affiliation(s)
- Francesco Serra
- Internal Medicine and Medical Therapy Department, University of Pavia, Pavia, Italy
- Medical Oncology Unit, Hospital Policlinico San Matteo of Pavia, Pavia, Italy
| | - Federica Valerio
- Internal Medicine and Medical Therapy Department, University of Pavia, Pavia, Italy
- Medical Oncology Unit, Hospital Policlinico San Matteo of Pavia, Pavia, Italy
| | - Paolo Pedrazzoli
- Internal Medicine and Medical Therapy Department, University of Pavia, Pavia, Italy
- Medical Oncology Unit, Hospital Policlinico San Matteo of Pavia, Pavia, Italy
| | - Jacopo Viganò
- General Surgery Unit, Hospital Policlinico San Matteo of Pavia, Pavia, Italy
| | - Riccardo Caccialanza
- Dietetics and Clinical Nutrition Unit, Hospital Policlinico San Matteo of Pavia, Pavia, Italy
| | - Daniela Cicognini
- Internal Medicine and Medical Therapy Department, University of Pavia, Pavia, Italy
- Medical Oncology Unit, Hospital Policlinico San Matteo of Pavia, Pavia, Italy
| | - Anna Pagani
- Internal Medicine and Medical Therapy Department, University of Pavia, Pavia, Italy
- Medical Oncology Unit, Hospital Policlinico San Matteo of Pavia, Pavia, Italy
| | - Salvatore Corallo
- Internal Medicine and Medical Therapy Department, University of Pavia, Pavia, Italy
- Medical Oncology Unit, Hospital Policlinico San Matteo of Pavia, Pavia, Italy
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Feng F, Hu P, Chen J, Peng L, Wang L, Tao X, Lian C. Mechanism research on inhibition of gastric cancer in vitro by the extract of Pinellia ternata based on network pharmacology and cellular metabolomics. Open Med (Wars) 2025; 20:20241131. [PMID: 39989612 PMCID: PMC11843166 DOI: 10.1515/med-2024-1131] [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: 05/25/2024] [Revised: 12/11/2024] [Accepted: 12/13/2024] [Indexed: 02/25/2025] Open
Abstract
Background and purpose Gastric cancer is a kind of malignant tumor with high incidence and high mortality, which has strong tumor heterogeneity. A classic Chinese medicine, Pinellia ternata (PT), was shown to exert therapeutic effects on gastric cancer cells. However, its chemical and pharmacological profiles remain to be elucidated. In the current study, we aimed to reveal the mechanism of PT in treating gastric cancer cells through metabolomic analysis and network pharmacology. Methods Metabolomic analysis of two strains of gastric cancer cells treated with the Pinellia ternata extract (PTE) was used to identify differential metabolites, and the metabolic pathways were enriched by MetaboAnalyst. Then, network pharmacology was applied to dig out the potential targets against gastric cancer cells induced by PTE. The integrated network of metabolomics and network pharmacology was constructed based on Cytoscape. Results The PTE was confirmed to significantly inhibit cell proliferation, migration, and invasion of HGC-27 and BGC-823 cells. The results of cellular metabolomics showed that 61 metabolites were differently expressed in gastric cancer cells of the experimental and control groups. Through pathway enrichment analysis, 16 metabolites were found to be involved in the glycerophospholipid metabolism, purine metabolism, sphingolipid metabolism, and tryptophan metabolism. Combined with network pharmacology, seven bioactive compounds were found in PT, and the networks of bioactive compound-target gene-metabolic enzyme-metabolite interactions were constructed. Conclusions In conclusion, this study revealed the complicated mechanisms of PT against gastric cancer. Our work provides a novel paradigm to identify the potential mechanisms of pharmacological effects derived from a natural compound.
