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Ng D, Cyr D, Khan S, Dossa F, Swallow C, Kazazian K. Molecular mechanisms of metastatic peritoneal dissemination in gastric adenocarcinoma. Cancer Metastasis Rev 2025; 44:50. [PMID: 40317360 PMCID: PMC12049340 DOI: 10.1007/s10555-025-10265-3] [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: 12/05/2024] [Accepted: 04/17/2025] [Indexed: 05/07/2025]
Abstract
Peritoneal dissemination portends a dismal prognosis in patients with gastric adenocarcinoma in the context of limited effective treatments. The underlying cellular processes that drive gastric peritoneal carcinomatosis remain unclear, limiting the application of novel targeted therapies. In this comprehensive review, we aimed to identify and summarize all existing context-dependent molecular mechanisms that have been implicated in peritoneal dissemination and peritoneal carcinomatosis establishment from primary gastric adenocarcinoma. We applied a multilevel examination including data from in vivo murine models using human gastric cancer cell lines, in vitro technique-based studies, ex vivo models, and genomic/proteomic and molecular profiling analyses to report on various aspects of gastric cancer peritoneal metastasis biology. Mechanisms promoting peritoneal dissemination were grouped into three main functional categories: (1) intrinsic cancer cell biology, (2) cancer cell-peritoneal surface adhesion, and (3) peritoneal tumor microenvironment. We identified significant overlap among the three categories, indicating a complex interplay between multiple molecular mechanisms. By interrupting these pathways, peritoneal-directed therapies have the potential to improve quality and length of life in patients with high-risk primary gastric cancer.
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Affiliation(s)
- Deanna Ng
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
- Institute of Medical Science, University of Toronto, Toronto, Canada
- Department of Surgery, University of Toronto, Toronto, Canada
| | - David Cyr
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
- Institute of Medical Science, University of Toronto, Toronto, Canada
- Department of Surgery, University of Toronto, Toronto, Canada
| | - Shawn Khan
- Institute of Medical Science, University of Toronto, Toronto, Canada
- Department of Surgery, University of Toronto, Toronto, Canada
| | - Fahima Dossa
- Complex General Surgical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Carol Swallow
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
- Institute of Medical Science, University of Toronto, Toronto, Canada
- Department of Surgery, University of Toronto, Toronto, Canada
| | - Karineh Kazazian
- Department of Surgery, University of Toronto, Toronto, Canada.
- Department of Surgical Oncology, Toronto General Hospital, University Health Network, 200 Elizabeth Street, 10 Eaton North, Room 219, Toronto, M5G 2 C4, Canada.
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2
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Xu R, Hao Y, Liu Y, Ji B, Tian W, Zhang W. Functional mechanisms and potential therapeutic strategies for lactylation in liver diseases. Life Sci 2025; 363:123395. [PMID: 39809380 DOI: 10.1016/j.lfs.2025.123395] [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: 11/07/2024] [Revised: 01/09/2025] [Accepted: 01/10/2025] [Indexed: 01/16/2025]
Abstract
Lactylation, a novel form of lactate-mediated protein post-translational modification (PTM), has been identified as a crucial regulator of gene expression and protein function through the modification of both histone and non-histone proteins. Liver disease is frequently characterized by a reprogramming of glucose metabolism and subsequent lactate accumulation. Recent research has implicated lactylation in a diverse array of hepatic pathologies, including liver injury, non-alcoholic fatty liver disease, liver fibrosis, and hepatocellular carcinoma. Consequently, lactylation has emerged as a pivotal regulatory mechanism in liver disease pathogenesis. This review aims to elucidate the intricate regulatory and functional mechanisms underlying lactylation, synthesize recent advancements in its role in various liver diseases, and highlight its potential as a therapeutic target for future interventions in hepatic disorders.
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Affiliation(s)
- Rong Xu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Yitong Hao
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Yahui Liu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Bai Ji
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Weibo Tian
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Wei Zhang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China.
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Hu J, Meng F, Lv L, Hong F, He Q, Zhu Q, Tian T, Chang N, Zhang S, Yi Q, Qian L. GPR37-enhanced ubiquitination of ATP1A1 inhibits tumor progression and radiation resistance in esophageal squamous cell carcinoma. Cell Death Dis 2024; 15:933. [PMID: 39730361 PMCID: PMC11681203 DOI: 10.1038/s41419-024-07240-1] [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: 07/18/2024] [Revised: 11/01/2024] [Accepted: 11/11/2024] [Indexed: 12/29/2024]
Abstract
Radiotherapy resistance is one of the main reasons for the dismal clinical outcome of patients with esophageal squamous cell carcinoma (ESCC). Therefore, clarifying the targets and molecular mechanisms of radiotherapy resistance in ESCC is of great theoretical and clinical significance to enhance the efficacy of radiotherapy. In this study, GPR37 was identified as a key factor facilitating ESCC radiosensitization. We found that GPR37 is lowly expressed in ESCC, especially in radioresistant ESCC tumors. And its insufficiency is related to the malignant characteristics and unfavorable prognosis in ESCC. Further investigation revealed that GPR37 level is inversely regulated by promoter methylation but positively regulated by ZNF750. Functionally, GPR37 could not only overcome radioresistance of ESCC, but also inhibit proliferation, migration, and invasion. Mechanistically, GPR37 interacts with the ATP1A1 protein, effectively promoting its ubiquitination-induced degradation, thereby limiting the activation of the AKT/mTOR signaling pathway. Additionally, GPR37 can be transported to recipient cells via exosomes and inhibit the malignant behavior of recipient cells. Overall, these findings suggest that GPR37-ATP1A1 axis holds potential as a therapeutic target for the management of ESCC, especially for overcoming radiation resistance.
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Affiliation(s)
- Jiaru Hu
- Department of Radiation Oncology, Anhui Provincial Cancer Hospital, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Fang Meng
- Department of Oncology & Hematology, Xishan People's Hospital of Wuxi City, Wuxi, 214105, China
| | - Lei Lv
- Department of Cancer Epigenetics Program, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Cancer Hospital, Hefei, 230031, China
| | - Fu Hong
- Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Cancer Hospital, Hefei, 230031, China
| | - Qing He
- Department of Radiation Oncology, Anhui Provincial Cancer Hospital, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Qi Zhu
- Department of Radiation Oncology, Anhui Provincial Cancer Hospital, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Tian Tian
- Department of Respiratory Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Cancer Hospital, Hefei, 230001, China
| | - Na Chang
- Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Cancer Hospital, Hefei, 230031, China
| | - Shiqiang Zhang
- Department of Oncology & Hematology, Xishan People's Hospital of Wuxi City, Wuxi, 214105, China
| | - Qiyi Yi
- Institute of Radiation Medicine, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui, China.
| | - Liting Qian
- Department of Radiation Oncology, Anhui Provincial Cancer Hospital, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.
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Yu L, Wu Q, Jiang S, Liu J, Liu J, Chen G. Controversial Roles of Regenerating Family Proteins in Tissue Repair and Tumor Development. Biomedicines 2024; 13:24. [PMID: 39857608 PMCID: PMC11762848 DOI: 10.3390/biomedicines13010024] [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: 12/06/2024] [Revised: 12/23/2024] [Accepted: 12/24/2024] [Indexed: 01/27/2025] Open
Abstract
Background: Over the past 40 years since the discovery of regenerating family proteins (Reg proteins), numerous studies have highlighted their biological functions in promoting cell proliferation and resisting cell apoptosis, particularly in the regeneration and repair of pancreatic islets and exocrine glands. Successively, short peptides derived from Reg3δ and Reg3α have been employed in clinical trials, showing favorable therapeutic effects in patients with type I and type II diabetes. However, continued reports have been limited, presumably attributed to the potential side effects. Methods: This review summarizes extensive research on Reg proteins over the past decade, combined with our own related studies, proposing that Reg proteins exhibit dimorphic effects. Results: The activity of Reg proteins is not as simplistic as previously perceived but shows auto-immunogenicity depending on different pathophysiological microenvironments. The immunogenicity of Reg proteins could recruit immune cells leading to an anti-tumor effect. Such functional diversity is correlated with their structural characteristics: the N-terminal region contributes to autoantigenicity, while the C-type lectin fragment near the C-terminal determines the trophic action. It should be noted that B-cell masking antigens might also reside within the C-type lectin domain. Conclusions: Reg proteins have dual functional roles under various physiological and pathological conditions. These theoretical foundations facilitate the subsequent development of diagnostic reagents and therapeutic drugs targeting Reg proteins.
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Affiliation(s)
- Luting Yu
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China; (L.Y.)
| | - Qingyun Wu
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China; (L.Y.)
| | - Shenglong Jiang
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China; (L.Y.)
| | - Jia Liu
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China; (L.Y.)
| | - Junli Liu
- MeDiC Program, The Research Institute of McGill University Health Centre, Montreal, QC H4A 3J1, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada
| | - Guoguang Chen
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China; (L.Y.)
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Zhou J, He X, Dai W, Li Q, Xiang Z, Wang Y, Zhang T, Xu W, Wang L, Mao A. GPR37 promotes colorectal cancer against ferroptosis by reprogramming lipid metabolism via p38-SCD1 axis. Apoptosis 2024; 29:1988-2001. [PMID: 39306652 DOI: 10.1007/s10495-024-02018-4] [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] [Accepted: 09/04/2024] [Indexed: 11/10/2024]
Abstract
Colorectal cancer (CRC) is a prevalent malignant tumor worldwide, leading to significant morbidity and disease burden. Diagnostic indicators and treatment objectives for CRC are urgently needed. This study demonstrates that GPR37, a GPCR receptor, is highly expressed in CRC. Depletion of GPR37 significantly reduced CRC tumor cell growth both in vitro and in vivo. Further tests showed that GPR37 protects cancer cells from ferroptosis by upregulating SCD1 expression, thereby modulating lipid metabolism, suppressing the level of reactive oxygen species, and mitigating ferroptosis. Mechanistic studies have shown that GPR37 modulates lipid metabolism in tumor cells by promoting SCD1 transcription via the MAPK-p38 signaling pathway. Our results reveal the pro-carcinogenic effect of GPR37 in primary CRC and suggest that targeting GPR37 could be a potential therapeutic target for CRC.
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Affiliation(s)
- Jiamin Zhou
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, P. R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Xigan He
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, P. R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Weixing Dai
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Colorectal Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Qingguo Li
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Colorectal Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Zhen Xiang
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, P. R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yixiu Wang
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, P. R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Ti Zhang
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, P. R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Weiqi Xu
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, P. R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Lu Wang
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, P. R. China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| | - Anrong Mao
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, P. R. China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
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Bian X, Wang Y, Zhang W, Ye C, Li J. GPR37 and its neuroprotective mechanisms: bridging osteocalcin signaling and brain function. Front Cell Dev Biol 2024; 12:1510666. [PMID: 39633709 PMCID: PMC11614806 DOI: 10.3389/fcell.2024.1510666] [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: 10/13/2024] [Accepted: 11/11/2024] [Indexed: 12/07/2024] Open
Abstract
Osteocalcin (OCN) is a hormone secreted by osteoblasts and has attracted widespread attention for its role in regulating brain function. Clinical studies indicate a positive correlation between levels of circulating OCN and cognitive performance. Indeed, lower circulating OCN has been detected in various neurodegenerative diseases (NDs), while OCN supplementation under certain conditions may improve cognitive function. GPR37, a G protein-coupled receptor, has recently been identified as a receptor for OCN. It exhibits distinct expression patterns across various brain regions and cell types, potentially influencing its functional roles within the brain. Research indicates that GPR37 regulates neuronal migration, cell proliferation, differentiation, and myelination. Furthermore, GPR37 has been shown to mitigate inflammation and apoptosis through various mechanisms, exerting neuroprotective effects. However, its regulatory influence on brain function exhibits inconsistency, highlighting a duality in its actions. Therefore, this review thoroughly summarizes the roles and mechanisms of GPR37 in modulating cellular physiological activities and its involvement in immune responses, stress reactions, and neuroprotection. It aims to enhance the understanding of how GPR37 modulates brain function and facilitate the identification of novel therapeutic targets or strategies for related diseases.
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Affiliation(s)
- Xuepeng Bian
- Department of Rehabilitation, School of International Medical Technology, Shanghai Sanda University, Shanghai, China
| | - Yangping Wang
- Physical Education College, Shanghai University, Shanghai, China
| | - Weijie Zhang
- Physical Education College, Shanghai University, Shanghai, China
| | - Changlin Ye
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Jingjing Li
- Physical Education College, Shanghai University, Shanghai, China
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7
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Wang X, Ju J, Xie Y, Hang L. Emerging roles of the G-protein-coupled receptor 37 in neurological diseases and pain. Neuroscience 2024; 559:199-208. [PMID: 39244010 DOI: 10.1016/j.neuroscience.2024.08.032] [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: 01/25/2024] [Revised: 08/11/2024] [Accepted: 08/21/2024] [Indexed: 09/09/2024]
Abstract
Neurological disorders and pain are prevalent clinical issues that severely impact patients' quality of life and daily functioning. With the advancing exploration of these disease mechanisms, G protein-coupled receptor 37 (GPR37) has emerged as a critical protein, garnering widespread attention in the scientific community. As a member of the G protein-coupled receptor family, GPR37 features a seven-transmembrane helix structure and is widely expressed in various brain regions, including the substantia nigra and striatum. In addition to neurons, GPR37 is also detected in immune cells within the nervous system, indicating its potential role in neuron-immune cell interactions. Research has shown that the expression level of GPR37 in neurological disorders can affect neuron survival, cellular signaling, and overall neurological health. Abnormal expression of GPR37 is often associated with disease progression and symptom exacerbation in neurological disorders such as Parkinson's disease and stroke. In the context of pain, GPR37 alleviates pain and inflammatory responses by regulating the phagocytic activity and polarization state of macrophages. This article aims to delve into the mechanistic roles of GPR37 in neurological disorders and pain. Through a comprehensive literature review, we summarize the latest research on GPR37's involvement in neurological diseases and pain, highlighting its critical roles in neural signaling, inflammatory responses, and neuroprotection. This understanding expands the comprehension of GPR37's biological functions and provides new perspectives for improving the clinical outcomes of patients with neurological disorders and pain.
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Affiliation(s)
- Xinxin Wang
- Department of Anesthesiology, Kunshan Hospital Affiliated to Jiangsu University, Suzhou, 215300, China.
| | - Jiajun Ju
- Gusu College, Nanjing Medical University, Department of Anesthesiology, The First People's Hospital of Kunshan, Suzhou 215300, China.
| | - Yafei Xie
- Department of Anesthesiology, Kunshan Hospital Affiliated to Jiangsu University, Suzhou, 215300, China.
| | - Lihua Hang
- Department of Anesthesiology, Kunshan Hospital Affiliated to Jiangsu University, Suzhou, 215300, China.
