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Jiang T, Zhang J, Zhao S, Zhang M, Wei Y, Liu X, Zhang S, Fan W, Liu Y, Lv Y, Zhang G. MCT4: a key player influencing gastric cancer metastasis and participating in the regulation of the metastatic immune microenvironment. J Transl Med 2025; 23:276. [PMID: 40045374 PMCID: PMC11884109 DOI: 10.1186/s12967-025-06279-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 02/20/2025] [Indexed: 03/09/2025] Open
Abstract
BACKGROUND MCT4 is a lactate transporter associated with glycolysis, which has been found to be associated with various tumorigenesis and development processes. Gastric cancer is a malignant disease with high incidence and mortality. The role of MCT4 in the occurrence and development of gastric cancer has not been clarified. METHODS In this study, we comprehensively utilized single-cell sequencing and external transcriptome sequencing databases to deeply analyze the mechanism of the impact of MCT4 on gastric cancer and its microenvironment. We verified the function of MCT4 in gastric cancer through in vitro cell line experiments and in vivo experiments using gastric cancer liver metastasis and subcutaneous tumor models. Meanwhile, we collected tumor and normal tissue samples from clinical gastric cancer patients and employed immunohistochemistry and multiplex immunofluorescence techniques to detect the expression and localization of relevant indicators, thereby validating the results of computer simulation analysis and providing a basis for revealing the internal relationship between MCT4 and gastric cancer. RESULTS The expression of MCT4 is upregulated in gastric cancer patients, and the upregulation is more significant than that in patients with gastric cancer metastasis. MCT4 can mediate the proliferation and migration of gastric cancer cells in vitro. MCT4 can mediate the metastasis of gastric cancer cells in vivo. Multi-omics analysis showed that the expression of MCT4 was related to the composition of the immune microenvironment, and it could mediate the emergence of the inhibitory immune microenvironment. The results of immunofluorescence and immunohistochemistry proved the robustness of the multi-omics analysis. CONCLUSION Our study found that MCT4 plays an important role in the occurrence and development of gastric cancer, which may mediate the occurrence of gastric cancer metastasis and shape the immunosuppressive tumor microenvironment.
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Affiliation(s)
- Tao Jiang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Blood-Stasis-Toxin Syndrome of Zhejiang Province, Hangzhou, China
| | - Jingcheng Zhang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Blood-Stasis-Toxin Syndrome of Zhejiang Province, Hangzhou, China
| | - Sicheng Zhao
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Blood-Stasis-Toxin Syndrome of Zhejiang Province, Hangzhou, China
| | - Mingsi Zhang
- School of Sport, Loughborough University, Loughborough, LE, UK
| | - Yunhai Wei
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, 313000, Zhejiang Province, China
| | - Xiaojuan Liu
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Blood-Stasis-Toxin Syndrome of Zhejiang Province, Hangzhou, China
| | - Shuo Zhang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Blood-Stasis-Toxin Syndrome of Zhejiang Province, Hangzhou, China
| | - Wei Fan
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Blood-Stasis-Toxin Syndrome of Zhejiang Province, Hangzhou, China
| | - Yueying Liu
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Blood-Stasis-Toxin Syndrome of Zhejiang Province, Hangzhou, China
| | - Yuanlin Lv
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Guangji Zhang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
- Key Laboratory of Blood-Stasis-Toxin Syndrome of Zhejiang Province, Hangzhou, China.
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Li L, Yu S, Dou N, Wang X, Gao Y, Li Y. A new tandem repeat-enriched lncRNA XLOC_008672 promotes gastric carcinogenesis by regulating G3BP1 expression. Cancer Sci 2024; 115:1851-1865. [PMID: 38581120 PMCID: PMC11145122 DOI: 10.1111/cas.16172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 03/11/2024] [Accepted: 03/23/2024] [Indexed: 04/08/2024] Open
Abstract
Aberrant expression of forkhead box transcription factor 1 (FOXM1) plays critical roles in a variety of human malignancies and predicts poor prognosis. However, little is known about the crosstalk between FOXM1 and long noncoding RNAs (lncRNAs) in tumorigenesis. The present study identifies a previously uncharacterized lncRNA XLOC_008672 in gastric cancer (GC), which is regulated by FOXM1 and possesses multiple copies of tandem repetitive sequences. LncRNA microarrays are used to screen differentially expressed lncRNAs in FOXM1 knockdown GC cells, and then the highest fold downregulation lncRNA XLOC_008672 is screened out. Sequence analysis reveals that the new lncRNA contains 62 copies of 37-bp tandem repeats. It is transcriptionally activated by FOXM1 and functions as a downstream effector of FOXM1 in GC cells through in vitro and in vivo functional assays. Elevated expression of XLOC_008672 is found in GC tissues and indicates worse prognosis. Mechanistically, XLOC_008672 can bind to small nuclear ribonucleoprotein polypeptide A (SNRPA), thereby enhancing mRNA stability of Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) and, consequently, facilitating GC cell proliferation and migration. Our study discovers a new uncharacterized lncRNA XLOC_008672 involved in GC carcinogenesis and progression. Targeting FOXM1/XLOC_008672/SNRPA/G3BP1 signaling axis might be a promising therapeutic strategy for GC.
