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Broszkiewicz W, Beda J, Domińska K. Effect of dexamethasone on biological properties and metabolic adaptations of normal prostate epithelial cells under mild serum conditions. Steroids 2025; 219:109625. [PMID: 40316041 DOI: 10.1016/j.steroids.2025.109625] [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: 02/18/2025] [Revised: 04/23/2025] [Accepted: 04/29/2025] [Indexed: 05/04/2025]
Abstract
Limiting serum concentration in culture medium constitutes an environmental stress that disrupts cellular homeostasis and activates adaptive metabolism. This study aims to examine the impact of dexamethasone (DEX) on biological properties (e.g. viability, adhesion, migration) and glucose and lipid metabolism of prostate epithelial cells under stress conditions. The study used a non-tumorigenic human prostate cell line, PNT1A. In mild serum deprivation conditions, DEX, commonly used in the treatment of castration-resistant prostate cancer, also arrests normal prostate cells in the G0/G1 phase. Observed reduction in metabolic activity and limiting apoptosis of PNT1A cells as related to decreased expression of the NF-κB family and FOXO3 genes. Moreover, DEX modulated PNT1A migration by regulating cell plasticity thought capacity of adhesion to ECM proteins such as fibronectin and collagen I and IV. This was associated with changes in mRNA levels for the genes VIM, ZEB1 and ZEB2. Finally, it seems that dexamethasone helps PNT1A cells adapt to stress and enhance antioxidant defense, possibly by reprogramming lipid metabolism (e.g., LDLR, CPT1, MGLL), but not necessarily glucose metabolism.
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Affiliation(s)
- Weronika Broszkiewicz
- Medical University of Lodz, Department of Comparative Endocrinology, Zeligowskiego 7/9, 90-752 Lodz, Poland
| | - Jakub Beda
- Medical University of Lodz, Department of Comparative Endocrinology, Zeligowskiego 7/9, 90-752 Lodz, Poland
| | - Kamila Domińska
- Medical University of Lodz, Department of Comparative Endocrinology, Zeligowskiego 7/9, 90-752 Lodz, Poland.
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2
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Mohammad SI, Vasudevan A, Nadhim Mohammed S, Uthirapathy S, M M R, Kundlas M, Siva Prasad GV, Kumari M, Mustafa YF, Ali Hussein Z. Anti-metastatic potential of flavonoids for the treatment of cancers: focus on epithelial-mesenchymal transition (EMT) process. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04235-3. [PMID: 40434422 DOI: 10.1007/s00210-025-04235-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 04/26/2025] [Indexed: 05/29/2025]
Abstract
The leading factor contributing to patient mortality is the local invasion and metastasis of tumors, which are influenced by the malignant progression of tumor cells. The epithelial-mesenchymal transition (EMT) is key to understanding malignancy development. EMT is a critical regulatory mechanism for differentiating cell populations initially observed during the neural crest and embryonic gastrulation formation. This process is closely associated with tumor metastasis in cancer and is also related to the maintenance of cancer stem cells. Flavonoids, known for their antioxidant properties, have been widely studied for their anticancer potential to protect plants from harmful environmental conditions. They have attracted considerable attention and have been the focus of numerous experimental and epidemiological studies to evaluate their potential in cancer treatment. In vitro and in vivo research has demonstrated that flavonoids can significantly impact cancer-related EMT. They may inhibit the EMT process by reducing the levels of Twist1, N-cadherin, ZEB1, integrins, SNAI1/2, CD44, MMPs, and vimentin while increasing E-cadherin levels and targeting the PI3K/AKT, NF-κB p65, and JAK2/STAT3 signaling pathways. In order to suppress the transcription of the E-cadherin promoter, several Zn-finger transcription factors, such as SNAI2, ZEB1, and ZEB2, and basic helix-loop-helix (bHLH) factors, such as Twist, may directly bind to its E-boxes. Overall, clinical cancer research should integrate the anticancer properties of flavonoids, which address all phases of carcinogenesis, including EMT, to improve the prospects for targeted cancer therapies in patients suffering from aggressive forms of tumors.
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Affiliation(s)
- Suleiman Ibrahim Mohammad
- Electronic Marketing and Social Media, Economic and Administrative Sciences Zarqa University, Zarqa, Jordan
- INTI International University, 71800, Negeri Sembilan, Malaysia
| | - Asokan Vasudevan
- Faculty of Business and Communications, INTI International University, 71800, Negeri Sembilan, Malaysia
- Shinawatra University, 99 Moo 10, Bangtoey, Samkhok, Pathum Thani, 12160, Thailand
| | - Sumaya Nadhim Mohammed
- Medical Laboratory Techniques Department, College of Health and Medical Technology, University of Al-Maarif, Anbar, Iraq.
| | - Subasini Uthirapathy
- Pharmacy Department, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Rekha M M
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Mayank Kundlas
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - G V Siva Prasad
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, 531162, India
| | - Mukesh Kumari
- Department of Applied Sciences-Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, India
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Zainab Ali Hussein
- Radiological Techniques Department, College of Health and Medical Techniques, Al-Mustaqbal University, 51001, Babylon, Iraq
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3
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Wang P, Xu J, You W, Li J, Yu J, Jiang F, Zhang Z, Hu W, Li B. CYP24A1 Binding to FUS Maintains Tumor Properties by Regulating the miR-200c/ZEB1/EMT Axis. Cancer Sci 2025; 116:910-922. [PMID: 39777777 PMCID: PMC11967274 DOI: 10.1111/cas.16445] [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: 10/31/2024] [Revised: 12/17/2024] [Accepted: 12/20/2024] [Indexed: 01/11/2025] Open
Abstract
The active vitamin D-degrading enzyme (CYP24A1) is commonly overexpressed in various types of cancer, which is associated with poor prognosis in cancer patients. Recent studies highlight the antagonism of CYP24A1 toward the anticancer role of active vitamin D. However, the impact of CYP24A1 on tumorigenesis and its underlying mechanisms largely remains unexplored. This study also found that high CYP24A1 mRNA expressions were associated with poor prognosis in ovarian cancer and lung adenocarcinoma (LUAD) patients. Moreover, we demonstrated that the overexpression of CYP24A1 accelerated the proliferation, migration, and invasion of ovarian cancer and LUAD cancer cells in vitro. Furthermore, knockdown of CYP24A1 displayed an anticancer effector both in vitro and in vivo. Mechanically, 87-297 amino acid motif of CYP24A1 bound specifically to FUS protein, consequentially reducing FUS affinity for miR-200c. Considering FUS promotes gene silencing by binding to microRNA targets, a decrease in miR-200c levels led to a notable activation of its target ZEB1, resulting in the promotion of the epithelial-mesenchymal transition (EMT) process. In conclusion, FUS binding specifically by CYP24A1 impaired miR-200c-mediated ZEB1 silencing, thereby augmenting EMT progression and tumorigenesis. These findings elucidate a fundamental mechanism by which CYP24A1 operates as an oncogene, offering potential targets for therapeutic interventions in cancer treatment.
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Affiliation(s)
- Ping Wang
- Department of Occupational and Environmental Health, School of Public HealthSuzhou Medical College of Soochow UniversitySuzhouChina
| | - Jiming Xu
- Department of Nutrition and Food Hygiene, School of Public HealthSuzhou Medical College of Soochow UniversitySuzhouChina
- Department of Infectious Disease Surveillance and Early WarningQingdao Municipal Health CommissionQingdaoChina
| | - Weijing You
- Department of Nutrition and Food Hygiene, School of Public HealthSuzhou Medical College of Soochow UniversitySuzhouChina
- Yantai Hi‐Tech Industrial Development Zone Center for Disease Control and PreventionYantaiChina
| | - Jie Li
- Department of Nutrition and Food Hygiene, School of Public HealthSuzhou Medical College of Soochow UniversitySuzhouChina
| | - Jing Yu
- Department of Nutrition and Food Hygiene, School of Public HealthSuzhou Medical College of Soochow UniversitySuzhouChina
- Department of Clinical Laboratory CenterThe First Affiliated Hospital of Guangxi Medical UniversityNanningChina
| | - Fei Jiang
- Department of Occupational and Environmental Health, School of Public HealthSuzhou Medical College of Soochow UniversitySuzhouChina
| | - Zengli Zhang
- Department of Occupational and Environmental Health, School of Public HealthSuzhou Medical College of Soochow UniversitySuzhouChina
| | - Wentao Hu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and ProtectionSoochow UniversitySuzhouChina
| | - Bingyan Li
- Department of Nutrition and Food Hygiene, School of Public HealthSuzhou Medical College of Soochow UniversitySuzhouChina
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Ge W, Wen S, Zhou X, Chen Y, Zeng D, Jiang J, Yang S. FOXA2 Loss in TGF-β1-Induced EMT Suppresses Bisecting-GlcNAc N-Glycan Synthesis in Lung Adenocarcinoma. Proteomics 2025; 25:e202400216. [PMID: 40051143 DOI: 10.1002/pmic.202400216] [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: 06/21/2024] [Revised: 12/12/2024] [Accepted: 02/18/2025] [Indexed: 04/25/2025]
Abstract
Glycosylation, a major posttranslational modification (PTM), is often dysregulated in cancer due to altered glycosyltransferase activity. Studies have shown specific changes in glycan structures associated with epithelial-mesenchymal transition (EMT) in cancer cells. However, the specific mechanism by which glycosyltransferases contribute to EMT remains unclear. In this study, we used bronchoalveolar lavage fluid (BALF) from lung adenocarcinoma (LUAD) patients to comparatively characterize glycopatterns and identify dysregulated glycosyltransferases in LUAD. We found a significant reduction in N-glycans containing the bisecting GlcNAc structure and confirmed by Western blot that N-acetylglucosaminyltransferase-III (MGAT3) is downregulated in LUAD. We observed a notable downregulation of both messenger RNA (mRNA) and protein expression of Forkhead box protein A2 (FOXA2) in early-stage LUAD, with FOXA2 loss emerging as an EMT promoter. Interestingly, cellular EMT models demonstrated that FOXA2 deficiency decreased MGAT3 expression during TGF-β1-driven EMT, leading to reduced levels of bisecting-GlcNAc N-glycans in LUAD cells. Our findings unveil a novel mechanism underlying the downregulation of MGAT3 and bisecting GlcNAc N-glycan expression during EMT, a process crucial for tumor metastasis.
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Affiliation(s)
- Wei Ge
- Department of Respiratory Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
- Center for Clinical Mass Spectrometry, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Shengye Wen
- Center for Clinical Mass Spectrometry, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
- Jiangsu Province Engineering Research Center of Precision Diagnostics, and Therapeutics Development, Suzhou, Jiangsu, China
| | - Xiaoli Zhou
- Department of Respiratory Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yan Chen
- Department of Respiratory Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
- Center for Clinical Mass Spectrometry, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
- Jiangsu Province Engineering Research Center of Precision Diagnostics, and Therapeutics Development, Suzhou, Jiangsu, China
| | - Daxiong Zeng
- Department of Respiratory Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Junhong Jiang
- Department of Respiratory Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Shuang Yang
- Department of Respiratory Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
- Center for Clinical Mass Spectrometry, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
- Jiangsu Province Engineering Research Center of Precision Diagnostics, and Therapeutics Development, Suzhou, Jiangsu, China
- Health Examination Center, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
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5
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Chen Y, Liu X, Kini A, Liu JY, Lu X, Gao L, Kaplan HJ, Dean DC, Liu Y. Involvement of tdTomato-Tagged RPE cells in a mouse PVR model with enzymatically compromised retina. Sci Rep 2025; 15:9737. [PMID: 40119078 PMCID: PMC11928672 DOI: 10.1038/s41598-025-93999-y] [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: 07/26/2024] [Accepted: 03/11/2025] [Indexed: 03/24/2025] Open
Abstract
Ocular trauma and surgery are considered the most common cause for proliferative vitreoretinopathy (PVR). Many retinal cell types are thought to be the cellular source for PVR although most risk factors for PVR are associated with intravitreal dispersion of the retinal pigment epithelium (RPE) cells. Major PVR animal models are rabbit and swine with an artificial implantation of exogenous cells into the vitreous to form epiretinal membrane (ERM) which does not recapitulate a real PVR pathology. To clarify and validate the participation of RPE cells, to mimic ocular trauma in situ, and to reveal the related macromolecule changes in PVR pathology, we utilized a dispase treatment to damage the retina in establishment of a reliable RPE-tagged PVR mouse model with ERM-like tissues formed within and on both surface of the retina. The immunostaining of patient epiretinal membranes with lineage markers confirms RPE is involved in PVR development. Quantitative PCR analysis indicates the dedifferentiation of RPE cells switches RPE from epithelial to mesenchymal phenotype to re-enter a proliferative and mobile state underlying PVR. Gene expression results of the mouse PVR model retinas are consistent with the microarray gene expression profile of human PVR retinas, validating that our mouse PVR model resembles human PVR and is thereby suitable for molecular mechanism and pharmaceutical studies.
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Affiliation(s)
- Yao Chen
- Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY, 40202, USA
- Department of Ophthalmology, Hunan Key Laboratory of Ophthalmology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Xiao Liu
- Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY, 40202, USA
- Department of Ophthalmology, the Second Affiliated Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Ashwini Kini
- Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - John Y Liu
- Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY, 40202, USA
- Department of Medicine, James Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Xiaoqin Lu
- Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY, 40202, USA
- Department of Medicine, James Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Ling Gao
- Department of Ophthalmology, the Second Affiliated Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Henry J Kaplan
- Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY, 40202, USA
- Department of Ophthalmology, St. Louis University School of Medicine, St. Louis, MO, 63110, USA
| | - Douglas C Dean
- Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
- Department of Medicine, James Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
| | - Yongqing Liu
- Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
- Department of Medicine, James Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
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6
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Srinivasan D, Subbarayan R, Krishnan M, Balakrishna R, Adtani P, Shrestha R, Chauhan A, Babu S, Radhakrishnan A. Radiation therapy-induced normal tissue damage: involvement of EMT pathways and role of FLASH-RT in reducing toxicities. RADIATION AND ENVIRONMENTAL BIOPHYSICS 2025; 64:1-16. [PMID: 39760753 DOI: 10.1007/s00411-024-01102-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 12/20/2024] [Indexed: 01/07/2025]
Abstract
Radiation therapy (RT) is fundamental to the fight against cancer because of its exceptional ability to target and destroy cancer cells. However, conventional radiation therapy can significantly affect the adjacent normal tissues, leading to fibrosis, inflammation, and decreased organ function. This tissue damage not only reduces the quality of life but also prevents the total elimination of cancer. The transformation of epithelial cells into mesenchymal-like cells, termed epithelial-mesenchymal transition (EMT), is essential for processes such as fibrosis, embryogenesis, and wound healing. Conventional radiation therapy increases the asymmetric activation of fibrotic and inflammatory pathways, and the resulting chronic fibrotic changes and organ dysfunction are linked to radiation-induced epithelial-mesenchymal transition. Recent advances in radiation therapy, namely flash radiation therapy (FLASH-RT), have the potential to widen the therapeutic index. Radiation delivered by FLASH-RT at very high dose rates (exceeding 40 Gy/s) can protect normal tissue from radiation-induced damage, a phenomenon referred to as the "FLASH effect". Preclinical studies have demonstrated that FLASH-RT successfully inhibits processes associated with fibrosis and epithelial-mesenchymal transition, mitigates damage to normal tissue, and enhances regeneration. Three distinct types of EMT have been identified: type-1, associated with embryogenesis; Type-2, associated with injury potential; and type-3, related with cancer spread. The regulation of EMT via pathways, including TGF-β/SMAD, WNT/β-catenin, and NF-κB, is essential for radiation-induced tissue remodelling. This study examined radiation-induced EMT, TGF-β activity, multiple signalling pathways in fibrosis, and the potential of FLASH-RT to reduce tissue damage. FLASH-RT is a novel approach to treat chronic tissue injury and fibrosis post-irradiation by maintaining epithelial properties and regulating mesenchymal markers including vimentin and N-cadherin. Understanding these pathways will facilitate the development of future therapies that can alleviate fibrosis, improve the efficacy of cancer therapy, and improve the quality of life of patients.
