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Manjunatha BS, Handge KT, Shah VS, Al-Thobaiti YE, Pateel DGS. Immunohistochemical expression of matrix metalloproteinase-9 and 13 in oral squamous cell carcinoma and their role in predicting lymph node metastasis. World J Methodol 2025; 15:94514. [DOI: 10.5662/wjm.v15.i2.94514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 09/23/2024] [Accepted: 10/20/2024] [Indexed: 11/27/2024] Open
Abstract
BACKGROUND One of the main characteristics of oral squamous cell carcinoma (OSCC) is that it metastasizes to cervical lymph nodes frequently with a high degree of local invasiveness. A primary feature of malignant tumors is their penetration of neighboring tissues, such as lymphatic and blood arteries, due to the tumor cells' capacity to break down the extracellular matrix (ECM). Matrix metalloproteinases (MMPs) constitute a family of proteolytic enzymes that facilitate tissue remodeling and the degradation of the ECM. MMP-9 and MMP-13 belong to the group of extracellular matrix degrading enzymes and their expression has been studied in OSCC because of their specific functions. MMP-13, a collagenase family member, is thought to play an essential role in the MMP activation cascade by breaking down the fibrillar collagens, whereas MMP-9 is thought to accelerate the growth of tumors. Elevated MMP-13 expression has been associated with tumor behavior and patient prognosis in a number of malignant cases.
AIM To assess the immunohistochemical expression of MMP-9 and MMP-13 in OSCC.
METHODS A total of 40 cases with histologically confirmed OSCC by incisional biopsy were included in this cross-sectional retrospective study. The protocols for both MMP-9 and MMP-13 immunohistochemical staining were performed according to the manufacturer’s recommendations along with the normal gingival epithelium as a positive control. All the observations were recorded and Pearson’s χ² test with Fisher exact test was used for statistical analysis.
RESULTS Our study showed no significant correlation between MMP-9 and MMP-13 staining intensity and tumor size. The majority of the patients were in advanced TNM stages (III and IV), and showed intense expression of MMP-9 and MMP-13.
CONCLUSION The present study suggests that both MMP-9 and MMP-13 play an important and independent role in OSCC progression and invasiveness. Intense expression of MMP-9 and MMP-13, irrespective of histological grade of OSCC, correlates well with TNM stage. Consequently, it is evident that MMP-9 and MMP-13 are important for the invasiveness and progression of tumors. The findings may facilitate the development of new approaches for evaluating lymph node metastases and interventional therapy techniques, hence enhancing the prognosis of patients diagnosed with OSCC.
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Affiliation(s)
- Bhari Sharanesha Manjunatha
- Department of Basic Oral Medicine and Allied Dental Sciences, Taif University, At`Taif 26571, Makkah, Saudi Arabia
| | - Keshav T Handge
- Department of Oral and Maxillofacial Pathology, Dr. Vasantrao Pawar Medical College, Hospital and Research Centre, Nashik 423101, Maharashtra, India
| | - Vandana Sandeep Shah
- Department of Oral Pathology and Microbiology, KM Shah Dental College and Hospital, Sumandeep Vidyapeeth, Vadodara 391760, Gujarat, India
| | - Yasser Eid Al-Thobaiti
- Department of Oral and Maxillofacial Surgery and Diagnostic Sciences, Faculty of Dentistry, Taif University, Al-Haweiah 26571 Makkah, Saudi Arabia
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Qi J, Luo Z, Li CY, Wang J, Ding W. Interpretable niche-based cell‒cell communication inference using multi-view graph neural networks. NATURE COMPUTATIONAL SCIENCE 2025:10.1038/s43588-025-00809-6. [PMID: 40425827 DOI: 10.1038/s43588-025-00809-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 04/22/2025] [Indexed: 05/29/2025]
Abstract
Cell‒cell communication (CCC) is a fundamental biological process for the harmonious functioning of biological systems. Increasing evidence indicates that cells of the same type or cluster may exhibit different interaction patterns under varying niches, yet most prevailing methods perform CCC inference at the cell type or cluster level while disregarding niche heterogeneity. Here we introduce the Spatial Transcriptomics-based cell‒cell Communication And Subtype Exploration (STCase) tool, which can describe CCC events at the single-cell/spot level based on spatial transcriptomics (ST). STCase includes an interpretable multi-view graph neural network via CCC-aware attention to identify niches for each cell type and uncover niche-specific CCC events. We show that STCase outperforms state-of-the-art approaches and accurately captures reported immune-related CCC events in human bronchial glands. We also identify three distinct niches of oral squamous cell carcinoma that may be obscured by agglomerative methods, and discover niche-specific CCC events that could influence tumor prognosis.
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Affiliation(s)
- Juntian Qi
- State Key Laboratory of Gene Function and Modulation Research, Laboratory of Bioinformatics and Genomic Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China
- Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Zhengchao Luo
- Department of Big Data and Biomedical AI, College of Future Technology, Peking University, Beijing, China
| | - Chuan-Yun Li
- State Key Laboratory of Gene Function and Modulation Research, Laboratory of Bioinformatics and Genomic Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China.
- Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
- University of Chinese Academy of Sciences, Beijing, China.
| | - Jinzhuo Wang
- Department of Big Data and Biomedical AI, College of Future Technology, Peking University, Beijing, China.
| | - Wanqiu Ding
- State Key Laboratory of Gene Function and Modulation Research, Laboratory of Bioinformatics and Genomic Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China.
- Bioinformatics Core Facility, College of Future Technology, Peking University, Beijing, China.
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Sonia N, Saikia S, Limaye AM. Estrogenic control of matrix metalloproteinases: a perspective on breast tumor invasion and metastasis. Mol Biol Rep 2025; 52:453. [PMID: 40358843 DOI: 10.1007/s11033-025-10555-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 04/29/2025] [Indexed: 05/15/2025]
Abstract
Metastasis is the major cause of mortality in breast cancer patients, and presents an invincible therapeutic challenge. It is a complex process of dissemination of tumor epithelial cells, which is associated with disruption of tissue homeostasis, and alterations in the tumor microenvironment through extracellular matrix (ECM) remodeling, stromal alteration, and epithelial-mesenchymal transition. Matrix metalloproteinases (MMPs) constitute a group of more than 25 zinc-dependent endopeptidases. By virtue of their ability to degrade a wide variety of ECM-associated proteins, they enable ECM remodelling during development, and disease. A large body of clinical data, and experimental evidences implicate MMPs in the invasion and metastasis of breast tumors. While MMPs are aberrantly expressed in breast tumors, few appear to have a dual role in disease progression; either promoting or inhibiting metastasis. Given the role of estrogen in breast cancer development, it is natural to ask whether this steroid hormone has any role in breast cancer metastasis. This review is a round-up of the prominent literature that presents estrogenic control of MMPs, which in turn implies its influence on the tumor microenvironment and metastasis.
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Affiliation(s)
- Ningthoujam Sonia
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India
| | - Snigdha Saikia
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India
| | - Anil Mukund Limaye
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India.
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Bayrak O, Alper M, Basbinar Y, Bayrak S. The role of thrombin in the paradoxical interplay of cancer metastasis and the vascular system: A driving dynamic. Biomed Pharmacother 2025; 186:118031. [PMID: 40215647 DOI: 10.1016/j.biopha.2025.118031] [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: 02/10/2025] [Revised: 03/26/2025] [Accepted: 03/28/2025] [Indexed: 04/25/2025] Open
Abstract
The coagulation system plays a complex role in cancer therapy. Endothelial damage and tissue factor increased by chemotherapy initiate the coagulation cascade, producing active FXa and releasing thrombin. Thrombin triggers tumor growth and metastasis, leading to severe thromboembolic events in cancer patients. Direct thrombin inhibitors do not have the expected anti-metastatic effect as PAR-2 remains active and increases the risk of bleeding. Therefore, dual inhibition of thrombin by FXa inhibition and plasmin inhibition, which converts fibrin to fibrinogen, is targeted. Clinical studies show that the use of tranexamic acid in patients on NOAC therapy may be beneficial without increasing the risk of bleeding. This approach offers a promising strategy to provide an anti-metastatic effect in cancer treatment.
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Affiliation(s)
- Ozge Bayrak
- Dokuz Eylul University, Institute of Health Sciences, Department of Oncology, Izmir, Turkey
| | - Meltem Alper
- Dokuz Eylul University, Institute of Oncology, Department of Translational Oncology, Izmir, Turkey
| | - Yasemin Basbinar
- Dokuz Eylul University, Institute of Oncology, Department of Translational Oncology, Izmir, Turkey
| | - Serdar Bayrak
- Dokuz Eylul University, Institute of Oncology, Department of Translational Oncology, Izmir, Turkey; Dokuz Eylul University, Faculty of Medicine, Department of Cardiovascular Surgery, Izmir, Turkey.
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Ding X, Liang Y, Zhou S, Wu Y, Sałata P, Mikolajczk-Martinez A, Khosrawipour V, Zhang Z. Targeting tumor extracellular matrix with nanoparticles to circumvent therapeutic resistance. J Control Release 2025; 383:113786. [PMID: 40306575 DOI: 10.1016/j.jconrel.2025.113786] [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: 03/07/2025] [Revised: 04/21/2025] [Accepted: 04/25/2025] [Indexed: 05/02/2025]
Abstract
Each stage of tumor development is intrinsically linked to the tumor microenvironment (TME), wherein the extracellular matrix (ECM) serves as a vital and abundant component in tumor tissues. The ECM is a non-cellular, three-dimensional macromolecular network scaffold that provides structural support to cells, stores bioactive molecules, and mediates signaling pathways through specific binding to cell surface receptors. Moreover, the ECM in tumor tissues plays a crucial role in impeding drug diffusion and resisting apoptosis induced by conventional anti-cancer therapies that primarily target cancer cells. Therefore, directing attentions towards the tumor ECM can facilitate the identification of novel targets and the development of new therapies. This review aims to summarize the composition, structure, remodeling, and function of tumor ECM, its association with drug resistance, and current targeting strategies, with a specific emphasis on nanoparticles (NPs).
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Affiliation(s)
- Xinyue Ding
- School of Pharmacy, Key laboratory of smart drug delivery (Ministry of Education) & National key laboratory of complex drug formulations for overcoming delivery barriers, Fudan University, Shanghai 201203, China
| | - Yiyu Liang
- School of Pharmacy, Key laboratory of smart drug delivery (Ministry of Education) & National key laboratory of complex drug formulations for overcoming delivery barriers, Fudan University, Shanghai 201203, China
| | - Siyuan Zhou
- School of Pharmacy, Key laboratory of smart drug delivery (Ministry of Education) & National key laboratory of complex drug formulations for overcoming delivery barriers, Fudan University, Shanghai 201203, China
| | - Yao Wu
- School of Pharmacy, Key laboratory of smart drug delivery (Ministry of Education) & National key laboratory of complex drug formulations for overcoming delivery barriers, Fudan University, Shanghai 201203, China
| | - Patricia Sałata
- Wrocław University of Environmental and Life Sciences, Wrocław, Poland
| | | | | | - Zhiwen Zhang
- School of Pharmacy, Key laboratory of smart drug delivery (Ministry of Education) & National key laboratory of complex drug formulations for overcoming delivery barriers, Fudan University, Shanghai 201203, China.
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Dawalibi A, Bakir M, Mohammad KS. The genetic architecture of bone metastases: unveiling the role of epigenetic and genetic modifications in drug resistance. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2025; 8:19. [PMID: 40342734 PMCID: PMC12059479 DOI: 10.20517/cdr.2025.28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 03/26/2025] [Accepted: 04/17/2025] [Indexed: 05/11/2025]
Abstract
Bone metastases represent frequent and severe complications in various cancers, notably impacting prognosis and quality of life. This review article delves into the genetic and epigenetic mechanisms underpinning drug resistance in bone metastases, a key challenge in effective cancer treatment. The development of drug resistance in cancer can manifest as either intrinsic or acquired, with genetic heterogeneity playing a pivotal role. Intrinsic resistance is often due to pre-existing mutations, while acquired resistance evolves through genetic and epigenetic alterations during treatment. These alterations include mutations in driver genes like TP53 and RB1, epigenetic modifications such as DNA methylation and histone changes, and pathway alterations, notably involving RANK-RANKL signaling and the PI3K/AKT/mTOR cascade. Recent studies underline the significance of the tumor microenvironment in fostering drug resistance, with components such as cancer-associated fibroblasts and hypoxia playing crucial roles. The interactions between metastatic cancer cells and the bone microenvironment facilitate survival and the proliferation of drug-resistant clones. This review highlights the necessity of understanding these complex interactions to develop targeted therapies that can overcome resistance and improve treatment outcomes. Current therapeutic strategies and future directions are discussed, emphasizing the integration of genomic profiling and targeted interventions in managing bone metastases. The evolving landscape of genetic research, including the application of next-generation sequencing and CRISPR technology, offers promising avenues for novel and more effective therapeutic strategies. This comprehensive exploration aims to provide insights into the molecular intricacies of drug resistance in bone metastases, paving the way for improved clinical management and patient care.