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Affiliation(s)
- Li Li
- Department of Oncology, Shanghai East HospitalTongji University School of MedicineShanghaiChina
| | - Shijun Yu
- Department of Oncology, Shanghai East HospitalTongji University School of MedicineShanghaiChina
| | - Ning Dou
- Department of Oncology, Shanghai East HospitalTongji University School of MedicineShanghaiChina
| | - Xiao Wang
- Department of Medical Oncology, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Yong Gao
- Department of Oncology, Shanghai East HospitalTongji University School of MedicineShanghaiChina
| | - Yandong Li
- Department of Oncology, Shanghai East HospitalTongji University School of MedicineShanghaiChina
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Zhan Y, Wang W, Wang H, Xu Y, Zhang Y, Ning Y, Zheng H, Luo J, Yang Y, Zang H, Zhou M, Fan S. G3BP1 Interact with JAK2 mRNA to Promote the Malignant Progression of Nasopharyngeal Carcinoma via Activating JAK2/STAT3 Signaling Pathway. Int J Biol Sci 2024; 20:94-112. [PMID: 38164170 PMCID: PMC10750281 DOI: 10.7150/ijbs.85341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 10/19/2023] [Indexed: 01/03/2024] Open
Abstract
Ras-GTPase-activating protein (GAP)-binding protein 1 (G3BP1) is an RNA-binding protein implicated in various malignancies. However, its role in nasopharyngeal carcinoma (NPC) remains elusive. This study elucidates the potential regulation mechanisms of G3BP1 and its significance in NPC advancement. Through knockdown and overexpression approaches, we validate G3BP1's oncogenic role by promoting proliferation, migration, and invasion in vitro and in vivo. Moreover, G3BP1 emerges as a key regulator of the JAK2/STAT3 signaling pathway, augmenting JAK2 expression via mRNA binding. Notably, epigallocatechin gallate (EGCG), a green tea-derived antioxidant, counteracts G3BP1-mediated pathway activation. Clinical analysis reveals heightened G3BP1, JAK2, and p-STAT3 as powerful prognostic markers, with G3BP1's expression standing as an independent indicator of poorer outcomes for NPC patients. In conclusion, the study unveils the oncogenic prowess of G3BP1, its orchestration of the JAK2/STAT3 signaling pathway, and its pivotal role in NPC progression.
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Affiliation(s)
- Yuting Zhan
- Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Weiyuan Wang
- Department of Pathology, Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Haihua Wang
- Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yue Xu
- Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuting Zhang
- Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yue Ning
- Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hongmei Zheng
- Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jiadi Luo
- Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yang Yang
- Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hongjing Zang
- Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ming Zhou
- Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China
| | - Songqing Fan
- Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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Otis JP, Mowry KL. Hitting the mark: Localization of mRNA and biomolecular condensates in health and disease. WILEY INTERDISCIPLINARY REVIEWS. RNA 2023; 14:e1807. [PMID: 37393916 PMCID: PMC10758526 DOI: 10.1002/wrna.1807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 05/29/2023] [Accepted: 06/06/2023] [Indexed: 07/04/2023]
Abstract
Subcellular mRNA localization is critical to a multitude of biological processes such as development of cellular polarity, embryogenesis, tissue differentiation, protein complex formation, cell migration, and rapid responses to environmental stimuli and synaptic depolarization. Our understanding of the mechanisms of mRNA localization must now be revised to include formation and trafficking of biomolecular condensates, as several biomolecular condensates that transport and localize mRNA have recently been discovered. Disruptions in mRNA localization can have catastrophic effects on developmental processes and biomolecular condensate biology and have been shown to contribute to diverse diseases. A fundamental understanding of mRNA localization is essential to understanding how aberrations in this biology contribute the etiology of numerous cancers though support of cancer cell migration and biomolecular condensate dysregulation, as well as many neurodegenerative diseases, through misregulation of mRNA localization and biomolecular condensate biology. This article is categorized under: RNA Export and Localization > RNA Localization RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development.
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Affiliation(s)
- Jessica P. Otis
- Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI, United States, 02912
| | - Kimberly L. Mowry
- Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI, United States, 02912
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Li Q, Yin LK. Comprehensive analysis of disulfidptosis related genes and prognosis of gastric cancer. World J Clin Oncol 2023; 14:373-399. [PMID: 37970110 PMCID: PMC10631345 DOI: 10.5306/wjco.v14.i10.373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 09/07/2023] [Accepted: 09/18/2023] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is a common malignant tumor of the digestive system. Disulfidptosis is a new programmed cell death mechanism, although its specific mechanism in GC is incompletely understood. AIM In this study, we used bioinformatics analysis to explore a disulfidptosis-based predictive model related to GC prognosis and to identify potential therapeutic targets and sensitive drugs for GC. METHODS We extracted GC-related data from The Cancer Genome Atlas and Gene Expression Omnibus databases. R software (version 4.2.1) was used for correlation analysis. RESULTS Through the above analysis, we found that the disulfidptosis related gene may be related to the prognosis of GC. Six genes, namely, PLS3, GRP, APOD, SGCE, COL8A1, and VAMP7, were found to constitute a predictive model for GC prognosis. APOD is a potential therapeutic target for treating GC. Bosutinib and other drugs are sensitive for the treatment of GC. CONCLUSION The results of this study indicate that disulfidptosis is related to the prognosis and treatment of GC, while APOD represents a potential therapeutic target for GC.
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Affiliation(s)
- Qian Li
- Department of Oncology, Fushun Hospital of Traditional Chinese Medicine, Zigong 643200, Sichuan Province, China
| | - Long-Kuan Yin
- Department of Gastrointestinal Surgery, Fushun People’s Hospital, Zigong 643200, Sichuan Province, China
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Zhou H, Luo J, Mou K, Peng L, Li X, Lei Y, Wang J, Lin S, Luo Y, Xiang L. Stress granules: functions and mechanisms in cancer. Cell Biosci 2023; 13:86. [PMID: 37179344 PMCID: PMC10182661 DOI: 10.1186/s13578-023-01030-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 04/11/2023] [Indexed: 05/15/2023] Open
Abstract
Stress granules (SGs) are non-enveloped structures formed primarily via protein and RNA aggregation under various stress conditions, including hypoxia and viral infection, as well as oxidative, osmotic, and heat-shock stress. SGs assembly is a highly conserved cellular strategy to reduce stress-related damage and promote cell survival. At present, the composition and dynamics of SGs are well understood; however, data on the functions and related mechanisms of SGs are limited. In recent years, SGs have continued to attract attention as emerging players in cancer research. Intriguingly, SGs regulate the biological behavior of tumors by participating in various tumor-associated signaling pathways, including cell proliferation, apoptosis, invasion and metastasis, chemotherapy resistance, radiotherapy resistance, and immune escape. This review discusses the roles and mechanisms of SGs in tumors and suggests novel directions for cancer treatment.
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Affiliation(s)
- Huan Zhou
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jing Luo
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Kelin Mou
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Lin Peng
- Department of Bone and Joint Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xiaoyue Li
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yulin Lei
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jianmei Wang
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Sheng Lin
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yuhao Luo
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China.
| | - Li Xiang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China.