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Affiliation(s)
- Dhasarathdev Srinivasan
- Centre for Advanced Biotherapeutics and Regenerative Medicine, Faculty of Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, 603103, Tamil Nadu, India
| | - Rajasekaran Subbarayan
- Centre for Advanced Biotherapeutics and Regenerative Medicine, Faculty of Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, 603103, Tamil Nadu, India.
- Centre for Herbal Pharmacology and Environmental Sustainability, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, 603103, Tamil Nadu, India.
| | - Madhan Krishnan
- Faculty of Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, 603103, Tamil Nadu, India
| | - Ranjith Balakrishna
- Centre for Advanced Biotherapeutics and Regenerative Medicine, Faculty of Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, 603103, Tamil Nadu, India
| | - Pooja Adtani
- Department of Basic Medical and Dental Sciences, Gulf Medical University, Ajman, United Arab Emirates
| | - Rupendra Shrestha
- Department of Natural and Applied Sciences, Nexus Institute of Research and Innovation (NIRI), Lalitpur, Nepal.
| | - Ankush Chauhan
- Centre for Herbal Pharmacology and Environmental Sustainability, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, 603103, Tamil Nadu, India
| | - Shyamaladevi Babu
- Faculty of Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, 603103, Tamil Nadu, India
| | - Arunkumar Radhakrishnan
- Department of Pharmacology, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, India
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Kanwal R, Esposito JE, Jawed B, Zakir SK, Pulcini R, Martinotti R, Botteghi M, Gaudio F, Martinotti S, Toniato E. Exploring the Role of Epithelial-Mesenchymal Transcriptional Factors Involved in Hematological Malignancy and Solid Tumors: A Systematic Review. Cancers (Basel) 2025; 17:529. [PMID: 39941895 PMCID: PMC11817253 DOI: 10.3390/cancers17030529] [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: 12/04/2024] [Revised: 01/13/2025] [Accepted: 01/26/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND The epithelial mesenchymal transition (EMT) is a biological process in which epithelial cells lose their polarity and adhesion characteristics, and adopt a mesenchymal phenotype. While the EMT naturally occurs during tissue fibrosis, wound healing, and embryonic development, it can be exploited by cancer cells and is strongly associated with cancer stem cell formation, tissue invasiveness, apoptosis, and therapy resistance. Transcription factors (TFs) such as SNAIL, ZEB, and TWIST play a pivotal role in driving the EMT. This systematic review aims to assess the impact of EMT-TFs on hematological malignancy and solid tumors. METHODS English-language literature published between 2010 and 2024 was systematically reviewed, utilizing databases such as PubMed and Google Scholar. RESULTS A total of 3250 studies were extracted. Of these, 92 publications meeting the inclusion criteria were analyzed to elucidate the role of EMT-TFs in cancer. The results demonstrated that the EMT-TFs play a critical role in both hematological and solid tumor development and progression. They promote invasive, migratory, and metastatic properties in these tumors, and contribute to therapeutic challenges by enhancing chemoresistance. A strong correlation between EMT-TFs and poor overall survival has been identified. CONCLUSIONS Our research concluded that EMT-TFs may serve as important predictive and prognostic factors, as well as potential therapeutic targets to mitigate cancer progression.
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Affiliation(s)
- Rimsha Kanwal
- Centre of Advanced Studies and Technology, Department of Innovative Technology in Medicine and Dentistry, G.d’ Annunzio University, 66100 Chieti, Italy; (R.K.); (J.E.E.); (B.J.); (S.K.Z.); (R.P.); (E.T.)
- Unit of Clinical Pathology and Microbiology, Miulli Generale Hospital, 70021 Acquaviva delle Fonti, Italy
| | - Jessica Elisabetta Esposito
- Centre of Advanced Studies and Technology, Department of Innovative Technology in Medicine and Dentistry, G.d’ Annunzio University, 66100 Chieti, Italy; (R.K.); (J.E.E.); (B.J.); (S.K.Z.); (R.P.); (E.T.)
| | - Bilal Jawed
- Centre of Advanced Studies and Technology, Department of Innovative Technology in Medicine and Dentistry, G.d’ Annunzio University, 66100 Chieti, Italy; (R.K.); (J.E.E.); (B.J.); (S.K.Z.); (R.P.); (E.T.)
- Unit of Clinical Pathology and Microbiology, Miulli Generale Hospital, 70021 Acquaviva delle Fonti, Italy
| | - Syed Khuram Zakir
- Centre of Advanced Studies and Technology, Department of Innovative Technology in Medicine and Dentistry, G.d’ Annunzio University, 66100 Chieti, Italy; (R.K.); (J.E.E.); (B.J.); (S.K.Z.); (R.P.); (E.T.)
- Unit of Clinical Pathology and Microbiology, Miulli Generale Hospital, 70021 Acquaviva delle Fonti, Italy
| | - Riccardo Pulcini
- Centre of Advanced Studies and Technology, Department of Innovative Technology in Medicine and Dentistry, G.d’ Annunzio University, 66100 Chieti, Italy; (R.K.); (J.E.E.); (B.J.); (S.K.Z.); (R.P.); (E.T.)
| | - Riccardo Martinotti
- Residency Program in Clinical Oncology, Faculty of Medicine, Umberto I University Hospital, University of Rome “La Sapienza”, 00185 Rome, Italy;
| | - Matteo Botteghi
- Experimental Pathology Research Group, Department of Clinical and Molecular Sciences, Universita Politecnica delle Marche, 60126 Ancona, Italy;
| | - Francesco Gaudio
- Unit of Haematology, Department of Medicine and Surgeon, F. Miulli University Hospital, LUM University, Casamassima, 70010 Bari, Italy
| | - Stefano Martinotti
- Unit of Clinical Pathology, Department of Medicine and Surgeon, F. Miulli University Hospital, LUM University, Casamassima, 70010 Bari, Italy
| | - Elena Toniato
- Centre of Advanced Studies and Technology, Department of Innovative Technology in Medicine and Dentistry, G.d’ Annunzio University, 66100 Chieti, Italy; (R.K.); (J.E.E.); (B.J.); (S.K.Z.); (R.P.); (E.T.)
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8
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Chen D, Jiang J, Zhang W, Li X, Ge Q, Liu X, Li X. Tripartite motif-containing protein 50 suppresses triple-negative breast cancer progression by regulating the epithelial-mesenchymal transition. Cancer Biol Ther 2024; 25:2427410. [PMID: 39538371 PMCID: PMC11572070 DOI: 10.1080/15384047.2024.2427410] [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: 05/31/2024] [Revised: 11/02/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Tripartite motif-containing protein 50 (TRIM50) is a recently discovered E3 ubiquitin ligase that participates in tumor progression. TRIM50 is overexpressed in many cancers, although few studies focused on TRIM50's role in breast cancer. METHODS We overexpressed TRIM50 in triple-negative breast cancer cell lines using plasmid and found that TRIM50 upregulation markedly reduced breast cancer cell proliferation, clone formation, and migration, as well as promoted breast cancer cell apoptosis. Western blotting revealed that accumulated TRIM50 resulted in both mRNA and protein depletion of SNAI1, and partially attenuated the epithelial-mesenchymal transition (EMT) induced by SNAI1. RESULTS In this study, we demonstrate that TRIM50 is downregulated in human breast cancer and that its overexpression closely correlates with diminished invasion capacity in breast cancer, suggesting that TRIM50 may serve as a diagnostic marker and therapeutic target. CONCLUSION TRIM50 plays a key role in breast cancer proliferation and potentially serves as a prognostic and therapeutic target.
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Affiliation(s)
- Danxiang Chen
- Department of Oncology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, PR China
- Department of Breast Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Jing Jiang
- Department of Oncology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, PR China
- Department of Breast Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Wei Zhang
- Department of Oncology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, PR China
- Department of Breast Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Xinlin Li
- Department of Oncology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, PR China
- Department of Breast Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Qidong Ge
- Department of Oncology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, PR China
- Department of Breast Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Xia Liu
- Department of Anesthesiology, Ningbo 1st Hospital, Ningbo, Zhejiang, China
| | - Xujun Li
- Department of Oncology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, PR China
- Department of Breast Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
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9
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Shen M, Mao Y, Wang X, Huang J, Zhang Q, Zhang J. LncRNA DNM1P35 sponges hsa-mir-326 to promote ovarian cancer progression. Sci Rep 2024; 14:31502. [PMID: 39732940 PMCID: PMC11682247 DOI: 10.1038/s41598-024-83170-4] [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: 08/30/2024] [Accepted: 12/12/2024] [Indexed: 12/30/2024] Open
Abstract
Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in cancer progression. We found lncRNA DNM1P35 is elevated in ovarian tumors compared to normal tissues, and demonstrated that lncRNA DNM1P35 promoted cancer cell proliferation, migration and invasion in SK-OV-3 and OVCAR-3 cell lines. Furthermore, lncRNA DNM1P35 also facilitated the epithelial-mesenchymal transition (EMT) of ovarian cancer cells. Mechanistic studies identified microRNA-326 (miR-326) as a target of lncRNA DNM1P35. Overexpression of miR-326 diminished the tumor-promoting activity of lncRNA DNM1P35, resulting in reduction of Zinc finger E-box-binding homeobox 1 (ZEB1) expression and EMT features. We further revealed that ZEB1, a master transcription factor for EMT that is negatively regulated by miR-326, was essential for lncRNA DNM1P35-mediated cancer cell progression and EMT. Loss of ZEB1 led to compromised pro-tumoral activity of lncRNA DNM1P35. In vivo studies using a xenograft mouse model of ovarian cancer revealed that tumors with higher levels of lncRNA DNM1P35 led to shorter survival, increased tumor burden, as well as elevated expression of proliferative marker Ki67 and EMT marker ZEB1. Our comprehensive study underscored the significance of lncRNA DNM1P35 in ovarian cancer progression, elucidating the underlying mechanism through miR-326/ZEB1 axis to promote ovarian cancer progression.
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Affiliation(s)
- Mei Shen
- Department of Gynaecology, The Affiliated Wuxi People's Hospital of Nanjing Medical University/Wuxi Medical Center, Nanjing Medical University/Wuxi People's Hospital, 299 Qingyang Road, Wuxi, 214023, Jiangsu, China
| | - Yun Mao
- Department of Infection Management, The Affiliated Wuxi People's Hospital of Nanjing Medical University/Wuxi Medical Center, Nanjing Medical University/Wuxi People's Hospital, Wuxi, 214023, Jiangsu, China
| | - Xiaoshi Wang
- Department of Gynaecology, The Affiliated Wuxi People's Hospital of Nanjing Medical University/Wuxi Medical Center, Nanjing Medical University/Wuxi People's Hospital, 299 Qingyang Road, Wuxi, 214023, Jiangsu, China
| | - Jinsong Huang
- Department of Gynaecology, The Affiliated Wuxi People's Hospital of Nanjing Medical University/Wuxi Medical Center, Nanjing Medical University/Wuxi People's Hospital, 299 Qingyang Road, Wuxi, 214023, Jiangsu, China
| | - Qingsong Zhang
- Department of Gynaecology, The Affiliated Wuxi People's Hospital of Nanjing Medical University/Wuxi Medical Center, Nanjing Medical University/Wuxi People's Hospital, 299 Qingyang Road, Wuxi, 214023, Jiangsu, China
| | - Jinwei Zhang
- Department of Gynaecology, The Affiliated Wuxi People's Hospital of Nanjing Medical University/Wuxi Medical Center, Nanjing Medical University/Wuxi People's Hospital, 299 Qingyang Road, Wuxi, 214023, Jiangsu, China.
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Yuan S, Bi X, Shayiti F, Niu Y, Chen P. Relationship between circulating miRNA-222-3p and miRNA-136-5p and the efficacy of docetaxel chemotherapy in metastatic castration-resistant prostate cancer patients. BMC Urol 2024; 24:275. [PMID: 39709424 DOI: 10.1186/s12894-024-01666-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 12/02/2024] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND Metastatic castration-resistant prostate cancer is the most dangerous stage of prostate cancer, with a high mortality rate. Docetaxel chemotherapy is one of the most effective treatment methods currently, but some patients do not respond to chemotherapy. To avoid unnecessary toxicity in non-responders, this study explores the potential of circulating microRNAs as early biomarkers of docetaxel response in patients with metastatic castration-resistant prostate cancer. METHODS PC3 cells and DU145 cells were divided into the control, NC mimics, and miRNA-136-5p-mimics groups. Cell viability was measured using the CCK-8 assay. Cell apoptosis was determined by flow cytometry. Cell migration and invasion abilities were evaluated using the Transwell assay. Real-time quantitative PCR was used to measure the miRNA levels in cells and peripheral blood of patients. The miRNA-136-5p target genes were predicted by using the PITA, TargetScan, and miRanda databases. The target genes were analyzed with KEGG pathway analysis. RESULTS In both PC3 and DU145 cells, the miRNA-136-5p-mimics group exhibited significantly increased cell survival rates, migration and invasion numbers, and significantly decreased apoptosis rates than the control group (p < 0.05). The miRNA-222-3p and miRNA-136-5p levels were significantly increased in docetaxel-resistant PC3 and DU145 cells (p < 0.05). The levels of circulating miRNA-222-3p and miRNA-136-5p were significantly associated with docetaxel treatment (p < 0.05). Higher levels of miRNA-222-3p were observed in non-responsive patients (p < 0.05). The area under the curve for miRNA-222-3p was 0.76 (95%CI: 0.55-0.97), indicating its effectiveness as a predictive factor for non-responsive patients to docetaxel. Patients with high expression of miRNA-34c-5p after docetaxel chemotherapy had shorter overall survival times (P < 0.05). Bioinformatics analysis identified 110 potential target genes of miRNA-136-5p. KEGG revealed that these genes were mainly distributed in three pathways. Among them, the PI3K-AKT pathway was closely related to the metastasis of prostate cancer cells. CONCLUSION Our study demonstrates that miRNA-136-5p promotes the proliferation and invasion of PC3 and DU145 cells while inhibiting apoptosis. Circulating miRNA-222-3p may serve as a biomarker for early therapeutic response to docetaxel, and further clinical investigation is warranted. Additionally, miRNA-136-5p may have anti-cancer effects during docetaxel chemotherapy in metastatic castration-resistant prostate cancer.
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Affiliation(s)
- Shuai Yuan
- Department of Urology, Affiliated Cancer Hospital of Xinjiang Medical University, No. 789 Suzhou East Street, Urumqi,Xinjiang, 830011, P.R. China
| | - Xing Bi
- Department of Urology, Affiliated Cancer Hospital of Xinjiang Medical University, No. 789 Suzhou East Street, Urumqi,Xinjiang, 830011, P.R. China
| | - Furhati Shayiti
- Department of Urology, Affiliated Cancer Hospital of Xinjiang Medical University, No. 789 Suzhou East Street, Urumqi,Xinjiang, 830011, P.R. China
| | - Yue Niu
- Department of Urology, Affiliated Cancer Hospital of Xinjiang Medical University, No. 789 Suzhou East Street, Urumqi,Xinjiang, 830011, P.R. China
| | - Peng Chen
- Department of Urology, Affiliated Cancer Hospital of Xinjiang Medical University, No. 789 Suzhou East Street, Urumqi,Xinjiang, 830011, P.R. China.