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Yan L, Wen Z, Yang Y, Liu A, Li F, Zhang Y, Yang C, Li Y, Zhang Y. Dissecting the roles of prosaposin as an emerging therapeutic target for tumors and its underlying mechanisms. Biomed Pharmacother 2024; 180:117551. [PMID: 39405903 DOI: 10.1016/j.biopha.2024.117551] [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: 07/27/2024] [Revised: 09/22/2024] [Accepted: 10/08/2024] [Indexed: 11/14/2024] Open
Abstract
As a dual-function protein, prosaposin (PSAP) is a lysosome-associated protein that participates in a variety of cellular processes. In the lysosome, PSAP is processed to activate enzymes that degrade lipids. In addition, PSAP proteins located extracellularly are involved in cancer progression, such as proliferation and tumor death suppression signaling. Moreover, under different situations, PSAP exhibits distinct metastasis potentials in tumors. However, comprehensive insight into PSAP in cancer progression has been lacking. Here, we provide a framework of the role of PSAP in cancer and its clinical application in cancer patients, providing a novel perspective on the clinical translation of PSAP.
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Affiliation(s)
- Lirong Yan
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, Liaoning Province 110001, China
| | - Zhenpeng Wen
- Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China
| | - Yi Yang
- Department of Laboratory Animal Science, China Medical University, Shenyang, China
| | - Aoran Liu
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, Liaoning Province 110001, China
| | - Fang Li
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, Liaoning Province 110001, China
| | - Yuzhe Zhang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, Liaoning Province 110001, China
| | - Chunjiao Yang
- Department of Oncology, The Fifth Affiliated Hospital of Guangxi Medical University & The First People's Hospital of Nanning, Nanning, Guangxi, China
| | - Yanke Li
- Department of Anorectal Surgery, the First Hospital of China Medical University, Shenyang, China.
| | - Ye Zhang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, Liaoning Province 110001, China.
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Tezcan G, Yakar N, Hasturk H, Van Dyke TE, Kantarci A. Resolution of chronic inflammation and cancer. Periodontol 2000 2024; 96:229-249. [PMID: 39177291 DOI: 10.1111/prd.12603] [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: 06/13/2024] [Revised: 07/26/2024] [Accepted: 08/09/2024] [Indexed: 08/24/2024]
Abstract
Chronic inflammation poses challenges to effective cancer treatment. Although anti-inflammatory therapies have shown short-term benefits, their long-term implications may be unfavorable because they fail to initiate the necessary inflammatory responses. Recent research underscores the promise of specialized pro-resolving mediators, which play a role in modulating the cancer microenvironment by promoting the resolution of initiated inflammatory processes and restoring tissue hemostasis. This review addresses current insights into how inflammation contributes to cancer pathogenesis and explores recent strategies to resolve inflammation associated with cancer.
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Affiliation(s)
- Gulcin Tezcan
- ADA Forsyth Institute, Cambridge, Massachusetts, USA
- Department of Fundamental Sciences, Faculty of Dentistry, Bursa Uludag University, Bursa, Turkey
| | - Nil Yakar
- ADA Forsyth Institute, Cambridge, Massachusetts, USA
| | - Hatice Hasturk
- ADA Forsyth Institute, Cambridge, Massachusetts, USA
- Department of Oral Microbiology and Infection, Harvard School of Dental Medicine, Boston, Massachusetts, USA
| | - Thomas E Van Dyke
- ADA Forsyth Institute, Cambridge, Massachusetts, USA
- Department of Oral Microbiology and Infection, Harvard School of Dental Medicine, Boston, Massachusetts, USA
| | - Alpdogan Kantarci
- ADA Forsyth Institute, Cambridge, Massachusetts, USA
- Department of Oral Microbiology and Infection, Harvard School of Dental Medicine, Boston, Massachusetts, USA
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Zhang J, Xie L, Li H, Li S, Gao X, Zhang M. Selenomethionine Promotes Milk Protein and Fat Synthesis and Proliferation of Mammary Epithelial Cells through the GPR37-mTOR-S6K1 Signaling. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:19505-19516. [PMID: 39177123 DOI: 10.1021/acs.jafc.4c03911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/24/2024]
Abstract
Selenomethionine (SeMet) is an important nutrient, but its role in milk synthesis and the GPCR related to SeMet sensing is still largely unknown. Here, we determined the dose-dependent role of SeMet on milk protein and fat synthesis and proliferation of mammary epithelial cells (MECs), and we also uncovered the GPCR-mediating SeMet function. At 24 h postdelivery, lactating mother mice were fed a maintenance diet supplemented with 0, 5, 10, 20, 40, and 80 mg/kg SeMet, and the feeding process lasted for 18 days. The 10 mg/kg group had the best increase in milk production, weight gain of offspring mice, and mammary gland weight and acinar size, whereas a higher concentration of SeMet gradually decreased the weight gain of the offspring mice and showed toxic effects. Transcriptome sequencing was performed to find the differentially expressed genes (DEGs) between the mammary gland tissues of mother mice in the 10 mg/kg SeMet treatment group and the control group. A total of 258 DEGs were screened out, including 82 highly expressed genes including GPR37 and 176 lowly expressed genes. SeMet increased milk protein and fat synthesis in HC11 cells and cell proliferation, mTOR and S6K1 phosphorylation, and expression of GPR37 in a dose-dependent manner. GPR37 knockdown decreased milk protein and fat synthesis in HC11 cells and cell proliferation and blocked SeMet stimulation on mTOR and S6K1 phosphorylation. Taken together, our data demonstrate that SeMet can promote milk protein and fat synthesis and proliferation of MECs and functions through the GPR37-mTOR-S6K1 signaling pathway.
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Affiliation(s)
- Jinlong Zhang
- College of Animal Science and Technology, Yangtze University, Jingmi Road 88, Jingzhou 434025, China
| | - Liping Xie
- College of Animal Science and Technology, Yangtze University, Jingmi Road 88, Jingzhou 434025, China
| | - Heqian Li
- College of Animal Science and Technology, Yangtze University, Jingmi Road 88, Jingzhou 434025, China
| | - Siqi Li
- College of Animal Science and Technology, Yangtze University, Jingmi Road 88, Jingzhou 434025, China
| | - Xuejun Gao
- College of Animal Science and Technology, Yangtze University, Jingmi Road 88, Jingzhou 434025, China
| | - Minghui Zhang
- College of Animal Science and Technology, Yangtze University, Jingmi Road 88, Jingzhou 434025, China
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Wen B, Zhang P, Xie J, Zhou Z, Zhang G, Zhang L, Zhang Z. Deciphering the prognostic role of endoplasmic reticulum stress in lung adenocarcinoma: integrating prognostic prediction and immunotherapy strategies. Clin Exp Med 2024; 24:169. [PMID: 39052154 PMCID: PMC11272744 DOI: 10.1007/s10238-024-01439-4] [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: 06/09/2024] [Accepted: 07/16/2024] [Indexed: 07/27/2024]
Abstract
Endoplasmic reticulum stress (ERS) is a critical factor influencing lung adenocarcinoma (LUAD) progression and patient outcomes. In this study, we analyzed gene expression data from LUAD samples sourced from The Cancer Genomic Atlas and Gene Expression Omnibus databases. Utilizing advanced statistical methods including LASSO and Cox regression, we developed a ERS-associated signature (ERAS) based on ten ERS-related genes. This model stratified patients into high- and low-risk groups, with the high-risk group exhibiting decreased survival rates, elevated tumor mutational burden, and heightened chemotherapy sensitivity. Additionally, we observed lower immune and ESTIMATE scores in the high-ERAS group, indicating a potentially compromised immune response. Experimental validation through quantitative real-time polymerase chain reaction confirmed the utility of our model. Furthermore, we constructed a nomogram to predict 1-, 3-, and 5-year survival rates, providing clinicians with a valuable tool for personalized patient management. In conclusion, our study demonstrates the efficacy of the ERAS in identifying high-ERAS LUAD patients, offering promising implications for improved prognostication and treatment strategies.
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Affiliation(s)
- Bing Wen
- Department of Lung Cancer, Tianjin Lung Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- Department of Cardiothoracic Surgery, The Second People's Hospital of Yibin, Yibin, Sichuan, China
| | - Pengpeng Zhang
- Department of Lung Cancer, Tianjin Lung Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Jiping Xie
- Department of Lung Cancer, Tianjin Lung Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Zhaokai Zhou
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ge Zhang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lianmin Zhang
- Department of Lung Cancer, Tianjin Lung Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
| | - Zhenfa Zhang
- Department of Lung Cancer, Tianjin Lung Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
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12
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Öz-Arslan D, Yavuz M, Kan B. Exploring orphan GPCRs in neurodegenerative diseases. Front Pharmacol 2024; 15:1394516. [PMID: 38895631 PMCID: PMC11183337 DOI: 10.3389/fphar.2024.1394516] [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: 03/01/2024] [Accepted: 05/15/2024] [Indexed: 06/21/2024] Open
Abstract
Neurodegenerative disorders represent a significant and growing health burden worldwide. Unfortunately, limited therapeutic options are currently available despite ongoing efforts. Over the past decades, research efforts have increasingly focused on understanding the molecular mechanisms underlying these devastating conditions. Orphan receptors, a class of receptors with no known endogenous ligands, emerge as promising druggable targets for diverse diseases. This review aims to direct attention to a subgroup of orphan GPCRs, in particular class A orphans that have roles in neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Multiple sclerosis. We highlight the diverse roles orphan receptors play in regulating critical cellular processes such as synaptic transmission, neuronal survival and neuro-inflammation. Moreover, we discuss the therapeutic potential of targeting orphan receptors for the treatment of neurodegenerative disorders, emphasizing recent advances in drug discovery and preclinical studies. Finally, we outline future directions and challenges in orphan receptor research.
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Affiliation(s)
- Devrim Öz-Arslan
- Department of Biophysics, Acibadem MAA University, School of Medicine, Istanbul, Türkiye
- Department of Neurosciences, Acibadem MAA University, Institute of Health Sciences, İstanbul, Türkiye
| | - Melis Yavuz
- Department of Neurosciences, Acibadem MAA University, Institute of Health Sciences, İstanbul, Türkiye
- Department of Pharmacology, Acibadem MAA University, School of Pharmacy, Istanbul, Türkiye
| | - Beki Kan
- Department of Biophysics, Acibadem MAA University, School of Medicine, Istanbul, Türkiye
- Department of Neurosciences, Acibadem MAA University, Institute of Health Sciences, İstanbul, Türkiye
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13
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Zhang Y, Li D. An original aneuploidy-related gene model for predicting lung adenocarcinoma survival and guiding therapy. Sci Rep 2024; 14:8135. [PMID: 38584220 PMCID: PMC10999435 DOI: 10.1038/s41598-024-58020-y] [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: 11/02/2023] [Accepted: 03/25/2024] [Indexed: 04/09/2024] Open
Abstract
Aneuploidy is a hallmark of cancers, but the role of aneuploidy-related genes in lung adenocarcinoma (LUAD) and their prognostic value remain elusive. Gene expression and copy number variation (CNV) data were enrolled from TCGA and GEO database. Consistency clustering analysis was performed for molecular cluster. Tumor microenvironment was assessed by the xCell and ESTIMATE algorithm. Limma package was used for selecting differentially expressed genes (DEGs). LASSO and stepwise multivariate Cox regression analysis were used to establish an aneuploidy-related riskscore (ARS) signature. GDSC database was conducted to predict drug sensitivity. A nomogram was designed by rms R package. TCGA-LUAD patients were stratified into 3 clusters based on CNV data. The C1 cluster displayed the optimal survival advantage and highest inflammatory infiltration. Based on integrated intersecting DEGs, we constructed a 6-gene ARS model, which showed effective prediction for patient's survival. Drug sensitivity test predicted possible sensitive drugs in two risk groups. Additionally, the nomogram exhibited great predictive clinical treatment benefits. We established a 6-gene aneuploidy-related signature that could effectively predict the survival and therapy for LUAD patients. Additionally, the ARS model and nomogram could offer guidance for the preoperative estimation and postoperative therapy of LUAD.
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Affiliation(s)
- Yalei Zhang
- Department of Thoracic Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510032, China.
| | - Dongmei Li
- Department of Thoracic Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510032, China
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14
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Zhou J, Xu W, Wu Y, Wang M, Zhang N, Wang L, Feng Y, Zhang T, Wang L, Mao A. GPR37 promotes colorectal cancer liver metastases by enhancing the glycolysis and histone lactylation via Hippo pathway. Oncogene 2023; 42:3319-3330. [PMID: 37749229 DOI: 10.1038/s41388-023-02841-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 09/04/2023] [Accepted: 09/13/2023] [Indexed: 09/27/2023]
Abstract
Liver metastases are commonly detected in a range of malignancies including colorectal cancer (CRC), unfortunately no effectively strategies for CRC liver metastasis (CRLM). In this study, we found GPR37 expression dramatically increased in human CRLM specimens and associated poor prognosis. GPR37 depletion greatly suppressed the liver metastasis in the mouse models of CRLM. Functional experiments showed that GPR37 knockdown inhibited the growth by reducing the glycolysis of CRC cells. Also, GPR37 knockdown in tumor cells produced decreased levels of two chemokines involved in neutrophil accumulation, which abrogated neutrophil recruitment in the tumor microenvironment of CRLM. Finally, the mechanism studies revealed that GPR37 could activate the hippo pathway, thereby promoting LDHA expression and glycolysis. This leads to increased lactylation of H3K18la, resulting in up-regulation of CXCL1 and CXCL5. These results support a role of the GPR37 in modulating the tumor metabolism and microenvironment in CRLM and GPR37 could be a potential therapeutic target.
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Affiliation(s)
- Jiamin Zhou
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China
| | - Weiqi Xu
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China
| | - Yibin Wu
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China
| | - Miao Wang
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China
| | - Ning Zhang
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China
| | - Longrong Wang
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China
| | - Yun Feng
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China
| | - Ti Zhang
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China
| | - Lu Wang
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China.
| | - Anrong Mao
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China.