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Affiliation(s)
- Ahmad Dawalibi
- Department of Anatomy, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Mohamad Bakir
- Department of Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Khalid S. Mohammad
- Department of Anatomy, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
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Saadh MJ, Bishoyi AK, Ballal S, Singh A, Kareem RA, Devi A, Sharma GC, Naidu KS, Sead FF. MicroRNAs as behind-the-scenes molecules in breast cancer metastasis and their therapeutic role through novel microRNA-based delivery strategies. Gene 2025; 944:149272. [PMID: 39894085 DOI: 10.1016/j.gene.2025.149272] [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: 12/18/2024] [Accepted: 01/20/2025] [Indexed: 02/04/2025]
Abstract
Breast cancer is the primary cause of cancer-related death and the most frequent malignancy among women in Western countries. Although there have been advancements in combination treatments and targeted therapies for the metastatic diseases management, metastatic breast cancer is still the second most common cause of cancer-related deaths among U.S. women. The routes of metastasis encompass invasion, intravasation, circulation, extravasation, infiltration into a remote location to establish a metastatic niche, and the formation of micro-metastases in a new environment. Each of these processes is regulated by changes in gene expression. MicroRNAs (miRNAs) are widely expressed by a variety of organisms and have a key role in cell activities including suppressing or promoting cancer through regulating various pathways. Target gene expression is post-transcriptionally regulated by miRNAs, which contribute to the development, spread, and metastasis of breast cancer. In this study, we comprehensively discussed the role of miRNAs as predictors of breast cancer metastasis, their correlation with the spread of the disease to certain organs, and their potential application as targets for breast cancer treatment. We also provided molecular mechanisms of miRNAs in the progression of breast cancer, as well as current challenges in miRNA-based therapeutic approaches. Furthermore, as one of the primary issues with the treatment of solid malignancies is the efficient delivery of miRNAs, we examined a number of cutting-edge carriers for miRNA-based therapies and CRISPR/Cas9 as a targeted therapy for breast cancer.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan.
| | - Ashok Kumar Bishoyi
- Marwadi University Research Center, Department of Microbiology, Faculty of Science, Marwadi University, Rajkot 360003, Gujarat, India
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Abhayveer Singh
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura 140401, Punjab, India
| | | | - Anita Devi
- Department of Chemistry Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali 140307, Punjab, India
| | - Girish Chandra Sharma
- Department of Applied Sciences-Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, India
| | - K Satyam Naidu
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh 531162, India
| | - Fadhil Faez Sead
- Department of Dentistry, College of Dentistry, The Islamic University, Najaf, Iraq; Department of Medical Analysis, Medical Laboratory Technique College, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
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Rejeb M, Lahmar A, Ghedira MB, Selmi A, Kosksi T, Debbabi N, Ghedira LC. Fish and bovine collagen promote higher migration and adhesion of dermal cells pre-treated with wound-healing herbal extracts. Tissue Cell 2025; 93:102762. [PMID: 39919404 DOI: 10.1016/j.tice.2025.102762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 01/01/2025] [Accepted: 01/25/2025] [Indexed: 02/09/2025]
Abstract
PURPOSE Dermal cells fabricate and interact with the extracellular matrix to preserve structural integrity and further healthy function during wound healing. Collagen is a critical component of the matrix, challenging collagen's stability during wound injury. Natural sources especially plant extracts can promote wound healing and interact with collagen to increase its action. In this context, we studied the effect of extracted fish and bovine collagen in controlling cell proliferation, migration, and adhesion in dermal cells pretreated with plant extract. METHODS An acid-solubilization procedure was used to extract collagen fish (CF) and bovine (CB). Three different hydro-ethanolic extracts were prepared Pistacia lentiscus leaves (PL), Calendula officinalis leaves (FL), and flowers (FS). Migration potency was determined using scratch assay. The covered surface area was estimated after 16 hours and 24 hours after cell seeding. The chemotaxis was determined by the Boyden chamber, and the film was coated with CF or CB (10 µg/mL). or poly-L-lysine (50 µg/mL). FINDINGS We show that CF and CB increase adherence and migration of 3T3-L1 cells, which are pretreated with PL, FL, and FS. In addition, we highlighted a significantly higher cell adhesion on the CF matrix compared to CB. However, in the case of cells pre-treated with PL, the attachment to CF and CB increased significantly compared to untreated cells. The exposition of Hacat cells to plant extracts regulates the secretion of MMP2 and MMP and the production of reactive oxygen species. CONCLUSION CF and CB promote higher migration and adhesion of dermal cells pre-treated with wound-healing herbal extracts. In future studies, composite dressings based on collagen, P. lentiscus, and C. officinalis extracts can potentially be developed for tissue regeneration.
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Affiliation(s)
- Marwa Rejeb
- Research Laboratory, Bioactive Natural Products and Biotechnology LR24ES14, Faculty of Dental Medicine of Monastir, University of Monastir, Avicenne Street, Monastir 5000, Tunisia.
| | - Aida Lahmar
- Research Laboratory, Bioactive Natural Products and Biotechnology LR24ES14, Faculty of Dental Medicine of Monastir, University of Monastir, Avicenne Street, Monastir 5000, Tunisia.
| | - Mohamed Bayrem Ghedira
- Research Laboratory, Bioactive Natural Products and Biotechnology LR24ES14, Faculty of Dental Medicine of Monastir, University of Monastir, Avicenne Street, Monastir 5000, Tunisia
| | - Arem Selmi
- Research Laboratory, Bioactive Natural Products and Biotechnology LR24ES14, Faculty of Dental Medicine of Monastir, University of Monastir, Avicenne Street, Monastir 5000, Tunisia
| | - Tahsine Kosksi
- Research Laboratory, Bioactive Natural Products and Biotechnology LR24ES14, Faculty of Dental Medicine of Monastir, University of Monastir, Avicenne Street, Monastir 5000, Tunisia
| | - Nawres Debbabi
- Research Laboratory, Bioactive Natural Products and Biotechnology LR24ES14, Faculty of Dental Medicine of Monastir, University of Monastir, Avicenne Street, Monastir 5000, Tunisia
| | - Leila Chekir Ghedira
- Research Laboratory, Bioactive Natural Products and Biotechnology LR24ES14, Faculty of Dental Medicine of Monastir, University of Monastir, Avicenne Street, Monastir 5000, Tunisia
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Sun X, Hu X. Unveiling Matrix Metalloproteinase 13's Dynamic Role in Breast Cancer: A Link to Physical Changes and Prognostic Modulation. Int J Mol Sci 2025; 26:3083. [PMID: 40243781 PMCID: PMC11988641 DOI: 10.3390/ijms26073083] [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: 02/21/2025] [Revised: 03/21/2025] [Accepted: 03/25/2025] [Indexed: 04/18/2025] Open
Abstract
The biomechanical properties of the extracellular matrix (ECM) including its stiffness, viscoelasticity, collagen architecture, and temperature constitute critical biomechanical cues governing breast cancer progression. Matrix metalloproteinase 13 (MMP13) is an important marker of breast cancer and plays important roles in matrix remodelling and cell metastasis. Emerging evidence highlights MMP13 as a dynamic modulator of the ECM's physical characteristics through dual mechanoregulatory mechanisms. While MMP13-mediated collagen degradation facilitates microenvironmental softening, thus promoting tumour cell invasion, paradoxically, its crosstalk with cancer-associated fibroblasts (CAFs) and tumour-associated macrophages (TAMs) drives pathological stromal stiffening via aberrant matrix deposition and crosslinking. This biomechanical duality is amplified through feedforward loops with an epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) populations, mediated by signalling axes such as TGF-β/Runx2. Intriguingly, MMP13 exhibits context-dependent mechanomodulatory effects, demonstrating anti-fibrotic activity and inhibiting the metastasis of breast cancer. At the same time, angiogenesis and increased metabolism are important mechanisms through which MMP13 promotes a temperature increase in breast cancer. Targeting the spatiotemporal regulation of MMP13's mechanobiological functions may offer novel therapeutic strategies for disrupting the tumour-stroma vicious cycle.
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Affiliation(s)
- Xiaomeng Sun
- Queen Mary School, Jiangxi Medical College, Nanchang University, Xuefu Avenue, Honggutan District, Nanchang 330031, China;
| | - Xiaojuan Hu
- Queen Mary School, Jiangxi Medical College, Nanchang University, Xuefu Avenue, Honggutan District, Nanchang 330031, China;
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Xuefu Avenue, Honggutan District, Nanchang 330031, China
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Ge M, Sun W, Xu T, Yang R, Zhang K, Li J, Zhao Z, Gong M, Fu W. Multi-omics analysis of synovial tissue and fluid reveals differentially expressed proteins and metabolites in osteoarthritis. J Transl Med 2025; 23:285. [PMID: 40050855 PMCID: PMC11887128 DOI: 10.1186/s12967-025-06310-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: 01/14/2025] [Accepted: 02/23/2025] [Indexed: 03/09/2025] Open
Abstract
BACKGROUND Knee osteoarthritis is a common degenerative joint disease involving multiple pathological processes, including energy metabolism, cartilage repair, and osteogenesis. To investigate the alterations in critical metabolic pathways and differential proteins in osteoarthritis patients through metabolomic and proteomic analyses and to explore the potential mechanisms underlying synovial osteogenesis during osteoarthritis progression. METHODS Metabolomics was used to analyze metabolites in the synovial fluid and synovium of osteoarthritis patients (osteoarthritis group: 10; control group: 10), whereas proteomics was used to examine differential protein expression. Alkaline phosphatase activity was assessed to evaluate osteogenesis. RESULTS Upregulation of the tricarboxylic acid cycle: Significant upregulation of the tricarboxylic acid cycle in the synovial fluid and synovium of osteoarthritis patients indicated increased energy metabolism and cartilage repair activity. Arginine metabolism and collagen degradation: Elevated levels of ornithine, proline, and hydroxyproline in the synovial fluid reflect active collagen degradation and metabolism, contributing to joint cartilage breakdown. Abnormal Phenylalanine Metabolism: Increased phenylalanine and tyrosine metabolite levels in osteoarthritis patients suggest their involvement in cartilage destruction and osteoarthritis progression. Synovial osteogenesis: Increased expression of type I collagen in the synovium and elevated alkaline phosphatase activity confirmed the occurrence of osteogenesis, potentially driven by the differentiation of synovial fibroblasts, mesenchymal stem cells, and hypertrophic chondrocytes. Relationships between differential proteins and osteogenesis: FN1 and TGFBI are closely associated with synovial osteogenesis, while the upregulation of energy metabolism pathways provides the energy source for osteogenic transformation. CONCLUSIONS Alterations in energy metabolism, cartilage repair, and osteogenic mechanisms are critical. The related metabolites and proteins have potential as diagnostic and therapeutic targets for osteoarthritis.
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Affiliation(s)
- Minghao Ge
- Sports Medicine Center, Department of Orthopedic Surgery, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Weihao Sun
- Sports Medicine Center, Department of Orthopedic Surgery, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
- Beijing Jishuitan Hospital, Capital Medical, 31 Dongjiekou East Street, Xicheng District, Beijing, 110000, China
| | - Tianhao Xu
- Sports Medicine Center, Department of Orthopedic Surgery, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Runze Yang
- Sports Medicine Center, Department of Orthopedic Surgery, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Kaibo Zhang
- Sports Medicine Center, Department of Orthopedic Surgery, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Jian Li
- Sports Medicine Center, Department of Orthopedic Surgery, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Zhiwei Zhao
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, Sichuan, 610041, China.
| | - Meng Gong
- Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
| | - Weili Fu
- Sports Medicine Center, Department of Orthopedic Surgery, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
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Nalkiran I, Sevim Nalkiran H. Repurposing ProTAME for Bladder Cancer: A Combined Therapeutic Approach Targeting Cell Migration and MMP Regulation. BIOLOGY 2025; 14:263. [PMID: 40136519 PMCID: PMC11939954 DOI: 10.3390/biology14030263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 02/24/2025] [Accepted: 03/03/2025] [Indexed: 03/27/2025]
Abstract
Bladder cancer, the fourth most common cancer type among men, remains a therapeutic challenge due to its heterogeneity and frequent development of chemoresistance. Cisplatin-based chemotherapy, often combined with gemcitabine, is the standard treatment, yet resistance and off-target effects in non-cancerous tissues limit its efficacy. This study evaluated the effects of cisplatin, gemcitabine, and the APC/C inhibitor proTAME, both individually and in combination, on cell migration and MMP2/MMP9 expression in RT4 bladder cancer and ARPE-19 normal epithelial cells. Molecular docking analyses were conducted to investigate the interactions of these compounds with MMP2 and MMP9. IC20 values for gemcitabine, cisplatin, and proTAME were applied in scratch-wound healing and quantitative real-time PCR (qRT-PCR) assays. Docking results predicted that proTAME may interact favorably with MMP2 (-9.2 kcal/mol) and MMP9 (-8.7 kcal/mol), showing high computational binding affinities and potential key hydrogen bonds; however, these interactions require further experimental validation. Scratch-wound healing and qRT-PCR assays demonstrated that proTAME-containing combinations were associated with reduced cell migration and decreased MMP2 and MMP9 expression in RT4 cells. Cisplatin combined with proTAME showed the most pronounced reduction in MMP expression and cell migration, with proTAME alone also exhibiting notable inhibitory effects. In ARPE-19 cells, gemcitabine and cisplatin upregulated MMP2 and MMP9 expression, suggesting a potential stress response, whereas proTAME mitigated this effect. These differential effects show the importance of tumor-specific responses in RT4 cells, where proTAME shows promise in enhancing the efficacy of chemotherapy by modulating MMP-related pathways involved in tumor migration and invasion. In conclusion, this study highlights the potential of proTAME as a repurposed agent in bladder cancer treatment due to its association with reduced cell migration and MMP downregulation. While these in vitro and in silico findings suggest a promising role for proTAME in combination therapies, further validation in advanced preclinical models is necessary to assess its therapeutic applicability and safety.
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Affiliation(s)
| | - Hatice Sevim Nalkiran
- Department of Medical Biology, Faculty of Medicine, Recep Tayyip Erdogan University, 53020 Rize, Türkiye;
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12
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Sheikh KA, Amjad M, Irfan MT, Anjum S, Majeed T, Riaz MU, Jassim AY, Sharif EAM, Ibrahim WN. Exploring TGF-β Signaling in Cancer Progression: Prospects and Therapeutic Strategies. Onco Targets Ther 2025; 18:233-262. [PMID: 39989503 PMCID: PMC11846535 DOI: 10.2147/ott.s493643] [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: 08/29/2024] [Accepted: 11/19/2024] [Indexed: 02/25/2025] Open
Abstract
Cancer persists as a ubiquitous global challenge despite the remarkable advances. It is caused by uncontrolled cell growth and metastasis. The Transforming Growth Factor-beta (TGF-β) signaling pathway is considered a primary regulator of various normal physiological processes in the human body. Recently, factors determining the nature of TGF-β response have received attention, specifically its signaling pathway which can be an attractive therapeutic target for various cancer treatments. The TGF-β receptor is activated by its ligands and undergoes transduction of signals via canonical (SMAD dependent) or non-canonical (SMAD independent) signaling pathways regulating several cellular functions. Furthermore, the cross talk of the TGF-β signaling pathway cross with other signaling pathways has shown the controlled regulation of cellular functions. This review highlights the cross talk between various major signaling pathways and TGF-β. These signaling pathways include Wnt, NF-κB, PI3K/Akt, and Hedgehog (Hh). TGF-β signaling pathway has a dual role at different stages. It can suppress tumor formation at early stages and promote progression at advanced stages. This complex behaviour of TGF-β has made it a promising target for therapeutic interventions. Moreover, many strategies have been designed to control TGF-β signaling pathways at different levels, inhibiting tumor-promoting while enhancing tumor-suppressive effects, each with unique molecular mechanisms and clinical implications. This review also discusses various therapeutic inhibitors including ligand traps, small molecule inhibitors (SMIs), monoclonal antibodies (mAbs), and antisense oligonucleotides which target specific components of TGF-β signaling pathway to inhibit TGF-β signaling and are studied in both preclinical and clinical trials for different types of cancer. The review also highlights the prospect of TGF-β signaling in normal physiology and in the case of dysregulation, TGF-β inhibitors, and different therapeutic effects in cancer therapy along with the perspective of combinational therapies to treat cancer.