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11
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Sun Y, Zhou X, Hu X. Constructing a doxycycline-inducible system for an epithelial-to-mesenchymal transition model in MCF10A cells. Biol Open 2024; 13:bio061790. [PMID: 39648980 PMCID: PMC11655024 DOI: 10.1242/bio.061790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 11/18/2024] [Indexed: 12/10/2024] Open
Abstract
Epithelial to mesenchymal transition (EMT) has been shown to play an essential role in the early stages of cancer cell invasion and metastasis. Inducible EMT models can initiate EMT in a controlled manner, thereby providing the opportunity to determine whether a cancer-associated gene influences cancer metastasis by triggering EMT. Moreover, different inducible EMT models enable the investigation of specific mechanisms of EMT modulation by various genes, facilitating a more precise understanding of how these genes influence cancer metastasis through the induction of EMT. Unfortunately, current inducible EMT models still present unmet needs. Therefore, we aimed to establish an inducible EMT model in MCF10A cells, a spontaneously immortalized human fibrocystic mammary cell line, by manipulating the expression of mouse Twist1 (mTwist1). In this study, we first compared the EMT induction capacity between human TWIST1 (hTWIST1) and mTwist1, and selected mTwist1 for further investigation. By monitoring the changes in epithelial and mesenchymal markers at different induction time points, we examined the EMT process in both polyclonal and monoclonal MCF10A cells that express doxycycline (DOX)-inducible mTwist1. Furthermore, our results showed that doxycycline-induced mTwist1 expression triggered EMT at a similar rate to TGFβ1-induced EMT in MCF10A cells. Additionally, this process was reversible upon DOX withdrawal. Thus, we have established a robust inducible EMT model in MCF10A cells, which can be used to further study cancer metastasis-driving genes.
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Affiliation(s)
- Yaxuan Sun
- Department of Pathology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
| | - Xun Zhou
- Department of Pathology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
| | - Xiaohui Hu
- Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
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12
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Zhang X, Liu J, Zuo C, Peng X, Xie J, Shu Y, Ao D, Zhang Y, Ye Q, Cai J. Role of SIK1 in tumors: Emerging players and therapeutic potentials (Review). Oncol Rep 2024; 52:169. [PMID: 39422046 PMCID: PMC11544583 DOI: 10.3892/or.2024.8828] [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: 08/23/2024] [Accepted: 10/07/2024] [Indexed: 10/19/2024] Open
Abstract
Salt‑induced kinase 1 (SIK1) is a serine/threonine protein kinase that is a member of the AMP‑activated protein kinase family. SIK is catalytically activated through its phosphorylation by the upstream kinase LKB1. SIK1 has been reported to be associated with numerous types of cancer. The present review summarizes the structure, regulatory factors and inhibitors of SIK1, and also describes how SIK1 is a signal regulatory factor that fulfills connecting roles in various signal regulatory pathways. Furthermore, the anti‑inflammatory effects of SIK1 during the early stage of tumor occurrence and its different regulatory effects following tumor occurrence, are summarized, and through collating the tumor signal regulatory mechanisms in which SIK1 participates, it has been demonstrated that SIK1 acts as a necessary node in cancer signal transduction. In conclusion, SIK1 is discussed independent of the SIKs family, its research results and recent progress in oncology are summarized in detail with a focus on SIK1, and its potential as a therapeutic target is highlighted, underscoring the need for SIK1‑targeted regulatory strategies in future cancer therapy.
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Affiliation(s)
- Xinran Zhang
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Jing Liu
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
| | - Chenyang Zuo
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
| | - Xiaochun Peng
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
- Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434000, P.R. China
| | - Jinyuan Xie
- Department of Joint Surgery and Sports Medicine, Jingmen Central Hospital, Jingmen, Hubei 448000, P.R. China
| | - Ya Shu
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Dongxu Ao
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
| | - Yang Zhang
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
| | - Qingqing Ye
- Department of Breast Surgery, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
| | - Jun Cai
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
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Tamtaji Z, Sheikhsagha E, Behnam M, Nabavizadeh F, Shafiee Ardestani M, Rahmati-Dehkordi F, Aschner M, Mirzaei H, Tamtaji OR. Berberine and Lung Cancer: From Pure Form to Its Nanoformulations. Asia Pac J Clin Oncol 2024. [PMID: 39568275 DOI: 10.1111/ajco.14134] [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: 04/29/2023] [Revised: 05/31/2024] [Accepted: 10/28/2024] [Indexed: 11/22/2024]
Abstract
Lung cancer is the most fatal cancer worldwide. The etiology of lung cancer has yet to be fully characterized. Smoking and air pollution are several risk factors for lung cancer. Berberine, an isoquinoline alkaloid, is an antihyperglycemic, antidepressant, antioxidative, anti-inflammatory, and anticancer compound. Evidence substantiates that berberine has antitumor effects, exerting its effects by targeting a variety of cellular and molecular processes, such as apoptosis, autophagy, cell cycle arrest, migration, and metastasis. Although the beneficial effects of berberine have been reported, some limitations including low bioavailability and absorption as well as poor aqueous solubility have hindered its clinical application. Nanotechnology and nanodelivery bioformulation approaches may bypass these limitations. In addition, the combination of berberine with other therapies has been shown to result in greater treatment efficacy for lung cancer. Herein, we summarize cellular and molecular pathways that are affected by berberine, its clinical efficacy upon various combinations, and the potential for nanotechnology in lung cancer therapy.
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Affiliation(s)
- Zeinab Tamtaji
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
| | - Elham Sheikhsagha
- Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk, Poland
| | - Mohammad Behnam
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
| | - Fatemeh Nabavizadeh
- Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - Mehdi Shafiee Ardestani
- Department of Radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - Fatemeh Rahmati-Dehkordi
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
| | - Omid R Tamtaji
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
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Liu Z, He M, Yu Z, Ma L, Wang X, Ning F. TIFA enhances glycolysis through E2F1 and promotes the progression of glioma. Cell Signal 2024; 125:111498. [PMID: 39481822 DOI: 10.1016/j.cellsig.2024.111498] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 10/17/2024] [Accepted: 10/28/2024] [Indexed: 11/03/2024]
Abstract
OBJECTIVE TRAF interacting protein with forkhead associated domain (TIFA) influence progression of many cancers. However, its role in glioma remains to be explored. This study investigated the function of TIFA in glioma. METHODS The TIFA expression in glioma and patient outcomes were analyzed using online database. Gene set enrichment analysis (GSEA) revealed related mechanisms of TIFA in glioma. TIFA's effects on glioma glycolysis and growth were assessed using in vitro and in vivo experiments. Moreover, luciferase reporter and ChIP were employed to explore the interactions among E2F1, GLUT1, HK2, and LDHA. The subcutaneous xenograft assay further elaborated the effects of TIFA in glioma. RESULTS We found overexpressed TIFA in glioma. Moreover, the high TIFA expression was associated with poor prognosis of glioma. Furthermore, GSEA indicated that overexpressed TIFA promoted E2F1 and glycolysis. Knockdown of TIFA decreased glioma development in cell and mice. TIFA knockdown down-regulated the expression of E2F1, GLUT1, HK2, and LDHA. CONCLUSIONS The study provides evidence that TIFA regulates E2F1 expression in glioma cells and promotes the proliferation, migration, and glycolysis. TIFA might be an advantageous therapeutic strategy against glioma.
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Affiliation(s)
- Zhibing Liu
- Department of Oncology, Binzhou Medical University Hospital, Binzhou 256603, Shandong, China; Department of Oncology, Qilu Hospital of Shandong University, Jinan 256600, Shandong, China
| | - Miaolong He
- School of Clinical Medicine, Tsinghua University, Beijing 100084, China
| | - Zeshun Yu
- Department of Oncology, Binzhou Medical University Hospital, Binzhou 256603, Shandong, China
| | - Longbo Ma
- Department of Oncology, Binzhou Medical University Hospital, Binzhou 256603, Shandong, China
| | - Xiuwen Wang
- Department of Oncology, Qilu Hospital of Shandong University, Jinan 256600, Shandong, China.
| | - Fangling Ning
- Department of Oncology, Binzhou Medical University Hospital, Binzhou 256603, Shandong, China.
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15
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Masaeli F, Omoomi S, Shafiee F. DNA fragmentation factor 40-based therapeutic approaches for cancer: a review article. Med Oncol 2024; 41:264. [PMID: 39397131 DOI: 10.1007/s12032-024-02511-5] [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: 08/05/2024] [Accepted: 09/18/2024] [Indexed: 10/15/2024]
Abstract
DNA Fragmentation Factor (DFF) is a heterodimer protein involved in DNA fragmentation during apoptosis, which acts as a trigger downstream of caspase-3 activation. DFF40 catalytically active homo-oligomers break down chromosomal DNA. Previous scientific investigations have revealed a link between DFF40 expression changes and various cancers. DFF40 deletion or down-regulation has been observed in some cancers. Consequently, therapeutic strategies involving the DFF40 molecule compensating led to an increased rate of cancer cell apoptosis. In this review article, we aimed to introduce cancers with low expression of this protein first. The second part of this paper focuses on studies that utilized exogenous DFF40 protein produced by recombinant DNA technology and surveyed during in vitro and in vivo tests. Finally, compensation for diminished expression of the mentioned protein via gene therapy-based techniques to make up for this apoptotic molecule's low expression is the topic of the last part of this review article.
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Affiliation(s)
- Faezeh Masaeli
- Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Hezar Jarib Ave., Isfahan, Iran
| | - Saba Omoomi
- Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Hezar Jarib Ave., Isfahan, Iran
| | - Fatemeh Shafiee
- Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Hezar Jarib Ave., Isfahan, Iran.
- Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
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16
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Zhang L, Tian S, Chang J, Quan S, Yang T, Zhao M, Wang L, Yang X. Activation of the CCL22/CCR4 causing EMT process remodeling under EZH2-mediated epigenetic regulation in cervical carcinoma. J Cancer 2024; 15:6299-6314. [PMID: 39513112 PMCID: PMC11540513 DOI: 10.7150/jca.101881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 09/21/2024] [Indexed: 11/15/2024] Open
Abstract
Cervical cancer (CC) is an important public health problem for women, gene expression patterns which were governed by epigenetic modifications can result in CC, CC-chemokine receptor 4 (CCR4) interacts with C-C-motif ligand 22 (CCL22) is associated with tumor progression or metastasis. A previous study by the present authors revealed the levels of chemokine CCL22 and its receptor CCR4 are increased in CC tissues, nevertheless, the regulatory mechanisms governing its expression remain poorly understood. The present study aimed to investigate the potential role of enhancer of zeste homolog 2 (EZH2)-induced epigenetic activation of CCL22/CCR4 and caused epithelial-to-mesenchymal transition (EMT) remodeling in CC. CCL22 and CCR4 were significantly up-regulated in CC samples compared with normal cervix tissues, and obvious induction of promoter DNA methylation levels of CCL22 and CCR4 was found in CC tissues. Demethylation reactivated the transcription of CCL22 and CCR4. DNA methyltransferase 3A (DNMT3A) was found to directly bind to the CCL22 and CCR4 promoter regions in vitro. Downregulation of the expression of EZH2 in CC cell lines altered DNMT3A expression and induced CCL22 and CCR4 promoters' methylation levels, while CCL22 and CCR4 mRNA expression decreased. An in vivo assay showed that EZH2 regulated the expression of CCL22/CCR4 components through DNMT3A, consistent with the in vitro results. In EZH2-silenced CC cells, migration was reduced, levels of EMT-related markers, including vimentin, slug, snail and β-catenin, were all reduced and zona occludens 1 (ZO-1) increased. In DNMT3A-silenced CC cells, migration was induced, vimentin, slug, snail and β-catenin were all induced and ZO-1 was reduced. Inhibition of CCL22 protein significantly decreased migration of CC cells and vimentin, slug, snail and β-catenin levels, while ZO-1 increased. In conclusion, EZH2 appears to regulate CCL22/CCR4 expression via epigenetic activation, causing EMT process remodeling in CC progression.
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Affiliation(s)
| | | | | | | | | | | | | | - Xiaofeng Yang
- Department of Gynecology and Obstetrics, the First Affiliated Hospital of Xi'an Jiaotong University, No.277 West Yanta Road, Xi'an 710061, China
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17
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Jia P, Che J, Xie X, Han Q, Ma Y, Guo Y, Zheng Y. The role of ZEB1 in mediating the protective effects of metformin on skeletal muscle atrophy. J Pharmacol Sci 2024; 156:57-68. [PMID: 39179335 DOI: 10.1016/j.jphs.2024.07.004] [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: 04/17/2024] [Revised: 07/06/2024] [Accepted: 07/16/2024] [Indexed: 08/26/2024] Open
Abstract
Metformin is an important antidiabetic drug that has the potential to reduce skeletal muscle atrophy and promote the differentiation of muscle cells. However, the exact molecular mechanism underlying these functions remains unclear. Previous studies revealed that the transcription factor zinc finger E-box-binding homeobox 1 (ZEB1), which participates in tumor progression, inhibits muscle atrophy. Therefore, we hypothesized that the protective effect of metformin might be related to ZEB1. We investigated the positive effect of metformin on IL-1β-induced skeletal muscle atrophy by regulating ZEB1 in vitro and in vivo. Compared with the normal cell differentiation group, the metformin-treated group presented increased myotube diameters and reduced expression levels of atrophy-marker proteins. Moreover, muscle cell differentiation was hindered, when we artificially interfered with ZEB1 expression in mouse skeletal myoblast (C2C12) cells via ZEB1-specific small interfering RNA (si-ZEB1). In response to inflammatory stimulation, metformin treatment increased the expression levels of ZEB1 and three differentiation proteins, MHC, MyoD, and myogenin, whereas si-ZEB1 partially counteracted these effects. Moreover, marked atrophy was induced in a mouse model via the administration of lipopolysaccharide (LPS) to the skeletal muscles of the lower limbs. Over a 4-week period of intragastric administration, metformin treatment ameliorated muscle atrophy and increased the expression levels of ZEB1. Metformin treatment partially alleviated muscle atrophy and stimulated differentiation. Overall, our findings may provide a better understanding of the mechanism underlying the effects of metformin treatment on skeletal muscle atrophy and suggest the potential of metformin as a therapeutic drug.
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Affiliation(s)
- Peiyu Jia
- Department of Pain, Huadong Hospital, Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai, 200040, China
| | - Ji Che
- Department of Pain, Huadong Hospital, Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai, 200040, China
| | - Xiaoting Xie
- School of Kinesiology, Shanghai University of Sport, Shanghai, 200438, China
| | - Qi Han
- Department of Pain, Huadong Hospital, Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai, 200040, China
| | - Yantao Ma
- Department of Pain, Huadong Hospital, Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai, 200040, China
| | - Yong Guo
- Department of Anesthesiology and Critical Care Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
| | - Yongjun Zheng
- Department of Pain, Huadong Hospital, Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai, 200040, China.
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Jin L, Zhang L, Yan C, Liu M, Dean DC, Liu Y. Corneal injury repair and the potential involvement of ZEB1. EYE AND VISION (LONDON, ENGLAND) 2024; 11:20. [PMID: 38822380 PMCID: PMC11143703 DOI: 10.1186/s40662-024-00387-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 05/07/2024] [Indexed: 06/03/2024]
Abstract
The cornea, consisting of three cellular and two non-cellular layers, is the outermost part of the eyeball and frequently injured by external physical, chemical, and microbial insults. The epithelial-to-mesenchymal transition (EMT) plays a crucial role in the repair of corneal injuries. Zinc finger E-box binding homeobox 1 (ZEB1), an important transcription factor involved in EMT, is expressed in the corneal tissues. It regulates cell activities like migration, transformation, and proliferation, and thereby affects tissue inflammation, fibrosis, tumor metastasis, and necrosis by mediating various major signaling pathways, including transforming growth factor (TGF)-β. Dysfunction of ZEB1 would impair corneal tissue repair leading to epithelial healing delay, interstitial fibrosis, neovascularization, and squamous cell metaplasia. Understanding the mechanism underlying ZEB1 regulation of corneal injury repair will help us to formulate a therapeutic approach to enhance corneal injury repair.
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Affiliation(s)
- Lin Jin
- Department of Ophthalmology, The Third People's Hospital of Dalian, Dalian Medical University, Dalian, 116033, China
| | - Lijun Zhang
- Department of Ophthalmology, The Third People's Hospital of Dalian, Dalian Medical University, Dalian, 116033, China
| | - Chunxiao Yan
- Department of Ophthalmology, The Third People's Hospital of Dalian, Dalian Medical University, Dalian, 116033, China
| | - Mengxin Liu
- Department of Ophthalmology, The Third People's Hospital of Dalian, Dalian Medical University, Dalian, 116033, China
| | - Douglas C Dean
- James Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
| | - Yongqing Liu
- James Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
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Zhou Y, Tao L, Qiu J, Xu J, Yang X, Zhang Y, Tian X, Guan X, Cen X, Zhao Y. Tumor biomarkers for diagnosis, prognosis and targeted therapy. Signal Transduct Target Ther 2024; 9:132. [PMID: 38763973 PMCID: PMC11102923 DOI: 10.1038/s41392-024-01823-2] [Citation(s) in RCA: 128] [Impact Index Per Article: 128.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 03/07/2024] [Accepted: 04/02/2024] [Indexed: 05/21/2024] Open
Abstract
Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.