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7
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Ling X, Dong S, Zhang L. Low dose TGF-β1 can improve vohwinkel syndrome by promoting the proliferation of keratinocytes. Acta Histochem 2023; 125:152010. [PMID: 36738515 DOI: 10.1016/j.acthis.2023.152010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 01/19/2023] [Accepted: 01/27/2023] [Indexed: 02/05/2023]
Abstract
Vohwinkel syndrome (VS) is a very rare autosomal dominant disorder that can cause disability and deformity in severe cases. Mutations of the LOR (loricrin) and GJB2 (Cx26) genes have been found in VS so far. Many studies have indicated that the differentiation and growth of epidermal keratinocytes are regulated by mutant Cx26, and it may explain the pathogenesis of VS. It has been found that transforming growth factor β1 (TGF-β1) expression was lower in G130V (OE1) and D66H (OE2) mutant keratinocytes in the VS model with GJB2 mutation as compared to normal keratinocytes (NC). TGF-β is a cytokine involved in the regulation of processes like cell proliferation and differentiation in different types of cells. At present, many in vitro studies focus on TGF- β 1 inhibition of keratinocyte growth.However, the relationship between TGF-β1 and VS remains unknown. This study aimed at elucidating the role and potential pathogenic mechanism of TGF-β in VS. The results indicated that the down-regulation expression of TGF-β1 in VS was linked to cell proliferation inhibition through p-Smad3/c-myc. In contrast, low-dose TGF-β1 treatment of VS keratinocytes can improve their proliferation inhibition and up-regulate the expression Cyclin D1. This suggests that low doses of TGF-β1 can improve the proliferation of VS and provide new insights into its treatment.
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Affiliation(s)
- Xia Ling
- Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China; Shandong First Medical University, Jinan 250117, Shandong, China
| | - Shujing Dong
- Department of Dermatology, Affiliated Hospital of Shandong University of traditional Chinese Medicine, Jinan 250012, Shandong, China
| | - Li Zhang
- Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China.
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8
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Hu M, Song HY, Chen L. Quercetin acts via the G3BP1/YWHAZ axis to inhibit glycolysis and proliferation in oral squamous cell carcinoma. Toxicol Mech Methods 2023; 33:141-150. [PMID: 35945655 DOI: 10.1080/15376516.2022.2103480] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
There is increasing evidence that the GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) plays important roles in the formation of various tumors. However, the biological functions and mechanism of G3BP1 in promoting the progression of oral squamous cell carcinoma remain largely unknown. The impacts of quercetin on glycolysis and proliferation of the CAL27 oral squamous cell carcinoma line were investigated, and the mediating role of the G3BP1/YWHAZ pathway was explored. CAL27 cells stably over- or underexpressing G3BP1 were treated with quercetin, and then cell proliferation was assayed together with the expression of proteins involved in glucose uptake, glycolysis, and lactate production, as well as the activity of hexokinase, pyruvate kinase, and lactate dehydrogenase. CAL27 cells expressed G3BP1 and YWHAZ at significantly higher levels than normal oral squamous cells. CAL27 cells showed the highest expression of both proteins among the three carcinoma lines (TSCCA, SCC15, 42 CAL27). Overexpressing G3BP1 in CAL27 cells markedly induced glucose uptake, glycolysis, cell proliferation, and YWHAZ expression. Knocking down G3BP1 or YWHAZ exerted the opposite effects, which were similar to the effects of inhibiting glycolysis. Quercetin repressed glucose uptake, glycolysis, cell proliferation, and G3BP1/YWHAZ signaling in a dose-dependent way, and these effects were antagonized by G3BP1 overexpression. Quercetin can inhibit glycolysis and cell proliferation of oral squamous cell carcinoma, apparently by inhibiting the G3BP1/YWHAZ axis.
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Affiliation(s)
- Meng Hu
- Department of Cosmetic Surgery, Wuhan Third Hospital (Tongren Hospital of Wuhan University), Wuhan, China
| | - Hong-Yan Song
- Department of Pharmacy, Wuhan Third Hospital (Tongren Hospital of Wuhan University), Wuhan, China
| | - Ling Chen
- Department of Pharmacy, Wuhan Third Hospital (Tongren Hospital of Wuhan University), Wuhan, China
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9
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Liu S, Tian S, Lin T, He X, Eze Ideozu J, Wang R, Wang Y, Yue D, Geng H. G3BP1 regulates breast cancer cell proliferation and metastasis by modulating PKCζ. Front Genet 2022; 13:1034889. [PMID: 36330442 PMCID: PMC9623284 DOI: 10.3389/fgene.2022.1034889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 10/05/2022] [Indexed: 11/30/2022] Open
Abstract
Breast cancer is a leading cause of death and morbidity among female cancers. Several factors, including hormone levels, lifestyle, and dysregulated RNA-binding proteins, have been associated with the development of breast cancer. Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) and protein kinase C, Zeta isoform (PKCζ) are oncogenes implicated in numerous cancers, including breast cancer. However, their interaction and role in promoting breast cancer proliferation and metastasis have not been well-characterized. In the present study, we demonstrated that G3BP1 expression was elevated in breast cancer and that knockdown of G3BP1 diminished the proliferation and metastasis of breast cancer cells. Mechanistically, we identified proliferation and a series of metastasis-related properties, including chemotaxis, migration, Golgi polarity localization, and actin polymerization, that were modulated by G3BP1 knockdown. We found that G3BP1 and PKCζ were co-localized and interacted intracellularly, and they co-underwent membrane translocation under EGF stimulation. Following the knockdown of G3BP1, we observed the membrane translocation and phosphorylation of PKCζ were significantly impaired, suggesting that G3BP1 regulates the activation of PKCζ. Our findings indicate that G3BP1 plays multiple roles in breast cancer cell proliferation and metastasis. The activation of PKCζ by G3BP1 may be the specific mechanism underlying the process.