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15
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Liang K, Guo Z, Zhang S, Chen D, Zou R, Weng Y, Peng C, Xu Z, Zhang J, Liu X, Pang X, Ji Y, Liao D, Lai M, Peng H, Ke Y, Wang Z, Wang Y. GPR37 expression as a prognostic marker in gliomas: a bioinformatics-based analysis. Aging (Albany NY) 2023; 15:10146-10167. [PMID: 37837549 PMCID: PMC10599758 DOI: 10.18632/aging.205063] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 08/21/2023] [Indexed: 10/16/2023]
Abstract
BACKGROUND Gliomas are the most frequently diagnosed primary brain tumors, and are associated with multiple molecular aberrations during their development and progression. GPR37 is an orphan G protein-coupled receptor (GPCR) that is implicated in different physiological pathways in the brain, and has been linked to various malignancies. The aim of this study was to explore the relationship between GPR37 gene expression and the clinicopathological factors, patient prognosis, tumor-infiltrating immune cell signature GSEA and methylation levels in glioma. METHODS We explored the diagnostic value, clinical relevance, and molecular function of GPR37 in glioma using TCGA, STRING, cBioPortal, Tumor Immunity Estimation Resource (TIMER) database and MethSurv databases. Besides, the "ssGSEA" algorithm was conducted to estimate immune cells infiltration abundance, with 'ggplot2' package visualizing the results. Immunohistochemical staining of clinical samples were used to verify the speculations of bioinformatics analysis. RESULTS GPR37 expression was significantly higher in the glioma tissues compared to the normal brain tissues, and was linked to poor prognosis. Functional annotation of GPR37 showed enrichment of ether lipid metabolism, fat digestion and absorption, and histidine metabolism. In addition, GSEA showed that GPR37 was positively correlated to the positive regulation of macrophage derived foam cell differentiation, negative regulation of T cell receptor signaling pathway, neuroactive ligand receptor interaction, calcium signaling pathway, and negatively associated with immunoglobulin complex, immunoglobulin complex circulating, ribosome and spliceosome mediated by circulating immunoglobulin etc. TIMER2.0 and ssGSEA showed that GPR37 expression was significantly associated with the infiltration of T cells, CD8 T cell, eosinophils, macrophages, neutrophils, NK CD56dim cells, NK cells, plasmacytoid DCs (pDCs), T helper cells and T effector memory (Tem) cells. In addition, high GPR37 expression was positively correlated with increased infiltration of M2 macrophages, which in turn was associated with poor prognosis. Furthermore, GPR37 was positively correlated with various immune checkpoints (ICPs). Finally, hypomethylation of the GPR37 promoter was associated with its high expression levels and poor prognosis in glioma. CONCLUSION GPR37 had diagnostic and prognostic value in glioma. The possible biological mechanisms of GPR37 provide novel insights into the clinical diagnosis and treatment of glioma.
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Affiliation(s)
- Kairong Liang
- Institute of Neuroscience, Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Zhaoxiong Guo
- Science and Technology Innovation Center, Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Shizhen Zhang
- Institute of Neuroscience, Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Danmin Chen
- Institute of Neuroscience, Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Renheng Zou
- Institute of Neuroscience, Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Yuhao Weng
- Institute of Neuroscience, Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Chengxiang Peng
- Institute of Neuroscience, Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Zhichao Xu
- Institute of Neuroscience, Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Jingbai Zhang
- Institute of Neuroscience, Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Xiaorui Liu
- Department of Pharmacy, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou 510095, China
| | - Xiao Pang
- Institute of Neuroscience, Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Yunxiang Ji
- Institute of Neuroscience, Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Degui Liao
- Institute of Neuroscience, Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Miaoling Lai
- Institute of Neuroscience, Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Huaidong Peng
- Department of Pharmacy, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Yanbin Ke
- Institute of Neuroscience, Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Zhaotao Wang
- Institute of Neuroscience, Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Yezhong Wang
- Institute of Neuroscience, Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
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Liu H, Zhu Y, Niu H, Jie J, Hua S, Bai X, Wang S, Song L. Activation of PI3K/Akt pathway by G protein-coupled receptor 37 promotes resistance to cisplatin-induced apoptosis in non-small cell lung cancer. Cancer Med 2023; 12:19777-19793. [PMID: 37732632 PMCID: PMC10587962 DOI: 10.1002/cam4.6543] [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: 05/28/2023] [Revised: 08/29/2023] [Accepted: 09/05/2023] [Indexed: 09/22/2023] Open
Abstract
OBJECTIVES Lung cancer is a major public health concern and represents the most common cause of cancer-related death worldwide. Among eukaryotes, the G protein-coupled receptor (GPCR) family stands as the largest group of membrane proteins. Alterations in GPCR gene expression and dysregulation of signal transduction have been recognized as the markers of malignancy. As a member of the GPCR family, G protein-coupled receptor 37 (GPR37) exhibits unknown functions in tumors, particularly in non-small-cell lung cancer (NSCLC) METHODS: We explored the expression and prognosis of GPR37 in NSCLC through TCGA, GTEx, GEO, and GEPIA2. We detected the expression of GPR37 in NSCLC tissues and cell lines. The study explored the influence of GPR37 on tumor cell proliferation. Furthermore, we examined the effects of GPR37 on tumor cell apoptosis and invasion. Most importantly, we investigated whether GPR37 affects cisplatin-induced drug resistance in NSCLC. Furthermore, by conducting animal experiments, we assessed the impact of GPR37 on NSCLC and delved into underlying mechanisms. RESULTS (1) In NSCLC, the expression of GPR37 is markedly higher than that in corresponding normal tissues. We found that elevated GPR37 expression predicts an unfavorable prognosis. (2) It was demonstrated that GPR37 positively regulates NSCLC cell invasion, migration, and proliferation, suppresses cell apoptosis, heightens resistance to cisplatin, and promotes tumor formation and growth. Conversely, we observed that GPR37 knockdown suppresses NSCLC cell invasion, migration, and proliferation, promotes cell apoptosis, increases sensitivity to cisplatin, and affects tumor formation and growth. (3) GPR37 activates PI3K/Akt/mTOR signal transduction pathways to mediate epithelial-mesenchymal transition (EMT), thereby promoting the progression of NSCLC. CONCLUSIONS It was suggested that GPR37 acts a crucial role in promoting the occurrence and development of NSCLC. Knockdown of GPR37 significantly inhibits the occurrence and development of NSCLC. Therefore, our findings demonstrated that GPR37 may represent a viable therapeutic target for NSCLC.
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Affiliation(s)
- Han Liu
- Department of Respiratory MedicineThe First Hospital of Jilin UniversityChangchunJilinChina
| | - Yingjie Zhu
- Department of Respiratory and Critical Care MedicineThe Second Affiliated Hospital of Fujian Medical UniversityQuanzhouFujianChina
| | - Huikun Niu
- Department of Respiratory MedicineThe First Hospital of Jilin UniversityChangchunJilinChina
| | - Jing Jie
- Department of Respiratory MedicineThe First Hospital of Jilin UniversityChangchunJilinChina
| | - Shucheng Hua
- Department of Respiratory MedicineThe First Hospital of Jilin UniversityChangchunJilinChina
| | - Xiaoxue Bai
- Department of General PracticeThe First Hospital of Jilin UniversityChangchunJilinChina
| | - Shuai Wang
- Department of Vascular Surgery, General Surgery CenterThe First Hospital of Jilin UniversityChangchunJilinChina
| | - Lei Song
- Department of Respiratory MedicineThe First Hospital of Jilin UniversityChangchunJilinChina
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Zhang CY, Zhang R, Zhang L, Wang ZM, Sun HZ, Cui ZG, Zheng HC. Regenerating gene 4 promotes chemoresistance of colorectal cancer by affecting lipid droplet synthesis and assembly. World J Gastroenterol 2023; 29:5104-5124. [PMID: 37744296 PMCID: PMC10514755 DOI: 10.3748/wjg.v29.i35.5104] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 08/10/2023] [Accepted: 08/25/2023] [Indexed: 09/14/2023] Open
Abstract
BACKGROUND Regenerating gene 4 (REG4) has been proved to be carcinogenic in some cancers, but its manifestation and possible carcinogenic mechanisms in colorectal cancer (CRC) have not yet been elucidated. Our previous study found that the drug resistance of CRC cells may be closely linked to their fat metabolism. AIM To explore the role of REG4 in CRC and its association with lipid droplet formation and chemoresistance. METHODS We conducted a meta-analysis and bioinformatics and pathological analyses of REG4 expression in CRC. The effects of REG4 on the phenotypes and related protein expression were also investigated in CRC cells. We detected the impacts of REG4 on the chemoresistance and lipid droplet formation in CRC cells. Finally, we analyzed how REG4 regulated the transcription and proteasomal degradation of lipogenic enzymes in CRC cells. RESULTS Compared to normal mucosa, REG4 mRNA expression was high in CRC (P < 0.05) but protein expression was low. An inverse correlation existed between lymph node and distant metastases, tumor-node-metastasis staging or short overall survival and REG4 mRNA overexpression (P < 0.05), but vice versa for REG4 protein expression. REG4-related genes included: Chemokine activity; taste receptors; protein-DNA and DNA packing complexes; nucleosomes and chromatin; generation of second messenger molecules; programmed cell death signals; epigenetic regulation and DNA methylation; transcription repression and activation by DNA binding; insulin signaling pathway; sugar metabolism and transfer; and neurotransmitter receptors (P < 0.05). REG4 exposure or overexpression promoted proliferation, antiapoptosis, migration, and invasion of DLD-1 cells in an autocrine or paracrine manner by activating the epidermal growth factor receptor-phosphoinositide 3-kinase-Akt-nuclear factor-κB pathway. REG4 was involved in chemoresistance not through de novo lipogenesis, but lipid droplet assembly. REG4 inhibited the transcription of acetyl-CoA carboxylase 1 (ACC1) and ATP-citrate lyase (ACLY) by disassociating the complex formation of anti-acetyl (AC)-acetyl-histone 3-AC-histone 4-inhibitor of growth protein-5-si histone deacetylase;-sterol-regulatory element binding protein 1 in their promoters and induced proteasomal degradation of ACC1 or ACLY. CONCLUSION REG4 may be involved in chemoresistance through lipid droplet assembly. REG4 reduces expression of de novo lipid synthesis key enzymes by inhibiting transcription and promoting ubiquitination-mediated proteasomal degradation.
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Affiliation(s)
- Cong-Yu Zhang
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| | - Rui Zhang
- Department of Colorectal Surgery, Liaoning Cancer Hospital, Shenyang 110042, Liaoning Province, China
| | - Li Zhang
- Department of Oncology, The Affiliated Hospital of Chengde Medical University, Chengde 067000, Hebei Province, China
| | - Zi-Mo Wang
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| | - Hong-Zhi Sun
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| | - Zheng-Guo Cui
- Department of Environmental Health, University of Fukui School of Medical Sciences, Fukui 910-1193, Japan
| | - Hua-Chuan Zheng
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
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Bolinger AA, Frazier A, La JH, Allen JA, Zhou J. Orphan G Protein-Coupled Receptor GPR37 as an Emerging Therapeutic Target. ACS Chem Neurosci 2023; 14:3318-3334. [PMID: 37676000 PMCID: PMC11144446 DOI: 10.1021/acschemneuro.3c00479] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/08/2023] Open
Abstract
G protein-coupled receptors (GPCRs) are successful druggable targets, making up around 35% of all FDA-approved medications. However, a large number of receptors remain orphaned, with no known endogenous ligand, representing a challenging but untapped area to discover new therapeutic targets. Among orphan GPCRs (oGPCRs) of interest, G protein-coupled receptor 37 (GPR37) is highly expressed in the central nervous system (CNS), particularly in the spinal cord and oligodendrocytes. While its cellular signaling mechanisms and endogenous receptor ligands remain elusive, GPR37 has been implicated in several important neurological conditions, including Parkinson's disease (PD), inflammation, pain, autism, and brain tumors. GPR37 structure, signaling, emerging physiology, and pharmacology are reviewed while integrating a discussion on potential therapeutic indications and opportunities.
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Affiliation(s)
- Andrew A. Bolinger
- Department of Pharmacology and Toxicology, Center for Addiction Sciences and Therapeutics, University of Texas Medical Branch, Galveston, Texas 77555, United States
| | - Andrew Frazier
- Department of Pharmacology and Toxicology, Center for Addiction Sciences and Therapeutics, University of Texas Medical Branch, Galveston, Texas 77555, United States
| | - Jun-Ho La
- Department of Neurobiology, University of Texas Medical Branch, Galveston, Texas 77555, United States
| | - John A. Allen
- Department of Pharmacology and Toxicology, Center for Addiction Sciences and Therapeutics, University of Texas Medical Branch, Galveston, Texas 77555, United States
| | - Jia Zhou
- Department of Pharmacology and Toxicology, Center for Addiction Sciences and Therapeutics, University of Texas Medical Branch, Galveston, Texas 77555, United States
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Patel M, Arora A, Mukherjee D, Mukherjee S. Effect of hyperthermic intraperitoneal chemotherapy on survival and recurrence rates in advanced gastric cancer: a systematic review and meta-analysis. Int J Surg 2023; 109:2435-2450. [PMID: 37158149 PMCID: PMC10442139 DOI: 10.1097/js9.0000000000000457] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 05/01/2023] [Indexed: 05/10/2023]
Abstract
BACKGROUND Around 5-20% of patients who undergo surgery for advanced gastric cancer (AGC), which invades into the muscularis propria or beyond, have peritoneal carcinomatosis. The peritoneal recurrence rate is 10-54%, which is associated with a poor prognosis. The role of hyperthermic intraperitoneal chemotherapy (HIPEC) in AGC with and without peritoneal carcinomatosis is not clearly defined. METHODS The authors conducted a meta-analysis, in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, of the clinical trials and high-quality nonrandomized studies evaluating the role of HIPEC in AGC over the last 10 years. The studies were searched in PubMed, EMBASE, MEDLINE, and Cochrane databases between January 2011 to December 2021. Clinical data including overall survival, recurrence free survival, overall recurrence rate, peritoneal recurrence rate, and complications analyzed using RevMan 5.4. RESULTS Six randomized controlled trials and 10 nonrandomized studies, comprising a total of 1700 patients were included. HIPEC was associated with significantly improved OS at 3 [odd ratio (OR) 1.89, 95% CI: 1.17-3.05] and 5 years (OR 1.87, 95% CI: 1.29-2.71). HIPEC was associated with reduced overall recurrence (OR 0.49, 95% CI: 0.31-0.80) and peritoneal recurrence (OR 0.22, 95% CI: 0.11-0.47). HIPEC was not associated with increased complications. The occurrence of postoperative renal dysfunction was significantly higher in the HIPEC group (OR 3.94, 95% CI: 1.85-8.38). CONCLUSION The role of HIPEC in AGC has evolved over the past decade. HIPEC may improve survival rates and reduce recurrence rates in patients with AGC, without significant increase in complications and with a favorable impact on 3 and 5-year survival.