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Affiliation(s)
- Khansa Ali Sheikh
- Department of Biotechnology, Kinnaird College for Women, Lahore, Pakistan
| | - Momna Amjad
- Department of Biotechnology, Kinnaird College for Women, Lahore, Pakistan
| | | | - Sumaira Anjum
- Department of Biotechnology, Kinnaird College for Women, Lahore, Pakistan
| | - Tanveer Majeed
- Department of Biotechnology, Kinnaird College for Women, Lahore, Pakistan
| | - Muhammad Usman Riaz
- School of Computer Science, University College Dublin, Belfield, Dublin 4, Ireland
| | | | - Elham Abdullatif M Sharif
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
| | - Wisam Nabeel Ibrahim
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
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13
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Kim HM, Lee D, Song JH, Kim H, Lee S, Shin S, Park SD, Kim YW, Choi YH, Kim WJ, Moon SK. The edible ethanol extract of Rosa hybrida suppresses colon cancer progression by inhibiting the proliferation-cell signaling-metastasis axis. Nutr Res Pract 2025; 19:14-29. [PMID: 39959743 PMCID: PMC11821778 DOI: 10.4162/nrp.2025.19.1.14] [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: 07/03/2024] [Revised: 08/31/2024] [Accepted: 09/12/2024] [Indexed: 02/18/2025] Open
Abstract
BACKGROUND/OBJECTIVES Rosa hybrida has been demonstrated to exert biological effects on several cell types. This study investigated the efficacy of the edible ethanol extract of R. hybrida (EERH) against human colorectal carcinoma cell line (HCT116) cells. MATERIALS/METHODS HCT116 cells were cultured with different concentrations of EERH (0, 400, 600, 800, and 1,000 µg/mL) in Dulbecco's modified Eagle medium. Cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide and viable cell counting assays. Cell cycle pattern was observed by flow cytometry analysis. The wound-healing migration assay, invasion assay, and zymography were used to determine the migratory and invasive level of HCT116 cells treated with EERH. The protein expression and binding ability level of HCT116 cells following EERH treatment were analyzed via immunoblotting and the electrophoretic mobility shift assay. RESULTS EERH suppressed HCT116 cell proliferation, thus arresting the G1-phase cell cycle. It also reduced cyclin-dependent kinases and cyclins, which are associated with p27KIP1 expression. Additionally, EERH differentially regulated the phosphorylation of extracellular signal-regulated kinase 1/2, c-Jun NH2-terminal kinase, p38, and protein kinase B. Moreover, EERH treatment inhibited the enzymatic activity of matrix metalloproteinase-9 (MMP-9) and MMP-2, resulting in HCT116 cell migration and invasion. The EERH-induced inhibition of MMP-9 and MMP-2 was attributed to the reduced transcriptional binding of activator protein-1, specificity protein-1, and nuclear factor-κB motifs in HCT116 cells. Kaempferol was identified as the main compound contributing to EERH's antitumor activity. CONCLUSION EERH inhibits HCT116 cell proliferation and metastatic potential. Therefore, it is potentially useful as a preventive and curative nutraceutical agent against colorectal cancer.
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Affiliation(s)
- Hong-Man Kim
- Department of Food and Nutrition, Chung-Ang University, Anseong 17546, Korea
| | - Daeun Lee
- Department of Food and Nutrition, Chung-Ang University, Anseong 17546, Korea
| | - Jun-Hui Song
- Department of Food and Nutrition, Chung-Ang University, Anseong 17546, Korea
| | - Hoon Kim
- Department of Food and Nutrition, Chung-Ang University, Anseong 17546, Korea
| | - Sanghyun Lee
- Department of Plant Science and Technology, Chung-Ang University, Anseong 17546, Korea
| | - Sangah Shin
- Department of Food and Nutrition, Chung-Ang University, Anseong 17546, Korea
| | - Sun-Dong Park
- Department of Herbal Prescription, School of Korean Medicine, Dongguk University, Goyang 10326, Korea
| | - Young Woo Kim
- Department of Herbal Prescription, School of Korean Medicine, Dongguk University, Goyang 10326, Korea
| | - Yung Hyun Choi
- Department of Biochemistry, College of Oriental Medicine, Dongeui University, Busan 47340, Korea
| | | | - Sung-Kwon Moon
- Department of Food and Nutrition, Chung-Ang University, Anseong 17546, Korea
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14
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Mansoori S, Hashemy SI, Eskandari M, Khorrami A, Homayouni M, Ghahremanloo A. Investigating the anticancer properties of urolithin B in triple negative breast cancer: In vivo and in vitro insights. Toxicol Appl Pharmacol 2025; 495:117224. [PMID: 39755131 DOI: 10.1016/j.taap.2024.117224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 12/27/2024] [Accepted: 12/30/2024] [Indexed: 01/06/2025]
Abstract
Breast cancer (BC) is a leading cause of cancer-related mortality among women worldwide, with incidence rates rising globally. Urolithin B (UB), a bioactive metabolite of ellagic acid, has demonstrated promising anticancer effects in various cancer models. This study aimed to evaluate the effects of UB on the growth, angiogenesis, and metastasis of BC cells using both in vivo and in vitro approaches. Cytotoxic effects of UB were assessed on MDA-MB-231 cells and normal HFF cells using the MTT assay. Scratch assays and gelatin zymography demonstrated UB's suppression of cell migration and reduced enzymatic activities of MMP-2 and MMP-9. In a xenograft mouse model, UB significantly reduced tumor growth, enhanced necrosis, and decreased vascularity in tumor tissues. It downregulated mRNA expression levels of VEGF, VEGFR, MMP-2, and MMP-9, indicating potent anti-angiogenic and anti-metastatic properties. Additionally, UB exhibited antioxidant effects by increasing total thiol content and the activities of superoxide dismutase (SOD) and catalase (CAT) while reducing malondialdehyde (MDA) levels in tumor tissues. In conclusion, our results highlight the anticancer potential of UB, through its ability to suppress the proliferation, angiogenesis, and metastatic properties of BC both in vitro and in vivo. Coupled with its antioxidant properties, UB emerges as a promising and safe candidate for further pre-clinical and clinical research and therapeutic applications in BC management.
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Affiliation(s)
- Saeide Mansoori
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Isaac Hashemy
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Moein Eskandari
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Azar Khorrami
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Masoud Homayouni
- Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran.
| | - Atefeh Ghahremanloo
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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15
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Tong Z, Shen Y, Yuan Q, Yu H. GALNT6, transcriptionally inhibited by KLF9, promotes osteosarcoma progression by increasing EFEMP1 expression via O-glycosylation modification. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2025; 1872:119879. [PMID: 39581475 DOI: 10.1016/j.bbamcr.2024.119879] [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: 04/26/2024] [Revised: 11/04/2024] [Accepted: 11/15/2024] [Indexed: 11/26/2024]
Abstract
Osteosarcoma (OS) is one of the deadliest malignancies in adolescents and its treatment status and prognosis remain unsatisfactory. N-acetylgalactosamine transferase 6 (GALNT6), one of the key enzymes regulating O-glycosylation, functions vary in different types of cancer. Currently, the function of GALNT6 in OS is unclear. Our results showed that GALNT6 was highly expressed in OS tissues, and the patients with higher GALNT6 expression exhibited a lower overall survival rate than patients with lower GALNT6 expression. We constructed the GALNT6-knockdown and GALNT6-overexpression vectors based on Tet-on system and packaged lentiviral particles to modulate GALNT6 expression. GALNT6 silencing impaired OC cell growth and metastasis both in vivo and vitro. Kruppel-like factor 9 (KLF9), a transcription factor known to suppress OS progression, was found to block GALNT6 transcription by binding to its promoter. Meanwhile, GALNT6 overexpression restored the effects caused by KLF9 upregulation. GALNT6 was known to affect protein stability by O-glycosylation regulation, thus the label-free proteomics combined with co-immunoprecipitation/mass-spectrum (MS) analysis were conducted to identify the potential mechanism of GALNT6 in promoting OS progression. EGF-containing fibulin extracellular matrix protein 1 (EFEMP1), contained several O-glycosylation sites and was upregulated in GALNT6 overexpressing cells (Log2FC = 1.3195, p = 0.0160), attracted our attention. We demonstrated that GALNT6 interacted with EFEMP1 at protein level. The O-glycosylation of EFEMP1 was increased by GALNT6 overexpression, which slowed the degradation rate of EFEMP1. EFEMP1 knockdown reversed the effects of GALNT6 overexpression. Collectively, our observations demonstrate that KLF9/GALNT6/EFEMP1 may be a promising direction for OS treatment.
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Affiliation(s)
- Ziyuan Tong
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Yuan Shen
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Quan Yuan
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang 110004, China.
| | - Honghao Yu
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang 110004, China.
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16
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Naponelli V, Piscazzi A, Mangieri D. Cellular and Molecular Mechanisms Modulated by Genistein in Cancer. Int J Mol Sci 2025; 26:1114. [PMID: 39940882 PMCID: PMC11818640 DOI: 10.3390/ijms26031114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/21/2025] [Accepted: 01/23/2025] [Indexed: 02/16/2025] Open
Abstract
Genistein (4',5,7-trihydroxyisoflavone) is a phytoestrogen belonging to a subclass of natural flavonoids that exhibits a wide range of pharmacological functions, including antioxidant and anti-inflammatory properties. These characteristics make genistein a valuable phytochemical compound for the prevention and/or treatment of cancer. Genistein effectively inhibits tumor growth and dissemination by modulating key cellular mechanisms. This includes the suppression of angiogenesis, the inhibition of epithelial-mesenchymal transition, and the regulation of cancer stem cell proliferation. These effects are mediated through pivotal signaling pathways such as JAK/STAT, PI3K/Akt/mTOR, MAPK/ERK, NF-κB, and Wnt/β-catenin. Moreover, genistein interferes with the function of specific cyclin/CDK complexes and modulates the activation of Bcl-2/Bax and caspases, playing a critical role in halting tumor cell division and promoting apoptosis. The aim of this review is to discuss in detail the key cellular and molecular mechanisms underlying the pleiotropic anticancer effects of this flavonoid.
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Affiliation(s)
- Valeria Naponelli
- Department of Medicine and Surgery, University of Parma, Plesso Biotecnologico Integrato, Via Volturno 39, 43126 Parma, Italy
| | - Annamaria Piscazzi
- Department of Clinical and Experimental Medicine, University of Foggia, Via Pinto 1, 71122 Foggia, Italy
| | - Domenica Mangieri
- Department of Clinical and Experimental Medicine, University of Foggia, Via Pinto 1, 71122 Foggia, Italy
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17
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Vo HVT, Kim N, Lee HJ. Vitamin Bs as Potent Anticancer Agents through MMP-2/9 Regulation. FRONT BIOSCI-LANDMRK 2025; 30:24072. [PMID: 39862072 DOI: 10.31083/fbl24072] [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: 04/26/2024] [Revised: 08/17/2024] [Accepted: 08/28/2024] [Indexed: 01/27/2025]
Abstract
In recent years, the role of coenzymes, particularly those from the vitamin B group in modulating the activity of metalloenzymes has garnered significant attention in cancer treatment strategies. Metalloenzymes play pivotal roles in various cellular processes, including DNA repair, cell signaling, and metabolism, making them promising targets for cancer therapy. This review explores the complex interplay between coenzymes, specifically vitamin Bs, and metalloenzymes in cancer pathogenesis and treatment. Vitamins are an indispensable part of daily life, essential for optimal health and well-being. Beyond their recognized roles as essential nutrients, vitamins have increasingly garnered attention for their multifaceted functions within the machinery of cellular processes. In particular, vitamin Bs have emerged as a pivotal regulator within this intricate network, exerting profound effects on the functionality of metalloenzymes. Their ability to modulate metalloenzymes involved in crucial cellular pathways implicated in cancer progression presents a compelling avenue for therapeutic intervention. Key findings indicate that vitamin Bs can influence the activity and expression of metalloenzymes, thereby affecting processes such as DNA repair and cell signaling, which are critical in cancer development and progression. Understanding the mechanisms by which these coenzymes regulate metalloenzymes holds great promise for developing novel anticancer strategies. This review summarizes current knowledge on the interactions between vitamin Bs and metalloenzymes, highlighting their potential as anticancer agents and paving the way for innovative, cell-targeted cancer treatments.
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Affiliation(s)
- Ha Vy Thi Vo
- Department of Chemistry Education, Kongju National University, 32588 Gongju, Chungcheongnam-do, Republic of Korea
| | - Namdoo Kim
- Department of Chemistry, Kongju National University, 32588 Gongju, Chungcheongnam-do, Republic of Korea
| | - Hyuck Jin Lee
- Department of Chemistry Education, Kongju National University, 32588 Gongju, Chungcheongnam-do, Republic of Korea
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18
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Gautam D, Clarke EM, Roweth HG, Smith MR, Battinelli EM. Platelets and circulating (tumor) cells: partners in promoting metastatic cancer. Curr Opin Hematol 2025; 32:52-60. [PMID: 39508182 DOI: 10.1097/moh.0000000000000852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2024]
Abstract
PURPOSE OF REVIEW Despite being discovered decades ago, metastasis remains a formidable challenge in cancer treatment. During the intermediate phase of metastasis, tumor cells detach from primary tumor or metastatic sites and travel through the bloodstream and lymphatic system to distant tissues. These tumor cells in the circulation are known as circulating tumor cells (CTCs), and a higher number of CTCs has been linked to poor prognoses in various cancers. The blood is an inhospitable environment for any foreign cells, including CTCs, as they face numerous challenges, such as the shear stress within blood vessels and their interactions with blood and immune cells. However, the exact mechanisms by which CTCs survive the hostile conditions of the bloodstream remain enigmatic. Platelets have been studied for their interactions with tumor cells, promoting their survival, growth, and metastasis. This review explores the latest clinical methods for enumerating CTCs, recent findings on platelet-CTC crosstalk, and current research on antiplatelet therapy as a potential strategy to inhibit metastasis, offering new therapeutic insights. RECENT FINDINGS Laboratory and clinical data have provided insights into the role of platelets in promoting CTC survival, while clinical advancements in CTC enumeration offer improved prognostic tools. SUMMARY CTCs play a critical role in metastasis, and their interactions with platelets aid their survival in the hostile environment of the bloodstream. Understanding this crosstalk offers insights into potential therapeutic strategies, including antiplatelet therapy, to inhibit metastasis and improve cancer treatment outcomes.