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Affiliation(s)
- Yue Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lei Tao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiahao Qiu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Xu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinyu Yang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Yu Zhang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
- School of Medicine, Tibet University, Lhasa, 850000, China
| | - Xinyu Tian
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinqi Guan
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaobo Cen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yinglan Zhao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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20
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Do KK, Wang F, Sun X, Zhang Y, Liang W, Liu JY, Jiang DY, Lu X, Wang W, Zhang L, Dean DC, Liu Y. Conditional deletion of Zeb1 in Csf1r + cells reduces inflammatory response of the cornea to alkali burn. iScience 2024; 27:109694. [PMID: 38660397 PMCID: PMC11039400 DOI: 10.1016/j.isci.2024.109694] [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: 10/31/2023] [Revised: 01/29/2024] [Accepted: 04/05/2024] [Indexed: 04/26/2024] Open
Abstract
ZEB1 is an essential factor in embryonic development. In adults, it is often highly expressed in malignant tumors with low expression in normal tissues. The major biological function of ZEB1 in developing embryos and progressing cancers is to transdifferentiate cells from an epithelial to mesenchymal phenotype; but what roles ZEB1 plays in normal adult tissues are largely unknown. We previously reported that the reduction of Zeb1 in monoallelic global knockout (Zeb1+/-) mice reduced corneal inflammation-associated neovascularization following alkali burn. To uncover the cellular mechanism underlying the Zeb1 regulation of corneal inflammation, we functionally deleted Zeb1 alleles in Csf1r+ myeloid cells using a conditional knockout (cKO) strategy and found that Zeb1 cKO reduced leukocytes in the cornea after alkali burn. The reduction of immune cells was due to their increased apoptotic rate and linked to a Zeb1-downregulated apoptotic pathway. We conclude that Zeb1 facilitates corneal inflammatory response by maintaining Csf1r+ cell viability.
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Affiliation(s)
- Khoi K. Do
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Fuhua Wang
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
- Eye Institute and Eye Hospital of Shangdong First Medical University, Jinan 250021, China
| | - Xiaolei Sun
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
- Eye Institute and Eye Hospital of Shangdong First Medical University, Jinan 250021, China
| | - Yingnan Zhang
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
- The Rosenberg School of Optometry, University of the Incarnate Word, San Antonio, TX 78229, USA
| | - Wei Liang
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
- Department of Ophthalmology, Third People’s Hospital of Dalian, Dalian Medical University, Dalian 116033, China
| | - John Y. Liu
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Daniel Y. Jiang
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Xiaoqin Lu
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Wei Wang
- Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Lijun Zhang
- Department of Ophthalmology, Third People’s Hospital of Dalian, Dalian Medical University, Dalian 116033, China
| | - Douglas C. Dean
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
- Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY 40202, USA
- James Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Yongqing Liu
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
- Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY 40202, USA
- James Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA
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21
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Sun Y, Guo G, Zhang Y, Chen X, Lu Y, Hong R, Xiong J, Li J, Hu X, Wang S, Liu Y, Zhang Z, Yang X, Nan Y, Huang Q. IKBKE promotes the ZEB2-mediated EMT process by phosphorylating HMGA1a in glioblastoma. Cell Signal 2024; 116:111062. [PMID: 38242271 DOI: 10.1016/j.cellsig.2024.111062] [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: 08/08/2023] [Revised: 01/15/2024] [Accepted: 01/16/2024] [Indexed: 01/21/2024]
Abstract
IKBKE (Inhibitor of Nuclear Factor Kappa-B Kinase Subunit Epsilon) is an important oncogenic protein in a variety of tumors, which can promote tumor growth, proliferation, invasion and drug resistance, and plays a critical regulatory role in the occurrence and progression of malignant tumors. HMGA1a (High Mobility Group AT-hook 1a) functions as a cofactor for proper transcriptional regulation and is highly expressed in multiple types of tumors. ZEB2 (Zinc finger E-box Binding homeobox 2) exerts active functions in epithelial mesenchymal transformation (EMT). In our current study, we confirmed that IKBKE can increase the proliferation, invasion and migration of glioblastoma cells. We then found that IKBKE can phosphorylate HMGA1a at Ser 36 and/or Ser 44 sites and inhibit the degradation process of HMGA1a, and regulate the nuclear translocation of HMGA1a. Crucially, we observed that HMGA1a can regulate ZEB2 gene expression by interacting with ZEB2 promoter region. Hence, HMGA1a was found to promote the ZEB2-related metastasis. Consequently, we demonstrated that IKBKE can exert its oncogenic functions via the IKBKE/HMGA1a/ZEB2 signalling axis, and IKBKE may be a prominent biomarker for the treatment of glioblastoma in the future.
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Affiliation(s)
- Yan Sun
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Department of Neurosurgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong 264000, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China
| | - Gaochao Guo
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Department of Neurosurgery, Henan Provincial People's Hospital, Cerebrovascular Disease Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China
| | - Yu Zhang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China
| | - Xingjie Chen
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China
| | - Yalin Lu
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China
| | - Rujun Hong
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China
| | - Jinbiao Xiong
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China
| | - Jiabo Li
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China
| | - Xue Hu
- Department of Clinical Nutrition, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong 264000, China
| | - Shuaishuai Wang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China
| | - Yang Liu
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Department of Neurosurgery, Henan Provincial People's Hospital, Cerebrovascular Disease Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China
| | - Zhimeng Zhang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Department of Neurosurgery, Ningbo Hospital of Zhejiang University, Ningbo, Zhejiang 315000, China
| | - Xuejun Yang
- Department of Neurosurgery, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China
| | - Yang Nan
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China
| | - Qiang Huang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China.
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22
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Ali NejadKasbakhi N, Vavrincová D, Čepcová D. In vitro effect of 1-methyltryptophan isomers on epithelial-mesenchymal transition transcription factors in tubular epithelial cells after ischemia-reperfusion injury. ARCHIVES OF RAZI INSTITUTE 2024; 79:307-314. [PMID: 39463718 PMCID: PMC11512173 DOI: 10.32592/ari.2024.79.2.307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Accepted: 09/18/2023] [Indexed: 10/29/2024]
Abstract
The compound 1-methyltryptophan (1-MT) has been shown to act protectively in renal ischemia-reperfusion injury. Toll-like receptor 4 signaling is also a regular process of epithelial-mesenchymal transition (EMT) that can after ischemia-reperfusion injury (IRI) result in an increase in renal fibrosis. EMT is associated with specific transcription factors: Snai1, Snai2, Zeb1, and Twist. 1-MT could regulate EMT and act as an antifibrotic agent. This study aimed to investigate the effect of 1-MT on EMT transcription factors in tubular epithelial cells that underwent 30 min. Renal tubular epithelial cells (TECs) were isolated from Lewis rats using a standard protocol with Fe2O3 magnetic separation and selective media as previously mentioned. Cells were cultivated and divided into 4 groups, namely C-TECs: control cells, IRI-TECs: IRI-induced TECs, D-IRI-TECs: IRI-induced TECs treated with 1-methyl-D-tryptophan, and L-IRI-TECs: IRI-induced TECs treated with 1-methyl-L-tryptophan. IRI was induced in all groups for 30 min by mineral oil (except for C-TECs) followed by 48-hour reperfusion. RNA and proteins were isolated from harvested cells. Using a semi-quantitative polymerase chain reaction, we assessed the relative mRNA expression of EMT transcription factors Snai1, Snai2, Zeb1, and Twist. Hereby, we showed that the treatment of ischemia-induced TECs with both 1-MT isomers lowered the expression of EMT transcription factors Snai1 and Zeb1 which were increased by ischemia and reperfusion of TECs. This could act favorably in renal IRI decreasing EMT and renal fibrosis, therefore showing the potential of 1-MT as a part of therapy in renal transplantation aimed at renal ischemia-reperfusion injury.
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Affiliation(s)
- N Ali NejadKasbakhi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Slovak Republic
| | - D Vavrincová
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Slovak Republic
| | - D Čepcová
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Slovak Republic
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23
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Hou C, Wu X, Shi R, Xing X, Tian S, Eléouët M, Qiao C, Ma J, Xu G. Subtle structural alteration in indisulam switches the molecular mechanisms for the inhibitory effect on the migration of gastric cancer cells. Biomed Pharmacother 2024; 172:116259. [PMID: 38359488 DOI: 10.1016/j.biopha.2024.116259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 02/03/2024] [Accepted: 02/06/2024] [Indexed: 02/17/2024] Open
Abstract
Gastric cancer is a highly metastatic malignant tumor with high morbidity and mortality globally. Recent studies reported that sulfonamide derivatives such as indisulam exhibited inhibitory effects on the viability and migration of cancer cells. However, multiple clinical trials revealed that indisulam did not significantly prevent cancer progression due to metastasis and drug resistance. Therefore, it is necessary to discover new potent derivatives to explore alternative therapeutic strategies. Here, we synthesize multiple indisulam derivatives and examine their inhibitory effects on the viability and migration of gastric cancer cells. Among them, compounds SR-3-65 and WXM-1-170 exhibit better inhibitory effects on the migration of gastric cancer cells than indisulam. Mechanistically, we discover that they could attenuate the PI3K/AKT/GSK-3β/β-catenin signaling pathway and lead to the suppression of epithelial-to-mesenchymal transition (EMT)-related transcription factors. The influence of SR-3-65 on the migration of gastric cancer cells is blocked by the PI3K inhibitor LY294002 while SR-3-65 and WXM-1-170 reverse the effect of PI3K activator 740 Y-P on the migration of gastric cancer cells. Molecular docking and molecular dynamics simulation further confirm that PI3K is the target of SR-3-65. Our study unveils a novel mechanism by which SR-3-65 and WXM-1-170 inhibit the migration of gastric cancer cells. Together with the previous discovery, we reveal that subtle structural change in indisulam results in a striking switch on the molecular targets and their associated signaling pathways for the inhibition of the migration of gastric cancer cells. These findings might provide informative insights for the development of targeted therapy for gastric cancer.
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Affiliation(s)
- Changxu Hou
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, Jiangsu 215123, China
| | - Xiaomei Wu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China
| | - Rui Shi
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China
| | - Xiaoqi Xing
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China
| | - Sheng Tian
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China
| | - Morgane Eléouët
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, Jiangsu 215123, China; Synbio Technologies Company, BioBay C20, 218 Xinghu Street, Suzhou, Jiangsu, 215123, China
| | - Chunhua Qiao
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China.
| | - Jingjing Ma
- Department of Pharmacy, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, Jiangsu 215123, China.
| | - Guoqiang Xu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, Jiangsu 215123, China; Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China.
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24
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BharathwajChetty B, Sajeev A, Vishwa R, Aswani BS, Alqahtani MS, Abbas M, Kunnumakkara AB. Dynamic interplay of nuclear receptors in tumor cell plasticity and drug resistance: Shifting gears in malignant transformations and applications in cancer therapeutics. Cancer Metastasis Rev 2024; 43:321-362. [PMID: 38517618 DOI: 10.1007/s10555-024-10171-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 01/19/2024] [Indexed: 03/24/2024]
Abstract
Recent advances have brought forth the complex interplay between tumor cell plasticity and its consequential impact on drug resistance and tumor recurrence, both of which are critical determinants of neoplastic progression and therapeutic efficacy. Various forms of tumor cell plasticity, instrumental in facilitating neoplastic cells to develop drug resistance, include epithelial-mesenchymal transition (EMT) alternatively termed epithelial-mesenchymal plasticity, the acquisition of cancer stem cell (CSC) attributes, and transdifferentiation into diverse cell lineages. Nuclear receptors (NRs) are a superfamily of transcription factors (TFs) that play an essential role in regulating a multitude of cellular processes, including cell proliferation, differentiation, and apoptosis. NRs have been implicated to play a critical role in modulating gene expression associated with tumor cell plasticity and drug resistance. This review aims to provide a comprehensive overview of the current understanding of how NRs regulate these key aspects of cancer biology. We discuss the diverse mechanisms through which NRs influence tumor cell plasticity, including EMT, stemness, and metastasis. Further, we explore the intricate relationship between NRs and drug resistance, highlighting the impact of NR signaling on chemotherapy, radiotherapy and targeted therapies. We also discuss the emerging therapeutic strategies targeting NRs to overcome tumor cell plasticity and drug resistance. This review also provides valuable insights into the current clinical trials that involve agonists or antagonists of NRs modulating various aspects of tumor cell plasticity, thereby delineating the potential of NRs as therapeutic targets for improved cancer treatment outcomes.
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Affiliation(s)
- Bandari BharathwajChetty
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Anjana Sajeev
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Ravichandran Vishwa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Babu Santha Aswani
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, 61421, Saudi Arabia
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, 61421, Saudi Arabia
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India.
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25
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Ferrer-Mayorga G, Muñoz A, González-Sancho JM. Vitamin D and colorectal cancer. FELDMAN AND PIKE'S VITAMIN D 2024:859-899. [DOI: 10.1016/b978-0-323-91338-6.00039-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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26
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Wu H, Chen Y, Lin H, Xu Y, Guo Z, Li Z. The clinical significance of SNAIL, TWIST, and E-Cadherin expression in gastric mesentery tumor deposits of advanced gastric cancer. INDIAN J PATHOL MICR 2024; 67:21-28. [PMID: 38358184 DOI: 10.4103/ijpm.ijpm_659_22] [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] [Indexed: 02/16/2024] Open
Abstract
Objective To explore the relationships among the epithelial to mesenchymal transition (EMT)-related factors (SNAIL, TWIST, and E-Cadherin) and clinicopathological parameters and gastric mesangial tumor deposits (TDs) in advanced gastric cancer (AGC) patients and their value in gastric cancer prognosis judgment. Materials and Methods The data of 190 patients who underwent radical resection of ACG were analyzed retrospectively, including 75 cases of TDs (+) and 115 cases of TDs (-). The expression of EMT-related transforming factors Snail, Twist, and E-cadherin in the primary tumor, paracancerous normal tissues, and TDs was detected by immunohistochemistry. Results SNAIL and TWIST were overexpressed in primary tumors and TDs, whereas E-Cadherin was down-expressed in primary tumors. SNAIL was correlated significantly with tumor differentiation, lymph node metastases, and TDs (P < 0.05); TWIST was correlated strongly with tumor location, lymph node metastases, and TDs (P < 0.05); E-Cadherin was correlated closely with tumor differentiation and lymph node metastases (P < 0.05). Kaplan-Meier curves showed that SNAIL expression was correlated with DFS (P < 0.05), and TWIST expression was correlated with OS (P < 0.05). Tumor differentiation, lymph node metastasis, and TWIST expression were prognostic-independent risk factors of AGC patients (P < 0.05). Conclusion The occurrence and development of gastric cancer and the formation of TDs may be related to EMT, analyzing the expression of EMT-related transforming proteins may be helpful to judge the prognosis of gastric cancer.