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Affiliation(s)
- Maitreyi Patel
- Department of General Surgery, Queen’s and King George’s Hospital, Barking, Havering and Redbridge University NHS Trust, Rom Valley Way, Romford, United Kingdom
| | - Amandeep Arora
- Department of Uro-Oncology, Tata Memorial Hospital, Mumbai, India
| | - Dipankar Mukherjee
- Department of General Surgery, Queen’s and King George’s Hospital, Barking, Havering and Redbridge University NHS Trust, Rom Valley Way, Romford, United Kingdom
| | - Samrat Mukherjee
- Department of General Surgery, Queen’s and King George’s Hospital, Barking, Havering and Redbridge University NHS Trust, Rom Valley Way, Romford, United Kingdom
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20
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Chen J, Long MD, Sribenja S, Ma SJ, Yan L, Hu Q, Liu S, Khoury T, Hong CC, Bandera E, Singh AK, Repasky EA, Bouchard EG, Higgins M, Ambrosone CB, Yao S. An epigenome-wide analysis of socioeconomic position and tumor DNA methylation in breast cancer patients. Clin Epigenetics 2023; 15:68. [PMID: 37101222 PMCID: PMC10131486 DOI: 10.1186/s13148-023-01470-4] [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: 06/06/2022] [Accepted: 03/21/2023] [Indexed: 04/28/2023] Open
Abstract
BACKGROUND Disadvantaged socioeconomic position (SEP), including lower educational attainment and household income, may influence cancer risk and outcomes. We hypothesized that DNA methylation could function as an intermediary epigenetic mechanism that internalizes and reflects the biological impact of SEP. METHODS Based on tumor DNA methylation data from the Illumina 450 K array from 694 breast cancer patients in the Women's Circle of Health Study, we conducted an epigenome-wide analysis in relation to educational attainment and household income. Functional impact of the identified CpG sites was explored in silico using data from publicly available databases. RESULTS We identified 25 CpG sites associated with household income at an array-wide significance level, but none with educational attainment. Two of the top CpG sites, cg00452016 and cg01667837, were in promoter regions of NNT and GPR37, respectively, with multiple epigenetic regulatory features identified in each region. NNT is involved in β-adrenergic stress signaling and inflammatory responses, whereas GPR37 is involved in neurological and immune responses. For both loci, gene expression was inversely correlated to the levels of DNA methylation. The associations were consistent between Black and White women and did not differ by tumor estrogen receptor (ER) status. CONCLUSIONS In a large breast cancer patient population, we discovered evidence of the significant biological impact of household income on the tumor DNA methylome, including genes in the β-adrenergic stress and immune response pathways. Our findings support biological effects of socioeconomic status on tumor tissues, which might be relevant to cancer development and progression.
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Affiliation(s)
- Jianhong Chen
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Mark D Long
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Sirinapa Sribenja
- Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Sung Jun Ma
- Department of Radiation Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Li Yan
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Qiang Hu
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Song Liu
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Thaer Khoury
- Department of Pathology and Laboratory Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Chi-Chen Hong
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Elisa Bandera
- Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, The State University of New Jersey, New Brunswick, NJ, USA
| | - Anurag K Singh
- Department of Radiation Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Elizabeth A Repasky
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Elizabeth G Bouchard
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Michael Higgins
- Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Christine B Ambrosone
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Song Yao
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.
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Inflammation and Infection in Pain and the Role of GPR37. Int J Mol Sci 2022; 23:ijms232214426. [PMID: 36430912 PMCID: PMC9692891 DOI: 10.3390/ijms232214426] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/15/2022] [Accepted: 11/17/2022] [Indexed: 11/22/2022] Open
Abstract
Inflammation is known to cause pain, and pain is of one of the cardinal signs of inflammation. Mounting evidence suggests that acute inflammation also resolves pain through specialized pro-resolving mediators (SPMs) and macrophage signaling. GPR37 is expressed by neurons and oligodendrocytes in the brain and has been implicated in multiple disorders, such as demyelination, Parkinson's disease, stroke, and cancer. Recent studies have demonstrated that GPR37 is expressed by macrophages and confers protection against infection by bacteria and parasites. Furthermore, GPR37 promotes the resolution of inflammatory pain and infection-induced pain, as the duration of pain after tissue injury and infection is prolonged in mice lacking Gpr37. Mechanistically, activation of GPR37 enhances macrophage phagocytosis, and Gpr37-deficient macrophages exhibit dysregulations of pro-inflammatory and anti-inflammatory cytokines, switching from M2- to M1-like phenotypes. We also discuss novel ligands of GPR37, including neuroprotectin D1 (NPD1), a SPM derived from docosahexaenoic acid (DHA), and bone-derived hormone osteocalcin (OCN), which can suppress oligodendrocyte differentiation and myelination. NPD1 stimulates macrophage phagocytosis via GPR37 and exhibits potent analgesic actions in various animal models of inflammatory and neuropathic pain. Targeting GPR37 may lead to novel therapeutics for treating inflammation, infection, pain, and neurological diseases.
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22
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Xiang LW, Xue H, Ha MW, Yu DY, Xiao LJ, Zheng HC. The effects of REG4 expression on chemoresistance of ovarian cancer. J OBSTET GYNAECOL 2022; 42:3149-3157. [PMID: 35929918 DOI: 10.1080/01443615.2022.2106834] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Although ovarian cancer usually responds well to platinum- and taxane-based first-line chemotherapy, most patients develop recurrence and chemoresistance. Regenerating gene 4 (REG4) is a secretory protein involved in cell differentiation and proliferation. We found higher REG4 expression in ovarian cancer than in normal tissues (p < .05). Regenerating gene 4 expression was negatively associated with overall, progression-free or post-progression survival rates of patients with ovarian cancer receiving platinum or paclitaxel treatment (p < .05) according to a Kaplan-Meier plotter. Regenerating gene 4 overexpression resulted in either cisplatin or paclitaxel resistance, and apoptosis resistance in CAOV3 ovarian cancer cells (p < .05). REG4-transfected ovarian cancer cells showed stronger migration and invasion treated with cisplatin or paclitaxel (p < .05). Additionally, cisplatin or paclitaxel exposure led to the overexpression of phosphorylated phosphoinositide 3-kinase (p-PI3K), p-Akt, phosphorylated mammalian target of rapamycin (p-mTOR), glutathione S-transferase-π, survivin, and B-cell lymphoma 2 in REG4 transfectants compared with control cells (p < .05). These findings suggested that REG4 expression was up-regulated in ovarian cancer, and associated with poor survival and chemotherapy resistance. REG4 promoted the occurrence, development, and chemotherapy resistance of ovarian cancer by regulating cell proliferation, apoptosis, migration, and invasion, and PI3K/Akt/m-TOR signalling pathways. IMPACT STATEMENTWhat is already known on this subject? REG4 mRNA expression is up-regulated in many digestive cancers. High REG4 expression was associated with an adverse prognosis, high tumour and nodal stages, poor differentiation, and hepatic and peritoneal metastases of digestive cancers. REG4 expression conferred cancer cells with increased resistance to chemoradiotherapy, especially 5-FU-based treatment, by activating the MAPK/Erk/Bim signalling pathway.What do the results of this study add? REG4 was highly expressed in ovarian cancer. The expression of p-PI3K, p-AKT, p-mTOR, GST-π, survivin, and Bcl-2 was increased in REG4-overexpressing cells. High REG4 expression was significantly associated with inferior OS, PFS, and PPS rates in patients with ovarian cancer receiving platinum chemotherapy. REG4 mediated cisplatin and paclitaxel resistance in CAOV3 ovarian cancer cells. The percentage of apoptotic cells was markedly lower in REG4-transfected compared to mock-transfected cells after cisplatin or paclitaxel treatment.What are the implications of these findings for clinical practice and/or further research? This study aimed to evaluate the prognostic significance of REG4 expression in ovarian cancer treated with platinum and paclitaxel, to explore REG4 chemoresistance mechanisms to platinum and paclitaxel, and to provide a scientific experimental basis for the clinical treatment and outcome evaluation of ovarian cancer. In order to provide comprehensive clinical treatment of ovarian cancer, it is helpful to improve our understanding of multi-drug resistance and identify new cancer diagnostic biomarkers.
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Affiliation(s)
- Li-Wei Xiang
- Department of Oncology and Experimental Center, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Hang Xue
- Department of Oncology and Experimental Center, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Min-Wen Ha
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Da-Yong Yu
- Department of Cell Biology, Basic Medicine College of Chengde Medical University, Chengde, China
| | - Li-Jun Xiao
- Department of Immunology, Basic Medicine College of Chengde Medical University, Chengde, China
| | - Hua-Chuan Zheng
- Department of Oncology and Experimental Center, The Affiliated Hospital of Chengde Medical University, Chengde, China
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23
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Zheng HC, Xue H, Zhang CY. REG4 promotes the proliferation and anti-apoptosis of cancer. Front Cell Dev Biol 2022; 10:1012193. [PMID: 36172286 PMCID: PMC9511136 DOI: 10.3389/fcell.2022.1012193] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 08/26/2022] [Indexed: 11/27/2022] Open
Abstract
Regenerating islet-derived 4 (REG4) gene was discovered by high-throughput sequencing of ulcerative colitis cDNA libraries. REG4 is involved in infection and inflammation by enhancing macrophage polarization to M2, via activation of epidermal growth factor receptor (EGFR)/Akt/cAMP-responsive element binding and the killing inflammatory Escherichia coli, and closely linked to tumorigenesis. Its expression was transcriptionally activated by caudal type homeobox 2, GATA binding protein 6, GLI family zinc finger 1, SRY-box transcription factor 9, CD44 intracytoplasmic domain, activating transcription factor 2, and specificity protein 1, and translationally activated by miR-24. REG4 can interact with transmembrane CD44, G protein-coupled receptor 37, mannan and heparin on cancer cells. Its overexpression was observed in gastric, colorectal, pancreatic, gallbladder, ovarian and urothelial cancers, and is closely linked to their aggressive behaviors and a poor prognosis. Additionally, REG4 expression and recombinant REG4 aggravated such cellular phenotypes as tumorigenesis, proliferation, anti-apoptosis, chemoradioresistance, migration, invasion, peritoneal dissemination, tumor growth, and cancer stemness via EGFR/Akt/activator protein-1 and Akt/glycogen synthase kinase three β/β-catenin/transcription factor 4 pathways. Sorted REG4-positive deep crypt secretory cells promote organoid formation of single Lgr5 (+) colon stem cells by Notch inhibition and Wnt activation. Histologically, REG4 protein is specifically expressed in neuroendocrine tumors and signet ring cell carcinomas of the gastrointestinal tract, pancreas, ovary, and lung. It might support the histogenesis of gastric intestinal–metaplasia–globoid dysplasia–signet ring cell carcinoma. In this review, we summarized the structure, biological functions, and effects of REG4 on inflammation and cancer. We conclude that REG4 may be employed as a biomarker of tumorigenesis, subsequent progression and poor prognosis of cancer, and may be a useful target for gene therapy.
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Affiliation(s)
- Hua-Chuan Zheng
- Department of Oncology and Central Laboratory, The Affiliated Hospital of Chengde Medical University, Chengde, China
- *Correspondence: Hua-Chuan Zheng,
| | - Hang Xue
- Department of Oncology and Central Laboratory, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Cong-Yu Zhang
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
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24
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Xie X, Cai X, Zhou F, Li Y, Liu Q, Cai L, Zhu W, Wei J, Jin C, Liu Z, Jiang C, Zhao H, Yang L, Zhao C, Huang X. GPR37 promotes cancer growth by binding to CDK6 and represents a new theranostic target in lung adenocarcinoma. Pharmacol Res 2022; 183:106389. [PMID: 35934193 DOI: 10.1016/j.phrs.2022.106389] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 08/02/2022] [Accepted: 08/03/2022] [Indexed: 01/11/2023]
Abstract
Lung adenocarcinoma (LUAD) is associated with poor prognosis. Identifying novel cancer targets and helpful therapeutic strategies remains a serious clinical challenge. This study detected differentially expressed genes in The Cancer Genome Atlas (TCGA) LUAD data collection. We also identified a predictive DNA biomarker, G protein-coupled receptor 37 (GPR37), which was verified as a prognostic biomarker with a critical role in tumor progression. In human LUAD specimens and microarray analyses, we determined that GPR37 was significantly upregulated and associated with a poor prognosis. GPR37 downregulation markedly inhibited the proliferation and migration of LUAD both in vitro and in vivo. Mechanistically, GPR37 could bind to CDK6, thereby facilitating tumor progression in LUAD by inducing cell cycle arrest at the G1 phase. GPR37 also facilitates tumorigenesis in xenograft tumors in vivo. High-throughput screening for GPR37-targeted drugs was performed using the Natural Products Library, which revealed the potential of Hypocrellin B to inhibit GPR37 and cell growth in LUAD. We demonstrated that Hypocrellin B suppressed LUAD cell proliferation and migration both in vitro and in vivo via GPR37 inhibition. Collectively, our findings reveal the role of GPR37 in LUAD progression and migration and the potential of GPR37 as a target for the treatment of LUAD. Thus, the specific inhibition of GPR37 by the natural product Hypocrellin B may possess the potential for the treatment of LUAD.
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Affiliation(s)
- Xiaona Xie
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, China; Department of Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xueding Cai
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, China
| | - Feng Zhou
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, China
| | - Yaozhe Li
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, China
| | - Qianzi Liu
- The Institute of Life Sciences, Wenzhou University, University Town, Wenzhou, Zhejiang 325035, China
| | - Luqiong Cai
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, China
| | - Wenjing Zhu
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, China
| | - Jinqiu Wei
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, China
| | - Chenying Jin
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Zitian Liu
- Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chunhui Jiang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Haiyang Zhao
- The Institute of Life Sciences, Wenzhou University, University Town, Wenzhou, Zhejiang 325035, China
| | - Lehe Yang
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, China.
| | - Chengguang Zhao
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.
| | - Xiaoying Huang
- Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, China.