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Affiliation(s)
- Deepa Gautam
- Division of Hematology, Department of Medicine; Brigham and Women's Hospital
- Harvard Medical School, Boston, Massachusetts, USA
| | - Emily M Clarke
- Division of Hematology, Department of Medicine; Brigham and Women's Hospital
| | - Harvey G Roweth
- Division of Hematology, Department of Medicine; Brigham and Women's Hospital
- Harvard Medical School, Boston, Massachusetts, USA
| | - Margaret R Smith
- Division of Hematology, Department of Medicine; Brigham and Women's Hospital
- Harvard Medical School, Boston, Massachusetts, USA
| | - Elisabeth M Battinelli
- Division of Hematology, Department of Medicine; Brigham and Women's Hospital
- Harvard Medical School, Boston, Massachusetts, USA
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19
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Varshini MS, Krishnamurthy PT, Reddy RA, Wadhwani A, Chandrashekar VM. Insights into the Emerging Therapeutic Targets of Triple-negative Breast Cancer. Curr Cancer Drug Targets 2025; 25:3-25. [PMID: 38385495 DOI: 10.2174/0115680096280750240123054936] [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: 09/23/2023] [Revised: 12/24/2023] [Accepted: 01/09/2024] [Indexed: 02/23/2024]
Abstract
Triple-negative Breast Cancer (TNBC), the most aggressive breast cancer subtype, is characterized by the non-appearance of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Clinically, TNBC is marked by its low survival rate, poor therapeutic outcomes, high aggressiveness, and lack of targeted therapies. Over the past few decades, many clinical trials have been ongoing for targeted therapies in TNBC. Although some classes, such as Poly (ADP Ribose) Polymerase (PARP) inhibitors and immunotherapies, have shown positive therapeutic outcomes, however, clinical effects are not much satisfiable. Moreover, the development of drug resistance is the major pattern observed in many targeted monotherapies. The heterogeneity of TNBC might be the cause for limited clinical benefits. Hence,, there is a need for the potential identification of new therapeutic targets to address the above limitations. In this context, some novel targets that can address the above-mentioned concerns are emerging in the era of TNBC therapy, which include Hypoxia Inducible Factor (HIF-1α), Matrix Metalloproteinase 9 (MMP-9), Tumour Necrosis Factor-α (TNF-α), β-Adrenergic Receptor (β-AR), Voltage Gated Sodium Channels (VGSCs), and Cell Cycle Regulators. Currently, we summarize the ongoing clinical trials and discuss the novel therapeutic targets in the management of TNBC.
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Affiliation(s)
- Magham Sai Varshini
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, 643001, TN, India
| | | | - Ramakamma Aishwarya Reddy
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, 643001, TN, India
| | - Ashish Wadhwani
- Department of Pharmaceutical Biotechnology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, 643001, TN, India
- Faculty of Health Sciences, School of Pharmacy, JSS Academy of Higher Education and Research, Mauritius, Vacoas, 73304, Mauritius
| | - V M Chandrashekar
- Department of Pharmacology, HSK College of Pharmacy, Bagalkot, 587101, Karnataka, India
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20
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Lin BJ, Fujie H, Yamazaki M, Sakamoto N. The dual effect of fiber density and matrix stiffness on A549 tumor multicellular migration. Biochem Biophys Res Commun 2024; 741:151018. [PMID: 39579534 DOI: 10.1016/j.bbrc.2024.151018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 11/17/2024] [Indexed: 11/25/2024]
Abstract
The tumor microenvironment features dynamic biomechanical interactions between extracellular matrix physics and tumor progression. Tumor growth compresses the supportive matrix, and the stiffness-gradient guides tumor invasion. From the mechanical perspective, the complexity of the matrix topology involving durotaxis-driven metastasis remains lacking in a comprehensive description. In this study, A549 adenocarcinoma spheroids were exposed to a stiffness-and fiber-adjusted collagen matrix to examine the influence of collective motility. Centrifugated compression on the collagen constructs was adopted to mimic the matrix deformation in response to solid tumor development. Centrifugated compression physically stiffened and condensed collagen constructs simultaneously. Cultured with A549 spheroids for 7 days, compressed collagen constructs disadvantaged spheroid expansion without the effect of tumor proliferation potency but promoted matrix metalloproteinase activity corresponding to softened rigidity. Results suggested that the fibrous structure may counterbalance the matrix stiffness-induced motility.
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Affiliation(s)
- Bo-Jiang Lin
- Department of Mechanical Systems Engineering, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji, Tokyo, 1920397, Japan.
| | - Hiromichi Fujie
- Department of Mechanical Systems Engineering, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji, Tokyo, 1920397, Japan; Research Center for Medicine-Engineering Collaboration, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji, Tokyo, 1920397, Japan.
| | - Masashi Yamazaki
- Department of Mechanical Systems Engineering, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji, Tokyo, 1920397, Japan; Research Center for Medicine-Engineering Collaboration, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji, Tokyo, 1920397, Japan.
| | - Naoya Sakamoto
- Department of Mechanical Systems Engineering, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji, Tokyo, 1920397, Japan; Research Center for Medicine-Engineering Collaboration, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji, Tokyo, 1920397, Japan.
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21
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Shatat AAS, Mahgoup EM, Rashed MH, Saleh IG, Akool ES. Molecular mechanisms of extracellular-ATP-mediated colorectal cancer progression: Implication of purinergic receptors-mediated nucleocytoplasmic shuttling of HuR. Purinergic Signal 2024; 20:669-680. [PMID: 38801618 PMCID: PMC11554961 DOI: 10.1007/s11302-024-10021-2] [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: 11/28/2023] [Accepted: 05/09/2024] [Indexed: 05/29/2024] Open
Abstract
One of the leading causes of cancer-related deaths worldwide is colorectal cancer (CRC). Extracellular ATP (e-ATP) and purinergic receptors (P2R) play a central role in CRC proliferation and progression. Human antigen R (HuR) is becoming more and more understood to be essential for the expression of genes linked to cancer. The current study demonstrates that ATP can mediate CRC (Caco-2 cells) progression via induction of HuR nucleocytoplasmic shuttling and subsequent expression of cancer-related genes, a consequence mostly mediated via the P2R receptor. It was also noted that suppression of HuR activity by using dihydrotanshinone I (DHTS) prevents cancer-related gene expression and subsequent CRC (Caco-2 cells) progression induced by ATP. The expression of cyclin A2/cyclin-dependent kinase 2 (CDK2), Bcl-2, ProT-α, hypoxia-inducible factor1-α (HIF1-α), vascular endothelial growth factor A (VEGF-A), transforming growth factor-β (TGF-β) and matrix metallopeptidase 9 (MMP-9) induced by ATP were highly reduced in the presence of either PPADS (non-selective P2R antagonist) or DHTS. In addition, e-ATP-induced Caco-2 cell proliferation as well as cell survival were highly reduced in the presence of either PPADS or DHTS or selective CDK-2 inhibitor (Roscovitine) or selective Bcl-2 inhibitor (ABT-263). Furthermore, it was found that MMP-9 is critical for Caco-2 cells migration induced by e-ATP as demonstrated by a clear reduction in cells migration in the presence of a selective MMP-9 inhibitor (Marimastat). Collectively, these data demonstrate that ATP through P2R activation can induce HuR nucleocytoplasmic shuttling that could be translated into an increase in cancer-related genes expression and subsequent, cell proliferation and progression.
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Affiliation(s)
- Abdel-Aziz S Shatat
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Elsayed M Mahgoup
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Mohammed H Rashed
- Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Ibrahim G Saleh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Sinai University, Kantra, Ismailia, Egypt
| | - El-Sayed Akool
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
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Wang KJ, Ye SZ, Jia XL, Wang KY, Meng XY, Fei X, Ye SJ, Ma Q. RON receptor tyrosine kinase as a critical determinant in promoting tumorigenic behaviors of bladder cancer cells through regulating MMP12 and HIF-2α pathways. Cell Death Dis 2024; 15:844. [PMID: 39557851 PMCID: PMC11574271 DOI: 10.1038/s41419-024-07245-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 11/11/2024] [Accepted: 11/12/2024] [Indexed: 11/20/2024]
Abstract
The RON receptor tyrosine kinase is critical in the pathogenesis of various cancer types, however, its role in bladder cancer invasive growth is still largely unknown. Here, we found that over 90% of bladder cancer samples exhibit elevated levels of RON expression, with significantly higher expression levels observed in invasive bladder cancer compared to non-invasive bladder cancer. In vitro, RON activation resulted in increased bladder cancer cell migration and invasiveness. Results from mRNA sequencing and transcriptome analysis further demonstrated that MMP12, a downstream molecule of RON, is functionally involved in regulating RON-mediated bladder cancer cell migration and invasiveness. The underlying mechanism appeared to be the RON-mediated inhibition of HIF-2α ubiquitination, which is channeled through the activation of the JNK signaling pathway. Consequently, the activated JNK pathway increased MMP12 expression, ultimately driving bladder cancer cell migration and invasion. As evident in bioinformatics and dual-luciferase reporter assays, the RON mRNA at its 3'-untranslated regions specifically interacted with hsa-miR-659-3p. The binding of hsa-miR-659-3p downregulated the RON gene expression, attenuating the receptor-mediated tumorigenic activities of bladder cancer cells in vitro and in vivo. In conclusion, aberrant RON expression in bladder cancer cells and MMP12 and HIF-2α activities form a functional axis that causes increased bladder cancer cell migration and invasion. The fact that hsa-miR-659-3p downregulates RON expression indicates its critical role in attenuating RON-mediated tumorigenic effect on bladder cancer cells. These findings highlight the importance of RON targeting as a therapeutic means for potential bladder cancer therapy.
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Affiliation(s)
- Ke-Jie Wang
- Translational Research Laboratory for Urological Diseases, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China
- Comprehensive Genitourinary Cancer Center, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Sha-Zhou Ye
- Translational Research Laboratory for Urological Diseases, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China
- Comprehensive Genitourinary Cancer Center, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Xiao-Long Jia
- Department of Urology, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Kai-Yun Wang
- Department of Urology, the Affiliated People's Hospital of Ningbo University, Ningbo, Zhejiang, P.R. China
| | - Xiang-Yu Meng
- Translational Research Laboratory for Urological Diseases, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China
- Comprehensive Genitourinary Cancer Center, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Xin Fei
- Health Science Center, Ningbo University, Ningbo, Zhejiang, P.R. China
| | - Shi-Jie Ye
- Health Science Center, Ningbo University, Ningbo, Zhejiang, P.R. China
| | - Qi Ma
- Comprehensive Genitourinary Cancer Center, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China.
- Yi-huan Genitourinary Cancer Group, Ningbo, Zhejiang, P.R. China.
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Sun J, Han S, Yang R, Guo L, Li J, Li C, Xu L, Liu H, Dong B. Combining hybrid cell membrane modified magnetic nanoparticles and inverted microfluidic chip for in situ CTCs capture and inactivation. Biosens Bioelectron 2024; 263:116575. [PMID: 39067413 DOI: 10.1016/j.bios.2024.116575] [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: 05/10/2024] [Revised: 06/25/2024] [Accepted: 07/13/2024] [Indexed: 07/30/2024]
Abstract
Circulating tumor cells (CTCs) serve as crucial indicators for tumor occurrence, progression, and prognosis monitoring. However, achieving high sensitivity and high purity capture of CTCs remains challenging. Additionally, in situ capture and synchronous clearance hold promise as methods to impede tumor metastasis, but further exploration is needed. In this study, biomimetic cell membrane-coated magnetic nanoparticles (NPs) were designed to address the issue of nonspecific adsorption of capture probes by the immune system during blood circulation. Membranes from human breast cancer cells (tumor cell membranes, TMs) and leukocytes (white blood cell membranes, WMs) were extracted and fused to form a hybrid membrane (HM), which was further modified onto the surface of porous magnetic NPs loaded with indocyanine green (ICG). The incorporation of TM enhanced the material's target specificity, thus increasing capture efficiency, while WM coating reduced interference from homologous white blood cells (WBCs), further enhancing capture purity. Additionally, in conjunction with our novel inverted microfluidic chip, this work introduces the first use of polymer photonic crystals as the capture interface for CTCs. Besides providing an advantageous surface structure for CTC attachment, the 808 nm photonic bandgap effectively amplifies the 808 nm excitation light at the capture surface position. Therefore, upon capturing CTCs, the ICG molecules in the probes facilitate enhanced photothermal (PTT) and photodynamic (PDT) synergistic effects, directly inactivating the captured CTCs. This method achieves capture efficiency and purity exceeding 95% and permits in situ inactivation post-capture, providing an important approach for future research on impeding tumor metastasis in vivo.
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Affiliation(s)
- Jiao Sun
- State Key Laboratory on Integrated Optoelectronics, College of Electronic Science and Engineering, Jilin University, 2699 Qianjin Street, Changchun, 130012, China; Department of Cell Biology, College of Basic Medical Science, Jilin University, Changchun, 130021, China
| | - Songrui Han
- State Key Laboratory on Integrated Optoelectronics, College of Electronic Science and Engineering, Jilin University, 2699 Qianjin Street, Changchun, 130012, China
| | - Rui Yang
- State Key Laboratory on Integrated Optoelectronics, College of Electronic Science and Engineering, Jilin University, 2699 Qianjin Street, Changchun, 130012, China
| | - Lihua Guo
- State Key Laboratory on Integrated Optoelectronics, College of Electronic Science and Engineering, Jilin University, 2699 Qianjin Street, Changchun, 130012, China
| | - Jiawei Li
- Department of Plastic and Reconstructive Surgery, The First Hospital of Jilin University, Chang Chun, 130021, China
| | - Chunxia Li
- Institute of Molecular Sciences and Engineering, Shandong University, Qingdao, China
| | - Lin Xu
- State Key Laboratory on Integrated Optoelectronics, College of Electronic Science and Engineering, Jilin University, 2699 Qianjin Street, Changchun, 130012, China
| | - Haipeng Liu
- Department of Plastic and Reconstructive Surgery, The First Hospital of Jilin University, Chang Chun, 130021, China.
| | - Biao Dong
- State Key Laboratory on Integrated Optoelectronics, College of Electronic Science and Engineering, Jilin University, 2699 Qianjin Street, Changchun, 130012, China.