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Affiliation(s)
- Shuang Liu
- Department of Microbiology, School of Medical Laboratory, Tianjin Medical University, Tianjin, China
| | - Shaoping Tian
- Department of Microbiology, School of Medical Laboratory, Tianjin Medical University, Tianjin, China
| | - Tianyu Lin
- Department of Microbiology, School of Medical Laboratory, Tianjin Medical University, Tianjin, China
| | - Xin He
- Department of Microbiology, School of Medical Laboratory, Tianjin Medical University, Tianjin, China
- Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - Justin Eze Ideozu
- Genomic Medicine, Genomic Research Center, AbbVie, North Chicago, IL, United States
| | - Rui Wang
- Department of Microbiology, School of Medical Laboratory, Tianjin Medical University, Tianjin, China
| | - Yong Wang
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Tianjin, China
| | - Dan Yue
- Department of Microbiology, School of Medical Laboratory, Tianjin Medical University, Tianjin, China
- *Correspondence: Dan Yue, ; Hua Geng,
| | - Hua Geng
- Department of Microbiology, School of Medical Laboratory, Tianjin Medical University, Tianjin, China
- Center for Intestinal and Liver Inflammation Research, Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United States
- Center Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- *Correspondence: Dan Yue, ; Hua Geng,
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Sun M, Wu S, Kang S, Liao J, Zhang L, Xu Z, Chen H, Xu L, Zhang X, Qin Q, Wei J. Critical Roles of G3BP1 in Red-Spotted Grouper Nervous Necrosis Virus-Induced Stress Granule Formation and Viral Replication in Orange-Spotted Grouper (Epinephelus coioides). Front Immunol 2022; 13:931534. [PMID: 35935992 PMCID: PMC9354888 DOI: 10.3389/fimmu.2022.931534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 06/22/2022] [Indexed: 11/13/2022] Open
Abstract
Viral infection causes changes in the internal environment of host cells, and a series of stress responses are generated to respond to these changes and help the cell survive. Stress granule (SG) formation is a type of cellular stress response that inhibits viral replication. However, the relationship between red-spotted grouper nervous necrosis virus (RGNNV) infection and SGs, and the roles of the SG marker protein RAS GTPase-activating protein (SH3 domain)-binding protein 1 (G3BP1) in viral infection remain unclear. In this study, RGNNV infection induced grouper spleen (GS) cells to produce SGs. The SGs particles co-located with the classic SG marker protein eIF3η, and some SGs depolymerized under treatment with the translation inhibitor, cycloheximide (CHX). In addition, when the four kinases of the eukaryotic translation initiation factor 2α (eIF2α)-dependent pathway were inhibited, knockdown of HRI and GCN2 with small interfering RNAs and inhibition of PKR with 2-aminopurine had little effect on the formation of SGs, but the PERK inhibitor significantly inhibited the formation of SGs and decreased the phosphorylation of eIF2α. G3BP1 of Epinephelus coioides (named as EcG3BP1) encodes 495 amino acids with a predicted molecular weight of 54.12 kDa and 65.9% homology with humans. Overexpression of EcG3BP1 inhibited the replication of RGNNV in vitro by up-regulating the interferon and inflammatory response, whereas knockdown of EcG3BP1 promoted the replication of RGNNV. These results provide a better understanding of the relationship between SGs and viral infection in fish.
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Affiliation(s)
- Mengshi Sun
- College of Marine Sciences, South China Agricultural University, Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Siting Wu
- College of Marine Sciences, South China Agricultural University, Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Shaozhu Kang
- College of Marine Sciences, South China Agricultural University, Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Jiaming Liao
- College of Marine Sciences, South China Agricultural University, Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Luhao Zhang
- College of Marine Sciences, South China Agricultural University, Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Zhuqing Xu
- College of Marine Sciences, South China Agricultural University, Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Hong Chen
- College of Marine Sciences, South China Agricultural University, Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Linting Xu
- College of Marine Sciences, South China Agricultural University, Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Xin Zhang
- College of Marine Sciences, South China Agricultural University, Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Qiwei Qin
- College of Marine Sciences, South China Agricultural University, Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
- Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, China
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
- *Correspondence: Jingguang Wei, ; Qiwei Qin,
| | - Jingguang Wei
- College of Marine Sciences, South China Agricultural University, Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
- *Correspondence: Jingguang Wei, ; Qiwei Qin,
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11
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Flavokawain B Weakens Gastric Cancer Progression via the TGF-β1/SMAD4 Pathway and Attenuates M2 Macrophage Polarization. J Immunol Res 2022; 2022:4903333. [PMID: 35879950 PMCID: PMC9308533 DOI: 10.1155/2022/4903333] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/30/2022] [Accepted: 06/08/2022] [Indexed: 11/30/2022] Open
Abstract
This study was designed to observe the treatment effects of flavokawain B (FKB) on gastric cancer both in SGC-7901 cells and nude mice. When SGC-7901 cells were exposed to 10 μg/mL FKB, cellular proliferative and apoptotic capacities and cell cycle were detected utilizing CCK-8 and flow cytometry assays. The results showed that FKB treatment induced cell apoptosis and G2/M arrest and suppressed cell proliferation for SGC-7901 cells. Western blot results showed that FKB upregulated proapoptotic proteins as well as downregulated antiapoptotic and cell cycle-related proteins in SGC-7901 cells. SMAD4, TGF-β1, and TSPAN12 proteins were tested in FKB-induced SGC-7901 cells. Following exposure to FKB, SMAD4, TGF-β1, and TSPAN12 expression was augmented in SGC-7901 cells. si-SMAD4 transfection weakened cell apoptosis and accelerated cell proliferation. Furthermore, FKB reversed the change in apoptotic and cell cycle-related proteins induced by si-SMAD4. A nude mouse tumorigenesis model was constructed, which was treated by FKB. In the nude mouse tumorigenesis model, FKB activated the TSPAN12 expression and TGF-β1/SMAD4 pathway. Also, FKB treatment prolonged the survival time of nude mice and lowered tumor weight. iNOS and CD86 expression was significantly enhanced, and Arg-1 and CD206 expression was significantly decreased in THP-1 cells cultured in conditioned media from FKB-treated SGC-7901 cells. Additionally, FKB-treated SGC-7901 cells weakened macrophage migration. Collectively, this evidence suggested that FKB accelerated apoptosis and suppressed the proliferation of gastric cancer cells and attenuated M2 macrophage polarization, thereby exerting an anticancer effect on gastric cancer.