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Affiliation(s)
- Haiyan Wu
- Department of Pathology, Teaching Hospital of Putian First Hospital of Fujian Medical University, Putian; The Graduate School of Fujian Medical University, Fuzhou, Fujian, China
| | - Yanping Chen
- Department of Pathology, Clinical Oncology School of Fujian Medical University and Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Huimei Lin
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian, China
| | - Yanchang Xu
- Gastrointestinal Surgery Unit 1, Teaching Hospital of Putian First Hospital of Fujian Medical University, Putian; The School of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian, China
| | - Zipei Guo
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian, China
| | - Zhixiong Li
- Gastrointestinal Surgery Unit 1, Teaching Hospital of Putian First Hospital of Fujian Medical University, Putian; The School of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian, China
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27
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Tangsiri M, Hheidari A, Liaghat M, Razlansari M, Ebrahimi N, Akbari A, Varnosfaderani SMN, Maleki-Sheikhabadi F, Norouzi A, Bakhtiyari M, Zalpoor H, Nabi-Afjadi M, Rahdar A. Promising applications of nanotechnology in inhibiting chemo-resistance in solid tumors by targeting epithelial-mesenchymal transition (EMT). Biomed Pharmacother 2024; 170:115973. [PMID: 38064969 DOI: 10.1016/j.biopha.2023.115973] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 11/25/2023] [Accepted: 11/29/2023] [Indexed: 01/10/2024] Open
Abstract
The resistance of cancer cells to chemotherapy, also known as chemo-resistance, poses a significant obstacle to cancer treatment and can ultimately result in patient mortality. Epithelial-mesenchymal transition (EMT) is one of the many factors and processes responsible for chemo-resistance. Studies have shown that targeting EMT can help overcome chemo-resistance, and nanotechnology and nanomedicine have emerged as promising approaches to achieve this goal. This article discusses the potential of nanotechnology in inhibiting EMT and proposes a viable strategy to combat chemo-resistance in various solid tumors, including breast cancer, lung cancer, pancreatic cancer, glioblastoma, ovarian cancer, gastric cancer, and hepatocellular carcinoma. While nanotechnology has shown promising results in targeting EMT, further research is necessary to explore its full potential in overcoming chemo-resistance and discovering more effective methods in the future.
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Affiliation(s)
- Mona Tangsiri
- Department of Medical Entomology and Vector Control, School of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Hheidari
- Department of Mechanical Engineering, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Mahsa Liaghat
- Department of Medical Laboratory sciences, Faculty of Medical Sciences, Kazerun Branch, Islamic Azad University, Kazerun, Iran; Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Mahtab Razlansari
- Faculty of Mathematics and Natural Sciences, Tübingen University, Tübingen 72076, Germany
| | - Narges Ebrahimi
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Abdullatif Akbari
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran; Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Fahimeh Maleki-Sheikhabadi
- Department of Hematology and Blood Banking, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Norouzi
- Dental Research Center, Faculty of Dentistry, Mazandaran University of Medical Sciences, Sari, Iran
| | - Maryam Bakhtiyari
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran; Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Hamidreza Zalpoor
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran; Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Mohsen Nabi-Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Abbas Rahdar
- Department of Physics, University of Zabol, Zabol 98613-35856, Iran.
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Chen Z, Li C, Huang H, Shi YL, Wang X. Research Progress of Aging-related MicroRNAs. Curr Stem Cell Res Ther 2024; 19:334-350. [PMID: 36892029 DOI: 10.2174/1574888x18666230308111043] [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: 10/22/2022] [Revised: 01/02/2023] [Accepted: 01/11/2023] [Indexed: 03/10/2023]
Abstract
Senescence refers to the irreversible state in which cells enter cell cycle arrest due to internal or external stimuli. The accumulation of senescent cells can lead to many age-related diseases, such as neurodegenerative diseases, cardiovascular diseases, and cancers. MicroRNAs are short non-coding RNAs that bind to target mRNA to regulate gene expression after transcription and play an important regulatory role in the aging process. From nematodes to humans, a variety of miRNAs have been confirmed to alter and affect the aging process. Studying the regulatory mechanisms of miRNAs in aging can further deepen our understanding of cell and body aging and provide a new perspective for the diagnosis and treatment of aging-related diseases. In this review, we illustrate the current research status of miRNAs in aging and discuss the possible prospects for clinical applications of targeting miRNAs in senile diseases.
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Affiliation(s)
- Zhongyu Chen
- School of Basic Medicine, Dali University, Dali, Yunnan, 671000, China
| | - Chenxu Li
- School of Basic Medicine, Dali University, Dali, Yunnan, 671000, China
| | - Haitao Huang
- School of Basic Medicine, Dali University, Dali, Yunnan, 671000, China
| | - Yi-Ling Shi
- School of Basic Medicine, Dali University, Dali, Yunnan, 671000, China
| | - Xiaobo Wang
- School of Basic Medicine, Dali University, Dali, Yunnan, 671000, China
- Key Laboratory of University Cell Biology, Dali, Yunnan, 671000, China
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29
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Martinez-Campanario MC, Cortés M, Moreno-Lanceta A, Han L, Ninfali C, Domínguez V, Andrés-Manzano MJ, Farràs M, Esteve-Codina A, Enrich C, Díaz-Crespo FJ, Pintado B, Escolà-Gil JC, García de Frutos P, Andrés V, Melgar-Lesmes P, Postigo A. Atherosclerotic plaque development in mice is enhanced by myeloid ZEB1 downregulation. Nat Commun 2023; 14:8316. [PMID: 38097578 PMCID: PMC10721632 DOI: 10.1038/s41467-023-43896-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 11/23/2023] [Indexed: 12/17/2023] Open
Abstract
Accumulation of lipid-laden macrophages within the arterial neointima is a critical step in atherosclerotic plaque formation. Here, we show that reduced levels of the cellular plasticity factor ZEB1 in macrophages increase atherosclerotic plaque formation and the chance of cardiovascular events. Compared to control counterparts (Zeb1WT/ApoeKO), male mice with Zeb1 ablation in their myeloid cells (Zeb1∆M/ApoeKO) have larger atherosclerotic plaques and higher lipid accumulation in their macrophages due to delayed lipid traffic and deficient cholesterol efflux. Zeb1∆M/ApoeKO mice display more pronounced systemic metabolic alterations than Zeb1WT/ApoeKO mice, with higher serum levels of low-density lipoproteins and inflammatory cytokines and larger ectopic fat deposits. Higher lipid accumulation in Zeb1∆M macrophages is reverted by the exogenous expression of Zeb1 through macrophage-targeted nanoparticles. In vivo administration of these nanoparticles reduces atherosclerotic plaque formation in Zeb1∆M/ApoeKO mice. Finally, low ZEB1 expression in human endarterectomies is associated with plaque rupture and cardiovascular events. These results set ZEB1 in macrophages as a potential target in the treatment of atherosclerosis.
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Affiliation(s)
- M C Martinez-Campanario
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036, Barcelona, Spain
| | - Marlies Cortés
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036, Barcelona, Spain
| | - Alazne Moreno-Lanceta
- Department of Biomedicine, University of Barcelona School of Medicine, 08036, Barcelona, Spain
| | - Lu Han
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036, Barcelona, Spain
| | - Chiara Ninfali
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036, Barcelona, Spain
| | - Verónica Domínguez
- Transgenesis Facility, National Center of Biotechnology (CNB) and Center for Molecular Biology Severo Ochoa (UAM-CBMSO), Spanish National Research Council (CSIC) and Autonomous University of Madrid (UAM), Cantoblanco, 28049, Madrid, Spain
| | - María J Andrés-Manzano
- Group of Molecular and Genetic Cardiovascular Pathophysiology, Spanish National Center for Cardiovascular Research (CNIC), 28029, Madrid, Spain
- Center for Biomedical, Research Network in Cardiovascular Diseases (CIBERCV), Carlos III Health Institute, 28029, Madrid, Spain
| | - Marta Farràs
- Department of Biochemistry and Molecular Biology, Institute of Biomedical Research Sant Pau, University Autonomous of Barcelona, 08041, Barcelona, Spain
- Center for Biomedical Research Network in Diabetes and Associated Metabolic Diseases (CIBERDEM), Carlos III Health Institute, 28029, Madrid, Spain
| | | | - Carlos Enrich
- Department of Biomedicine, University of Barcelona School of Medicine, 08036, Barcelona, Spain
- Group of signal transduction, intracellular compartments and cancer, IDIBAPS, 08036, Barcelona, Spain
| | - Francisco J Díaz-Crespo
- Department of Pathology, Hospital General Universitario Gregorio Marañón, 28007, Madrid, Spain
| | - Belén Pintado
- Transgenesis Facility, National Center of Biotechnology (CNB) and Center for Molecular Biology Severo Ochoa (UAM-CBMSO), Spanish National Research Council (CSIC) and Autonomous University of Madrid (UAM), Cantoblanco, 28049, Madrid, Spain
| | - Joan C Escolà-Gil
- Department of Biochemistry and Molecular Biology, Institute of Biomedical Research Sant Pau, University Autonomous of Barcelona, 08041, Barcelona, Spain
- Center for Biomedical Research Network in Diabetes and Associated Metabolic Diseases (CIBERDEM), Carlos III Health Institute, 28029, Madrid, Spain
| | - Pablo García de Frutos
- Center for Biomedical, Research Network in Cardiovascular Diseases (CIBERCV), Carlos III Health Institute, 28029, Madrid, Spain
- Department Of Cell Death and Proliferation, Institute for Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036, Barcelona, Spain
- Group of Hemotherapy and Hemostasis, IDIBAPS, 08036, Barcelona, Spain
| | - Vicente Andrés
- Group of Molecular and Genetic Cardiovascular Pathophysiology, Spanish National Center for Cardiovascular Research (CNIC), 28029, Madrid, Spain
- Center for Biomedical, Research Network in Cardiovascular Diseases (CIBERCV), Carlos III Health Institute, 28029, Madrid, Spain
| | - Pedro Melgar-Lesmes
- Department of Biomedicine, University of Barcelona School of Medicine, 08036, Barcelona, Spain
- Department of Biochemistry and Molecular Genetics, Hospital Clínic, 08036, Barcelona, Spain
- Center for Biomedical Research Network in Gastrointestinal and Liver Diseases (CIBEREHD), Carlos III Health Institute, 28029, Madrid, Spain
- Institute for Medical Engineering & Science, Massachusetts Institute of Technology (MIT), Cambridge, MA, 02139, USA
| | - Antonio Postigo
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036, Barcelona, Spain.
- Center for Biomedical Research Network in Gastrointestinal and Liver Diseases (CIBEREHD), Carlos III Health Institute, 28029, Madrid, Spain.
- Molecular Targets Program, Division of Oncology, Department of Medicine, J.G. Brown Cancer Center, Louisville, KY, 40202, USA.
- ICREA, 08010, Barcelona, Spain.
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Fernandez-De-Los-Reyes I, Gomez-Dorronsoro M, Monreal-Santesteban I, Fernandez-Fernandez A, Fraga M, Azcue P, Alonso L, Fernandez-Marlasca B, Suarez J, Cordoba-Iturriagagoitia A, Guerrero-Setas D. ZEB1 hypermethylation is associated with better prognosis in patients with colon cancer. Clin Epigenetics 2023; 15:193. [PMID: 38093305 PMCID: PMC10720242 DOI: 10.1186/s13148-023-01605-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 11/19/2023] [Indexed: 12/17/2023] Open
Abstract
BACKGROUND Colon cancer (CC) is a heterogeneous disease that is categorized into four Consensus Molecular Subtypes (CMS) according to gene expression. Patients with loco-regional CC (stages II/III) lack prognostic factors, making it essential to analyze new molecular markers that can delineate more aggressive tumors. Aberrant methylation of genes that are essential in crucial mechanisms such as epithelial mesenchymal transition (EMT) contributes to tumor progression in CC. We evaluate the presence of hyper- and hypomethylation in subrogate IHC markers used for CMS classification (CDX2, FRMD6, HTR2B, ZEB1) of 144 stage II/III patients and CC cell lines by pyrosequencing. ZEB1 expression was also studied in control and shRNA-silenced CC cell lines and in paired normal tissue/tumors by quantitative PCR. The pattern of ZEB1 staining was also analyzed in methylated/unmethylated tumors by immunohistochemistry. RESULTS We describe for the first time the hypermethylation of ZEB1 gene and the hypomethylation of the FRMD6 gene in 32.6% and 50.9% of tumors, respectively. Additionally, we confirm the ZEB1 re-expression by epigenetic drugs in methylated cell lines. ZEB1 hypermethylation was more frequent in CMS1 patients and, more importantly, was a good prognostic factor related to disease-free survival (p = 0.015) and overall survival (p = 0.006) in our patient series, independently of other significant clinical parameters such as patient age, stage, lymph node involvement, and blood vessel and perineural invasion. CONCLUSIONS Aberrant methylation is present in the subrogate genes used for CMS classification. Our results are the first evidence that ZEB1 is hypermethylated in CC and that this alteration is an independent factor of good prognosis.
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Affiliation(s)
- Irene Fernandez-De-Los-Reyes
- Department of Pathology, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008, Pamplona, Spain
- Molecular Pathology of Cancer Group, Navarrabiomed, Universidad Pública de Navarra (UPNA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008, Pamplona, Spain
| | - Marisa Gomez-Dorronsoro
- Department of Pathology, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008, Pamplona, Spain
- Oncogenetic and Hereditary Cancer Group, Universidad Pública de Navarra (UPNA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008, Pamplona, Spain
| | - Iñaki Monreal-Santesteban
- Molecular Pathology of Cancer Group, Navarrabiomed, Universidad Pública de Navarra (UPNA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008, Pamplona, Spain
| | - Agustín Fernandez-Fernandez
- Nanomaterials and Nanotechnology Research Center (CINN-CSIC), 33940, El Entrego, Spain
- Health Research Institute of Asturias (ISPA), 33011, Oviedo, Spain
- University Institute of Oncology (IUOPA), University of Oviedo, 33006, Oviedo, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), 28029, Madrid, Spain
| | - Mario Fraga
- Nanomaterials and Nanotechnology Research Center (CINN-CSIC), 33940, El Entrego, Spain
- Health Research Institute of Asturias (ISPA), 33011, Oviedo, Spain
- University Institute of Oncology (IUOPA), University of Oviedo, 33006, Oviedo, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), 28029, Madrid, Spain
| | - Pablo Azcue
- Department of Health Science, Public University of Navarra, Irunlarrea 3, 31008, Pamplona, Spain
| | - Laura Alonso
- Department of Pathology, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008, Pamplona, Spain
| | | | - Javier Suarez
- Department of Surgery, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008, Pamplona, Spain
| | - Alicia Cordoba-Iturriagagoitia
- Department of Pathology, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008, Pamplona, Spain
- Molecular Pathology of Cancer Group, Navarrabiomed, Universidad Pública de Navarra (UPNA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008, Pamplona, Spain
| | - David Guerrero-Setas
- Department of Pathology, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008, Pamplona, Spain.
- Molecular Pathology of Cancer Group, Navarrabiomed, Universidad Pública de Navarra (UPNA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008, Pamplona, Spain.
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Rodas F, Vidal-Vidal JA, Herrera D, Brown-Brown DA, Vera D, Veliz J, Püschel P, Erices JI, Sánchez Hinojosa V, Tapia JC, Silva-Pavez E, Quezada-Monrás C, Mendoza-Soto P, Salazar-Onfray F, Carrasco C, Niechi I. Targeting the Endothelin-1 pathway to reduce invasion and chemoresistance in gallbladder cancer cells. Cancer Cell Int 2023; 23:318. [PMID: 38072958 PMCID: PMC10710704 DOI: 10.1186/s12935-023-03145-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 11/14/2023] [Indexed: 01/03/2025] Open
Abstract
BACKGROUND Gallbladder cancer (GBC) is a prevalent and deadly biliary tract carcinoma, often diagnosed at advanced stages with limited treatment options. The 5-year survival rate varies widely from 4 to 60%, mainly due to differences in disease stage detection. With only a small fraction of patients having resectable tumors and a high incidence of metastasis, advanced GBC stages are characterized by significant chemoresistance. Identification of new therapeutic targets is crucial, and recent studies have shown that the Endothelin-1 (ET-1) signaling pathway, involving ETAR and/or ETBR receptors (ETRs), plays a crucial role in promoting tumor aggressiveness in various cancer models. Blocking one or both receptors has been reported to reduce invasiveness and chemoresistance in cancers like ovarian, prostate, and colon. Furthermore, transcriptomic studies have associated ET-1 levels with late stages of GBC; however, it remains unclear whether its signaling or its inhibition has implications for its aggressiveness. Although the role of ET-1 signaling in gallbladder physiology is minimally understood, its significance in other tumor models leads us to hypothesize its involvement in GBC malignancy. RESULTS In this study, we investigated the expression of ET-1 pathway proteins in three GBC cell lines and a primary GBC culture. Our findings demonstrated that both ETAR and ETBR receptors are expressed in GBC cells and tumor samples. Moreover, we successfully down-regulated ET-1 signaling using a non-selective ETR antagonist, Macitentan, which resulted in reduced migratory and invasive capacities of GBC cells. Additionally, Macitentan treatment chemosensitized the cells to Gemcitabine, a commonly used therapy for GBC. CONCLUSION For the first time, we reveal the role of the ET-1 pathway in GBC cells, providing insight into the potential therapeutic targeting of its receptors to mitigate invasion and chemoresistance in this cancer with limited treatment options. These findings pave the way for further exploration of Macitentan or other ETR antagonists as potential therapeutic strategies for GBC management. In summary, our study represents a groundbreaking contribution to the field by providing the first evidence of the ET 1 pathway's pivotal role in modulating the behavior and aggressiveness of GBC cells, shedding new light on potential therapeutic targets.