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24
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Laghezza Masci V, Ovidi E, Tomassi W, De Vita D, Garzoli S. Exploring the Bioactive Potential of Taraxacum officinale F.H. Wigg Aerial Parts on MDA Breast Cancer Cells: Insights into Phytochemical Composition, Antioxidant Efficacy, and Gelatinase Inhibition within 3D Cellular Models. PLANTS (BASEL, SWITZERLAND) 2024; 13:2829. [PMID: 39409699 PMCID: PMC11482471 DOI: 10.3390/plants13192829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 10/08/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024]
Abstract
In this work, aerial parts of Taraxacum officinale F.H. Wigg. produced in Umbria, Italy, were chemically investigated by solid-phase microextraction/gas chromatography-mass spectrometry (SPME/GC-MS) to describe their volatile profile. The results obtained showed the preponderant presence of monoterpenes, with limonene and 1,8-cineole as the main components. Further analyses by GC/MS after derivatization reaction were performed to characterize the non-volatile fraction highlighting the presence of fatty acids and di- and triterpenic compounds. T. officinale methanol and dichloromethane extracts, first analyzed by HRGC/MS, were investigated to evaluate the antioxidant activity, cytotoxicity, and antiproliferative properties of MDA cells on the breast cancer cell line and MCF 10A normal epithelial cells as well as the antioxidant activity by colorimetric assays. The impact on matrix metalloproteinases MMP-9 and MMP-2 was also explored in 3D cell systems to investigate the extracts' efficacy in reducing cell invasiveness. The extracts tested showed no cytotoxic activity with EC50 > 250 µg/mL on both cell lines. The DPPH assay revealed higher antioxidant activity in the MeOH extract compared with the DCM extract, while the FRAP assay showed a contrasting result, with the DCM extract exhibiting slightly greater antioxidant capacity. After treatment for 24 h with a non-cytotoxic concentration of 500 µg/mL of the tested extracts, gelatin zymography and Western blot analyses demonstrated that both MeOH and DCM extracts influenced the expression of MMP-9 and MMP-2 in MDA cells within the 3D cell model, leading to a significant decrease in the levels of these gelatinases, which are crucial markers of tumor invasiveness.
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Affiliation(s)
- Valentina Laghezza Masci
- Department for Innovation in Biological, Agro-Food and Forest Systems (DIBAF), University of Tuscia, Largo dell’Università, 01100 Viterbo, Italy; (V.L.M.); (E.O.); (W.T.)
| | - Elisa Ovidi
- Department for Innovation in Biological, Agro-Food and Forest Systems (DIBAF), University of Tuscia, Largo dell’Università, 01100 Viterbo, Italy; (V.L.M.); (E.O.); (W.T.)
| | - William Tomassi
- Department for Innovation in Biological, Agro-Food and Forest Systems (DIBAF), University of Tuscia, Largo dell’Università, 01100 Viterbo, Italy; (V.L.M.); (E.O.); (W.T.)
| | - Daniela De Vita
- Dipartimento di Biologia Ambientale, Università di Roma “La Sapienza”, Piazzale Aldo Moro 5, 00185 Rome, Italy;
| | - Stefania Garzoli
- Department of Chemistry and Technologies of Drug, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy
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Guo GX, Qiu YH, Liu Y, Yu LL, Zhang X, Tsim KWK, Qin QW, Hu WH. Fucoxanthin Attenuates Angiogenesis by Blocking the VEGFR2-Mediated Signaling Pathway through Binding the Vascular Endothelial Growth Factor. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:21610-21623. [PMID: 39292861 DOI: 10.1021/acs.jafc.4c05464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/20/2024]
Abstract
Fucoxanthin, a dietary carotenoid, is predominantly found in edible brown algae and is commonly consumed worldwide. Fucoxanthin has been shown to possess beneficial health activities such as antidiabetic, anti-inflammatory, antimutagenic, and antiobesity; however, the effects of fucoxanthin on VEGF-mediated angiogenesis and its possible binding with VEGF are unknown. Here, different lines of evidence supported the suppressive roles of fucoxanthin in VEGF-mediated angiogenesis. In human umbilical vein endothelial cells, fucoxanthin remarkedly suppressed VEGF-mediated cell proliferative, migration, and invasive abilities, as well as tube formation, without cytotoxicity. In addition, fucoxanthin inhibited the subintestinal vessel formation of zebrafish in vivo. In signaling cascades, fucoxanthin was proposed to interact with VEGF, thus attenuating VEGF's functions in activating the VEGF receptor and its related downstream signaling, i.e., phosphorylations of MEK and Erk. Fucoxanthin also significantly blocked VEGF-triggered ROS formation. Furthermore, the outcomes of applying fucoxanthin in cancer cells were identified, which included (i) inhibiting VEGF-mediated cell proliferation and migration and (ii) inhibiting NF-κB translocation via limiting MMP2 expression. These lines of investigations supported the antiangiogenic roles of fucoxanthin, as well as reviewing its signaling mechanisms, in blocking the VEGF-triggered responses. The results would benefit the potential development of fucoxanthin for the prevention and treatment of angiogenesis-related diseases.
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Affiliation(s)
- Guo-Xia Guo
- College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China
| | - Yu-Huan Qiu
- College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China
- Nansha-South China Agricultural University Fishery Research Institute, Guangzhou 511464, China
| | - Yang Liu
- College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China
| | - Le-Le Yu
- College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China
| | - Xiaoyong Zhang
- College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China
| | - Karl Wah-Keung Tsim
- Nansha-South China Agricultural University Fishery Research Institute, Guangzhou 511464, China
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China
- Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Hong Kong 999077, China
| | - Qi-Wei Qin
- College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China
- Nansha-South China Agricultural University Fishery Research Institute, Guangzhou 511464, China
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China
| | - Wei-Hui Hu
- College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China
- Nansha-South China Agricultural University Fishery Research Institute, Guangzhou 511464, China
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China
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26
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Hou W, Shen L, Zhu Y, Wang X, Du T, Yang F, Zhu Y. Fullerene Derivatives for Tumor Treatment: Mechanisms and Application. Int J Nanomedicine 2024; 19:9771-9797. [PMID: 39345909 PMCID: PMC11430870 DOI: 10.2147/ijn.s476601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 08/28/2024] [Indexed: 10/01/2024] Open
Abstract
Fullerenes hold tremendous potential as alternatives to conventional chemotherapy or radiotherapy for tumor treatment due to their abilities to photodynamically kill tumor cells, destroy the tumor vasculature, inhibit tumor metastasis and activate anti-tumor immune responses, while protecting normal tissue through antioxidative effects. The symmetrical hollow molecular structures of fullerenes with abundant C=C bonds allow versatile chemical modification with diverse functional groups, metal clusters and biomacromolecules to synthesize a wide range of fullerene derivatives with increased water solubility, improved biocompatibility, enhanced photodynamic properties and stronger targeting abilities. This review introduces the anti-tumor mechanisms of fullerenes and summarizes the most recent works on the functionalization of fullerenes and the application of fullerene derivatives in tumor treatment. This review aims to serve as a valuable reference for further development and clinical application of anti-tumor fullerene derivatives.
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Affiliation(s)
- Wenjia Hou
- Health Science Center, Ningbo University, Ningbo, 315211, People's Republic of China
- State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, 200438, People's Republic of China
| | - Lan Shen
- Health Science Center, Ningbo University, Ningbo, 315211, People's Republic of China
| | - Yimin Zhu
- Health Science Center, Ningbo University, Ningbo, 315211, People's Republic of China
| | - Xuanjia Wang
- Health Science Center, Ningbo University, Ningbo, 315211, People's Republic of China
| | - Tianyu Du
- Health Science Center, Ningbo University, Ningbo, 315211, People's Republic of China
| | - Fang Yang
- Health Science Center, Ningbo University, Ningbo, 315211, People's Republic of China
| | - Yabin Zhu
- Health Science Center, Ningbo University, Ningbo, 315211, People's Republic of China
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27
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Kaushik N, Jaiswal A, Bhartiya P, Choi EH, Kaushik NK. TFCP2 as a therapeutic nexus: unveiling molecular signatures in cancer. Cancer Metastasis Rev 2024; 43:959-975. [PMID: 38451384 DOI: 10.1007/s10555-024-10175-w] [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: 12/05/2023] [Accepted: 02/18/2024] [Indexed: 03/08/2024]
Abstract
Tumor suppressor genes and proto-oncogenes comprise most of the complex genomic landscape associated with cancer, with a minimal number of genes exhibiting dual-context-dependent functions. The transcription factor cellular promoter 2 (TFCP2), a pivotal transcription factor encoded by the alpha globin transcription factor CP2 gene, is a constituent of the TFCP2/grainyhead family of transcription factors. While grainyhead members have been extensively studied for their crucial roles in developmental processes, embryogenesis, and multiple cancers, the TFCP2 subfamily has been relatively less explored. The molecular mechanisms underlying TFCP2's involvement in carcinogenesis are still unclear even though it is a desirable target for cancer treatment and a therapeutic marker. This comprehensive literature review summarizes the molecular functions of TFCP2, emphasizing its involvement in cancer pathophysiology, particularly in the epithelial-mesenchymal transition and metastasis. It highlights TFCP2's critical function as a regulatory target and explores its potential as a prognostic marker for survival and inflammation in carcinomas. Its ambiguous association with carcinomas underlines the urgent need for an in-depth understanding to facilitate the development of more efficacious targeted therapeutic modality and diagnostic tools. This study aims to elucidate the multifaceted effects of TFCP2 regulation, through a comprehensive integration of the existing knowledge in cancer therapeutics. Furthermore, the clinical relevance and the inherent challenges encountered in investigating its intricate role in cancer pathogenesis have been discussed in this review.
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Affiliation(s)
- Neha Kaushik
- Department of Biotechnology, College of Engineering, The University of Suwon, Hwaseong, 18323, Korea
| | - Apurva Jaiswal
- Plasma Bioscience Research Center/Department of Electrical and Biological Physics, Kwangwoon University, Seoul, 01897, Korea
| | - Pradeep Bhartiya
- Department of Biotechnology, College of Engineering, The University of Suwon, Hwaseong, 18323, Korea
| | - Eun Ha Choi
- Plasma Bioscience Research Center/Department of Electrical and Biological Physics, Kwangwoon University, Seoul, 01897, Korea.
| | - Nagendra Kumar Kaushik
- Plasma Bioscience Research Center/Department of Electrical and Biological Physics, Kwangwoon University, Seoul, 01897, Korea.
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28
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Tamura K, Tomita Y, Kanazawa T, Shinohara H, Sakano M, Ishibashi S, Ikeda M, Kinoshita M, Minami J, Yamamoto K, Kato Y, Furukawa A, Haruki S, Tokunaga M, Kinugasa Y, Kurata M, Kitagawa M, Ohashi K, Yamamoto K. Lipid Peroxidation Regulators GPX4 and FSP1 as Prognostic Markers and Therapeutic Targets in Advanced Gastric Cancer. Int J Mol Sci 2024; 25:9203. [PMID: 39273151 PMCID: PMC11395505 DOI: 10.3390/ijms25179203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 08/20/2024] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
Gastric cancer is one of the most common cancers worldwide, and new therapeutic strategies are urgently needed. Ferroptosis is an intracellular iron-dependent cell death induced by the accumulation of lipid peroxidation, a mechanism different from conventional apoptosis and necrosis. Therefore, induction of ferroptosis is expected to be a new therapeutic strategy. Glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) have been identified as the major inhibitors of ferroptosis. Herein, we performed immunohistochemistry for GPX4, FSP1, and 4-HNE using tissues from patients with gastric cancer and investigated the relationship between these factors and prognosis. Patients with high GPX4 expression or high GPX4 expression and low 4-HNE accumulation tended to have a poor prognosis (p = 0.036, 0.023), whereas those with low FSP1 expression and high 4-HNE accumulation had a good prognosis (p = 0.033). The synergistic induction of cell death by inhibiting GPX4 and FSP1 in vitro was also observed, indicating that the cell death was non-apoptotic. Our results indicate that the expression and accumulation of lipid peroxidation-related factors play an important role in the clinicopathological significance of gastric cancer and that novel therapeutic strategies targeting GPX4 and FSP1 may be effective in treating patients with gastric cancer who have poor prognosis.
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Affiliation(s)
- Kazuhiro Tamura
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Yoshinobu Tomita
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Takumi Kanazawa
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
- Department of Clinical Laboratory Medicine, Faculty of Health Science Technology, Bunkyo Gakuin University, Tokyo 113-8668, Japan
| | - Hajime Shinohara
- Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Masayoshi Sakano
- Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Sachiko Ishibashi
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Masumi Ikeda
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Mayumi Kinoshita
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
- Department of Clinical Laboratory Medicine, Faculty of Health Science Technology, Bunkyo Gakuin University, Tokyo 113-8668, Japan
| | - Junko Minami
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Kurara Yamamoto
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Yuki Kato
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Asuka Furukawa
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Shigeo Haruki
- Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Masanori Tokunaga
- Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Yusuke Kinugasa
- Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Morito Kurata
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Masanobu Kitagawa
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Kenichi Ohashi
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Kouhei Yamamoto
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
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29
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Wang X, Yang Y, Zhao S, Wu D, Li L, Zhao Z. Chitosan-based biomaterial delivery strategies for hepatocellular carcinoma. Front Pharmacol 2024; 15:1446030. [PMID: 39161903 PMCID: PMC11330802 DOI: 10.3389/fphar.2024.1446030] [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: 06/08/2024] [Accepted: 07/23/2024] [Indexed: 08/21/2024] Open
Abstract
Background Hepatocellular carcinoma accounts for 80% of primary liver cancers, is the most common primary liver malignancy. Hepatocellular carcinoma is the third leading cause of tumor-related deaths worldwide, with a 5-year survival rate of approximately 18%. Chemotherapy, although commonly used for hepatocellular carcinoma treatment, is limited by systemic toxicity and drug resistance. Improving targeted delivery of chemotherapy drugs to tumor cells without causing systemic side effects is a current research focus. Chitosan, a biopolymer derived from chitin, possesses good biocompatibility and biodegradability, making it suitable for drug delivery. Enhanced chitosan formulations retain the anti-tumor properties while improving stability. Chitosan-based biomaterials promote hepatocellular carcinoma apoptosis, exhibit antioxidant and anti-inflammatory effects, inhibit tumor angiogenesis, and improve extracellular matrix remodeling for enhanced anti-tumor therapy. Methods We summarized published experimental papers by querying them. Results and Conclusions This review discusses the physicochemical properties of chitosan, its application in hepatocellular carcinoma treatment, and the challenges faced by chitosan-based biomaterials.