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25
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Ng D, Ali A, Lee K, Eymael D, Abe K, Luu S, Kazazian K, Lu YQ, Brar S, Conner J, Magalhaes M, Swallow CJ. Investigating the mechanisms of peritoneal metastasis in gastric adenocarcinoma using a novel ex vivo peritoneal explant model. Sci Rep 2022; 12:11499. [PMID: 35798764 PMCID: PMC9262973 DOI: 10.1038/s41598-022-13948-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 05/31/2022] [Indexed: 11/09/2022] Open
Abstract
Gastric adenocarcinoma, commonly known as stomach cancer, has a predilection for metastasis to the peritoneum, which portends limited survival. The peritoneal metastatic cascade remains poorly understood, and existing models fail to recapitulate key elements of the interaction between cancer cells and the peritoneal layer. To explore the underlying cellular and molecular mechanisms of peritoneal metastasis, we developed an ex vivo human peritoneal explant model. Fresh peritoneal tissue samples were suspended, mesothelial layer down but without direct contact, above a monolayer of red-fluorescent dye stained AGS human gastric adenocarcinoma cells for 24 h, then washed thoroughly. Implantation of AGS cells within the explanted peritoneum and invasion beyond the mesothelial layer were examined serially using real-time confocal fluorescence microscopy. Histoarchitecture of the explanted peritoneum was preserved over 5 days ex vivo. Both implantation and invasion were suppressed by restoration of functional E-cadherin through stable transfection of AGS cells, demonstrating sensitivity of the model to molecular manipulation. Thus, our ex vivo human peritoneal explant model permits meaningful investigation of the pathways and mechanism that contribute to peritoneal metastasis. The model will facilitate screening of new therapies that target peritoneal dissemination of gastric, ovarian and colorectal cancer.
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Affiliation(s)
- Deanna Ng
- Institute of Medical Science, University of Toronto, Toronto, Canada.,Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada.,Department of Surgery, University of Toronto, Toronto, Canada
| | - Aiman Ali
- Faculty of Dentistry, University of Toronto, Toronto, Canada
| | - Kiera Lee
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
| | - Denise Eymael
- Faculty of Dentistry, University of Toronto, Toronto, Canada
| | - Kento Abe
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
| | - Shelly Luu
- Institute of Medical Science, University of Toronto, Toronto, Canada.,Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada.,Department of Surgical Oncology and Division of General Surgery, Princess Margaret Cancer Centre, University Health Network/Mount Sinai Hospital, 600 University Avenue #1225, Toronto, ON, M5G 1X5, Canada.,Department of Surgery, University of Toronto, Toronto, Canada
| | - Karineh Kazazian
- Institute of Medical Science, University of Toronto, Toronto, Canada.,Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada.,Department of Surgical Oncology and Division of General Surgery, Princess Margaret Cancer Centre, University Health Network/Mount Sinai Hospital, 600 University Avenue #1225, Toronto, ON, M5G 1X5, Canada.,Department of Surgery, University of Toronto, Toronto, Canada
| | - Yi Qing Lu
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
| | - Savtaj Brar
- Department of Surgical Oncology and Division of General Surgery, Princess Margaret Cancer Centre, University Health Network/Mount Sinai Hospital, 600 University Avenue #1225, Toronto, ON, M5G 1X5, Canada.,Department of Surgery, University of Toronto, Toronto, Canada
| | - James Conner
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada
| | - Marco Magalhaes
- Institute of Medical Science, University of Toronto, Toronto, Canada.,Faculty of Dentistry, University of Toronto, Toronto, Canada
| | - Carol J Swallow
- Institute of Medical Science, University of Toronto, Toronto, Canada. .,Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada. .,Department of Surgical Oncology and Division of General Surgery, Princess Margaret Cancer Centre, University Health Network/Mount Sinai Hospital, 600 University Avenue #1225, Toronto, ON, M5G 1X5, Canada. .,Department of Surgery, University of Toronto, Toronto, Canada.
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26
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Qian Z, Liu C, Li H, Yang H, Wu J, Liu J, Li Y, Chen X, Xu J, Li X. Osteocalcin Alleviates Lipopolysaccharide-Induced Acute Inflammation via Activation of GPR37 in Macrophages. Biomedicines 2022; 10:1006. [PMID: 35625743 PMCID: PMC9138386 DOI: 10.3390/biomedicines10051006] [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: 03/25/2022] [Revised: 04/24/2022] [Accepted: 04/24/2022] [Indexed: 11/16/2022] Open
Abstract
The G protein-coupled receptor 37 (GPR37) has been reported to be expressed in macrophages and the activation of GPR37 by its ligand/agonist, and it can regulate macrophage-associated functions and inflammatory responses. Since our previous work identified that osteocalcin (OCN) acts as an endogenous ligand for GPR37 and can elicit various intracellular signals by interacting with GPR37, we thus hypothesized that OCN may also play a functional role in macrophage through the activation of GPR37. To verify the hypothesis, we conducted a series of in vivo and in vitro studies in lipopolysaccharide (LPS)-challenged mice and primary cultured macrophages. Our results reveal that the OCN gene deletion (OCN-/-) and wild type (WT) mice showed comparable death rates and inflammatory cytokines productions in response to a lethal dose of LPS exposure. However, the detrimental effects caused by LPS were significantly ameliorated by exogenous OCN treatments in both WT and OCN-/- mice. Notably, the protective effects of OCN were absent in GPR37-/- mice. In coordination with the in vivo results, our in vitro studies further illustrated that OCN triggered intracellular responses via GPR37 in peritoneal macrophages by regulating the release of inflammatory factors and macrophage phagocytic function. Finally, we exhibited that the adoptive transfer of OCN-treated macrophages from WT mice significantly inhibits the release of pro-inflammatory cytokines in GPR37-/- mice exposed to LPS. Taken together, these findings suggest a protective role of OCN against LPS-caused acute inflammation, by the activation of GPR37 in macrophages, and provide a potential application of the activation of the OCN/GPR37 regulatory axis as a therapeutic strategy for inflammatory diseases.
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Affiliation(s)
- Zhengjiang Qian
- Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, CAS Key Laboratory of Brain Connectome and Manipulation, Shenzhen Key Laboratory of Viral Vectors for Biomedicine, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen 518055, China; (Z.Q.); (C.L.); (H.L.); (H.Y.)
| | - Chunhua Liu
- Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, CAS Key Laboratory of Brain Connectome and Manipulation, Shenzhen Key Laboratory of Viral Vectors for Biomedicine, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen 518055, China; (Z.Q.); (C.L.); (H.L.); (H.Y.)
| | - Hongchao Li
- Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, CAS Key Laboratory of Brain Connectome and Manipulation, Shenzhen Key Laboratory of Viral Vectors for Biomedicine, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen 518055, China; (Z.Q.); (C.L.); (H.L.); (H.Y.)
| | - Haiyang Yang
- Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, CAS Key Laboratory of Brain Connectome and Manipulation, Shenzhen Key Laboratory of Viral Vectors for Biomedicine, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen 518055, China; (Z.Q.); (C.L.); (H.L.); (H.Y.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jianhao Wu
- Department of Traditional Chinese Medicine, Shenzhen University General Hospital, Shenzhen 518055, China; (J.W.); (J.L.); (J.X.)
| | - Jing Liu
- Department of Traditional Chinese Medicine, Shenzhen University General Hospital, Shenzhen 518055, China; (J.W.); (J.L.); (J.X.)
| | - Yanjiao Li
- Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China;
| | - Xuhui Chen
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen 518000, China;
| | - Jianyang Xu
- Department of Traditional Chinese Medicine, Shenzhen University General Hospital, Shenzhen 518055, China; (J.W.); (J.L.); (J.X.)
| | - Xiang Li
- Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, CAS Key Laboratory of Brain Connectome and Manipulation, Shenzhen Key Laboratory of Viral Vectors for Biomedicine, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen 518055, China; (Z.Q.); (C.L.); (H.L.); (H.Y.)
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Massimi M, Di Pietro C, La Sala G, Matteoni R. Mouse Mutants of Gpr37 and Gpr37l1 Receptor Genes: Disease Modeling Applications. Int J Mol Sci 2022; 23:ijms23084288. [PMID: 35457105 PMCID: PMC9025225 DOI: 10.3390/ijms23084288] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 02/05/2023] Open
Abstract
The vertebrate G protein–coupled receptor 37 and G protein–coupled receptor 37-like 1 (GPR37 and GPR37L1) proteins have amino acid sequence homology to endothelin and bombesin-specific receptors. The prosaposin glycoprotein, its derived peptides, and analogues have been reported to interact with and activate both putative receptors. The GPR37 and GPR37L1 genes are highly expressed in human and rodent brains. GPR37 transcripts are most abundant in oligodendrocytes and in the neurons of the substantia nigra and hippocampus, while the GPR37L1 gene is markedly expressed in cerebellar Bergmann glia astrocytes. The human GPR37 protein is a substrate of parkin, and its insoluble form accumulates in brain samples from patients of inherited juvenile Parkinson’s disease. Several Gpr37 and Gpr37l1 mouse mutant strains have been produced and applied to extensive in vivo and ex vivo analyses of respective receptor functions and involvement in brain and other organ pathologies. The genotypic and phenotypic characteristics of the different mouse strains so far published are reported and discussed, and their current and proposed applications to human disease modeling are highlighted.
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28
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Veiga RN, de Oliveira JC, Gradia DF. PBX1: a key character of the hallmarks of cancer. J Mol Med (Berl) 2021; 99:1667-1680. [PMID: 34529123 DOI: 10.1007/s00109-021-02139-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 08/17/2021] [Accepted: 09/08/2021] [Indexed: 12/13/2022]
Abstract
Pre-B-cell leukemia homeobox transcription factor 1 (PBX1) was first identified as part of a fusion protein resulting from the chromosomal translocation t(1;19) in pre-B cell acute lymphoblastic leukemias. Since then, PBX1 has been associated with important developmental programs, and its expression dysregulation has been related to multifactorial disorders, including cancer. As PBX1 overexpression in many cancers is correlated to poor prognosis, we sought to understand how this transcription factor contributes to carcinogenesis, and to organize PBX1's roles in the hallmarks of cancer. There is enough evidence to associate PBX1 with at least five hallmarks: sustaining proliferative signaling, activating invasion and metastasis, inducing angiogenesis, resisting cell death, and deregulating cellular energetics. The lack of studies investigating a possible role for PBX1 on the remaining hallmarks made it impossible to defend or refute its contribution on them. However, the functions of some of the PBX1's transcription targets indicate a potential engagement of PBX1 in the avoidance of immune destruction and in the tumor-promoting inflammation hallmarks. Interestingly, PBX1 might be a player in tumor suppression by activating the transcription of some DNA damage response genes. This is the first review organizing PBX1 roles into the hallmarks of cancer. Thus, we encourage future studies to uncover the PBX1's underlying mechanisms to promote carcinogenesis, for it is a promising diagnostic and prognostic biomarker, as well as a potential target in cancer treatment.
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Affiliation(s)
- Rafaela Nasser Veiga
- Laboratory of Human Cytogenetics and Oncogenetics, Department of Genetics, Postgraduate Program in Genetics, Universidade Federal Do Paraná, Rua Coronel Francisco Heráclito Dos Santos, 100, Jardim das AméricasCuritiba, CEP, 81531-980, Brazil
| | - Jaqueline Carvalho de Oliveira
- Laboratory of Human Cytogenetics and Oncogenetics, Department of Genetics, Postgraduate Program in Genetics, Universidade Federal Do Paraná, Rua Coronel Francisco Heráclito Dos Santos, 100, Jardim das AméricasCuritiba, CEP, 81531-980, Brazil
| | - Daniela Fiori Gradia
- Laboratory of Human Cytogenetics and Oncogenetics, Department of Genetics, Postgraduate Program in Genetics, Universidade Federal Do Paraná, Rua Coronel Francisco Heráclito Dos Santos, 100, Jardim das AméricasCuritiba, CEP, 81531-980, Brazil.
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Hertz E, Saarinen M, Svenningsson P. GM1 Is Cytoprotective in GPR37-Expressing Cells and Downregulates Signaling. Int J Mol Sci 2021; 22:ijms222312859. [PMID: 34884663 PMCID: PMC8657933 DOI: 10.3390/ijms222312859] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/15/2021] [Accepted: 11/17/2021] [Indexed: 01/02/2023] Open
Abstract
G-protein-coupled receptors (GPCRs) are commonly pharmacologically modulated due to their ability to translate extracellular events to intracellular changes. Previously, studies have mostly focused on protein–protein interactions, but the focus has now expanded also to protein–lipid connections. GM1, a brain-expressed ganglioside known for neuroprotective effects, and GPR37, an orphan GPCR often reported as a potential drug target for diseases in the central nervous system, have been shown to form a complex. In this study, we looked into the functional effects. Endogenous GM1 was downregulated when stably overexpressing GPR37 in N2a cells (N2aGPR37-eGFP). However, exogenous GM1 specifically rescued N2aGPR37-eGFP from toxicity induced by the neurotoxin MPP+. The treatment did not alter transcription levels of GPR37 or the enzyme responsible for GM1 production, both potential mechanisms for the effect. However, GM1 treatment inhibited cAMP-dependent signaling from GPR37, here reported as potentially consecutively active, possibly contributing to the protective effects. We propose an interplay between GPR37 and GM1 as one of the many cytoprotective effects reported for GM1.
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Affiliation(s)
- Ellen Hertz
- Correspondence: (E.H.); (P.S.); Tel.: +46-8517-74-614 (E.H.)
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The Potential Role of REG Family Proteins in Inflammatory and Inflammation-Associated Diseases of the Gastrointestinal Tract. Int J Mol Sci 2021; 22:ijms22137196. [PMID: 34281249 PMCID: PMC8268738 DOI: 10.3390/ijms22137196] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/22/2021] [Accepted: 06/30/2021] [Indexed: 12/12/2022] Open
Abstract
Regenerating gene (REG) family proteins serve as multifunctional secretory molecules with trophic, antiapoptotic, anti-inflammatory, antimicrobial and probably immuno-regulatory effects. Since their discovery, accumulating evidence has clarified the potential roles of the REG family in the occurrence, progression and development of a wide range of inflammatory and inflammation-associated diseases of the gastrointestinal (GI) tract. However, significant gaps still exist due to the undefined nature of certain receptors, regulatory signaling pathways and possible interactions among distinct Reg members. In this narrative review, we first describe the structural features, distribution pattern and purported regulatory mechanisms of REG family proteins. Furthermore, we summarize the established and proposed roles of REG proteins in the pathogenesis of various inflammation-associated pathologies of the GI tract and the body as a whole, focusing particularly on carcinogenesis in the ulcerative colitis—colitic cancer sequence and gastric cancer. Finally, the clinical relevance of REG products in the context of diagnosis, treatment and prognostication are also discussed in detail. The current evidence suggests a need to better understanding the versatile roles of Reg family proteins in the pathogenesis of inflammatory-associated diseases, and their broadened future usage as therapeutic targets and prognostic biomarkers is anticipated.