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Affiliation(s)
- Francisco Rodas
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Jetzabel A Vidal-Vidal
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Daniela Herrera
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - David A Brown-Brown
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Diego Vera
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Joaquín Veliz
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Pilar Püschel
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - José I Erices
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Verónica Sánchez Hinojosa
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Julio C Tapia
- Laboratorio de transformación celular, Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, 8380453, Santiago, Chile
| | - Eduardo Silva-Pavez
- Facultad de Odontología y Ciencias de la Rehabilitación, Universidad San Sebastián, Bellavista, Santiago, Chile
| | - Claudia Quezada-Monrás
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
- Millennium Institute on Immunology and Immunotherapy, Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Pablo Mendoza-Soto
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Flavio Salazar-Onfray
- Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, Universidad de Chile, 8380453, Santiago, Chile
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, 8380453, Santiago, Chile
| | - Cristian Carrasco
- Subdepartamento de Anatomía Patológica, Hospital Base de Valdivia, 5090000, Valdivia, Chile
| | - Ignacio Niechi
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile.
- Millennium Institute on Immunology and Immunotherapy, Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile.
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Fang K, Gong M, Liu D, Liang S, Li Y, Sang W, Zhu R. FOXM1/KIF20A axis promotes clear cell renal cell carcinoma progression via regulating EMT signaling and affects immunotherapy response. Heliyon 2023; 9:e22734. [PMID: 38125441 PMCID: PMC10730723 DOI: 10.1016/j.heliyon.2023.e22734] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 10/27/2023] [Accepted: 11/17/2023] [Indexed: 12/23/2023] Open
Abstract
Background The correlation between FOXM1 and KIF20A has not been revealed in clear cell renal cell carcinoma (ccRCC). Methods Public data was downloaded from The Cancer Genome Atlas (TCGA) database. R software was utilized for the execution of bioinformatic analysis. The expression levels of specific molecules (mRNA and protein) were detected using real-time quantitative PCR (qRT-PCR) and Western blot assays. The capacity of cell growth was assessed by employing CCK8 and colony formation assay. Cell invasion and migration ability were assessed using transwell assay. Results In our study, we illustrated the association between FOXM1 and KIF20A. Our results indicated that both FOXM1 and KIF20A were associated with poor prognosis and clinical performance. The malignant characteristics of ccRCC cells can be significantly suppressed by inhibiting FOXM1 and KIF20A, as demonstrated by in vitro experiments. Moreover, we found that FOXM1 can upregulate KIF20A. Then, EMT signaling was identified as the underlying pathway FOXM1 and KIF20A are involved. WB results indicated that FOXM1/KIF20A axis can activate EMT signaling. Moreover, we noticed that FOXM1 and KIF20A can affect the immunotherapy response and immune microenvironment of ccRCC patients. Conclusions Our results identified the role of the FOXM1/KIF20A axis in ccRCC progression and immunotherapy, making it the underlying target for ccRCC.
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Affiliation(s)
- Kai Fang
- Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Min Gong
- Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Dong Liu
- Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Shengjie Liang
- Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Yang Li
- Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Weicong Sang
- Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Rujian Zhu
- Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
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Cortés M, Brischetto A, Martinez-Campanario MC, Ninfali C, Domínguez V, Fernández S, Celis R, Esteve-Codina A, Lozano JJ, Sidorova J, Garrabou G, Siegert AM, Enrich C, Pintado B, Morales-Ruiz M, Castro P, Cañete JD, Postigo A. Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation. Nat Commun 2023; 14:7471. [PMID: 37978290 PMCID: PMC10656499 DOI: 10.1038/s41467-023-42277-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 10/05/2023] [Indexed: 11/19/2023] Open
Abstract
Acute inflammation can either resolve through immunosuppression or persist, leading to chronic inflammation. These transitions are driven by distinct molecular and metabolic reprogramming of immune cells. The anti-diabetic drug Metformin inhibits acute and chronic inflammation through mechanisms still not fully understood. Here, we report that the anti-inflammatory and reactive-oxygen-species-inhibiting effects of Metformin depend on the expression of the plasticity factor ZEB1 in macrophages. Using mice lacking Zeb1 in their myeloid cells and human patient samples, we show that ZEB1 plays a dual role, being essential in both initiating and resolving inflammation by inducing macrophages to transition into an immunosuppressed state. ZEB1 mediates these diverging effects in inflammation and immunosuppression by modulating mitochondrial content through activation of autophagy and inhibition of mitochondrial protein translation. During the transition from inflammation to immunosuppression, Metformin mimics the metabolic reprogramming of myeloid cells induced by ZEB1. Mechanistically, in immunosuppression, ZEB1 inhibits amino acid uptake, leading to downregulation of mTORC1 signalling and a decrease in mitochondrial translation in macrophages. These results identify ZEB1 as a driver of myeloid cell metabolic plasticity, suggesting that targeting its expression and function could serve as a strategy to modulate dysregulated inflammation and immunosuppression.
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Affiliation(s)
- Marlies Cortés
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036, Barcelona, Spain.
| | - Agnese Brischetto
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036, Barcelona, Spain
| | - M C Martinez-Campanario
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036, Barcelona, Spain
| | - Chiara Ninfali
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036, Barcelona, Spain
| | - Verónica Domínguez
- National Center of Biotechnology (CSIC-CNB) and Center for Molecular Biology Severo Ochoa (CSIC/UAM-CBMSO) Transgenesis Facility, Higher Research Council (CSIC) and Autonomous University of Madrid (UAM), Cantoblanco, 28049, Madrid, Spain
| | - Sara Fernández
- Medical Intensive Care Unit and Department of Internal Medicine, Hospital Clínic of Barcelona, Group of Muscle Research and Mitochondrial Function, IDIBAPS, and CIBERER, 08036, Barcelona, Spain
| | - Raquel Celis
- Arthritis Unit, Dept. of Rheumathology, Hospital Clínic and IDIBAPS, 08036, Barcelona, Spain
| | | | - Juan J Lozano
- Biomedical Research Networking Centers in Digestive and Hepatic Diseases (CIBERehd), Carlos III Health Institute, 08036, Barcelona, Spain
| | - Julia Sidorova
- Biomedical Research Networking Centers in Digestive and Hepatic Diseases (CIBERehd), Carlos III Health Institute, 08036, Barcelona, Spain
| | - Gloria Garrabou
- Medical Intensive Care Unit and Department of Internal Medicine, Hospital Clínic of Barcelona, Group of Muscle Research and Mitochondrial Function, IDIBAPS, and CIBERER, 08036, Barcelona, Spain
| | - Anna-Maria Siegert
- MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB1 0QQ, UK
| | - Carlos Enrich
- Department of Biomedicine, University of Barcelona School of Medicine and Health Sciences, 08036, Barcelona, Spain
| | - Belén Pintado
- National Center of Biotechnology (CSIC-CNB) and Center for Molecular Biology Severo Ochoa (CSIC/UAM-CBMSO) Transgenesis Facility, Higher Research Council (CSIC) and Autonomous University of Madrid (UAM), Cantoblanco, 28049, Madrid, Spain
| | - Manuel Morales-Ruiz
- Biomedical Research Networking Centers in Digestive and Hepatic Diseases (CIBERehd), Carlos III Health Institute, 08036, Barcelona, Spain
- Department of Biomedicine, University of Barcelona School of Medicine and Health Sciences, 08036, Barcelona, Spain
- Department of Biochemistry and Molecular Genetics, Hospital Clínic of Barcelona and IDIBAPS, 08036, Barcelona, Spain
| | - Pedro Castro
- Medical Intensive Care Unit and Department of Internal Medicine, Hospital Clínic of Barcelona, Group of Muscle Research and Mitochondrial Function, IDIBAPS, and CIBERER, 08036, Barcelona, Spain
| | - Juan D Cañete
- Arthritis Unit, Dept. of Rheumathology, Hospital Clínic and IDIBAPS, 08036, Barcelona, Spain
| | - Antonio Postigo
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036, Barcelona, Spain.
- Biomedical Research Networking Centers in Digestive and Hepatic Diseases (CIBERehd), Carlos III Health Institute, 08036, Barcelona, Spain.
- Molecular Targets Program, Division of Oncology, Department of Medicine, J.G. Brown Cancer Center, Louisville, KY, 40202, USA.
- ICREA, 08010, Barcelona, Spain.
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Ninfali C, Cortés M, Martínez-Campanario MC, Domínguez V, Han L, Tobías E, Esteve-Codina A, Enrich C, Pintado B, Garrabou G, Postigo A. The adaptive antioxidant response during fasting-induced muscle atrophy is oppositely regulated by ZEB1 and ZEB2. Proc Natl Acad Sci U S A 2023; 120:e2301120120. [PMID: 37948583 PMCID: PMC10655555 DOI: 10.1073/pnas.2301120120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 09/26/2023] [Indexed: 11/12/2023] Open
Abstract
Reactive oxygen species (ROS) serve important homeostatic functions but must be constantly neutralized by an adaptive antioxidant response to prevent supraphysiological levels of ROS from causing oxidative damage to cellular components. Here, we report that the cellular plasticity transcription factors ZEB1 and ZEB2 modulate in opposing directions the adaptive antioxidant response to fasting in skeletal muscle. Using transgenic mice in which Zeb1 or Zeb2 were specifically deleted in skeletal myofibers, we show that in fasted mice, the deletion of Zeb1, but not Zeb2, increased ROS production and that the adaptive antioxidant response to fasting essentially requires ZEB1 and is inhibited by ZEB2. ZEB1 expression increased in fasted muscles and protected them from atrophy; conversely, ZEB2 expression in muscles decreased during fasting and exacerbated muscle atrophy. In fasted muscles, ZEB1 reduces mitochondrial damage and increases mitochondrial respiratory activity; meanwhile, ZEB2 did the opposite. Treatment of fasting mice with Zeb1-deficient myofibers with the antioxidant triterpenoid 1[2-cyano-3,12-dioxool-eana-1,9(11)-dien-28-oyl] trifluoro-ethylamide (CDDO-TFEA) completely reversed their altered phenotype to that observed in fasted control mice. These results set ZEB factors as potential therapeutic targets to modulate the adaptive antioxidant response in physiopathological conditions and diseases caused by redox imbalance.
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Affiliation(s)
- Chiara Ninfali
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Barcelona08036, Spain
| | - Marlies Cortés
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Barcelona08036, Spain
| | - M. C. Martínez-Campanario
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Barcelona08036, Spain
| | - Verónica Domínguez
- National Center of Biotechnology (CSIC-CNB) and Center for Molecular Biology Severo Ochoa (CSIC-CBMSO), Transgenesis Facility, High Research Council (CSIC) and Autonomous University of Madrid, Cantoblanco, Madrid28049, Spain
| | - Lu Han
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Barcelona08036, Spain
| | - Ester Tobías
- Group of Muscle Research and Mitochondrial Function, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), University of Barcelona School of Medicine, Hospital Clínic of Barcelona, and Rare Diseases Networking Biomedical Research Center (CIBERer), Barcelona08036, Spain
| | | | - Carlos Enrich
- Department of Biomedicine, University of Barcelona School of Medicine, and Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Barcelona08036, Spain
| | - Belén Pintado
- National Center of Biotechnology (CSIC-CNB) and Center for Molecular Biology Severo Ochoa (CSIC-CBMSO), Transgenesis Facility, High Research Council (CSIC) and Autonomous University of Madrid, Cantoblanco, Madrid28049, Spain
| | - Gloria Garrabou
- Group of Muscle Research and Mitochondrial Function, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), University of Barcelona School of Medicine, Hospital Clínic of Barcelona, and Rare Diseases Networking Biomedical Research Center (CIBERer), Barcelona08036, Spain
| | - Antonio Postigo
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Barcelona08036, Spain
- Molecular Targets Program, Department of Medicine, James Graham Brown Cancer Center, Louisville, KY40202
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona08010, Spain
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Proença C, Freitas M, Ribeiro D, Rufino AT, Fernandes E, Ferreira de Oliveira JMP. The role of flavonoids in the regulation of epithelial-mesenchymal transition in cancer: A review on targeting signaling pathways and metastasis. Med Res Rev 2023; 43:1878-1945. [PMID: 37147865 DOI: 10.1002/med.21966] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 03/20/2023] [Accepted: 04/12/2023] [Indexed: 05/07/2023]
Abstract
One of the hallmarks of cancer is metastasis, a process that entails the spread of cancer cells to distant regions in the body, culminating in tumor formation in secondary organs. Importantly, the proinflammatory environment surrounding cancer cells further contributes to cancer cell transformation and extracellular matrix destruction. During metastasis, front-rear polarity and emergence of migratory and invasive features are manifestations of epithelial-mesenchymal transition (EMT). A variety of transcription factors (TFs) are implicated in the execution of EMT, the most prominent belonging to the Snail Family Transcriptional Repressor (SNAI) and Zinc Finger E-Box Binding Homeobox (ZEB) families of TFs. These TFs are regulated by interaction with specific microRNAs (miRNAs), as miR34 and miR200. Among the several secondary metabolites produced in plants, flavonoids constitute a major group of bioactive molecules, with several described effects including antioxidant, antiinflammatory, antidiabetic, antiobesogenic, and anticancer effects. This review scrutinizes the modulatory role of flavonoids on the activity of SNAI/ZEB TFs and on their regulatory miRNAs, miR-34, and miR-200. The modulatory role of flavonoids can attenuate mesenchymal features and stimulate epithelial features, thereby inhibiting and reversing EMT. Moreover, this modulation is concomitant with the attenuation of signaling pathways involved in diverse processes as cell proliferation, cell growth, cell cycle progression, apoptosis inhibition, morphogenesis, cell fate, cell migration, cell polarity, and wound healing. The antimetastatic potential of these versatile compounds is emerging and represents an opportunity for the synthesis of more specific and potent agents.