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Affiliation(s)
- Xianling Wang
- Department of Gastroenterology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Yan Yang
- Department of Gastroenterology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Shuang Zhao
- Endoscopy Center, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Di Wu
- First Digestive Endoscopy Department, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Le Li
- Department of Gastroenterology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhifeng Zhao
- Department of Gastroenterology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
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30
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Chu LY, Wu FC, Fang WK, Hong CQ, Huang LS, Zou HY, Peng YH, Chen H, Xie JJ, Xu YW. Secreted proteins encoded by super enhancer-driven genes could be promising biomarkers for early detection of esophageal squamous cell carcinoma. Biomed J 2024; 47:100662. [PMID: 37774793 PMCID: PMC11340493 DOI: 10.1016/j.bj.2023.100662] [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: 04/22/2023] [Revised: 08/25/2023] [Accepted: 09/22/2023] [Indexed: 10/01/2023] Open
Abstract
BACKGROUND Early detection of cancer remains an unmet need in clinical practice, and high diagnostic sensitivity and specificity biomarkers are urgently required. Here, we attempted to identify secreted proteins encoded by super-enhancer (SE)-driven genes as diagnostic biomarkers for esophageal squamous cell carcinoma (ESCC). METHODS We conducted an integrative analysis of multiple data sets including ChIP-seq data, secretome data, CCLE data and GEO data to screen secreted proteins encoded by SE-driven genes. Using ELISA, we further identified up-regulated secreted proteins through a small size of clinical samples and verified in a multi-centre validation stage (345 in test cohort and 231 in validation cohort). Receiver operating characteristic curves were used to calculate diagnostic accuracy. Artificial intelligence (AI) method named gradient boosting machine (GBM) were applied for model construction to enhance diagnostic accuracy. RESULTS Serum EFNA1 and MMP13 were identified, and showed significantly higher levels in ESCC patients compared to normal controls. An integrated Five-Biomarker Panel (iFBPanel) established by combining EFNA1, MMP13, carcino-embryonic antigen, Cyfra21-1 and squmaous cell carcinoma antigen had AUCs of 0.881 and 0.880 for ESCC in test and validation cohorts, respectively. Importantly, the iFBPanel also exhibited good performance in detecting early-stage ESCC patients (0.872 and 0.864). Furthermore, the iFBPanel was further empowered by AI technology which showed excellent diagnostic performance in early-stage ESCC (0.927 and 0.907). CONCLUSIONS Our study suggested that serum EFNA1 and MMP13 could potentially assist ESCC detection, and provided an easy-to-use detection model that might help the diagnosis of early-stage ESCC.
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Affiliation(s)
- Ling-Yu Chu
- Department of Clinical Laboratory Medicine, Cancer Hospital of Shantou University Medical College, Shantou, China; Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China
| | - Fang-Cai Wu
- Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shanto, China; Guangdong Esophageal Cancer Institute, Cancer Hospital of Shantou University Medical College, Shanto, China; Esophageal Cancer Prevention and Control Research Centre, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Wang-Kai Fang
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China
| | - Chao-Qun Hong
- Department of Oncological Laboratory Research, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Li-Sheng Huang
- Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shanto, China
| | - Hai-Ying Zou
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China
| | - Yu-Hui Peng
- Department of Clinical Laboratory Medicine, Cancer Hospital of Shantou University Medical College, Shantou, China; Guangdong Esophageal Cancer Institute, Cancer Hospital of Shantou University Medical College, Shanto, China
| | - Hao Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Centre, Guangzhou, China.
| | - Jian-Jun Xie
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China.
| | - Yi-Wei Xu
- Department of Clinical Laboratory Medicine, Cancer Hospital of Shantou University Medical College, Shantou, China; Guangdong Esophageal Cancer Institute, Cancer Hospital of Shantou University Medical College, Shanto, China; Esophageal Cancer Prevention and Control Research Centre, Cancer Hospital of Shantou University Medical College, Shantou, China.
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Cordeiro HG, Azevedo-Martins JM, Faria AVDS, Rocha-Brito KJP, Milani R, Peppelenbosch M, Fuhler G, de Fátima Â, Ferreira-Halder CV. Calix[6]arene dismantles extracellular vesicle biogenesis and metalloproteinases that support pancreatic cancer hallmarks. Cell Signal 2024; 119:111174. [PMID: 38604340 DOI: 10.1016/j.cellsig.2024.111174] [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: 12/18/2023] [Revised: 04/01/2024] [Accepted: 04/09/2024] [Indexed: 04/13/2024]
Abstract
Many challenges are faced in pancreatic cancer treatment due to late diagnosis and poor prognosis because of high recurrence and metastasis. Extracellular vesicles (EVs) and matrix metalloproteinases (MMPs), besides acting in intercellular communication, are key players in the cancer cell plasticity responsible for initiating metastasis. Therefore, these entities provide valuable targets for the development of better treatments. In this context, this study aimed to evaluate the potential of calix[6]arene to disturb the release of EVs and the activity of MMPs in pancreatic cancer cells. We found a correlation between the endocytic-associated mediators and the prognosis of pancreatic cancer patients. We observed a more active EV machinery in the pancreatic cancer cell line PANC-1, which was reduced three-fold by treatment with calix[6]arene at subtoxic concentration (5 μM; p 〈0,001). We observed the modulation of 186 microRNAs (164 miRNAs upregulated and 22 miRNAs downregulated) upon calix[6]arene treatment. Interestingly, some of them as miR-4443 and miR-3909, regulates genes HIF1A e KIF13A that are well known to play a role in transport of vesicles. Furthermore, Calix[6]arene downmodulated matrix metalloproteinases (MMPs) -2 and - 9 and disturbed the viability of pancreatic organoids which recapitulate the cellular heterogeneity, structure, and functions of primary tissues. Our findings shed new insights on calix[6]arene's antitumor mechanism, including its intracellular effects on vesicle production and trafficking, as well as MMP activity, which may harm the tumor microenvironment and contribute to a reduction in cancer cell dissemination, which is one of the challenges associated with high mortality in pancreatic cancer.
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Affiliation(s)
- Helon Guimarães Cordeiro
- Department of Biochemistry and Tissue Biology, Institute of Biology, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Jordana Maria Azevedo-Martins
- Department of Biochemistry and Tissue Biology, Institute of Biology, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Alessandra Valéria de Sousa Faria
- Department of Biochemistry and Tissue Biology, Institute of Biology, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brazil; Faculdade Israelita de Ciências da Saúde Albert Einstein, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | | | - Renato Milani
- Department of Biochemistry and Tissue Biology, Institute of Biology, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Maikel Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Gwenny Fuhler
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Ângelo de Fátima
- Department of Chemistry, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Carmen Veríssima Ferreira-Halder
- Department of Biochemistry and Tissue Biology, Institute of Biology, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brazil.
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Pilesi E, Tesoriere G, Ferriero A, Mascolo E, Liguori F, Argirò L, Angioli C, Tramonti A, Contestabile R, Volontè C, Vernì F. Vitamin B6 deficiency cooperates with oncogenic Ras to induce malignant tumors in Drosophila. Cell Death Dis 2024; 15:388. [PMID: 38830901 PMCID: PMC11148137 DOI: 10.1038/s41419-024-06787-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 05/26/2024] [Accepted: 05/28/2024] [Indexed: 06/05/2024]
Abstract
Vitamin B6 is a water-soluble vitamin which possesses antioxidant properties. Its catalytically active form, pyridoxal 5'-phosphate (PLP), is a crucial cofactor for DNA and amino acid metabolism. The inverse correlation between vitamin B6 and cancer risk has been observed in several studies, although dietary vitamin B6 intake sometimes failed to confirm this association. However, the molecular link between vitamin B6 and cancer remains elusive. Previous work has shown that vitamin B6 deficiency causes chromosome aberrations (CABs) in Drosophila and human cells, suggesting that genome instability may correlate the lack of this vitamin to cancer. Here we provide evidence in support of this hypothesis. Firstly, we show that PLP deficiency, induced by the PLP antagonists 4-deoxypyridoxine (4DP) or ginkgotoxin (GT), promoted tumorigenesis in eye larval discs transforming benign RasV12 tumors into aggressive forms. In contrast, PLP supplementation reduced the development of tumors. We also show that low PLP levels, induced by 4DP or by silencing the sgllPNPO gene involved in PLP biosynthesis, worsened the tumor phenotype in another Drosophila cancer model generated by concomitantly activating RasV12 and downregulating Discs-large (Dlg) gene. Moreover, we found that RasV12 eye discs from larvae reared on 4DP displayed CABs, reactive oxygen species (ROS) and low catalytic activity of serine hydroxymethyltransferase (SHMT), a PLP-dependent enzyme involved in thymidylate (dTMP) biosynthesis, in turn required for DNA replication and repair. Feeding RasV12 4DP-fed larvae with PLP or ascorbic acid (AA) plus dTMP, rescued both CABs and tumors. The same effect was produced by overexpressing catalase in RasV12 DlgRNAi 4DP-fed larvae, thus allowing to establish a relationship between PLP deficiency, CABs, and cancer. Overall, our data provide the first in vivo demonstration that PLP deficiency can impact on cancer by increasing genome instability, which is in turn mediated by ROS and reduced dTMP levels.
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Affiliation(s)
- Eleonora Pilesi
- Dept. of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, 00185, Rome, Italy
| | - Giulia Tesoriere
- Dept. of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, 00185, Rome, Italy
| | - Angelo Ferriero
- Dept. of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, 00185, Rome, Italy
| | - Elisa Mascolo
- Dept. of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, 00185, Rome, Italy
| | - Francesco Liguori
- Experimental Neuroscience and Neurological Disease Models, IRCCS Santa Lucia Foundation, 00143, Rome, Italy
- CNR, Institute for Systems Analysis and Computer Science, 00185, Rome, Italy
| | - Luca Argirò
- Dept. of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, 00185, Rome, Italy
| | - Chiara Angioli
- Dept. of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, 00185, Rome, Italy
| | - Angela Tramonti
- Institute of Molecular Biology and Pathology, 00185, Rome, Italy
| | - Roberto Contestabile
- Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza, University of Rome, 00185, Rome, Italy
- Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza, University of Rome, 00185, Rome, Italy
| | - Cinzia Volontè
- Experimental Neuroscience and Neurological Disease Models, IRCCS Santa Lucia Foundation, 00143, Rome, Italy
- CNR, Institute for Systems Analysis and Computer Science, 00185, Rome, Italy
| | - Fiammetta Vernì
- Dept. of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, 00185, Rome, Italy.
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Jacobson JC, Qiao J, Cochran ED, McCreery S, Chung DH. Migration, invasion, and metastasis are mediated by P-Rex1 in neuroblastoma. Front Oncol 2024; 14:1336031. [PMID: 38884093 PMCID: PMC11176429 DOI: 10.3389/fonc.2024.1336031] [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: 11/09/2023] [Accepted: 05/08/2024] [Indexed: 06/18/2024] Open
Abstract
Neuroblastoma accounts for approximately 15% of pediatric cancer-related deaths despite intensive multimodal therapy. This is due, in part, to high rates of metastatic disease at diagnosis and disease relapse. A better understanding of tumor biology of aggressive, pro-metastatic phenotypes is necessary to develop novel, more effective therapeutics against neuroblastoma. Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 (P-Rex1) has been found to stimulate migration, invasion, and metastasis in several adult malignancies. However, its role in neuroblastoma is currently unknown. In the present study, we found that P-Rex1 is upregulated in pro-metastatic murine models of neuroblastoma, as well as human neuroblastoma metastases. Correspondingly, silencing of P-Rex1 was associated with decreased migration and invasion in vitro. This was associated with decreased AKT-mTOR and ERK2 activity, dysregulation of Rac, and diminished secretion of matrix metalloproteinases. Furthermore, increased P-Rex1 expression was associated with inferior relapse-free and overall survival via tissue microarray and Kaplan-Meier survival analysis of a publicly available clinical database. Together, these findings suggest that P-Rex1 may be a novel therapeutic target and potential prognostic factor in neuroblastoma.
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Affiliation(s)
- Jillian C Jacobson
- Division of Pediatric Surgery, Department of Surgery, University of Texas Southwestern Medical Center and Children's Health, Dallas, TX, United States
| | - Jingbo Qiao
- Division of Pediatric Surgery, Department of Surgery, University of Texas Southwestern Medical Center and Children's Health, Dallas, TX, United States
| | - Elizabeth D Cochran
- Division of Pediatric Surgery, Department of Surgery, University of Texas Southwestern Medical Center and Children's Health, Dallas, TX, United States
| | - Sullivan McCreery
- Division of Pediatric Surgery, Department of Surgery, University of Texas Southwestern Medical Center and Children's Health, Dallas, TX, United States
| | - Dai H Chung
- Division of Pediatric Surgery, Department of Surgery, University of Texas Southwestern Medical Center and Children's Health, Dallas, TX, United States
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Yang S, Luo M, Yang S, Yuan M, Zeng H, Xia J, Wang N. Relationship between chemokine/chemokine receptor and glioma prognosis and outcomes: Systematic review and meta-analysis. Int Immunopharmacol 2024; 133:112047. [PMID: 38631221 DOI: 10.1016/j.intimp.2024.112047] [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: 02/26/2024] [Revised: 04/01/2024] [Accepted: 04/06/2024] [Indexed: 04/19/2024]
Abstract
BACKGROUND Glioma is a primary tumor originating from the central nervous system, and despite ongoing efforts to improve treatment, its overall survival rate remains low. There are a limited number of reports regarding the clinical grading, prognostic impact, and utility of chemokines. Therefore, conducting a meta-analysis is necessary to obtain convincing and conclusive results. METHODS A comprehensive literature search was conducted using various databases, including PubMed, Web of Science, The Cochrane Library, Embase, Ovid Medline, CNKI, Wanfang Database, VIP, and CBM. The search encompassed articles published from the inception of the databases until March 2024. The estimated odds ratio (ORs), standard mean difference (SMDs), and hazard ratio (HR) with their corresponding 95% confidence intervals (95% CI) were calculated to assess the predictive value of chemokine and receptor levels in glioma risk. Additionally, heterogeneity tests and bias tests were performed to evaluate the reliability of the findings. RESULTS This meta-analysis included a total of 36 studies, involving 2,480 patients diagnosed with glioma. The results revealed a significant association between the expression levels of CXCR4 (n = 8; OR = 22.28; 95 % CI = 11.47-43.30; p = 0.000), CXCL12 (n = 4; OR = 10.69; 95 % CI = 7.03-16.24; p = 0.000), CCL2 (n = 6; SMD = -0.83; 95 % CI = -0.98--0.67; p = 0.000), CXCL8 (n = 3; SMD = 0.75; 95 % CI = 0.47-1.04; p = 0.000), CXCR7 (n = 3; OR = 20.66; 95 % CI = 10.20-41.82; p = 0.000), CXCL10 (n = 2; SMD = 3.27; 95 % CI = 2.91-3.62; p = 0.000) and the risk of glioma. Additionally, a significant correlation was observed between CXCR4 (n = 8; OR = 4.39; 95 % CI = 3.04-6.32; p = 0.000), (n = 6; SMD = 1.37; 95 % CI = 1.09-1.65; p = 0.000), CXCL12 (n = 6; OR = 6.30; 95 % CI = 3.87-10.25; p = 0.000), (n = 5; ES = 2.25; 95 % CI = 1.15-3.34; p = 0.041), CCL2 (n = 3; OR = 9.65; 95 % CI = 4.55-20.45; p = 0.000), (n = 4; SMD = -1.47; 95 % CI = -1.68--1.26; p = 0.000), and CCL18 (n = 3; SMD = 1.62; 95 % CI = 1.30-1.93; p = 0.000) expression levels and high-grade glioma (grades 3-4). Furthermore, CXCR4 (HR = 2.38, 95 % CI = 1.66-3.40; p = 0.000) exhibited a strong correlation with poor overall survival (OS) rates in glioma patients. CONCLUSION The findings of this study showed a robust association between elevated levels of CXCR4, CXCL12, CCL2, CXCL8, CXCL10 and CXCR7 with a higher risk of glioma. Furthermore, the WHO grading system was validated by the strong correlation shown between higher expression of CXCR4, CXCL12, CCL2, and CCL18 and WHO high-grade gliomas (grades 3-4). Furthermore, the results of the meta-analysis suggested that CXCR4 might be a helpful biomarker for predicting the worse prognosis of glioma patients.