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Ge Y, Jin J, Li J, Ye M, Jin X. The roles of G3BP1 in human diseases (review). Gene X 2022; 821:146294. [PMID: 35176431 DOI: 10.1016/j.gene.2022.146294] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/24/2022] [Accepted: 02/03/2022] [Indexed: 11/04/2022] Open
Abstract
Ras-GTPase-activating protein binding protein 1 (G3BP1) is a multifunctional binding protein involved in a variety of biological functions, including cell proliferation, metastasis, apoptosis, differentiation and RNA metabolism. It has been revealed that G3BP1, as an antiviral factor, can interact with viral proteins and regulate the assembly of stress granules (SGs), which can inhibit viral replication. Furthermore, several viruses have the ability to hijack G3BP1 as a cofactor, recruiting translation initiation factors to promote viral proliferation. However, many functions of G3BP1 are associated with other diseases. In various cancers, G3BP1 is a cancer-promoting factor, which can promote the proliferation, invasion and metastasis of cancer cells. Moreover, compared with normal tissues, G3BP1 expression is higher in tumor tissues, indicating that it can be used as an indicator for cancer diagnosis. In this review, the structure of G3BP1 and the regulation of G3BP1 in multiple dimensions are described. In addition, the effects and potential mechanisms of G3BP1 on various carcinomas, viral infections, nervous system diseases and cardiovascular diseases are elucidated, which may provide a direction for clinical applications of G3BP1 in the future.
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Affiliation(s)
- Yidong Ge
- The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China; Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathphysiology, Medical School of Ningbo University, Ningbo 315211, China
| | - Jiabei Jin
- The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China; Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathphysiology, Medical School of Ningbo University, Ningbo 315211, China
| | - Jinyun Li
- The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China; Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathphysiology, Medical School of Ningbo University, Ningbo 315211, China
| | - Meng Ye
- The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China; Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathphysiology, Medical School of Ningbo University, Ningbo 315211, China.
| | - Xiaofeng Jin
- The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China; Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathphysiology, Medical School of Ningbo University, Ningbo 315211, China.
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G3BP1 promotes human breast cancer cell proliferation through coordinating with GSK-3β and stabilizing β-catenin. Acta Pharmacol Sin 2021; 42:1900-1912. [PMID: 33536604 PMCID: PMC8563869 DOI: 10.1038/s41401-020-00598-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 12/13/2020] [Indexed: 01/30/2023]
Abstract
Ras-GTPase activating SH3 domain-binding protein 1 (G3BP1) is a multifunctional binding protein involved in the development of a variety of human cancers. However, the role of G3BP1 in breast cancer progression remains largely unknown. In this study, we report that G3BP1 is upregulated and correlated with poor prognosis in breast cancer. Overexpression of G3BP1 promotes breast cancer cell proliferation by stimulating β-catenin signaling, which upregulates a number of proliferation-related genes. We further show that G3BP1 improves the stability of β-catenin by inhibiting its ubiquitin-proteasome degradation rather than affecting the transcription of β-catenin. Mechanistically, elevated G3BP1 interacts with and inactivates GSK-3β to suppress β-catenin phosphorylation and degradation. Disturbing the G3BP1-GSK-3β interaction accelerates the degradation of β-catenin, impairing the proliferative capacity of breast cancer cells. Our study demonstrates that the regulatory mechanism of the G3BP1/GSK-3β/β-catenin axis may be a potential therapeutic target for breast cancer.
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Asadi MR, Rahmanpour D, Moslehian MS, Sabaie H, Hassani M, Ghafouri-Fard S, Taheri M, Rezazadeh M. Stress Granules Involved in Formation, Progression and Metastasis of Cancer: A Scoping Review. Front Cell Dev Biol 2021; 9:745394. [PMID: 34604242 PMCID: PMC8485071 DOI: 10.3389/fcell.2021.745394] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 08/25/2021] [Indexed: 12/15/2022] Open
Abstract
The assembly of stress granules (SGs) is a well-known cellular strategy for reducing stress-related damage and promoting cell survival. SGs have become important players in human health, in addition to their fundamental role in the stress response. The critical role of SGs in cancer cells in formation, progression, and metastasis makes sense. Recent researchers have found that several SG components play a role in tumorigenesis and cancer metastasis via tumor-associated signaling pathways and other mechanisms. Gene-ontology analysis revealed the role of these protein components in the structure of SGs. Involvement in the translation process, regulation of mRNA stability, and action in both the cytoplasm and nucleus are among the main features of SG proteins. The present scoping review aimed to consider all studies on the effect of SGs on cancer formation, proliferation, and metastasis and performed based on a six-stage methodology structure and the PRISMA guideline. A systematic search of seven databases for qualified articles was conducted before July 2021. Publications were screened, and quantitative and qualitative analysis was performed on the extracted data. Go analysis was performed on seventy-one SGs protein components. Remarkably G3BP1, TIA1, TIAR, and YB1 have the largest share among the proteins considered in the studies. Altogether, this scoping review tries to demonstrate and provide a comprehensive summary of the role of SGs in the formation, progression, and metastasis of cancer by reviewing all studies.
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Affiliation(s)
- Mohammad Reza Asadi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dara Rahmanpour
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Hani Sabaie
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Hassani
- Student Research Committee, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Rezazadeh
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Sabbadini F, Bertolini M, De Matteis S, Mangiameli D, Contarelli S, Pietrobono S, Melisi D. The Multifaceted Role of TGF-β in Gastrointestinal Tumors. Cancers (Basel) 2021; 13:cancers13163960. [PMID: 34439114 PMCID: PMC8391793 DOI: 10.3390/cancers13163960] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/29/2021] [Accepted: 08/03/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary The transforming growth factor β signaling pathway elicits a broad range of physiological re-sponses, and its misregulation has been related to cancer. The secreted cytokine TGFβ exerts a tumor-suppressive effect that counteracts malignant transformation. However, once tumor has developed, TGFβ can support tumor progression regulating epithelial to mesenchymal transition, invasion and metastasis, stimulating fibrosis, angiogenesis and immune suppression. Here we review the dichotomous role of TGF-β in the progression of gastrointestinal tumors, as well as its intricate crosstalk with other signaling pathways. We also discuss about the therapeutic strate-gies that are currently explored in clinical trials to counteract TGF-β functions. Abstract Transforming growth factor-beta (TGF-β) is a secreted cytokine that signals via serine/threonine kinase receptors and SMAD effectors. Although TGF-β acts as a tumor suppressor during the early stages of tumorigenesis, it supports tumor progression in advanced stages. Indeed, TGF-β can modulate the tumor microenvironment by modifying the extracellular matrix and by sustaining a paracrine interaction between neighboring cells. Due to its critical role in cancer development and progression, a wide range of molecules targeting the TGF-β signaling pathway are currently under active clinical development in different diseases. Here, we focused on the role of TGF-β in modulating different pathological processes with a particular emphasis on gastrointestinal tumors.