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Affiliation(s)
- Fan Feng
- School of Biological and Food Engineering, Suzhou University, Anhui, 234000, China
| | - Ping Hu
- School of Biological and Food Engineering, Suzhou University, Anhui, 234000, China
| | - Jun Chen
- School of Biological and Food Engineering, Suzhou University, Anhui, 234000, China
| | - Lei Peng
- School of Biological and Food Engineering, Suzhou University, Anhui, 234000, China
| | - Luyao Wang
- Research Center of Clinical Laboratory Science, Bengbu Medical University, Bengbu, 233030, China
| | - Xingkui Tao
- School of Biological and Food Engineering, Suzhou University, Anhui, 234000, China
| | - Chaoqun Lian
- Research Center of Clinical Laboratory Science, Bengbu Medical University, Bengbu, 233030, China
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Zhu W, Yi Q, Wang J, Ouyang X, Yang K, Jiang B, Huang B, Liu J, Zhao L, Liu X, Zhong J, Zhong J, Wang B. Comprehensive analysis of CLEC family genes in gastric cancer prognosis immune response and treatment. Sci Rep 2025; 15:5956. [PMID: 39966377 PMCID: PMC11836380 DOI: 10.1038/s41598-024-80204-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 11/15/2024] [Indexed: 02/20/2025] Open
Abstract
Gastric cancer, a prevalent malignancy, often presents challenges due to its low early diagnosis rate and poor prognosis. This study aims to establish a prognostic model composed of genes from the CLEC family, aiming to predict the prognosis of gastric cancer patients effectively. Data Collection: mRNA expression matrices and clinical data were downloaded from the TCGA, GEO, and GTEx databases. Differential analysis, univariate Cox analysis, lasso regression analysis, and multivariate Cox analysis were conducted to identify three genes associated with the prognosis of the CLEC family for building a prognostic model. Prognostic Model Construction: A prognostic model comprising these three genes was constructed. The prognostic value was evaluated using Kaplan-Meier plots, time-dependent receiver operating characteristic curves, multivariable Cox regression analysis incorporating clinical information, and a nomogram. The predictive value of the three-gene signature was further validated using the GSE84437 dataset. Immune and Functional Analyses: Differences in immune status and signaling pathways between different risk groups were assessed through analyses of the tumor microenvironment, immune cell infiltration, immune function, and gene set enrichment. Through tumor mutation analysis, the molecular mechanisms of tumors were revealed. Finally, chemotherapy-sensitivity drugs were identified through drug analysis. Results revealed CD93, CLEC3A, and VCAN as three CLEC family genes associated with prognosis. Multivariable Cox regression analysis demonstrated that these three CLEC family genes were independent prognostic factors for overall survival in gastric cancer patients. Additionally, we constructed a prognostic nomogram that incorporated risk score, age, grade, and stage. Based on TCGA/GSE84437 data, calibration plots demonstrated its predictive solid performance. Furthermore, immune-related analyses and drug sensitivity assessments suggested a close association between the three-gene model and immune cell infiltration, indicating their potential as predictive indicators for chemotherapy sensitivity. We have identified a CLEC family gene model consisting of three genes associated with the prognosis of gastric cancer. This provides a basis for personalized prevention and treatment strategies.
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Affiliation(s)
- Weijian Zhu
- Gannan Medical University, Ganzhou, Jiangxi, China
| | - Qiang Yi
- Gannan Medical University, Ganzhou, Jiangxi, China
| | - Jiaqi Wang
- Gannan Medical University, Ganzhou, Jiangxi, China
| | | | - Kuan Yang
- Gannan Medical University, Ganzhou, Jiangxi, China
| | - Bowei Jiang
- Gannan Medical University, Ganzhou, Jiangxi, China
| | - Benben Huang
- Gannan Medical University, Ganzhou, Jiangxi, China
| | - Jin Liu
- Gannan Medical University, Ganzhou, Jiangxi, China
| | - Liwen Zhao
- Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xuejin Liu
- Gannan Medical University, Ganzhou, Jiangxi, China
| | | | - Jinghua Zhong
- Department of Oncology, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China.
| | - Biao Wang
- Department of Rheumatology, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China.
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Zhang W, Guo K, Zheng S. Immunotherapy Combined with Chemotherapy in the First-Line Treatment of Advanced Gastric Cancer: Systematic Review and Bayesian Network Meta-Analysis Based on Specific PD-L1 CPS. Curr Oncol 2025; 32:112. [PMID: 39996912 PMCID: PMC11854702 DOI: 10.3390/curroncol32020112] [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: 12/23/2024] [Revised: 02/05/2025] [Accepted: 02/14/2025] [Indexed: 02/26/2025] Open
Abstract
Objective: To compare the efficacy and safety of immunotherapy combined with chemotherapy as the first-line treatment for advanced gastric cancer. Data Sources: Phase III randomised controlled trials were searched from PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials databases, and several international conference databases, from inception to 15 November 2024. Results: A total of eight eligible trials involved 7898 patients and eight treatments. The network meta-analysis showed that cadonilimab plus chemotherapy was the most superior treatment in improving overall survival (versus conventional chemotherapy, hazard ratio 0.62, 95% credible interval 0.50 to 0.78) and progression-free survival (0.53, 0.43 to 0.65), and consistency of results were observed in specific PD-L1 combined positive score groups. All immune checkpoint inhibitors combined with chemotherapy improved patient prognosis, but nivolumab plus chemotherapy may lead to an increase in grade 3 or higher adverse events (odds ratio 1.68, 95% credible interval 1.04 to 2.54), and the toxicity of cadonilimab plus chemotherapy was more likely to force patients to discontinue treatment. Conclusions: These results showed that cadonilimab plus chemotherapy had the best overall survival and progression-free survival benefits for advanced gastric cancer patients with HER-2 negative, and was preferentially recommended to patients with positive PD-L1 CPS.
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Affiliation(s)
- Wenwei Zhang
- Department of Oncology, The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310006, China;
- Department of Oncology, Hangzhou First People’s Hospital, Hangzhou 310006, China;
| | - Kaibo Guo
- Department of Oncology, Hangzhou First People’s Hospital, Hangzhou 310006, China;
| | - Song Zheng
- Department of Oncology, The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310006, China;
- Department of Oncology, Hangzhou First People’s Hospital, Hangzhou 310006, China;
- Zhejiang University School of Medicine, Hangzhou 310006, China
- Key Laboratory of Clinical Cancer Pharmacology & Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Westlake University, Hangzhou 310006, China
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