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This study assesses ME3 in patients and mechanistically tests how ME3 knockdown or overexpression alters proliferation, metastasis, metabolites, oxidative stress, and hypoxia signaling. ME3 downregulation is linked to clinicopathological features and poor prognosis, suggesting prognostic and therapeutic relevance in gastric carcinoma.",{"@graph":14,"@context":72},[15,34,55],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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is the main research focus of this study on gastric cancer?","Question",{"text":62,"@type":63},"The study investigates how malic enzyme 3 (ME3) contributes to gastric carcinoma development and whether ME3 can serve as a prognostic and therapeutic target.","Answer",{"name":65,"@type":60,"acceptedAnswer":66},"How were ME3 expression levels measured in gastric cancer patients?",{"text":67,"@type":63},"ME3 mRNA and protein levels were evaluated using RT-qPCR, Western blotting (WB), and immunohistochemistry, and then correlated with clinicopathological indicators.",{"name":69,"@type":60,"acceptedAnswer":70},"What mechanistic pathway does the study propose for ME3’s effect on gastric carcinoma progression?",{"text":71,"@type":63},"The study proposes that ME3 downregulation promotes progression by regulating intracellular oxidative stress and stabilizing hypoxia-inducible factor-1α 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\n[https://doi.org/10.1007/s00018-024-05388-9](https://doi.org/10.1007/s00018-024-05388-9) Cellular and Molecular Life Sciences  \nORIGINAL ARTICLE  \nDownregulation of malic enzyme 3 facilitates progression of gastric carcinoma via regulating intracellular oxidative stress and hypoxiainducible factor-1α stabilization  \nYingying Huang1,2,3 · YanYang1 · Xiangliu Chen1 · Siying Zeng2 · Yiran Chen1 · Haiyong Wang1 · Xiadong Lv1 · Xun Hu2 · Lisong Teng1  \nReceived: 31 January 2024 / Revised: 4 July 2024 / Accepted: 29 July 2024 © The Author(s) 2024  \nAbstract  \nBackground Gastric cancer (GC) is one of the most malignant cancers worldwide. Metabolism disorder is a critical characteristic of malignant tumors related to tumor progression and metastasis. However, the expression and molecular mechanism of malic enzyme 3 (ME3) in GC are rarely reported. In this study, we aim to investigate the molecular mechanism of ME3 in the development of GC and to explore its potential value as a prognostic and therapeutic target in GC.  \nMethod ME3 mRNA and protein expression were evaluated in patients with GC using RT-qPCR, WB, and immunohistochemistry, as well as their correlation with clinicopathological indicators. The effect of ME3 on proliferation and metastasis was evaluated using Cell Counting Kit-8 (CCK-8), 5-ethynyl-20-deoxyuridine (EdU) assay, transwell assay, wound healing assay, and subcutaneous injection or tail vein injection of tumor cells in mice model. The effects of ME3 knockdown on the level of metabolites and hypoxia-inducible factor-1α (HIF-1α) protein were determined in GC cells. Oxidative phosphorylation was measured to evaluate adenosine triphosphate (ATP) production.  \nResults ME3 was downregulated in human GC tissues (P\u003C0.001) . The decreased ME3 mRNA expression was associated with younger age (P = 0.02), pathological staging (P = 0.049), and lymph node metastasis (P = 0.001), while low ME3 expression was associated with tumor size (P = 0.048), tumor invasion depth (P\u003C0.001), lymph node metastasis (P = 0.018), TNM staging (P\u003C0.001), and poor prognosis (OS, P = 0.0206; PFSP = 0.0453). ME3 knockdown promoted GC cell malignancy phenotypes. Moreover, α-ketoglutarate (α-KG) and NADPH/NADP+ ratios were reduced while malate was increased in the ME3 knockdown group under normoxia. When cells were incubated under hypoxia, the NADPH/NADP+ ratio and α-KG decreased while intracellular reactive oxygen species (ROS) increased significantly. The ME3 knockdown group exhibited an increase in ATP production and while ME3 overexpression group exhibited oppositely. We discovered that ME3 and HIF-1α expression were negatively correlated in GC cells and tissues, and proposed the hypothesis: downregulation of ME3 promotes GC progression via regulating intracellular oxidative stress and HIF-1α .  \nConclusion We provide evidence that ME3 downregulation is associated with poor prognosis in GC patients and propose a hypothesis for the ME3 regulatory mechanism in GC progression. The present study is of great scientific significance and clinical value for exploring the prognostic and therapeutic targets of GC, evaluating and improving the clinical efficacy of patients, reducing recurrence and metastasis, and improving the prognosis and quality of life of patients.  \nKeywords Malic enzyme 3 (ME3) · Gastric cancer · Α-ketoglutarate · Hypoxia-inducible factor-1α · Reactive oxygen species  \n􀀍 Lisong Teng[lsteng@zju.edu.cn](lsteng@zju.edu.cn)  \n1 Department of Oncological Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China  \n2 Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China  \n3 Department of Gynecology, Guangzhou First People’s","cbCaifcQrNTYzuTN","https://ap.wps.com/l/cbCaifcQrNTYzuTN","pdf",9834706,21,"English","# Abstract\n## Background\n## Method\n## Results\n## Conclusion\n# Introduction\n## Gastric cancer overview and research rationale","[{\"question\":\"What is the main research focus of this study on gastric cancer?\",\"answer\":\"The study investigates how malic enzyme 3 (ME3) contributes to gastric carcinoma development and whether ME3 can serve as a prognostic and therapeutic target.\"},{\"question\":\"How were ME3 expression levels measured in gastric cancer patients?\",\"answer\":\"ME3 mRNA and protein levels were evaluated using RT-qPCR, Western blotting (WB), and immunohistochemistry, and then correlated with clinicopathological indicators.\"},{\"question\":\"What mechanistic pathway does the study propose for ME3’s effect on gastric carcinoma progression?\",\"answer\":\"The study proposes that ME3 downregulation promotes progression by regulating intracellular oxidative stress and stabilizing hypoxia-inducible factor-1α (HIF-1α).\"}]","Downregulation of malic enzyme 3 facilitates progression of gastric carcinoma via regulating intracellular oxidative stress and hypoxiainducible factor-1α stabilization | PDF",1789992369,53]