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Affiliation(s)
- Fabio Sabbadini
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
| | - Monica Bertolini
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
| | - Serena De Matteis
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
- Department of Experimental, Diagnostic and Specialty Medicine, AlmaMater Studiorum, University of Bologna, 40126 Bologna, Italy
| | - Domenico Mangiameli
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
| | - Serena Contarelli
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
| | - Silvia Pietrobono
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
| | - Davide Melisi
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
- Experimental Cancer Medicine Unit, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy
- Correspondence:
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SILAC-based quantitative MS approach reveals Withaferin A regulated proteins in prostate cancer. J Proteomics 2021; 247:104334. [PMID: 34298187 DOI: 10.1016/j.jprot.2021.104334] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 06/30/2021] [Accepted: 07/16/2021] [Indexed: 01/06/2023]
Abstract
Withaferin A (WA) is a steroidal lactone extracted from Withania somnifera, commonly known as Ashwagandha. WA has several therapeutic benefits. The current study aims to identify proteins that are potentially regulated by WA in prostate cancer (PCA) cells. We used a SILAC-based proteomic approach to analyze the expression of proteins in response to WA treatment at 4 h and 24 h time points in three PCA cell lines: 22Rv1, DU-145, and LNCaP. Ontology analysis suggested that prolonged treatment with WA upregulated the expression of proteins involved in stress-response pathways. Treatment with WA increased oxidative stress, reduced global mRNA translation, and elevated the expression of cytoprotective stress granule (SG) protein G3BP1. WA treatment also enhanced the formation of SGs. The elevated expression of G3BP1 and the formation of SGs might constitute a mechanism of cytoprotection in PCA cells. Knockdown of G3BP1 blocked SG formation and enhanced the efficacy of WA to reduce PCA cell survival. SIGNIFICANCE: Withaferin A, a steroidal lactone, extracted from Withania somnifera is a promising anti-cancer drug. Using a SILAC-based quantitative proteomic approach, we identified proteins changed by WA-treatment at 4 h and 24 h in three prostate cancer (PCA) cell lines. WA-treatment induced the expression of proteins involved in apoptosis and reduced the expression of proteins involved in cell growth at 4 h. WA-treatment for 24 h enhanced the expression of proteins involved in stress response pathways. WA-treated cells exhibited increased oxidative stress, reduced mRNA translation and enhanced SG formation. PCA is characterized by higher metabolic rate and increased oxidative stress. PCA with a higher stress tolerance can effectively adapt to anti-cancer treatment stress, leading to drug resistance and cellular protection. Enhancing the level of oxidative stress along with inhibition of corresponding cytoprotective stress response pathways is a feasible option to prevent PCA from getting adapted to treatment stress. WA-treatment induced oxidative stress, in combination with blocking SGs by G3BP1 targeting, offers a therapeutic strategy to reduce PCA cell survival.
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Lavalée M, Curdy N, Laurent C, Fournié JJ, Franchini DM. Cancer cell adaptability: turning ribonucleoprotein granules into targets. Trends Cancer 2021; 7:902-915. [PMID: 34144941 DOI: 10.1016/j.trecan.2021.05.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/12/2021] [Accepted: 05/18/2021] [Indexed: 10/21/2022]
Abstract
Stress granules (SGs) and processing bodies (P-bodies) are membraneless cytoplasmic condensates of ribonucleoproteins (RNPs). They both regulate RNA fate under physiological and pathological conditions, and are thereby involved in the regulation and maintenance of cellular integrity. During tumorigenesis, cancer cells use these granules to thrive, to adapt to the harsh conditions of the tumor microenvironment (TME), and to protect themselves from anticancer treatments. This ability to provide multiple outcomes not only makes RNP granules promising targets for cancer therapy but also emphasizes the need for more knowledge about the biology of these granules to achieve clinical use. In this review we focus on the role of RNP granules in cancer, and on how their composition and regulation might be used to elaborate therapeutic strategies.
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Affiliation(s)
- Margot Lavalée
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1037, Centre National de la Recherche Scientifique (CNRS) UMR 5071, 31037 Toulouse, France; Université Toulouse III Paul Sabatier, 31330 Toulouse, France; Institut Universitaire du Cancer de Toulouse-Oncopole, 31100 Toulouse, France
| | - Nicolas Curdy
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1037, Centre National de la Recherche Scientifique (CNRS) UMR 5071, 31037 Toulouse, France; Université Toulouse III Paul Sabatier, 31330 Toulouse, France; Institut Universitaire du Cancer de Toulouse-Oncopole, 31100 Toulouse, France
| | - Camille Laurent
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1037, Centre National de la Recherche Scientifique (CNRS) UMR 5071, 31037 Toulouse, France; Université Toulouse III Paul Sabatier, 31330 Toulouse, France; Institut Universitaire du Cancer de Toulouse-Oncopole, 31100 Toulouse, France; Département de Pathologie, Centre Hospitalier Universitaire (CHU) de Toulouse, 31059 Toulouse, France
| | - Jean-Jacques Fournié
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1037, Centre National de la Recherche Scientifique (CNRS) UMR 5071, 31037 Toulouse, France; Université Toulouse III Paul Sabatier, 31330 Toulouse, France; Institut Universitaire du Cancer de Toulouse-Oncopole, 31100 Toulouse, France
| | - Don-Marc Franchini
- Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1037, Centre National de la Recherche Scientifique (CNRS) UMR 5071, 31037 Toulouse, France; Université Toulouse III Paul Sabatier, 31330 Toulouse, France; Institut Universitaire du Cancer de Toulouse-Oncopole, 31100 Toulouse, France.