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Carino A, Graziosi L, Marchianò S, Biagioli M, Marino E, Sepe V, Zampella A, Distrutti E, Donini A, Fiorucci S. Analysis of Gastric Cancer Transcriptome Allows the Identification of Histotype Specific Molecular Signatures With Prognostic Potential. Front Oncol 2021; 11:663771. [PMID: 34012923 PMCID: PMC8126708 DOI: 10.3389/fonc.2021.663771] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 04/06/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is the fifth most common malignancy but the third leading cause of cancer-associated mortality worldwide. Therapy for gastric cancer remain largely suboptimal making the identification of novel therapeutic targets an urgent medical need. In the present study we have carried out a high-throughput sequencing of transcriptome expression in patients with gastric cancers. Twenty-four patients, among a series of 53, who underwent an attempt of curative surgery for gastric cancers in a single center, were enrolled. Patients were sub-grouped according to their histopathology into diffuse and intestinal types, and the transcriptome of the two subgroups assessed by RNAseq analysis and compared to the normal gastric mucosa. The results of this investigation demonstrated that the two histopathology phenotypes express two different patterns of gene expression. A total of 2,064 transcripts were differentially expressed between neoplastic and non-neoplastic tissues: 772 were specific for the intestinal type and 407 for the diffuse type. Only 885 transcripts were simultaneously differentially expressed by both tumors. The per pathway analysis demonstrated an enrichment of extracellular matrix and immune dysfunction in the intestinal type including CXCR2, CXCR1, FPR2, CARD14, EFNA2, AQ9, TRIP13, KLK11 and GHRL. At the univariate analysis reduced levels AQP9 was found to be a negative predictor of 4 years survival. In the diffuse type low levels CXCR2 and high levels of CARD14 mRNA were negative predictors of 4 years survival. In summary, we have identified a group of genes differentially regulated in the intestinal and diffuse histotypes of gastric cancers with AQP9, CARD14 and CXCR2 impacting on patients' prognosis, although CXCR2 is the only factor independently impacting overall survival.
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Affiliation(s)
- Adriana Carino
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Luigina Graziosi
- S.C.Gastroenterologia, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Silvia Marchianò
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Michele Biagioli
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Elisabetta Marino
- S.C.Gastroenterologia, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Valentina Sepe
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | | | - Annibale Donini
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Pławińska-Czarnak J, Majewska A, Zarzyńska J, Bogdan J, Kaba J, Anusz K, Bagnicka E. Gene Expression Profile in Peripheral Blood Nuclear Cells of Small Ruminant Lentivirus-Seropositive and Seronegative Dairy Goats in Their First Lactation. Animals (Basel) 2021; 11:ani11040940. [PMID: 33810360 PMCID: PMC8066113 DOI: 10.3390/ani11040940] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 03/22/2021] [Accepted: 03/22/2021] [Indexed: 12/19/2022] Open
Abstract
Simple Summary Caprine arthritis encephalitis, caused by small ruminant lentivirus (SRLV), is a disease that develops with various signs in adult goats, e.g., arthritis, mastitis, and progressive weight loss, while in goat kids, the disease presents with only neuropathy and extremely rarely. The disease results in reduced milk production and economic losses in herds of goats. Previously described changes in single gene expression do not fully explain all the processes occurring in the infected goats. Therefore, the present study describes the first use of a transcriptomic array designed specifically for goats in Poland. Its aim was to investigate the gene expression profiles of peripheral blood nuclear cells from SRLV-seropositive and SRLV-seronegative goats using a custom-made Capra hircus gene expression array. Just four genes out of ~50,000 were found to have differential expression; moreover, changes in their expression suggest an active inflammatory mechanism in SRLV-seropositive goats at the early stage of SRLV infection. Abstract The immune response to a viral antigen causes inflammatory cell infiltration to the tissue, which creates a suitable environment for the replication of the virus in macrophages, and the recruitment of more monocytes to the site of infection, or latently infected monocytes. The aim of the study was to analyze the transcriptomic profile of peripheral blood nuclear cells isolated from SRLV-seropositive and SRLV-negative goats at the peak of their first lactation. SRLV-seropositive goats were probably infected via colostrum. Custom transcriptomic microarrays for goats were designed and developed, namely the Capra hircus gene expression array, which features ~50,000 unique transcripts per microarray. Only four genes were differentially expressed, with up-regulated expression of the GIMAP2, SSC5D and SETX genes, and down-regulated expression of the GPR37 gene in SRLV-seropositive vs. SRLV-seronegative goats. However, in an RT-qPCR analysis, the result for the SETX gene was not confirmed. The differences in the expressions of the studied genes indicate an active inflammatory process in the SRLV-seropositive goats at the early stage of infection.
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Affiliation(s)
- Joanna Pławińska-Czarnak
- Department of Food Hygiene and Public Health Protection, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 159, 02-776 Warsaw, Poland; (J.Z.); (J.B.); (K.A.)
- Correspondence:
| | - Alicja Majewska
- Department of Physiology Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 159, 02-776 Warsaw, Poland;
| | - Joanna Zarzyńska
- Department of Food Hygiene and Public Health Protection, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 159, 02-776 Warsaw, Poland; (J.Z.); (J.B.); (K.A.)
| | - Janusz Bogdan
- Department of Food Hygiene and Public Health Protection, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 159, 02-776 Warsaw, Poland; (J.Z.); (J.B.); (K.A.)
| | - Jarosław Kaba
- Division of Epidemiology and Veterinary Management, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 159c, 02-776 Warsaw, Poland;
| | - Krzysztof Anusz
- Department of Food Hygiene and Public Health Protection, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 159, 02-776 Warsaw, Poland; (J.Z.); (J.B.); (K.A.)
| | - Emilia Bagnicka
- Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Postepu 36A, Jastrzebiec, 05-552 Magdalenka, Poland;
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Chai D, Du H, Li K, Zhang X, Li X, Zhao X, Lian X, Xu Y. CDX2 and Reg IV expression and correlation in gastric cancer. BMC Gastroenterol 2021; 21:92. [PMID: 33639844 PMCID: PMC7913228 DOI: 10.1186/s12876-021-01678-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 02/15/2021] [Indexed: 01/10/2023] Open
Abstract
Background Ectopic expression of CDX2 is associated with the development and progression of gastric cancer. Previous studies showed that CDX2 may be an upstream regulator of Reg IV expression in gastric cancer, and our previous report showed that Reg IV upregulated SOX9 expression and enhanced cell migration and invasion in gastric cancer cells. However, the regulatory roles of CDX2 have not been clarified in gastric cancer, and the correlation between CDX2 and Reg IV requires further study. Methods CDX2 and Reg IV were examined in gastric cancer specimens and paired adjacent tissues via real-time PCR and immunohistochemistry (IHC). The association between CDX2 and Reg IV was assessed using the χ2-test and Spearman’s rank correlation. To verify their relationship, knockdown and exogenous expression of CDX2 or Reg IV were performed in AGS and MKN-45 gastric cancer cells, and their expression was subsequently analyzed via a real-time PCR and western blotting. Wound-healing and Transwell assays were used to examine migration and invasion in AGS and MKN-45 cells following CDX2 silencing or overexpression. Results A positive correlation was observed between CDX2 and Reg IV expression at the mRNA and protein levels in gastric cancer tissues. CDX2 silencing significantly downregulated Reg IV expression, and CDX2 overexpression significantly upregulated Reg IV expression in AGS and MKN-45 cells. Neither Reg IV silencing nor overexpression had any effect on CDX2 protein expression in AGS or MKN-45 cells, even though both affected the expression of CDX2 mRNA. Functionally, CDX2 silencing significantly inhibited cell migration and invasion, and CDX2 overexpression significantly promoted cell migration and invasion in AGS and MKN-45 cells. Conclusions Our findings demonstrate that CDX2 expression was positively correlated with that of Reg IV in gastric cancer, and CDX2 promoted cell migration and invasion through upregulation of Reg IV expression in AGS and MKN-45 cells.
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Affiliation(s)
- Dandan Chai
- Department of Medicine Biotechnology, Gansu Provincial Academic Institute for Medical Research, Xiaoxihu East Street No. 2, Lanzhou, 730050, Gansu, China
| | - Huifen Du
- Department of Medicine Biotechnology, Gansu Provincial Academic Institute for Medical Research, Xiaoxihu East Street No. 2, Lanzhou, 730050, Gansu, China
| | - Kesheng Li
- Department of Medicine Biotechnology, Gansu Provincial Academic Institute for Medical Research, Xiaoxihu East Street No. 2, Lanzhou, 730050, Gansu, China.
| | - Xueliang Zhang
- Department of Internal Medicine, Gansu Provincial Cancer Hospital, Lanzhou, Gansu, China
| | - Xiaoqin Li
- Department of Pathology, Gansu Provincial Cancer Hospital, Lanzhou, Gansu, China
| | - Xiaoning Zhao
- Department of Surgery, Gansu Provincial Cancer Hospital, Lanzhou, Gansu, China
| | - Xiaowen Lian
- Department of Medicine Biotechnology, Gansu Provincial Academic Institute for Medical Research, Xiaoxihu East Street No. 2, Lanzhou, 730050, Gansu, China
| | - Yang Xu
- Department of Medicine Biotechnology, Gansu Provincial Academic Institute for Medical Research, Xiaoxihu East Street No. 2, Lanzhou, 730050, Gansu, China
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34
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Sninsky JA, Bishnupuri KS, González I, Trikalinos NA, Chen L, Dieckgraefe BK. Reg4 and its downstream transcriptional activator CD44ICD in stage II and III colorectal cancer. Oncotarget 2021; 12:278-291. [PMID: 33659040 PMCID: PMC7899555 DOI: 10.18632/oncotarget.27896] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 01/26/2021] [Indexed: 12/15/2022] Open
Abstract
Reg4 is highly expressed in gastrointestinal malignancies and acts as a mitogenic and pro-invasive factor. Our recent works suggest that Reg4 binds with CD44 and induces its proteolytic cleavage to release intra-cytoplasmic domain of CD44 (CD44ICD). The goal of this study is to demonstrate clinical significance of the Reg4-CD44/CD44ICD pathway in stage II/III colon cancer and its association with clinical parameters of aggression. We constructed a tissue microarray (TMA) of 93 stage II/III matched colon adenocarcinoma patients, 23 with recurrent disease. The TMA was immunohistochemically stained for Reg4, CD44, and CD44ICD proteins and analyzed to identify associations with tumor characteristics, recurrence and overall survival. The TMA data analysis showed a significant correlation between Reg4 and CD44 (r2 = 0.23, P = 0.028), CD44 and CD44ICD (r2 = 0.36, p = 0.0004), and Reg4 and CD44ICD (r2 = 0.45, p ≤ 0.0001). Reg4 expression was associated with larger tumor size (r2 = 0.23, p = 0.026). Although, no association was observed between Reg4, CD44, or CD44ICD expression and disease recurrence, Reg4-positive patients had a median survival of 4 years vs. 7 years for Reg4-negative patients (p = 0.04) in patients who recurred. Inhibition of the Reg4-CD44/CD44ICD pathway may be a future therapeutic target for colon cancer patients.
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Affiliation(s)
- Jared A Sninsky
- Division of Gastroenterology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
| | - Kumar S Bishnupuri
- Division of Gastroenterology, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Iván González
- Division of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Nikolaos A Trikalinos
- Division of Oncology, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Ling Chen
- Division of Biostatistics, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Brian K Dieckgraefe
- Division of Gastroenterology, Washington University School of Medicine, Saint Louis, MO 63110, USA
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Cao Y, Tian Y, Liu Y, Su Z. Reg3β: A Potential Therapeutic Target for Tissue Injury and Inflammation-Associated Disorders. Int Rev Immunol 2021; 41:160-170. [PMID: 33426979 DOI: 10.1080/08830185.2020.1869731] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Since regenerating islet-derived 3β (Reg3β) was first reported, various studies have been conducted to explore the involvement of Reg3β in a gamut of maladies, such as diabetes, pancreatitis, pancreatic ductal adenocarcinoma, and extrapancreatic maladies such as inflammatory bowel disease, acute liver failure, and myocardial infarction. Surprisingly, there is currently no systematic review of Reg3β. Therefore, we summarize the structural characteristics, transcriptional regulation, putative receptors, and signaling pathways of Reg3β. The exact functional roles in various diseases, especially gastrointestinal and liver diseases, are also discussed. Reg3β plays multiple roles in promoting proliferation, inducing differentiation, preventing apoptosis, and resisting bacteria. The present review may provide new directions for the diagnosis and treatment of gastrointestinal, liver, and pancreatic diseases.
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Affiliation(s)
- Yuwen Cao
- International Genome Center, Jiangsu University, Zhenjiang, China.,Department of Immunology, Jiangsu University, Zhenjiang, China
| | - Yu Tian
- International Genome Center, Jiangsu University, Zhenjiang, China.,Department of Immunology, Jiangsu University, Zhenjiang, China
| | - Yueqin Liu
- Laboratory Center, the Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Zhaoliang Su
- International Genome Center, Jiangsu University, Zhenjiang, China.,Department of Immunology, Jiangsu University, Zhenjiang, China.,Laboratory Center, the Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
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36
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Zhang J, Zhu Z, Miao Z, Huang X, Sun Z, Xu H, Wang Z. The Clinical Significance and Mechanisms of REG4 in Human Cancers. Front Oncol 2021; 10:559230. [PMID: 33489872 PMCID: PMC7819868 DOI: 10.3389/fonc.2020.559230] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 11/23/2020] [Indexed: 11/13/2022] Open
Abstract
Regenerating islet-derived type 4 (REG4), a member of the calcium-dependent lectin gene superfamily, is abnormally expressed in various cancers, such as colorectal, gastric, gallbladder, pancreatic, ovarian, prostate, and lung cancer. REG4 is associated with a relatively unfavorable prognosis and clinicopathologic features in cancers, including advanced tumor and nodal stage, histological differentiation, and liver and peritoneal metastasis. Moreover, REG4-positive cancer cells show more frequent resistance to chemoradiotherapy, especially 5-FU-based chemotherapy. REG4 participates in many aspects of carcinogenesis, including cell proliferation, apoptosis, cell cycle, invasion, metastasis, and drug resistance. The underlying mechanisms are complex and involve a series of signaling mediators and multiple pathways. Thus, REG4 may be a potential diagnostic and prognostic biomarker as well as a candidate therapeutic target in cancer patients. In this review, we systematically summarize the advances about the clinical significance, biological functions, and mechanisms underlying REG4 in cancer to provide new directions for future cancer research.