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Affiliation(s)
- Shaobo Yang
- Department of Neurosurgery, Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde city), NO. 818 Renmin Road, Changde, Hunan, 415003, China
| | - Minjie Luo
- Department of Pathology, Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City), Changde, Hunan, China; Department of Pathophysiology, Xiangya School of Medicine, Central South University, Hunan, China
| | - Shun Yang
- Department of Neurosurgery, Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde city), NO. 818 Renmin Road, Changde, Hunan, 415003, China
| | - Min Yuan
- Department of Neurosurgery, Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde city), NO. 818 Renmin Road, Changde, Hunan, 415003, China
| | - Hu Zeng
- Department of Neurosurgery, Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde city), NO. 818 Renmin Road, Changde, Hunan, 415003, China
| | - Jun Xia
- Department of Neurosurgery, Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde city), NO. 818 Renmin Road, Changde, Hunan, 415003, China
| | - Nianhua Wang
- Department of Neurosurgery, Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde city), NO. 818 Renmin Road, Changde, Hunan, 415003, China.
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Wang X, Zhou Y, Wang L, Haseeb A, Li H, Zheng X, Guo J, Cheng X, Yin W, Sun N, Sun P, Zhang Z, Yang H, Fan K. Fascin-1 Promotes Cell Metastasis through Epithelial-Mesenchymal Transition in Canine Mammary Tumor Cell Lines. Vet Sci 2024; 11:238. [PMID: 38921985 PMCID: PMC11209228 DOI: 10.3390/vetsci11060238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/15/2024] [Accepted: 05/23/2024] [Indexed: 06/27/2024] Open
Abstract
Canine mammary tumors (CMTs) are the most common type of tumor in female dogs. In this study, we obtained a metastatic key protein, Fascin-1, by comparing the proteomics data of in situ tumor and metastatic cell lines from the same individual. However, the role of Fascin-1 in the CMT cell line is still unclear. Firstly, proteomics was used to analyze the differential expression of Fascin-1 between the CMT cell lines CHMm and CHMp. Then, the overexpression (CHMm-OE and CHMp-OE) and knockdown (CHMm-KD and CHMp-KD) cell lines were established by lentivirus transduction. Finally, the differentially expressed proteins (DEPs) in CHMm and CHMm-OE cells were identified through proteomics. The results showed that the CHMm cells isolated from CMT abdominal metastases exhibited minimal expression of Fascin-1. The migration, adhesion, and invasion ability of CHMm-OE and CHMp-OE cells increased, while the migration, adhesion, and invasion ability of CHMm-KD and CHMp-KD cells decreased. The overexpression of Fascin-1 can upregulate the Tetraspanin 4 (TSPAN4) protein in CHMm cells and increase the number of migrations. In conclusion, re-expressed Fascin-1 could promote cell EMT and increase lamellipodia formation, resulting in the enhancement of CHMm cell migration, adhesion, and invasion in vitro. This may be beneficial to improve female dogs' prognosis of CMT.
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Affiliation(s)
- Xin Wang
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Ye Zhou
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Linhao Wang
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Abdul Haseeb
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Hongquan Li
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Xiaozhong Zheng
- Medical Research Council (MRC) Centre for Inflammation Research, Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Jianhua Guo
- Department of Veterinary Pathobiology, Schubot Exotic Bird Health Center, Texas A&M University, College Station, TX 77843, USA
| | - Xiaoliang Cheng
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Wei Yin
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Na Sun
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Panpan Sun
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Zhenbiao Zhang
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Huizhen Yang
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Kuohai Fan
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
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Silva LGDO, Lemos FFB, Luz MS, Rocha Pinheiro SL, Calmon MDS, Correa Santos GL, Rocha GR, de Melo FF. New avenues for the treatment of immunotherapy-resistant pancreatic cancer. World J Gastrointest Oncol 2024; 16:1134-1153. [PMID: 38660642 PMCID: PMC11037047 DOI: 10.4251/wjgo.v16.i4.1134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 01/26/2024] [Accepted: 03/04/2024] [Indexed: 04/10/2024] Open
Abstract
Pancreatic cancer (PC) is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide. However, due to its complexity, it ranks 7th in the list of the most lethal cancers worldwide. The pathogenesis of PC involves several complex processes, including familial genetic factors associated with risk factors such as obesity, diabetes mellitus, chronic pancreatitis, and smoking. Mutations in genes such as KRAS, TP53, and SMAD4 are linked to the appearance of malignant cells that generate pancreatic lesions and, consequently, cancer. In this context, some therapies are used for PC, one of which is immunotherapy, which is extremely promising in various other types of cancer but has shown little response in the treatment of PC due to various resistance mechanisms that contribute to a drop in immunotherapy efficiency. It is therefore clear that the tumor microenvironment (TME) has a huge impact on the resistance process, since cellular and non-cellular elements create an immunosuppressive environment, characterized by a dense desmoplastic stroma with cancer-associated fibroblasts, pancreatic stellate cells, extracellular matrix, and immunosuppressive cells. Linked to this are genetic mutations in TP53 and immunosuppressive factors that act on T cells, resulting in a shortage of CD8+ T cells and limited expression of activation markers such as interferon-gamma. In this way, finding new strategies that make it possible to manipulate resistance mechanisms is necessary. Thus, techniques such as the use of TME modulators that block receptors and stromal molecules that generate resistance, the use of genetic manipulation in specific regions, such as microRNAs, the modulation of extrinsic and intrinsic factors associated with T cells, and, above all, therapeutic models that combine these modulation techniques constitute the promising future of PC therapy. Thus, this study aims to elucidate the main mechanisms of resistance to immunotherapy in PC and new ways of manipulating this process, resulting in a more efficient therapy for cancer patients and, consequently, a reduction in the lethality of this aggressive cancer.
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Affiliation(s)
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Mariana dos Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Lima Correa Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Reis Rocha
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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Wang W, Niu Y, Zhang N, Wan Y, Xiao Y, Zhao L, Zhao B, Chen W, Huang D. Cascade-Catalyzed Nanogel for Amplifying Starvation Therapy by Nitric Oxide-Mediated Hypoxia Alleviation. ACS APPLIED MATERIALS & INTERFACES 2024; 16:17313-17322. [PMID: 38534029 DOI: 10.1021/acsami.4c01866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/28/2024]
Abstract
Glucose oxidase (Gox)-mediated starvation therapy offers a prospective advantage for malignancy treatment by interrupting the glucose supply to neoplastic cells. However, the negative charge of the Gox surface hinders its enrichment in tumor tissues. Furthermore, Gox-mediated starvation therapy infiltrates large amounts of hydrogen peroxide (H2O2) to surround normal tissues and exacerbate intracellular hypoxia. In this study, a cascade-catalyzed nanogel (A-NE) was developed to boost the antitumor effects of starvation therapy by glucose consumption and cascade reactive release of nitric oxide (NO) to relieve hypoxia. First, the surface cross-linking structure of A-NE can serve as a bioimmobilization for Gox, ensuring Gox stability while improving the encapsulation efficiency. Then, Gox-mediated starvation therapy efficiently inhibited the proliferation of tumor cells while generating large amounts of H2O2. In addition, covalent l-arginine (l-Arg) in A-NE consumed H2O2 derived from glucose decomposition to generate NO, which augmented starvation therapy on metastatic tumors by alleviating tumor hypoxia. Eventually, both in vivo and in vitro studies indicated that nanogels remarkably inhibited in situ tumor growth and hindered metastatic tumor recurrence, offering an alternative possibility for clinical intervention.
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Affiliation(s)
- Wei Wang
- Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing 211198, China
| | - Yafan Niu
- Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing 211198, China
| | - Ni Zhang
- Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing 211198, China
| | - Yuqing Wan
- Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing 211198, China
| | - Yiqing Xiao
- Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing 211198, China
| | - Lingzhi Zhao
- School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Bingbing Zhao
- Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing 211198, China
| | - Wei Chen
- Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing 211198, China
| | - Dechun Huang
- Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing 211198, China
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Islam MT, Jang NH, Lee HJ. Natural Products as Regulators against Matrix Metalloproteinases for the Treatment of Cancer. Biomedicines 2024; 12:794. [PMID: 38672151 PMCID: PMC11048580 DOI: 10.3390/biomedicines12040794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 03/21/2024] [Accepted: 03/29/2024] [Indexed: 04/28/2024] Open
Abstract
Cancers are currently the major cause of mortality in the world. According to previous studies, matrix metalloproteinases (MMPs) have an impact on tumor cell proliferation, which could lead to the onset and progression of cancers. Therefore, regulating the expression and activity of MMPs, especially MMP-2 and MMP-9, could be a promising strategy to reduce the risk of cancers. Various studies have tried to investigate and understand the pathophysiology of cancers to suggest potent treatments. In this review, we summarize how natural products from marine organisms and plants, as regulators of MMP-2 and MMP-9 expression and enzymatic activity, can operate as potent anticancer agents.
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Affiliation(s)
- Md. Towhedul Islam
- Department of Chemistry, Faculty of Science, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh
| | - Nak Han Jang
- Department of Chemistry Education, Kongju National University, Gongju 32588, Chungcheongnam-do, Republic of Korea
| | - Hyuck Jin Lee
- Department of Chemistry Education, Kongju National University, Gongju 32588, Chungcheongnam-do, Republic of Korea
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Song C, Chen L. Circ_0051428 targeting miR-885-3p/MMP2 axis enhances the malignancy of cervical cancer. Open Med (Wars) 2024; 19:20230858. [PMID: 38584845 PMCID: PMC10996931 DOI: 10.1515/med-2023-0858] [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: 12/06/2022] [Revised: 10/23/2023] [Accepted: 10/30/2023] [Indexed: 04/09/2024] Open
Abstract
Circular RNAs (circRNAs) are key regulators of cervical cancer (CC) progression. This study aimed to elucidate the role and mechanism of circ_0051428, a novel circRNA, in CC tumorigenesis. Quantitative real-time polymerase chain reaction and western blotting analyses confirmed that circ_0051428 and matrix metalloprotein-2 (MMP2) were overexpressed in CC, whereas the microRNA miR-885-3p was poorly expressed. After performing a series of in vitro and in vivo experiments, circ_0051428 knockdown was shown to repress CC cell invasion and proliferation in vitro, and hamper tumor formation in vivo. Dual-luciferase reporter and RNA-binding protein immunoprecipitation experiments verified that circ_0051428 interacts with miR-885-3p to regulate the target gene MMP2 of miR-885-3p in CC. In addition, miR-885-3p knockdown offset the anticancer effects of circ_0051428 or MMP2 knockdown on CC cell malignancy. Overall, this study revealed that circ_0051428 executes a tumor-promoting function in CC pathogenesis by modulating the miR-885-3p/MMP2 axis. Our findings provide a novel approach for CC treatment.
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Affiliation(s)
- Caixian Song
- Department of Gynecology and Obstetrics, Wuhan Fourth Hospital, Wuhan430030, Hubei, China
| | - Liping Chen
- Department of Gynecology and Obstetrics, Wuhan Fourth Hospital, No. 76 Jiefang Avenue, Qiaokou District, Wuhan430030, Hubei, China
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40
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Fang RY, Liu YW, Goan YG, Lin JJ, Su JH, Wu WT, Wu YJ. Suppression of Migration and Invasion by 4-Carbomethoxyl-10-Epigyrosanoldie E from the Cultured Soft Coral Sinularia sandensis through the MAPKs Pathway on Oral Cancer Cells. Adv Pharmacol Pharm Sci 2024; 2024:6695837. [PMID: 38374934 PMCID: PMC10876307 DOI: 10.1155/2024/6695837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 12/27/2023] [Accepted: 01/20/2024] [Indexed: 02/21/2024] Open
Abstract
The primary reason for cancer-related fatalities is metastasis. The compound 4-carbomethoxyl-10-epigyrosanoldie E, derived from the Sinularia sandensis soft coral species grown in cultures, exhibits properties that counteract inflammation. Moreover, it has been observed to trigger both apoptosis and autophagy within cancerous cells. This research focuses on examining the inhibitory impact of 4-carbomethoxyl-10-epigyrosanoldie E on the migration and invasion processes in Cal-27 and Ca9-22 oral cancer cell lines. To assess how this compound affects cell migration and invasion, the Boyden chamber assay was employed. Furthermore, Western blot analysis was utilized to explore the underlying molecular mechanisms. In a dose-dependent manner, 4-carbomethoxyl-10-epigyrosanoldie E notably decreased the levels of matrix metalloproteinase-2 (MMP-2) and MMP-9, along with urokinase-type plasminogen activator (uPA), in both Cal-27 and Ca9-22 cell lines. Conversely, it elevated the concentrations of tissue inhibitors of metalloproteinases-1 (TIMP-1) and TIMP-2. In addition, the treatment with this compound led to the inhibition of phosphorylation in extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). It also curtailed the expression of several key proteins including focal adhesion kinase (FAK), protein kinase C (PKC), growth factor receptor-bound protein 2 (GRB2), Rac, Ras, Rho A, mitogen-activated protein kinase kinase kinase 3 (MEKK3), and mitogen-activated protein kinase kinase 7 (MKK7). Furthermore, the expression levels of IQ-domain GTPase-activating protein 1 (IQGAP1) and zonula occludens-1 (ZO-1) were significantly reduced by the compound. The ability of 4-carbomethoxyl-10-epigyrosanoldie E to inhibit the migration and invasion of Cal-27 and Ca9-22 oral cancer cells was observed to be dose dependent. This inhibitory effect is primarily attributed to the suppression of MMP-2 and MMP-9 expression, as well as the downregulation of the mitogen-activated protein kinase (MAPK) signaling pathway.