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Wang C, Cui Q, Du R, Liu S, Tian S, Huang H, Jiang Y, Chen R, Niu Y, Yue D, Wang Y. Expression of G3BP1 in benign and malignant human prostate tissues. Transl Androl Urol 2021; 10:1665-1675. [PMID: 33968655 PMCID: PMC8100838 DOI: 10.21037/tau-20-1450] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Background Prostate cancer (PCa) is the world’s leading type of cancer in men. GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is overexpressed in a variety of tumors. However, there are limited studies in PCa concerning G3BP1. This present study was to investigates the expression of G3BP1 and the mechanism of action on PCa. Methods We explored the G3BP1 expression in PCa using the TCGA database and verified it using clinical samples by immunohistochemistry (IHC) methods. G3BP1 and Androgen receptor (AR) status of 104 human PCa and 50 benign prostate hyperplasia (BPH) samples were analyzed by IHC and the association between G3BP1 expression and biochemical recurrence was determined. Moreover, we generated G3BP1 knockdown cell lines in human PCa LNCaP cell lines, to observe AR changes. Results G3BP1 and AR were overexpressed in PCa compared to BPH tissues. The expression of G3BP1 and AR was positively correlated with the malignant degree of the tumor. Higher G3BP1 expression showed a trend toward biochemical recurrence. Western blot showed downregulation of G3BP1 affected AR expression levels. Conclusions Our study suggested that G3BP1 was frequently upregulated in PCa and closely related to AR expression and tumor metastasis. Besides, G3BP1 might be associated with biochemical recurrence. These results supply potential target for the management of the PCa.
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Affiliation(s)
- Chao Wang
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology and School of Medical Laboratory, Tianjin Medical University, Tianjin, China
| | - Qiqi Cui
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology and School of Medical Laboratory, Tianjin Medical University, Tianjin, China
| | - Runxuan Du
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology and School of Medical Laboratory, Tianjin Medical University, Tianjin, China
| | - Shuang Liu
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology and School of Medical Laboratory, Tianjin Medical University, Tianjin, China
| | - Shaoping Tian
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology and School of Medical Laboratory, Tianjin Medical University, Tianjin, China
| | - Hua Huang
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology and School of Medical Laboratory, Tianjin Medical University, Tianjin, China
| | - Yihua Jiang
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology and School of Medical Laboratory, Tianjin Medical University, Tianjin, China
| | - Ruibing Chen
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Yuanjie Niu
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology and School of Medical Laboratory, Tianjin Medical University, Tianjin, China
| | - Dan Yue
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology and School of Medical Laboratory, Tianjin Medical University, Tianjin, China
| | - Yong Wang
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology and School of Medical Laboratory, Tianjin Medical University, Tianjin, China
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Tong Y, Liu L, Wang R, Yang T, Wen J, Wei S, Jing M, Zou W, Zhao Y. Berberine Attenuates Chronic Atrophic Gastritis Induced by MNNG and Its Potential Mechanism. Front Pharmacol 2021; 12:644638. [PMID: 33841162 PMCID: PMC8026873 DOI: 10.3389/fphar.2021.644638] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 02/11/2021] [Indexed: 12/13/2022] Open
Abstract
The purpose of this study was to investigate the therapeutic effect of berberine (BBR) on MNNG-induced chronic atrophic gastritis (CAG) and the possible mechanism of BBR through TGF-β1/PI3K signal pathway. GES-1 were pretreated with MNNG for 2 h before BBR treatment in all procedures. Cell viability was quantified by cell counting kit-8, and GES-1 morphology and proliferation were detected by high content screening (HCS) assay. The rat model of CAG was established by MNNG, and the therapeutic effect of BBR on stomach histopathology and serum supernatant were analyzed in vivo. In addition, the possible mechanism of BBR was further discussed, and the expression of related genes and proteins in TGF-β1/PI3K signal pathway was detected. The results showed that BBR could significantly improve the survival rate and morphological changes of GES-1, improve the gastric tissue injury of CAG rats, and reduce the expression of G-17 and inflammatory factors IL-8, TNF-α, IL-6 and IL-1β. In addition, BBR down-regulated the expression of TGF-β1 axis-related signals such as TGF-β1, PI3K, p-Akt/Akt, p-mTOR/mTOR and P70S6K, and promoted the expression of PTEN, LC3-II and Beclin-1. In Conclusion, BBR can improve CAG which may be closely related to TGF-β1/PI3K signal pathway.
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Affiliation(s)
- Yuling Tong
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
| | - Liping Liu
- Integrative Medical Center, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Ruilin Wang
- Integrative Medical Center, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Tao Yang
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China.,College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jianxia Wen
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
| | - Shizhang Wei
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
| | - Manyi Jing
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
| | - Wenjun Zou
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yanling Zhao
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
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Liu S, Chen L, Chen H, Xu K, Peng X, Zhang M. Circ_0119872 promotes uveal melanoma development by regulating the miR-622/G3BP1 axis and downstream signalling pathways. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:66. [PMID: 33579337 PMCID: PMC7881613 DOI: 10.1186/s13046-021-01833-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 01/07/2021] [Indexed: 12/12/2022]
Abstract
Background The abnormal expression of circular RNAs (circRNAs) in uveal melanoma (UM) has been revealed, but the specific underlying molecular mechanism of their association with UM development has not been fully explored. Methods The levels of circ_0119872, G3BP1 and miR-622 in UM cell lines and tissues were determined by quantitative real-time PCR (qRT-PCR) and western blotting assays. In vitro and in vivo assays were performed to investigate the function of circ_0119872 in the tumorigenesis of UM cells. The relationships among circ_0119872, miR-622 and G3BP1 were predicted using bioinformatic tools and verified by RNA-FISH, RNA pull-down and dual-luciferase reporter assays. The effects of circ_0119872 on Wnt/β-catenin and mTOR signalling pathways were determined by gene set enrichment analysis (GSEA) and western blotting. Results We found that circ_0119872 is upregulated in UM cell lines and tissues. Moreover, overexpression of circ_0119872 promotes the malignancy of UM cells, while silencing of circ_0119872 inhibits it. In addition, circ_0119872 can directly interact with miR-622 as a miRNA sponge that regulates the expression of the miR-622 target gene G3BP1 as well as downstream Wnt/β-catenin and mTOR signalling pathways. Conclusions Circ_0119872 may act as an oncogene in UM through a novel circ_0119872/miR-622/G3BP1 axis, activating the Wnt/β-catenin and mTOR signalling pathways, which in turn may provide potential biomarkers and therapeutic targets for the management of UM. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-01833-w.