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Affiliation(s)
- Carina Proença
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Marisa Freitas
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Daniela Ribeiro
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Ana T Rufino
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Eduarda Fernandes
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - José Miguel P Ferreira de Oliveira
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
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Zhang Z, Wang X, Kim M, He D, Wang C, Fong KW, Liu X. Downregulation of EZH2 inhibits epithelial-mesenchymal transition in enzalutamide-resistant prostate cancer. Prostate 2023; 83:1458-1469. [PMID: 37475584 PMCID: PMC11618820 DOI: 10.1002/pros.24602] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 06/27/2023] [Accepted: 07/10/2023] [Indexed: 07/22/2023]
Abstract
BACKGROUND Androgen signaling inhibitors (ASI) have been approved for treatment of metastatic castration-resistant prostate cancer (mCRPC). However, the limited success of ASI in clinic justifies an urgent need to identify new targets and develop novel approaches for treatment. EZH2 significantly increases in prostate cancer (PCa). Little is understood, however, regarding the roles of EZH2 in Enzalutamide-resistant (EnzR) mCRPC. METHODS We firstly investigated the levels of EZH2 and the altered pathways in public database which was comprised with primary and metastatic PCa patient tumors. To elucidate the roles of EZH2 in mCRPC, we manipulated EZH2 in EnzR PCa cell lines to examine epithelial-mesenchymal transition (EMT). To dissect the underlying mechanisms, we measured the transcription levels of EMT-associated transcription factors (TFs). RESULTS We found that EZH2 was highly expressed in mCRPC than that of primary PCa tumors and that EnzR PCa cells gained more EMT characteristics than those of enzalutamide-sensitive counterparts. Further, loss of EZH2-induced inhibition of EMT is independent of polycomb repressive complex 2 (PRC2). Mechanistically, downregulation of EZH2 inhibits transcription of EMT-associated TFs by repressing formation of H3K4me3 to the promotor regions of the TFs. CONCLUSION We identified the novel roles of EZH2 in EnzR mCRPC. EnzR PCa gains more EMT properties than that of enzalutamide-sensitive PCa. Loss of EZH2-assocaited inhibition of EMT is PRC2 independent. Downregulation of EZH2 suppresses EMT by impairing formation of H3K4me3 at the promotor regions, thus repressing expression of EMT-associated TFs.
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Affiliation(s)
- Zhuangzhuang Zhang
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, USA
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA
| | - Xinyi Wang
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, USA
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA
| | - Miyeong Kim
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, USA
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA
| | - Daheng He
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA
| | - Chi Wang
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA
| | - Ka Wing Fong
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, USA
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA
| | - Xiaoqi Liu
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, USA
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA
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Ninfali C, Siles L, Esteve-Codina A, Postigo A. The mesodermal and myogenic specification of hESCs depend on ZEB1 and are inhibited by ZEB2. Cell Rep 2023; 42:113222. [PMID: 37819755 DOI: 10.1016/j.celrep.2023.113222] [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: 03/12/2022] [Revised: 08/02/2023] [Accepted: 09/20/2023] [Indexed: 10/13/2023] Open
Abstract
Human embryonic stem cells (hESCs) can differentiate into any cell lineage. Here, we report that ZEB1 and ZEB2 promote and inhibit mesodermal-to-myogenic specification of hESCs, respectively. Knockdown and/or overexpression experiments of ZEB1, ZEB2, or PAX7 in hESCs indicate that ZEB1 is required for hESC Nodal/Activin-mediated mesodermal specification and PAX7+ human myogenic progenitor (hMuP) generation, while ZEB2 inhibits these processes. ZEB1 downregulation induces neural markers, while ZEB2 downregulation induces mesodermal/myogenic markers. Mechanistically, ZEB1 binds to and transcriptionally activates the PAX7 promoter, while ZEB2 binds to and activates the promoter of the neural OTX2 marker. Transplanting ZEB1 or ZEB2 knocked down hMuPs into the muscles of a muscular dystrophy mouse model, showing that hMuP engraftment and generation of dystrophin-positive myofibers depend on ZEB1 and are inhibited by ZEB2. The mouse model results suggest that ZEB1 expression and/or downregulating ZEB2 in hESCs may also enhance hESC regenerative capacity for human muscular dystrophy therapy.
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Affiliation(s)
- Chiara Ninfali
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036 Barcelona, Spain
| | - Laura Siles
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036 Barcelona, Spain
| | | | - Antonio Postigo
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036 Barcelona, Spain; Molecular Targets Program, J.G. Brown Center, Louisville University Healthcare Campus, Louisville, KY 40202, USA; ICREA, 08010 Barcelona, Spain.
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Sánchez-Tilló E, Pedrosa L, Vila I, Chen Y, Győrffy B, Sánchez-Moral L, Siles L, Lozano JJ, Esteve-Codina A, Darling DS, Cuatrecasas M, Castells A, Maurel J, Postigo A. The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas. JCI Insight 2023; 8:e164629. [PMID: 37870961 PMCID: PMC10619495 DOI: 10.1172/jci.insight.164629] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 09/05/2023] [Indexed: 10/25/2023] Open
Abstract
Despite being in the same pathway, mutations of KRAS and BRAF in colorectal carcinomas (CRCs) determine distinct progression courses. ZEB1 induces an epithelial-to-mesenchymal transition (EMT) and is associated with worse progression in most carcinomas. Using samples from patients with CRC, mouse models of KrasG12D and BrafV600E CRC, and a Zeb1-deficient mouse, we show that ZEB1 had opposite functions in KRAS- and BRAF-mutant CRCs. In KrasG12D CRCs, ZEB1 was correlated with a worse prognosis and a higher number of larger and undifferentiated (mesenchymal or EMT-like) tumors. Surprisingly, in BrafV600E CRC, ZEB1 was associated with better prognosis; fewer, smaller, and more differentiated (reduced EMT) primary tumors; and fewer metastases. ZEB1 was positively correlated in KRAS-mutant CRC cells and negatively in BRAF-mutant CRC cells with gene signatures for EMT, cell proliferation and survival, and ERK signaling. On a mechanistic level, ZEB1 knockdown in KRAS-mutant CRC cells increased apoptosis and reduced clonogenicity and anchorage-independent growth; the reverse occurred in BRAFV600E CRC cells. ZEB1 is associated with better prognosis and reduced EMT signature in patients harboring BRAF CRCs. These data suggest that ZEB1 can function as a tumor suppressor in BRAF-mutant CRCs, highlighting the importance of considering the KRAS/BRAF mutational background of CRCs in therapeutic strategies targeting ZEB1/EMT.
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Affiliation(s)
- Ester Sánchez-Tilló
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Department of Oncology and Hematology, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Group of Gastrointestinal and Pancreatic Oncology, Department of Liver, Digestive System and Metabolism, IDIBAPS, Barcelona, Spain
- Biomedical Research Network in Gastrointestinal and Liver Diseases (CIBEREHD), Carlos III National Health Institute (ISCIII), Barcelona, Spain
| | - Leire Pedrosa
- Group of Translational Genomics and Targeted Therapeutics in Solid Tumors, IDIBAPS, and Department of Medical Oncology, Hospital Clinic, Barcelona, Spain
| | - Ingrid Vila
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Department of Oncology and Hematology, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Yongxu Chen
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Department of Oncology and Hematology, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Balázs Győrffy
- Cancer Biomarker Research Group, Research Centre for Natural Sciences (TKK), and Department of Bioinformatics and 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Lidia Sánchez-Moral
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Department of Oncology and Hematology, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Laura Siles
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Department of Oncology and Hematology, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Juan J. Lozano
- Bioinformatics Platform, CIBEREHD, ISCIII, Barcelona, Spain
| | - Anna Esteve-Codina
- National Centre for Genomic Analysis (CNAG) Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Department of Medicine and Health Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Douglas S. Darling
- Department of Oral Immunology, and Center for Genetics and Molecular Medicine, University of Louisville, Louisville, Kentucky, USA
| | - Miriam Cuatrecasas
- Biomedical Research Network in Gastrointestinal and Liver Diseases (CIBEREHD), Carlos III National Health Institute (ISCIII), Barcelona, Spain
- Group of Molecular Pathology of Inflammatory Conditions and Solid Tumours, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain
- Department of Pathology, Hospital Clínic and University of Barcelona School of Medicine, Barcelona, Spain
| | - Antoni Castells
- Group of Gastrointestinal and Pancreatic Oncology, Department of Liver, Digestive System and Metabolism, IDIBAPS, Barcelona, Spain
- Biomedical Research Network in Gastrointestinal and Liver Diseases (CIBEREHD), Carlos III National Health Institute (ISCIII), Barcelona, Spain
- Department of Gastroenterology, Hospital Clinic and University of Barcelona School of Medicine, Barcelona, Spain
| | - Joan Maurel
- Biomedical Research Network in Gastrointestinal and Liver Diseases (CIBEREHD), Carlos III National Health Institute (ISCIII), Barcelona, Spain
- Group of Translational Genomics and Targeted Therapeutics in Solid Tumors, IDIBAPS, and Department of Medical Oncology, Hospital Clinic, Barcelona, Spain
| | - Antonio Postigo
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, Department of Oncology and Hematology, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Biomedical Research Network in Gastrointestinal and Liver Diseases (CIBEREHD), Carlos III National Health Institute (ISCIII), Barcelona, Spain
- Molecular Targets Program, Department of Medicine, J.G. Brown Cancer Center, Louisville, Kentucky, USA
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
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Clarkson-Paredes C, Karl MT, Popratiloff A, Miller RH. A unique cell population expressing the Epithelial-Mesenchymal Transition-transcription factor Snail moderates microglial and astrocyte injury responses. PNAS NEXUS 2023; 2:pgad334. [PMID: 37901440 PMCID: PMC10612478 DOI: 10.1093/pnasnexus/pgad334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 09/26/2023] [Indexed: 10/31/2023]
Abstract
Insults to the central nervous system (CNS) elicit common glial responses including microglial activation evidenced by functional, morphological, and phenotypic changes, as well as astrocyte reactions including hypertrophy, altered process orientation, and changes in gene expression and function. However, the cellular and molecular mechanisms that initiate and modulate such glial response are less well-defined. Here we show that an adult cortical lesion generates a population of ultrastructurally unique microglial-like cells that express Epithelial-Mesenchymal Transcription factors including Snail. Knockdown of Snail with antisense oligonucleotides results in a postinjury increase in activated microglial cells, elevation in astrocyte reactivity with increased expression of C3 and phagocytosis, disruption of astrocyte junctions and neurovascular structure, increases in neuronal cell death, and reduction in cortical synapses. These changes were associated with alterations in pro-inflammatory cytokine expression. By contrast, overexpression of Snail through microglia-targeted an adeno-associated virus (AAV) improved many of the injury characteristics. Together, our results suggest that the coordination of glial responses to CNS injury is partly mediated by epithelial-mesenchymal transition-factors (EMT-Fsl).
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Affiliation(s)
- Cheryl Clarkson-Paredes
- Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, George Washington University, 2300 Eye Street NW, Ross 735, Washington, DC 20052, USA
- Nanofabrication and Imaging Center, The George Washington University, 800 22nd Street NW, Washington, DC 20052, USA
| | - Molly T Karl
- Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, George Washington University, 2300 Eye Street NW, Ross 735, Washington, DC 20052, USA
| | - Anastas Popratiloff
- Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, George Washington University, 2300 Eye Street NW, Ross 735, Washington, DC 20052, USA
- Nanofabrication and Imaging Center, The George Washington University, 800 22nd Street NW, Washington, DC 20052, USA
| | - Robert H Miller
- Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, George Washington University, 2300 Eye Street NW, Ross 735, Washington, DC 20052, USA
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Zhang Y, Wang X, Duan X, Du T, Chen X. The synergistic effect of EMT regulators and m6A modification on prognosis-related immunological signatures for ovarian cancer. Sci Rep 2023; 13:14872. [PMID: 37684273 PMCID: PMC10491820 DOI: 10.1038/s41598-023-41554-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023] Open
Abstract
Recently, there has been growing interest among researchers in exploring the effects of epithelial-mesenchymal transformation (EMT) or N6-Methyladenosine (m6A) modification regulators on tumor development. However, the synergistic efficiency of these regulators in relation to ovarian cancer development remains unclear. This study aims to explore the transcription patterns of main regulators, including 19 EMT and 22 m6A, in ovarian cancer samples from TCGA datasets and normal samples from GTEx datasets. After conducting a LASSO regression analysis, ten prognostic signatures were identified, namely KIAA1429, WTAP, SNAI1, AXL, IGF2BP1, ELAVL1, CBLL1, CDH2, NANOG and ALKBH5. These signatures were found to have a comprehensive effect on immune infiltrating signatures and the final prognostic outcome. Next, utilizing the ssGSEA algorithm and conducting overall survival analyses, we have identified the key prognosis-related immunological signatures in ovarian cancer to be ALKBH5, WTAP, ELAVL1, and CDH2 as the regulators. The characteristic immune response and related genetic expression have revealed a significant correlation between the alteration of m6A regulators and EMT regulators, indicating a synergistic effect between these two factors in the development of ovarian cancer. In summary, our research offers a novel perspective and strategy to enhance the occurrence, progression, and prognosis of ovarian cancer.
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Affiliation(s)
- Yanna Zhang
- Department of Blood Transfusion, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, People's Republic of China
| | - Xun Wang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China
| | - Xiaogang Duan
- Chengdu Eighth People's Hospital/Geriatric Hospital of Chengdu Medical College, Chengdu, 610000, Sichuan, People's Republic of China
| | - Ting Du
- Noncoding RNA and Drug Discovery Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu, 610000, Sichuan, People's Republic of China.
| | - Xiancheng Chen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China.
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Li Z, Lu T, Chen Z, Yu X, Wang L, Shen G, Huang H, Li Z, Ren Y, Guo W, Hu Y. HOXA11 promotes lymphatic metastasis of gastric cancer via transcriptional activation of TGFβ1. iScience 2023; 26:107346. [PMID: 37539033 PMCID: PMC10393827 DOI: 10.1016/j.isci.2023.107346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/09/2023] [Accepted: 07/06/2023] [Indexed: 08/05/2023] Open
Abstract
Most gastric cancer (GC) patients with early stage often have no lymph node (LN) metastases, while LN metastases appear in the advanced stage. However, there are some patients who present with early stage LN metastases and no LN metastases in the advanced stage. To explore the deeper molecular mechanisms involved, we collected clinical samples from early and advanced stage GC with and without LN metastases, as well as metastatic lymph nodes. Herein, we identified a key target, HOXA11, that was upregulated in GC tissues and closely associated with lymphatic metastases. HOXA11 transcriptionally regulates TGFβ1 expression and activates the TGFβ1/Smad2 pathway, which not only promotes EMT development but also induces VEGF-C secretion and lymphangiogenesis. These findings provide a plausible mechanism for HOXA11-modulated tumor in lymphatic metastasis and suggest that HOXA11 may represent a potential therapeutic target for clinical intervention in LN-metastatic gastric cancer.
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Affiliation(s)
- Zhenyuan Li
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, P.R. China
| | - Tailiang Lu
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, P.R. China
| | - Zhian Chen
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, P.R. China
| | - Xiang Yu
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, P.R. China
| | - Lingzhi Wang
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, P.R. China
| | - Guodong Shen
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, P.R. China
| | - Huilin Huang
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, P.R. China
| | - Zhenhao Li
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, P.R. China
| | - Yingxin Ren
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, P.R. China
| | - Weihong Guo
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, P.R. China
| | - Yanfeng Hu
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, P.R. China
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Jamal Eddin TM, Nasr SM, Gupta I, Zayed H, Al Moustafa AE. Helicobacter pylori and epithelial mesenchymal transition in human gastric cancers: An update of the literature. Heliyon 2023; 9:e18945. [PMID: 37609398 PMCID: PMC10440535 DOI: 10.1016/j.heliyon.2023.e18945] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 07/25/2023] [Accepted: 08/03/2023] [Indexed: 08/24/2023] Open
Abstract
Gastric cancer, a multifactorial disease, is considered one of the most common malignancies worldwide. In addition to genetic and environmental risk factors, infectious agents, such as Epstein-Barr virus (EBV) and Helicobacter pylori (H.pylori) contribute to the onset and development of gastric cancer. H. pylori is a type I carcinogen that colonizes the gastric epithelium of approximately 50% of the world's population, thus increasing the risk of gastric cancer development. On the other hand, epithelial mesenchymal transition (EMT) is a fundamental process crucial to embryogenic growth, wound healing, organ fibrosis and cancer progression. Several studies associate gastric pathogen infection of the epithelium with EMT initiation, provoking cancer metastasis in the gastric mucosa through various molecular signaling pathways. Additionally, EMT is implicated in the progression and development of H. pylori-associated gastric cancer. In this review, we recapitulate recent findings elucidating the association between H. pylori infection in EMT promotion leading to gastric cancer progression and metastasis.