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Affiliation(s)
- Junyan Zhang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhi Zhu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhifeng Miao
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xuanzhang Huang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhe Sun
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Huimian Xu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
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Wang J, Xu M, Li DD, Abudukelimu W, Zhou XH. GPR37 promotes the malignancy of lung adenocarcinoma via TGF-β/Smad pathway. Open Med (Wars) 2020; 16:24-32. [PMID: 33364431 PMCID: PMC7730288 DOI: 10.1515/med-2021-0011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 09/30/2020] [Accepted: 10/20/2020] [Indexed: 12/12/2022] Open
Abstract
This paper aimed to research the function and in-depth mechanism of GPR37 in lung adenocarcinoma (LUAD). Herein, based on TCGA and Oncomine databases, we revealed that GPR37 was expressed at high levels in LUAD, and upregulation of GPR37 was related to the poor outcomes. Furthermore, biological function experiments in vitro were utilized to assess whether GPR37 impacts malignant phenotype of LUAD cells. Gain- or loss-of-function assays indicated that the upregulation of GPR37 contributed to improving the proliferation, migration, and invasion of LUAD cells in vitro, while knockdown of GPR37 can inhibit the malignant biological behaviors. Then, we found that depletion of GPR37 resulted in a decrease in the expression of TGF-β1 as well as the extents of Smad2 and Smad3 phosphorylation, while overexpression of GPR37 presented opposite outcomes. Altogether, our findings indicated that GPR37 is a potential oncogene of LUAD, and its promoting effects on the malignant progression of LUAD may be realized via TGF-β/Smad pathway.
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Affiliation(s)
- Jian Wang
- Department of Respiration, Midong Branch of People's Hospital of Xinjiang Autonomous Region, 1302-17 Midong South Road, Urumqi, Xinjiang, People's Republic of China
| | - Min Xu
- Department of Medical, Midong Branch of People's Hospital of Xinjiang Autonomous Region, Urumqi, Xinjiang, People's Republic of China
| | - Dan-Dan Li
- Department of Endocrinology, Midong Branch of People's Hospital of Xinjiang Autonomous Region, Xinjiang, Urumqi, People's Republic of China
| | - Wujikenayi Abudukelimu
- Department of Respiration, Midong Branch of People's Hospital of Xinjiang Autonomous Region, 1302-17 Midong South Road, Urumqi, Xinjiang, People's Republic of China
| | - Xiu-Hong Zhou
- Department of Respiration, Midong Branch of People's Hospital of Xinjiang Autonomous Region, 1302-17 Midong South Road, Urumqi, Xinjiang, People's Republic of China
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Xie TY, Wu D, Li S, Qiu ZY, Song QY, Guan D, Wang LP, Li XG, Duan F, Wang XX. Role of prophylactic hyperthermic intraperitoneal chemotherapy in patients with locally advanced gastric cancer. World J Gastrointest Oncol 2020; 12:782-790. [PMID: 32864045 PMCID: PMC7428793 DOI: 10.4251/wjgo.v12.i7.782] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/21/2020] [Accepted: 05/27/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Gastric cancer is the second most common malignant tumor in China, ranking third among all malignant tumor mortality rates. Hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to increase significantly the effectiveness of intraperitoneal chemotherapeutic drugs, prolong the action time of these drugs on intraperitoneal tumor cells, and enhance their diffusion in tumor tissues. HIPEC may be one of the best choices for the eradication of residual cancer cells in the abdominal cavity.
AIM The aim of this study was to study the role of preventive HIPEC after radical gastrectomy.
METHODS A prospective analysis was performed with patients with cT4N0-3M0 gastric cancer to compare the effects of postoperative prophylactic HIPEC plus intravenous chemotherapy with those of routine adjuvant chemotherapy. Patients’ medical records were analyzed, and differences in the peritoneal recurrence rate, disease-free survival time, and total survival time between groups were examined.
RESULTS The first site of tumor recurrence was the peritoneum in 11 cases in the conventional adjuvant chemotherapy group and in 2 cases in the HIPEC group (P = 0.020). The 1-year and 3-year disease-free survival rates were 91.9% and 60.4%, respectively, in the conventional adjuvant chemotherapy group and 92.1% and 63.0%, respectively, in the HIPEC group. The 1-year and 3-year overall survival rates were 95.2% and 66.3%, respectively, in the conventional adjuvant chemotherapy group and 96.1% and 68.6%, respectively, in the HIPEC group. No significant difference in postoperative or chemotherapy complications was observed between groups.
CONCLUSION In patients with cT4N0-3M0 gastric cancer, prophylactic HIPEC after radical tumor surgery is beneficial to reduce peritoneal tumor recurrence and prolong survival.
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Affiliation(s)
- Tian-Yu Xie
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Di Wu
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Shuo Li
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Zhao-Yan Qiu
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Qi-Ying Song
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Da Guan
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Li-Peng Wang
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Xiong-Guang Li
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Feng Duan
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Xin-Xin Wang
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
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Watkins LR, Orlandi C. Orphan G Protein Coupled Receptors in Affective Disorders. Genes (Basel) 2020; 11:E694. [PMID: 32599826 PMCID: PMC7349732 DOI: 10.3390/genes11060694] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 06/20/2020] [Accepted: 06/21/2020] [Indexed: 12/12/2022] Open
Abstract
G protein coupled receptors (GPCRs) are the main mediators of signal transduction in the central nervous system. Therefore, it is not surprising that many GPCRs have long been investigated for their role in the development of anxiety and mood disorders, as well as in the mechanism of action of antidepressant therapies. Importantly, the endogenous ligands for a large group of GPCRs have not yet been identified and are therefore known as orphan GPCRs (oGPCRs). Nonetheless, growing evidence from animal studies, together with genome wide association studies (GWAS) and post-mortem transcriptomic analysis in patients, pointed at many oGPCRs as potential pharmacological targets. Among these discoveries, we summarize in this review how emotional behaviors are modulated by the following oGPCRs: ADGRB2 (BAI2), ADGRG1 (GPR56), GPR3, GPR26, GPR37, GPR50, GPR52, GPR61, GPR62, GPR88, GPR135, GPR158, and GPRC5B.
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Affiliation(s)
| | - Cesare Orlandi
- Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA;
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40
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Zhang XQ, Yu LT, Du P, Yin TQ, Zhang ZY, Xu Y, Li X, Li YJ, Wang M, Luo C. Single-chain Antibody Against Reg4 Suppresses Gastric Cancer Cell Growth and Enhances 5-FU-induced Cell Death in vitro. Anticancer Agents Med Chem 2020; 19:610-619. [PMID: 30465515 DOI: 10.2174/1871520619666181122104720] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 08/15/2018] [Accepted: 11/13/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Regenerating islet-derived gene family member 4 (Reg4), a well-investigated growth factor in the regenerative pancreas, has recently been reported to be highly associated with a majority of gastrointestinal cancers. Pathological hyper-expression or artificial over-expression of Reg4 causes acceleration of tumor growth, migration, and resistance to chemotherapeutic 5-Fluorouracil (5-FU). Until now, no method has been successfully established for eliminating the effects of Reg4 protein. METHODS This study reports the production of an engineered immunoglobin, a single-chain variable fragment (scFv-Reg4), to specifically bind Reg4 and block the bioactivity. The complementary-determining regions (CDRs) against Reg4 were assigned using MOE and ZDOCK servers. The binding affinity (KD) was determined by bio-layer interferometry (BLI). MKN45 and AGS cell proliferation was determined by Thiazolyl blue tetrazolium bromide (MTT) method and the cell apoptosis was detected by flow cytometry assay. RESULTS The KD of scFv-Reg4 to Reg4 was determined to be 1.91×10-8. In MKN45 and AGS cell lines, scFv- Reg4 depressed Reg4-stimulated cell proliferation and the inhibitory rates were 27.7±1.5% and 17.3±2.6%, respectively. Furthermore, scFv significantly enhanced 5-FU-induced cell death, from 23.0±1.0% to 28.4±1.2% in MKN45 and 28.2±0.7% to 36.6±0.6% in AGS cells. Treatment with scFv alone could lyse cancer cells to a certain extent, but no significance has been observed. CONCLUSION The single-chain antibody (scFv-Reg4) significantly inhibited gastric cancer cell proliferation and synergistically enhanced the lethal effect of 5-FU. Thus, traditional chemo-/radio- therapeutics supplemented with scFv-Reg4 may provide advances in the strategy for gastrointestinal cancer treatment.
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Affiliation(s)
- Xue-Qing Zhang
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Lu-Ting Yu
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China.,Fraser Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada
| | - Pei Du
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Tian-Qi Yin
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Zhi-Yuan Zhang
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Ying Xu
- Jiangsu Celtec Biotechnology Co. Ltd, Jiangsu, China
| | - Xiang Li
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - You-Jie Li
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Min Wang
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China.,State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing, China
| | - Chen Luo
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China.,State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing, China
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Peritoneal metastatic gastric carcinoma cells exhibit more malignant behavior when co-cultured with HMrSV5 cells. Aging (Albany NY) 2020; 12:3238-3248. [PMID: 32139657 PMCID: PMC7066899 DOI: 10.18632/aging.102803] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 01/19/2020] [Indexed: 01/20/2023]
Abstract
Metastasis and recurrence are major causes of death in gastric cancer patients. Because there are no obvious clinical symptoms during the early stages of metastasis, we sought to isolate highly invasive metastatic gastric cancer cells for future drug screening. We first established a mouse model to observe gastric cancer metastasis in vivo. The incidence of peritoneal metastasis of gastric cancer was much higher than liver or lymph metastasis. Peritoneal metastatic and non-metastatic NUGC-4 cells were isolated from the mouse model. Cell proliferation was measured using CCK-8 assays, while migration and invasion were investigated in Transwell assays. Proteins involved in epithelial-mesenchymal transition were detected by Western blotting. Metastatic gastric carcinoma cells were more proliferative and invasive than primary NUGC-4 cells. The supernatants of metastatic gastric carcinoma cells notably altered the morphology of HMrSV5 peritoneal mesothelial cells and promoted their epithelial-mesenchymal transition. Moreover, primary or metastatic gastric cancer cells co-cultured with HMrSV5 cells markedly increased cancer cell proliferation and invasiveness. Moreover, peritoneal metastatic gastric carcinoma cells in the presence of HMrSV5 cells exhibited most malignant behaviors. Thus, peritoneal metastatic gastric carcinoma cells exhibited high capacities for proliferation and invasion, and could be used as a new drug screening tool for the treatment of advanced gastric cancer and peritoneal metastatic gastric cancer.
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42
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Chen Z, Downing S, Tzanakakis ES. Four Decades After the Discovery of Regenerating Islet-Derived (Reg) Proteins: Current Understanding and Challenges. Front Cell Dev Biol 2019; 7:235. [PMID: 31696115 PMCID: PMC6817481 DOI: 10.3389/fcell.2019.00235] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 09/30/2019] [Indexed: 12/15/2022] Open
Abstract
Regenerating islet-derived (Reg) proteins have emerged as multifunctional agents with pro-proliferative, anti-apoptotic, differentiation-inducing and bactericidal properties. Over the last 40 years since first discovered, Reg proteins have been implicated in a gamut of maladies including diabetes, various types of cancer of the digestive tract, and Alzheimer disease. Surprisingly though, a consensus is still absent on the regulation of their expression, and molecular underpinning of their function. Here, we provide a critical appraisal of recent findings in the field of Reg protein biology. Specifically, the structural characteristics are reviewed particularly in connection with established or purported functions of different members of the Reg family. Moreover, Reg expression patterns in different tissues both under normal and pathophysiological conditions are summarized. Putative receptors and cascades reported to relay Reg signaling inciting cellular responses are presented aiming at a better appreciation of the biological activities of the distinct Reg moieties. Challenges are also discussed that have hampered thus far the rapid progress in this field such as the use of non-standard nomenclature for Reg molecules among various research groups, the existence of multiple Reg members with significant degree of homology and possibly compensatory modes of action, and the need for common assays with robust readouts of Reg activity. Coordinated research is warranted going forward, given that several research groups have independently linked Reg proteins to diseased states and raised the possibility that these biomolecules can serve as therapeutic targets and biomarkers.
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Affiliation(s)
- Zijing Chen
- Department of Chemical and Biological Engineering, Tufts University, Medford, MA, United States
| | - Shawna Downing
- Clinical and Translational Science Institute, Tufts Medical Center, Boston, MA, United States
| | - Emmanuel S Tzanakakis
- Department of Chemical and Biological Engineering, Tufts University, Medford, MA, United States.,Clinical and Translational Science Institute, Tufts Medical Center, Boston, MA, United States
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43
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Enblad M, Graf W, Terman A, Pucholt P, Viklund B, Isaksson A, Birgisson H. Gains of Chromosome 1p and 15q are Associated with Poor Survival After Cytoreductive Surgery and HIPEC for Treating Colorectal Peritoneal Metastases. Ann Surg Oncol 2019; 26:4835-4842. [PMID: 31620944 PMCID: PMC6863794 DOI: 10.1245/s10434-019-07923-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Indexed: 12/21/2022]
Abstract
Purpose Genetic alterations in colorectal peritoneal metastases (PM) are largely unknown. This study was designed to analyze whole-genome copy number alterations (CNA) in colorectal PM and to identify alterations associated with prognosis after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Methods All patients with PM, originating from a colorectal adenocarcinoma, who were treated with CRS and HIPEC in Uppsala Sweden, between 2004 and 2015, were included (n = 114). DNA derived from formalin-fixed paraffin-embedded (FFPE) specimens were analyzed for CNA using molecular inversion probe arrays. Results There were extensive but varying degrees of CNA, ranging from minimal CNA to total aneuploidy. In particular, gain of parts of chromosome 1p and major parts of 15q were associated with poor survival. A combination of gains of 1p and 15q was associated with poor survival, also after adjustment for differences in peritoneal cancer index and completeness of cytoreduction score [hazard ratio (HR) 5.96; 95% confidence interval (CI) 2.19–16.18]. These patients had a mean copy number (CN) of 3.19 compared with 2.24 in patients without gains. Complete CN analysis was performed in 53 patients. Analysis was unsuccessful for the remaining patients due to insufficient amounts of DNA and signals caused by interstitial components and normal cells. There was no difference in survival between patients with successful and unsuccessful CN analysis. Conclusions This study shows that gains of parts of chromosome 1p and of major parts of chromosome 15q were significantly associated with poor survival after CRS and HIPEC, which could represent future prognostic biomarkers. Electronic supplementary material The online version of this article (10.1245/s10434-019-07923-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Malin Enblad
- Department of Surgical Sciences, Colorectal Surgery, Uppsala University, Uppsala, Sweden.
| | - Wilhelm Graf
- Department of Surgical Sciences, Colorectal Surgery, Uppsala University, Uppsala, Sweden
| | - Alexei Terman
- Department of Immunology, Genetics and Pathology, Experimental Pathology, Uppsala University, Uppsala, Sweden
| | - Pascal Pucholt
- Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Björn Viklund
- Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Anders Isaksson
- Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Helgi Birgisson
- Department of Surgical Sciences, Colorectal Surgery, Uppsala University, Uppsala, Sweden
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44
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Comparative RNA-seq analysis reveals dys-regulation of major canonical pathways in ERG-inducible LNCaP cell progression model of prostate cancer. Oncotarget 2019; 10:4290-4306. [PMID: 31303963 PMCID: PMC6611515 DOI: 10.18632/oncotarget.27019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Accepted: 05/30/2019] [Indexed: 11/25/2022] Open
Abstract
Prostate Cancer (CaP) is the second leading cause of cancer related death in USA. In human CaP, gene fusion between androgen responsive regulatory elements at the 5'-untranslated region of TMPRSS2 and ETS-related genes (ERG) is present in at least 50% of prostate tumors. Here we have investigated the unique cellular transcriptome associated with over-expression of ERG in ERG-inducible LNCaP cell model system of human CaP. Comprehensive transcriptome analyses reveal a distinct signature that distinguishes ERG dependent and independent CaP in LNCaP cells. Our data highlight a significant heterogeneity among the transcripts. Out of the 526 statistically significant differentially expressed genes, 232 genes are up-regulated and 294 genes are down-regulated in response to ERG. These ERG-associated genes are linked to several major cellular pathways, cell cycle regulation being the most significant. Consistently our data indicate that ERG plays a key role in modulating the expression of genes required for G1 to S phase transition, particularly those that affect cell cycle arrest at G1 phase. Moreover, cell cycle arrest in response to ERG appears to be promoted by induction of p21 in a p53 independent manner. These findings may provide new insights into mechanisms that promote growth and progression of CaP.