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Affiliation(s)
- Shuting Liu
- Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, HB, China
| | - Liang Chen
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, HB, China
| | - Hua Chen
- Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, HB, China
| | - Kangkang Xu
- Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, HB, China
| | - Xi Peng
- Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, HB, China
| | - Mingchang Zhang
- Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, HB, China.
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Song C, Zhou C. HOXA10 mediates epithelial-mesenchymal transition to promote gastric cancer metastasis partly via modulation of TGFB2/Smad/METTL3 signaling axis. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:62. [PMID: 33563300 PMCID: PMC7874610 DOI: 10.1186/s13046-021-01859-0] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 01/28/2021] [Indexed: 01/06/2023]
Abstract
Background Homeobox A10 (HOXA10) belongs to the HOX gene family, which plays an essential role in embryonic development and tumor progression. We previously demonstrated that HOXA10 was significantly upregulated in gastric cancer (GC) and promoted GC cell proliferation. This study was designed to investigate the role of HOXA10 in GC metastasis and explore the underlying mechanism. Methods Immunohistochemistry (IHC) was used to evaluate the expression of HOXA10 in GC. In vitro cell migration and invasion assays as well as in vivo mice metastatic models were utilized to investigate the effects of HOXA10 on GC metastasis. GSEA, western blot, qRT-PCR and confocal immunofluorescence experiments preliminarily analyzed the relationship between HOXA10 and EMT. ChIP-qPCR, dual-luciferase reporter (DLR), co-immunoprecipitation (CoIP), colorimetric m6A assay and mice lung metastasis rescue models were performed to explore the mechanism by which HOXA10 accelerated the EMT process in GC. Results In this study, we demonstrated HOXA10 was upregulated in GC patients and the difference was even more pronounced in patients with lymph node metastasis (LNM) than without. Functionally, HOXA10 promoted migration and invasion of GC cells in vitro and accelerated lung metastasis in vivo. EMT was an important mechanism responsible for HOXA10-involved metastasis. Mechanistically, we revealed HOXA10 enriched in the TGFB2 promoter region, promoted transcription, increased secretion, thus triggered the activation of TGFβ/Smad signaling with subsequent enhancement of Smad2/3 nuclear expression. Moreover, HOXA10 upregulation elevated m6A level and METTL3 expression in GC cells possible by regulating the TGFB2/Smad pathway. CoIP and ChIP-qPCR experiments demonstrated that Smad proteins played an important role in mediating METTL3 expression. Furthermore, we found HOXA10 and METTL3 were clinically relevant, and METTL3 was responsible for the HOXA10-mediated EMT process by performing rescue experiments with western blot and in vivo mice lung metastatic models. Conclusions Our findings indicated the essential role of the HOXA10/TGFB2/Smad/METTL3 signaling axis in GC progression and metastasis. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-01859-0.
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Affiliation(s)
- Chenlong Song
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chongzhi Zhou
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Identification of metabolism-associated genes and construction of a prognostic signature in bladder cancer. Cancer Cell Int 2020; 20:538. [PMID: 33292266 PMCID: PMC7643334 DOI: 10.1186/s12935-020-01627-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 10/26/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Bladder cancer (BC) is a commonly diagnosed malignant tumor in the urinary system, with a high morbidity and a high recurrence rate. Current studies indicated that metabolism-associated genes (MAGs) having critical roles in the etiology of BC. The present study aims to identify differentially expressed MAGs and construct a MAGs based prognostic risk signature for BC by using The Cancer Genome Atlas (TCGA) database and proteomics data. METHODS RNA-sequence data from the TCGA database and proteomics data from our BC samples were used to identify differentially expressed MAGs and construct a MAGs based prognostic signature in BC. Subsequently, survival analysis and nomogram were used to evaluate the prognostic and predictive value of the MAGs based signature in BC. RNA isolation and reverse transcription‑quantitative PCR (RT-qPCR) were further performed to investigate the expression levels of MAGs in BC cells and explore the relationship between MAGs and M2 tumor associated macrophages (TAMs) secreted transforming growth factor-β1 (TGF-β1) in BC cells. RESULTS A total of 23 differentially expressed MAGs were identified and five MAGs were finally used to construct a MAGs based signature. Survival analysis revealed that the MAGs based signature was closely correlated with the survival outcomes of patients with BC. A nomogram with the MAGs based signature risk score and clinical features was also constructed to facilitate the individualized prediction of BC patients. RT-qPCR showed that five MAGs were significantly differentially expressed and the expression levels of three MAGs were positively correlated with M2 TAMs secreted TGF-β1 in T24 cells. CONCLUSIONS Our study identified novel prognostic MAGs and constructed a MAGs based signature, which can be used as an independent factor in evaluating the prognosis of patients with BC. Furthermore, M2 TAMs may promote the expression of MAGs via the TGF-β1 signaling pathway in the microenvironment of BC. Further clinical trials and experimental explorations are needed to validate our observations in BC.
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Revisiting the Concept of Stress in the Prognosis of Solid Tumors: A Role for Stress Granules Proteins? Cancers (Basel) 2020; 12:cancers12092470. [PMID: 32882814 PMCID: PMC7564653 DOI: 10.3390/cancers12092470] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 08/27/2020] [Accepted: 08/28/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Stress Granules (SGs) were discovered in 1999 and while the first decade of research has focused on some fundamental questions, the field is now investigating their role in human pathogenesis. Since then, evidences of a link between SGs and cancerology are accumulating in vitro and in vivo. In this work we summarized the role of SGs proteins in cancer development and their prognostic values. We find that level of expression of protein involved in SGs formation (and not mRNA level) could serve a prognostic marker in cancer. With this review we strongly suggest that SGs (proteins) could be targets of choice to block cancer development and counteract resistance to improve patients care. Abstract Cancer treatments are constantly evolving with new approaches to improve patient outcomes. Despite progresses, too many patients remain refractory to treatment due to either the development of resistance to therapeutic drugs and/or metastasis occurrence. Growing evidence suggests that these two barriers are due to transient survival mechanisms that are similar to those observed during stress response. We review the literature and current available open databases to study the potential role of stress response and, most particularly, the involvement of Stress Granules (proteins) in cancer. We propose that Stress Granule proteins may have prognostic value for patients.
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