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Affiliation(s)
- Tala M. Jamal Eddin
- College of Health Sciences, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Shahd M.O. Nasr
- College of Health Sciences, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Ishita Gupta
- College of Medicine, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Hatem Zayed
- College of Health Sciences, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Ala-Eddin Al Moustafa
- College of Medicine, QU Health, Qatar University, PO Box 2713, Doha, Qatar
- Biomedical Research Center, Qatar University, PO Box 2713, Doha, Qatar
- Oncology Department, Faculty of Medicine, McGill University, Montreal, QC, H3G 2M1, Canada
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43
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Furukawa T, Mimami K, Nagata T, Yamamoto M, Sato M, Tanimoto A. Approach to Functions of BHLHE41/DEC2 in Non-Small Lung Cancer Development. Int J Mol Sci 2023; 24:11731. [PMID: 37511489 PMCID: PMC10380948 DOI: 10.3390/ijms241411731] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/17/2023] [Accepted: 07/19/2023] [Indexed: 07/30/2023] Open
Abstract
The circadian rhythm-related genes BHLHE40/DEC1 and BHLHE41/DEC2 have various functions under different cell and tissue conditions. BHLHE41/DEC2 has been reported to be both a cancer-suppressive and an oncogenic gene during cancer development. The effects of BHLHE41/DEC2 on differentiation have been examined using Bhlhe41/Dec2 knockout mice and/or in vitro differentiation models, and research has been conducted using genetic analysis of tumor cells, in vitro analysis of cancer cell lines, and immunohistochemical studies of the clinical samples. We summarize some of these studies, detail several problems, and consider possible reasons for contradictory results and the needs for further research.
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Affiliation(s)
- Tatsuhiko Furukawa
- Department of Pathology, Graduate School Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Kentaro Mimami
- Department of Pharmacy, University of Miyazaki Hospital, 5200 Kihara Kiyotake cho, Miyazaki 889-1692, Japan
| | - Toshiyuki Nagata
- Department of General Thoracic Surgery, Graduate School Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Masatasu Yamamoto
- Department of Molecular Oncology, Graduate School Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Masami Sato
- Department of General Thoracic Surgery, Graduate School Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Akihide Tanimoto
- Department of Pathology, Graduate School Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
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Poryazova E, Serteva D, Markov D, Chonov V, Markov G. Expression of Snail and Twist compared with clinical and pathological parameters in patients with gastric cancer. Folia Med (Plovdiv) 2023; 65:393-398. [PMID: 38351814 DOI: 10.3897/folmed.65.e84132] [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: 03/21/2022] [Accepted: 07/12/2022] [Indexed: 02/16/2024] Open
Abstract
INTRODUCTION Epithelial-mesenchymal transition (EMT) is a process of change in the cellular phenotype from epithelial to mesenchymal morphology. The changes at the cellular level can explain the great heterogeneity and plasticity in the different histological subtypes of gastric carcinomas, which causes difficulties in therapy. In it, epithelial cells reduce intercellular adhesion, which is crucial in the process of invasion and metastasis of gastric carcinomas. Inhibition of cell adhesion molecules such as E-cadherin is known to be influenced by a number of transcription factors, such as Snail and Twist.
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Leung DHL, Phon BWS, Sivalingam M, Radhakrishnan AK, Kamarudin MNA. Regulation of EMT Markers, Extracellular Matrix, and Associated Signalling Pathways by Long Non-Coding RNAs in Glioblastoma Mesenchymal Transition: A Scoping Review. BIOLOGY 2023; 12:818. [PMID: 37372103 PMCID: PMC10294841 DOI: 10.3390/biology12060818] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/26/2023] [Accepted: 05/31/2023] [Indexed: 06/29/2023]
Abstract
Glioblastoma (GBM) mesenchymal (MES) transition can be regulated by long non-coding RNAs (lncRNAs) via modulation of various factors (Epithelial-to-Mesenchymal (EMT) markers, biological signalling, and the extracellular matrix (ECM)). However, understanding of these mechanisms in terms of lncRNAs is largely sparse. This review systematically analysed the mechanisms by which lncRNAs influence MES transition in GBM from a systematic search of the literature (using PRISMA) performed in five databases (PubMed, MEDLINE, EMBASE, Scopus, and Web of Science). We identified a total of 62 lncRNAs affiliated with GBM MES transition, of which 52 were upregulated and 10 were downregulated in GBM cells, where 55 lncRNAs were identified to regulate classical EMT markers in GBM (E-cadherin, N-cadherin, and vimentin) and 25 lncRNAs were reported to regulate EMT transcription factors (ZEB1, Snai1, Slug, Twist, and Notch); a total of 16 lncRNAs were found to regulate the associated signalling pathways (Wnt/β-catenin, PI3k/Akt/mTOR, TGFβ, and NF-κB) and 14 lncRNAs were reported to regulate ECM components (MMP2/9, fibronectin, CD44, and integrin-β1). A total of 25 lncRNAs were found dysregulated in clinical samples (TCGA vs. GTEx), of which 17 were upregulated and 8 were downregulated. Gene set enrichment analysis predicted the functions of HOXAS3, H19, HOTTIP, MEG3, DGCR5, and XIST at the transcriptional and translational levels based on their interacting target proteins. Our analysis observed that the MES transition is regulated by complex interplays between the signalling pathways and EMT factors. Nevertheless, further empirical studies are required to elucidate the complexity in this process between these EMT factors and the signalling involved in the GBM MES transition.
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Affiliation(s)
| | | | | | | | - Muhamad Noor Alfarizal Kamarudin
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Malaysia
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Zhang Y, Do KK, Wang F, Lu X, Liu JY, Li C, Ceresa BP, Zhang L, Dean DC, Liu Y. Zeb1 facilitates corneal epithelial wound healing by maintaining corneal epithelial cell viability and mobility. Commun Biol 2023; 6:434. [PMID: 37081200 PMCID: PMC10119281 DOI: 10.1038/s42003-023-04831-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 04/11/2023] [Indexed: 04/22/2023] Open
Abstract
The cornea is the outmost ocular tissue and plays an important role in protecting the eye from environmental insults. Corneal epithelial wounding provokes pain and fear and contributes to the most ocular trauma emergency assessments worldwide. ZEB1 is an essential transcription factor in development; but its roles in adult tissues are not clear. We identify Zeb1 is an intrinsic factor that facilitates corneal epithelial wound healing. In this study, we demonstrate that monoallelic deletion of Zeb1 significantly expedites corneal cell death and inhibits corneal epithelial EMT-related cell migration upon an epithelial debridement. We provide evidence that Zeb1-regulation of corneal epithelial wound healing is through the repression of genes required for Tnfa-induced epithelial cell death and the induction of genes beneficial for epithelial cell migration. We suggest utilizing TNF-α antagonists would reduce TNF/TNFR1-induced cell death in the corneal epithelium and inflammation in the corneal stroma to help corneal wound healing.
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Affiliation(s)
- Yingnan Zhang
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USA
- The Rosenberg School of Optometry, University of the Incarnate Word, San Antonio, TX, 78229, USA
| | - Khoi K Do
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Fuhua Wang
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USA
- Eye Institute and Eye Hospital of Shangdong First Medical University, 250021, Jinan, China
| | - Xiaoqin Lu
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USA
- James Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - John Y Liu
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Chi Li
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USA
- James Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Brian P Ceresa
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Lijun Zhang
- Department of Ophthalmology, Third People's Hospital of Dalian, Dalian Medical University, 116033, Dalian, China
| | - Douglas C Dean
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
- James Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
- Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
| | - Yongqing Liu
- Department of Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
- James Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
- Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
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Meng L, Hu YT, Xu AM. F-box and leucine-rich repeat 6 promotes gastric cancer progression via the promotion of epithelial-mesenchymal transition. World J Gastrointest Oncol 2023; 15:490-503. [PMID: 37009323 PMCID: PMC10052668 DOI: 10.4251/wjgo.v15.i3.490] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 01/06/2023] [Accepted: 02/15/2023] [Indexed: 03/14/2023] Open
Abstract
BACKGROUND F-box and leucine-rich repeat 6 (FBXL6) have reportedly been associated with several cancer types. However, the role and mechanisms of FBXL6 in gastric cancer (GC) require further elucidation.
AIM To investigate the effect of FBXL6 in GC tissues and cells and the underlying mechanisms.
METHODS TCGA and GEO database analysis was performed to evaluate the expression of FBXL6 in GC tissues and adjacent normal tissues. Reverse transcription-quantitative polymerase chain reaction, immunofluorescence, and western blotting were used to detect the expression of FBXL6 in GC tissue and cell lines. Cell clone formation, 5-ethynyl-2’-deoxyuridine (EdU) assays, CCK-8, transwell migration assay, and wound healing assays were performed to evaluate the malignant biological behavior in GC cell lines after transfection with FBXL6-shRNA and the overexpression of FBXL6 plasmids. Furthermore, in vivo tumor assays were performed to prove whether FBXL6 promoted cell proliferation in vivo.
RESULTS FBXL6 expression was upregulated more in tumor tissues than in adjacent normal tissues and positively associated with clinicopathological characteristics. The outcomes of CCK-8, clone formation, and Edu assays demonstrated that FBXL6 knockdown inhibited cell proliferation, whereas upregulation of FBXL6 promoted proliferation in GC cells. Additionally, the transwell migration assay revealed that FBXL6 knockdown suppressed migration and invasion, whereas the overexpression of FBXL6 showed the opposite results. Through the subcutaneous tumor implantation assay, it was evident that the knockdown of FBXL6 inhibited GC graft tumor growth in vivo. Western blotting showed that the effects of FBXL6 on the expression of the proteins associated with the epithelial-mesenchymal transition-associated proteins in GC cells.
CONCLUSION Silencing of FBXL6 inactivated the EMT pathway to suppress GC malignancy in vitro. FBXL6 can potentially be used for the diagnosis and targeted therapy of patients with GC.
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Affiliation(s)
- Lei Meng
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China
| | - Yu-Ting Hu
- Department of Immunology, College of Basic Medicine, Anhui Medical University, Hefei 230022, Anhui Province, China
| | - A-Man Xu
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China
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48
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Furukawa T, Tabata S, Minami K, Yamamoto M, Kawahara K, Tanimoto A. Metabolic reprograming of cancer as a therapeutic target. Biochim Biophys Acta Gen Subj 2023; 1867:130301. [PMID: 36572257 DOI: 10.1016/j.bbagen.2022.130301] [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: 09/10/2022] [Revised: 12/07/2022] [Accepted: 12/21/2022] [Indexed: 12/25/2022]
Abstract
Our understanding of metabolic reprogramming in cancer has tremendously improved along with the technical progression of metabolomic analysis. Metabolic changes in cancer cells proved much more complicated than the classical Warburg effect. Previous studies have approached metabolic changes as therapeutic and/or chemopreventive targets. Recently, several clinical trials have reported anti-cancer agents associated with metabolism. However, whether cancer cells are dependent on metabolic reprogramming or favor suitable conditions remains nebulous. Both scenarios are possibly intertwined. Identification of downstream molecules and the understanding of mechanisms underlying reprogrammed metabolism can improve the effectiveness of cancer therapy. Here, we review several examples of the metabolic reprogramming of cancer cells and the therapies targeting the metabolism-related molecules as well as discuss practical approaches to improve the next generation of cancer therapies focused on the metabolic reprogramming of cancer.
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Affiliation(s)
- Tatsuhiko Furukawa
- Department of Pathology, Graduate School Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
| | - Sho Tabata
- Laboratory for Cell Systems, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Kentaro Minami
- Department of Pharmacy, University of Miyazaki Hospital, 5200 Kihara Kiyotake cho, Miyazaki 889-1692, Japan
| | - Masatatsu Yamamoto
- Department of Molecular Oncology, Graduate School Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Kohichi Kawahara
- Department of Molecular Oncology, Graduate School Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Akihide Tanimoto
- Department of Pathology, Graduate School Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
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Li D, Xia L, Huang P, Wang Z, Guo Q, Huang C, Leng W, Qin S. Heterogeneity and plasticity of epithelial-mesenchymal transition (EMT) in cancer metastasis: Focusing on partial EMT and regulatory mechanisms. Cell Prolif 2023:e13423. [PMID: 36808651 DOI: 10.1111/cpr.13423] [Citation(s) in RCA: 67] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 01/05/2023] [Accepted: 01/27/2023] [Indexed: 02/22/2023] Open
Abstract
Epithelial-mesenchymal transition (EMT) or mesenchymal-epithelial transition (MET) plays critical roles in cancer metastasis. Recent studies, especially those based on single-cell sequencing, have revealed that EMT is not a binary process, but a heterogeneous and dynamic disposition with intermediary or partial EMT states. Multiple double-negative feedback loops involved by EMT-related transcription factors (EMT-TFs) have been identified. These feedback loops between EMT drivers and MET drivers finely regulate the EMT transition state of the cell. In this review, the general characteristics, biomarkers and molecular mechanisms of different EMT transition states were summarized. We additionally discussed the direct and indirect roles of EMT transition state in tumour metastasis. More importantly, this article provides direct evidence that the heterogeneity of EMT is closely related to the poor prognosis in gastric cancer. Notably, a seesaw model was proposed to explain how tumour cells regulate themselves to remain in specific EMT transition states, including epithelial state, hybrid/intermediate state and mesenchymal state. Additionally, this article also provides a review of the current status, limitations and future perspectives of EMT signalling in clinical applications.
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Affiliation(s)
- Dandan Li
- Department of Stomatology, Taihe Hospital and Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China.,Laboratory of Tumor Biology, Academy of Bio-medicine Research, Hubei University of Medicine, Shiyan, China
| | - Lingyun Xia
- Department of Stomatology, Taihe Hospital and Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Pan Huang
- Laboratory of Tumor Biology, Academy of Bio-medicine Research, Hubei University of Medicine, Shiyan, China
| | - Zidi Wang
- Laboratory of Tumor Biology, Academy of Bio-medicine Research, Hubei University of Medicine, Shiyan, China
| | - Qiwei Guo
- Laboratory of Tumor Biology, Academy of Bio-medicine Research, Hubei University of Medicine, Shiyan, China
| | - Congcong Huang
- Laboratory of Tumor Biology, Academy of Bio-medicine Research, Hubei University of Medicine, Shiyan, China
| | - Weidong Leng
- Department of Stomatology, Taihe Hospital and Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Shanshan Qin
- Department of Stomatology, Taihe Hospital and Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China.,Laboratory of Tumor Biology, Academy of Bio-medicine Research, Hubei University of Medicine, Shiyan, China
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Winningham AH, Camper SA. Pituitary Stem Cell Regulation by Zeb2 and BMP Signaling. Endocrinology 2023; 164:bqad016. [PMID: 36683433 PMCID: PMC10091485 DOI: 10.1210/endocr/bqad016] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 01/15/2023] [Accepted: 01/18/2023] [Indexed: 01/24/2023]
Abstract
Epithelial to mesenchymal transition (EMT) is important for many developing organs, and for wound healing, fibrosis, and cancer. Pituitary stem cells undergo an EMT-like process as they migrate and initiate differentiation, but little is known about the input of signaling pathways or the genetic hierarchy of the transcriptional cascade. Prop1 mutant stem cells fail to undergo changes in cellular morphology, migration, and transition to the Pou1f1 lineage. We used Prop1 mutant mice to identify the changes in gene expression that are affiliated with EMT-like processes. BMP and TGF-β family gene expression was reduced in Prop1 mutants and Elf5, a transcription factor that characteristically suppresses EMT, had elevated expression. Genes involved in cell-cell contact such as cadherins and claudins were elevated in Prop1 mutants. To establish the genetic hierarchy of control, we manipulated gene expression in pituitary stem cell colonies. We determined that the EMT inducer, Zeb2, is necessary for robust BMP signaling and repression of Elf5. We demonstrated that inhibition of BMP signaling affects expression of target genes in the Id family, but it does not affect expression of other EMT genes. Zeb2 is necessary for expression of the SHH effector gene Gli2. However, knock down of Gli2 has little effect on the EMT-related genes, suggesting that it acts through a separate pathway. Thus, we have established the genetic hierarchy involved in the transition of pituitary stem cells to differentiation.
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Affiliation(s)
- Amanda H Winningham
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109-5618, USA
| | - Sally A Camper
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109-5618, USA
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