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45
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Ünlü B, Versteeg HH. Cancer-associated thrombosis: The search for the holy grail continues. Res Pract Thromb Haemost 2018; 2:622-629. [PMID: 30349879 PMCID: PMC6178660 DOI: 10.1002/rth2.12143] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 06/24/2018] [Indexed: 02/06/2023] Open
Abstract
Cancer patients have an increased risk of developing venous thromboembolism (VTE), a condition that is associated with increased morbidity and mortality. Although risk assessment tools have been developed, it is still very challenging to predict which cancer patients will suffer from VTE. The scope of this review is to summarize and discuss studies focusing on the link between genetic alterations and risk of cancer-associated thrombosis (CAT). Thus far, classical risk factors that contribute to VTE have been tried as risk factors of CAT, with low success. In support, hypercoagulant plasma profiles in patients with CAT differ from those with only VTE, indicating other risk factors that contribute to VTE in cancer. As germline mutations do not significantly contribute to elevated risk of VTE, somatic mutations in tumors may significantly associate with and contribute to CAT. As it is very time-consuming to investigate each and every mutation, an unbiased approach is warranted. In this light we discuss our own recent unbiased proof-of-principle study using RNA sequencing in isolated colorectal cancer cells. Our work has uncovered candidate genes that associate with VTE in colorectal cancer, and these gene profiles associated with VTE more significantly than classical parameters such as platelet counts, D-dimer, and P-selectin levels. Genes associated with VTE could be linked to pathways being involved in coagulation, inflammation and methionine degradation. We conclude that tumor cell-specific gene expression profiles and/or mutational status has superior potential as predictors of VTE in cancer patients.
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Affiliation(s)
- Betül Ünlü
- Department of Internal MedicineEinthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
| | - Henri H. Versteeg
- Department of Internal MedicineEinthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
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46
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Sawaki K, Kanda M, Kodera Y. Review of recent efforts to discover biomarkers for early detection, monitoring, prognosis, and prediction of treatment responses of patients with gastric cancer. Expert Rev Gastroenterol Hepatol 2018; 12:657-670. [PMID: 29902383 DOI: 10.1080/17474124.2018.1489233] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Gastric cancer (GC) is the leading cause of cancer-related death worldwide. Despite recent advances in diagnosis and therapy, the prognosis of patients with GC is poor. Many patients have inoperable disease upon diagnosis or experience recurrent disease after curative gastrectomy. Unfortunately, tumor markers for GC, such as serum carcinoembryonic antigen and carbohydrate antigen 19-9, lack sufficient sensitivity and specificity. Therefore, effective biomarkers are required to detect early GC and to predict tumor recurrence and chemosensitivity. Areas covered: Here we aimed to review recent developments in techniques that improve the detection of aberrant expression of GC-associated molecules, including protein coding genes, microRNAs, long noncoding RNAs, and methylated promoter DNAs. Expert commentary: Detection of genetic and epigenetic alterations in gastric tissue or in the circulation will likely improve the diagnosis and management of GC to achieve significantly improved outcomes.
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Affiliation(s)
- Koichi Sawaki
- a Department of Gastroenterological Surgery (Surgery II) , Nagoya University Graduate School of Medicine , Nagoya , Japan
| | - Mitsuro Kanda
- a Department of Gastroenterological Surgery (Surgery II) , Nagoya University Graduate School of Medicine , Nagoya , Japan
| | - Yasuhiro Kodera
- a Department of Gastroenterological Surgery (Surgery II) , Nagoya University Graduate School of Medicine , Nagoya , Japan
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47
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Zheng W, Zhou J, Luan Y, Yang J, Ge Y, Wang M, Wu B, Wu Z, Chen X, Li F, Li Z, Vakal S, Guo W, Chen JF. Spatiotemporal Control of GPR37 Signaling and Its Behavioral Effects by Optogenetics. Front Mol Neurosci 2018; 11:95. [PMID: 29643766 PMCID: PMC5882850 DOI: 10.3389/fnmol.2018.00095] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 03/12/2018] [Indexed: 12/18/2022] Open
Abstract
Despite the progress in deorphanization of G Protein-Coupled Receptors (GPCRs), ≈100 GPCRs are still classified as orphan receptors without identified endogenous ligands and with unknown physiological functions. The lack of endogenous ligands triggering GPCR signaling has hampered the study of orphan GPCR functions. Using GPR37 as an example, we provide here the first demonstration of the channelrhodopsin 2 (ChR2)-GPCR approach to bypass the endogenous ligand and selectively activate the orphan GPCR signal by optogenetics. Inspired by the opto-XR approach, we designed the ChR2-GPR37 chimera, in which the corresponding parts of GPR37 replaced the intracellular portions of ChR2. We showed that optogenetic activation of ChR2/opto-GPR37 elicited specific GPR37 signaling, as evidenced by reduced cAMP level, enhanced ERK phosphorylation and increased motor activity, confirming the specificity of opto-GPR37 signaling. Besides, optogenetic activation of opto-GPR37 uncovered novel aspects of GPR37 signaling (such as IP-3 signaling) and anxiety-related behavior. Optogenetic activation of opto-GPR37 permits the causal analysis of GPR37 activity in the defined cells and behavioral responses of freely moving animals. Importantly, given the evolutionarily conserved seven-helix transmembrane structures of ChR2 and orphan GPCRs, we propose that opto-GPR37 approach can be readily applied to other orphan GPCRs for their deorphanization in freely moving animals.
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Affiliation(s)
- Wu Zheng
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China.,State Key Laboratory of Optometry & Vision Science, Wenzhou, China
| | - Jianhong Zhou
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China.,State Key Laboratory of Optometry & Vision Science, Wenzhou, China
| | - Yanan Luan
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Jianglan Yang
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Yuanyuan Ge
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Muran Wang
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Beibei Wu
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Zhongnan Wu
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Xingjun Chen
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China.,State Key Laboratory of Optometry & Vision Science, Wenzhou, China
| | - Fei Li
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Zhihui Li
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China.,State Key Laboratory of Optometry & Vision Science, Wenzhou, China
| | - Sergii Vakal
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Wei Guo
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China.,State Key Laboratory of Optometry & Vision Science, Wenzhou, China
| | - Jiang-Fan Chen
- Molecular Neuropharmacology Laboratory, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China.,State Key Laboratory of Optometry & Vision Science, Wenzhou, China.,Department of Neurology, Boston University School of Medicine, Boston University, Boston, MA, United States
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48
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Saukkonen K, Hagström J, Mustonen H, Lehtinen L, Carpen O, Andersson LC, Seppänen H, Haglund C. Prognostic and diagnostic value of REG4 serum and tissue expression in pancreatic ductal adenocarcinoma. Tumour Biol 2018. [PMID: 29542402 DOI: 10.1177/1010428318761494] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Expression of regenerating islet-derived protein 4 (REG4), a secretory protein involved in cell differentiation and proliferation, is upregulated in inflammatory bowel diseases and in many gastrointestinal malignancies. The prognostic significance of its expression in pancreatic ductal adenocarcinoma is unknown. Our aim was to investigate tumor tissue and serum REG4 expression in pancreatic ductal adenocarcinoma patients. We also evaluated as a control the diagnostic value of serum REG4 level in patients with chronic pancreatitis. Immunohistochemical expression of REG4 was evaluated in 154 surgical specimens and serum REG4 level in 130 samples from pancreatic ductal adenocarcinoma patients treated at Helsinki University Hospital, Finland, in 2000-2011. REG4 tissue and serum expression was assessed in relation to clinicopathological parameters and patient survival. A chronic pancreatitis control group comprised 34 patients who underwent pancreatic resection because of suspicion of malignancy. Significant survival differences were detectable in subgroups: in tumor stages IA-IIA, high serum REG4 level predicted worse survival (p=0.046). In patients with grade I tumor, positive tissue REG4 expression predicted better survival (p=0.006). In multivariate analysis, neither tissue nor serum REG4 expression was independent prognostic factors. Serum REG4 levels were higher in pancreatic ductal adenocarcinoma than in chronic pancreatitis (p=0.002), with diagnostic sensitivity of 45% and specificity of 91%. In logistic regression analysis, a multivariate model with REG4, CA19-9, and age provided sensitivity of 82% and specificity of 79%. REG4 tissue expression is a prognostic marker in subgroups of pancreatic ductal adenocarcinoma patients. Serum REG4 level might be useful in differential diagnosis between pancreatic ductal adenocarcinoma and chronic pancreatitis.
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Affiliation(s)
- Kapo Saukkonen
- 1 Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,2 Translational Cancer Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Jaana Hagström
- 2 Translational Cancer Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.,3 Department of Pathology, Haartman Institute and HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Harri Mustonen
- 1 Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Laura Lehtinen
- 4 Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland
| | - Olli Carpen
- 3 Department of Pathology, Haartman Institute and HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,4 Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland.,5 Genome Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Leif C Andersson
- 3 Department of Pathology, Haartman Institute and HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Hanna Seppänen
- 1 Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Caj Haglund
- 1 Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,2 Translational Cancer Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
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49
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Hu L, Zang MD, Wang HX, Zhang BG, Wang ZQ, Fan ZY, Wu H, Li JF, Su LP, Yan M, Zhu ZQ, Yang QM, Huang Q, Liu BY, Zhu ZG. G9A promotes gastric cancer metastasis by upregulating ITGB3 in a SET domain-independent manner. Cell Death Dis 2018; 9:278. [PMID: 29449539 PMCID: PMC5833452 DOI: 10.1038/s41419-018-0322-6] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 01/02/2018] [Accepted: 01/12/2018] [Indexed: 12/11/2022]
Abstract
Tumor metastasis is the leading cause of death in patients with advanced gastric cancer (GC). Limited therapeutic regimens are available for this condition, which is associated with a poor prognosis, and the mechanisms underlying tumor metastasis remain unclear. In the present study, increased histone methyltransferase G9A expression in GC tissues correlated with advanced stage and shorter overall survival, and in vitro and in vivo experiments revealed that G9A promoted tumor invasion and metastasis. Moreover, we observed that Reg IV induced G9A via the p-ERK/p-SP1 pathway. SP1 directly binds the G9A promoter and enhances G9A expression, and upregulated G9A then forms a transcriptional activator complex with P300 and GR, thereby promoting ITGB3 expression induced by dexamethasone (DEX) and contributing to GC metastasis. However, the G9A-mediated increase in ITGB3 expression was not dependent on the SET domain and methyltransferase activity of G9A. This study demonstrates that G9A is an independent prognostic marker and promotes metastasis in GC, thus suggesting that it may be a tumor biomarker and potential therapeutic target in GC.
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Affiliation(s)
- Lei Hu
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, People's Republic of China
- Department of General Surgery, Affiliated Provincial Hospital of Anhui Medical University, 230001, Hefei, People's Republic of China
| | - Ming-de Zang
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, People's Republic of China
| | - He-Xiao Wang
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, People's Republic of China
| | - Bao-Gui Zhang
- Affiliated Hospital of Jining Medical University, 272000, Jining, People's Republic of China
| | - Zhen-Qiang Wang
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, People's Republic of China
| | - Zhi-Yuan Fan
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, People's Republic of China
| | - Huo Wu
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, People's Republic of China
| | - Jian-Fang Li
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, People's Republic of China
| | - Li-Ping Su
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, People's Republic of China
| | - Min Yan
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, People's Republic of China
| | - Zhi-Qiang Zhu
- Department of General Surgery, Affiliated Provincial Hospital of Anhui Medical University, 230001, Hefei, People's Republic of China
| | - Qiu-Meng Yang
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, People's Republic of China
| | - Qiang Huang
- Department of General Surgery, Affiliated Provincial Hospital of Anhui Medical University, 230001, Hefei, People's Republic of China
| | - Bing-Ya Liu
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, People's Republic of China.
| | - Zheng-Gang Zhu
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, People's Republic of China.
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50
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Leinartaité L, Svenningsson P. Folding Underlies Bidirectional Role of GPR37/Pael-R in Parkinson Disease. Trends Pharmacol Sci 2017. [PMID: 28629580 DOI: 10.1016/j.tips.2017.05.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Since conformational flexibility, which is required for the function of a protein, comes at the expense of structural stability, many proteins, including G-protein-coupled receptors (GPCRs), are under constant risk of misfolding and aggregation. In this regard GPR37 (also named PAEL-R and ETBR-LP-1) takes a prominent role, particularly in relation to Parkinson disease (PD). GPR37 is a substrate for parkin and accumulates abnormally in autosomal recessive juvenile parkinsonism, contributing to endoplasmic reticulum stress and death of dopaminergic neurons. GPR37 also constitutes a core structure of Lewy bodies, demonstrating a more general involvement in PD pathology. However, if folded and matured properly, GPR37 seems to be neuroprotective. Moreover, GPR37 modulates functionality of the dopamine transporter and the dopamine D2 receptor and stimulates dopamine neurotransmission. Here we review the multiple roles of GPR37 with relevance to potential disease modification and symptomatic therapies of PD and highlight unsolved issues in this field.
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Affiliation(s)
- Lina Leinartaité
- Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-171 76, Stockholm, Sweden.
| | - Per Svenningsson
- Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-171 76, Stockholm, Sweden.
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