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Affiliation(s)
- Rou-Yi Fang
- Department of Pharmacy, Kaohsiung Veterans General Hospital, Pingtung Branch, Kaohsiung, Taiwan
- Department of Nursing, Meiho University, Pingtung, Taiwan
| | - Yueh-Wen Liu
- Department of Cosmetics and Fashion Styling, Cheng Shiu University, Kaohsiung, Taiwan
| | - Yih-Gang Goan
- Division of Thoracic Surgery Department of Surgery, Pingtung Veterans General Hospital, Pingtung, Taiwan
| | - Jen-Jie Lin
- Yu Jun Biotechnology Co., Ltd., Kaohsiung, Taiwan
| | - Jui-Hsin Su
- National Museum of Marine Biology and Aquarium, Pingtung 94450, Taiwan
| | - Wen-Tung Wu
- Department of Food Science and Nutrition, Meiho University, Pingtung 91202, Taiwan
| | - Yu-Jen Wu
- Yu Jun Biotechnology Co., Ltd., Kaohsiung, Taiwan
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Bhuia MS, Chowdhury R, Sonia FA, Biswas S, Ferdous J, El-Nashar HAS, El-Shazly M, Islam MT. Efficacy of Rotundic Acid and Its Derivatives as Promising Natural Anticancer Triterpenoids: A Literature-Based Study. Chem Biodivers 2024; 21:e202301492. [PMID: 38150556 DOI: 10.1002/cbdv.202301492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 12/21/2023] [Accepted: 12/25/2023] [Indexed: 12/29/2023]
Abstract
Rotundic acid (RA) is a naturally occurring pentacyclic triterpene with a multitude of pharmacological activities. The primary emphasis of this study is on summarizing the anticancer properties with the underlying mechanisms of RA and its derivatives, as well as the pharmacokinetic features. Data was collected (up to date as of November 10, 2023) from various reliable and authentic literatures by searching in different academic search engines, including PubMed, Springer Link, Scopus, Wiley Online, Web of Science, ScienceDirect, and Google Scholar. The findings imply that RA and its synthetic derivatives possess promising anti-cancer properties against breast, colorectal, liver, and cervical cancers in various preclinical pharmacological test systems. The results also indicate that RA and its derivatives demonstrated anticancer effects via a number of cellular mechanisms, including apoptotic cell death, inhibition of oxidative stress, anti-inflammatory effect, cytotoxicity, cell cycle arrest, anti-proliferative effect, anti-angiogenic effect, and inhibition of cancer cell migration and invasion. It has been proposed that RA and its derived compounds have the capability to serve as a hopeful chemotherapeutic agent, so further extensive clinical research is necessary.
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Affiliation(s)
- Md Shimul Bhuia
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh
| | - Raihan Chowdhury
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh
| | - Fatema Akter Sonia
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh
| | - Shrabonti Biswas
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh
| | - Jannatul Ferdous
- Department of Biotechnology and Genetic Engineering, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh
| | - Heba A S El-Nashar
- Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, 11566, Abbassia, Cairo, Egypt
| | - Mohamed El-Shazly
- Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, 11566, Abbassia, Cairo, Egypt
| | - Muhammad Torequl Islam
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh
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42
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Rahman M, Nguyen TM, Lee GJ, Kim B, Park MK, Lee CH. Unraveling the Role of Ras Homolog Enriched in Brain (Rheb1 and Rheb2): Bridging Neuronal Dynamics and Cancer Pathogenesis through Mechanistic Target of Rapamycin Signaling. Int J Mol Sci 2024; 25:1489. [PMID: 38338768 PMCID: PMC10855792 DOI: 10.3390/ijms25031489] [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: 12/15/2023] [Revised: 01/14/2024] [Accepted: 01/17/2024] [Indexed: 02/12/2024] Open
Abstract
Ras homolog enriched in brain (Rheb1 and Rheb2), small GTPases, play a crucial role in regulating neuronal activity and have gained attention for their implications in cancer development, particularly in breast cancer. This study delves into the intricate connection between the multifaceted functions of Rheb1 in neurons and cancer, with a specific focus on the mTOR pathway. It aims to elucidate Rheb1's involvement in pivotal cellular processes such as proliferation, apoptosis resistance, migration, invasion, metastasis, and inflammatory responses while acknowledging that Rheb2 has not been extensively studied. Despite the recognized associations, a comprehensive understanding of the intricate interplay between Rheb1 and Rheb2 and their roles in both nerve and cancer remains elusive. This review consolidates current knowledge regarding the impact of Rheb1 on cancer hallmarks and explores the potential of Rheb1 as a therapeutic target in cancer treatment. It emphasizes the necessity for a deeper comprehension of the molecular mechanisms underlying Rheb1-mediated oncogenic processes, underscoring the existing gaps in our understanding. Additionally, the review highlights the exploration of Rheb1 inhibitors as a promising avenue for cancer therapy. By shedding light on the complicated roles between Rheb1/Rheb2 and cancer, this study provides valuable insights to the scientific community. These insights are instrumental in guiding the identification of novel targets and advancing the development of effective therapeutic strategies for treating cancer.
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Affiliation(s)
- Mostafizur Rahman
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea; (M.R.); (G.J.L.)
| | - Tuan Minh Nguyen
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea; (M.R.); (G.J.L.)
| | - Gi Jeong Lee
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea; (M.R.); (G.J.L.)
| | - Boram Kim
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea; (M.R.); (G.J.L.)
| | - Mi Kyung Park
- Department of BioHealthcare, Hwasung Medi-Science University, Hwaseong-si 18274, Republic of Korea
| | - Chang Hoon Lee
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea; (M.R.); (G.J.L.)
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Palladini G, Di Pasqua LG, Croce AC, Ferrigno A, Vairetti M. Recent Updates on the Therapeutic Prospects of Reversion-Inducing Cysteine-Rich Protein with Kazal Motifs (RECK) in Liver Injuries. Int J Mol Sci 2023; 24:17407. [PMID: 38139236 PMCID: PMC10743940 DOI: 10.3390/ijms242417407] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/06/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
The reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a membrane-anchored glycoprotein, negatively regulates various membrane proteins involved in the tissue governing extracellular matrix (ECM) remodeling such as metalloproteases (MMPs) and the sheddases ADAM10 and ADAM17. The significance of the present review is to summarize the current understanding of the pathophysiological role of RECK, a newly discovered signaling pathway associated with different liver injuries. Specifically, this review analyzes published data on the downregulation of RECK expression in hepatic ischemia/reperfusion (I/R) injury, liver-related cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), as well as in the progression of nonalcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). In addition, this review discusses the regulation of RECK by inducers, such as FXR agonists. The RECK protein has also been suggested as a potential diagnostic and prognostic marker for liver injury or as a biomarker with predictive value for drug treatment efficacy.
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Affiliation(s)
- Giuseppina Palladini
- Department of Internal Medicine and Therapeutics, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy; (G.P.); (L.G.D.P.); (M.V.)
- Internal Medicine Fondazione IRCCS Policlinico San Matteo, Viale Camillo Golgi 19, 27100 Pavia, Italy
| | - Laura Giuseppina Di Pasqua
- Department of Internal Medicine and Therapeutics, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy; (G.P.); (L.G.D.P.); (M.V.)
| | - Anna Cleta Croce
- Institute of Molecular Genetics, Italian National Research Council (CNR), Via Abbiategrasso 207, 27100 Pavia, Italy;
- Department of Biology & Biotechnology, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy
| | - Andrea Ferrigno
- Department of Internal Medicine and Therapeutics, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy; (G.P.); (L.G.D.P.); (M.V.)
| | - Mariapia Vairetti
- Department of Internal Medicine and Therapeutics, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy; (G.P.); (L.G.D.P.); (M.V.)
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Hiebinger F, Kudulyte A, Chi H, Burbano De Lara S, Ilic D, Helm B, Welsch H, Dao Thi VL, Klingmüller U, Binder M. Tumour cells can escape antiproliferative pressure by interferon-β through immunoediting of interferon receptor expression. Cancer Cell Int 2023; 23:315. [PMID: 38066598 PMCID: PMC10709914 DOI: 10.1186/s12935-023-03150-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 11/17/2023] [Indexed: 01/03/2025] Open
Abstract
Type I interferons (IFNs) play a central role not only in innate immunity against viral infection, but also in the antitumour response, e.g. through a direct impact on cell proliferation. Particularly for cancer arising in the context of chronic inflammation, constant exposure to IFNs may constitute a strong selective pressure during tumour evolution. Expansion of neoplastic subclones resistant to the antiproliferative effects of IFNs may contribute to immunoediting of tumours, leading to more aggressive disease. Experimental evidence for this development of IFN-insensitivity has been scarce and its molecular mechanism is unclear. In this study we demonstrate that six weeks exposure of cells to IFN-β in vitro reduces their sensitivity to its antiproliferative effects, and that this phenotype was stable for up to four weeks. Furthermore, we observed substantial differences in cellular sensitivity to growth inhibition by IFN-β in a panel of ten different liver cancer cell lines, most prominently in a pair of highly dedifferentiated cell lines, and least in cells from well-differentiated tumours. In both, long-term IFN selection and in dedifferentiated tumour cell lines, we found IFNAR2 expression to be substantially reduced, suggesting the receptor complex to be a sensitive target amenable to immunoediting. Beyond new insights into possible molecular processes in tumour evolution, these findings might prove valuable for the development of biomarkers allowing to stratify tumours for their sensitivity to IFN treatment in the context of patient tailored therapies.
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Affiliation(s)
- Felix Hiebinger
- Research Group "Dynamics of Early Viral Infection and the Innate Antiviral Response", Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Aiste Kudulyte
- Research Group "Dynamics of Early Viral Infection and the Innate Antiviral Response", Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Huanting Chi
- Schaller Research Group, Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
- German Centre for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany
| | - Sebastian Burbano De Lara
- Division of Systems Biology of Signal Transduction (B200), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Doroteja Ilic
- Research Group "Dynamics of Early Viral Infection and the Innate Antiviral Response", Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Barbara Helm
- Division of Systems Biology of Signal Transduction (B200), German Cancer Research Center (DKFZ), Heidelberg, Germany
- German Center for Lung Research (DZL) and Translational Lung Research Center Heidelberg (TRLC), Heidelberg, Germany
| | - Hendrik Welsch
- Research Group "Dynamics of Early Viral Infection and the Innate Antiviral Response", Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Viet Loan Dao Thi
- Schaller Research Group, Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
- German Centre for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany
| | - Ursula Klingmüller
- Division of Systems Biology of Signal Transduction (B200), German Cancer Research Center (DKFZ), Heidelberg, Germany
- German Center for Lung Research (DZL) and Translational Lung Research Center Heidelberg (TRLC), Heidelberg, Germany
| | - Marco Binder
- Research Group "Dynamics of Early Viral Infection and the Innate Antiviral Response", Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg, Germany.
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45
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Hazrati A, Malekpour K, Mirsanei Z, Khosrojerdi A, Rahmani-Kukia N, Heidari N, Abbasi A, Soudi S. Cancer-associated mesenchymal stem/stromal cells: role in progression and potential targets for therapeutic approaches. Front Immunol 2023; 14:1280601. [PMID: 38022534 PMCID: PMC10655012 DOI: 10.3389/fimmu.2023.1280601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 10/11/2023] [Indexed: 12/01/2023] Open
Abstract
Malignancies contain a relatively small number of Mesenchymal stem/stromal cells (MSCs), constituting a crucial tumor microenvironment (TME) component. These cells comprise approximately 0.01-5% of the total TME cell population. MSC differentiation potential and their interaction with the tumor environment enable these cells to affect tumor cells' growth, immune evasion, metastasis, drug resistance, and angiogenesis. This type of MSC, known as cancer-associated mesenchymal stem/stromal cells (CA-MSCs (interacts with tumor/non-tumor cells in the TME and affects their function by producing cytokines, chemokines, and various growth factors to facilitate tumor cell migration, survival, proliferation, and tumor progression. Considering that the effect of different cells on each other in the TME is a multi-faceted relationship, it is essential to discover the role of these relationships for targeting in tumor therapy. Due to the immunomodulatory role and the tissue repair characteristic of MSCs, these cells can help tumor growth from different aspects. CA-MSCs indirectly suppress antitumor immune response through several mechanisms, including decreasing dendritic cells (DCs) antigen presentation potential, disrupting natural killer (NK) cell differentiation, inducing immunoinhibitory subsets like tumor-associated macrophages (TAMs) and Treg cells, and immune checkpoint expression to reduce effector T cell antitumor responses. Therefore, if these cells can be targeted for treatment so that their population decreases, we can hope for the treatment and improvement of the tumor conditions. Also, various studies show that CA-MSCs in the TME can affect other vital aspects of a tumor, including cell proliferation, drug resistance, angiogenesis, and tumor cell invasion and metastasis. In this review article, we will discuss in detail some of the mechanisms by which CA-MSCs suppress the innate and adaptive immune systems and other mechanisms related to tumor progression.
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Affiliation(s)
- Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Mirsanei
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arezou Khosrojerdi
- Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Nasim Rahmani-Kukia
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Neda Heidari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ardeshir Abbasi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Gálvez-Rodríguez A, Ferino-Pérez A, Rodríguez-Riera Z, Guerra IR, Jáuregui-Haza UJ. In silico evaluation of new mangiferin-based Positron Emission Tomography radiopharmaceuticals through the inhibition of metalloproteinase-9. J Mol Graph Model 2023; 124:108569. [PMID: 37487370 DOI: 10.1016/j.jmgm.2023.108569] [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: 03/25/2023] [Revised: 07/16/2023] [Accepted: 07/17/2023] [Indexed: 07/26/2023]
Abstract
Metalloproteinase-9 (MMP-9) is a key protein in cancer advancement and metastasis owing to its ability to degrade some extracellular matrix components. Mangiferin, a natural polyphenolic compound, has demonstrated through experimental and theoretical studies to be a great anticancer agent for the selective inhibition of MMP-9. This work aimed to evaluate the utility of several fluorinated compounds obtained from MF as possible Positron Emission Tomography (PET) radiopharmaceuticals oriented to MMP-9. Density Functional Theory calculations of MF were made to obtain the most active sites toward electrophilic and nucleophilic reactions and propose a synthetic route to produce its fluorinated derivatives. The reactivity study allowed us to propose a late-stage synthetic route based on click chemistry to obtain three fluorinated MF-based derivatives. Molecular docking calculations suggested that the derivative F-propyl-MF could be suitable as PET radiopharmaceutical owing to the establishment of a five-coordinated complex with the catalytic Zn atom belonging to the active site of MMP-9, crucial factor in the inhibition of MMP-9.
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Affiliation(s)
- Andy Gálvez-Rodríguez
- Instituto Superior de Tecnologías y Ciencias Aplicadas (InSTEC), Universidad de La Habana, La Habana, CP 10600, Cuba
| | - Anthuan Ferino-Pérez
- Department of Chemistry, KU Leuven Chem&Tech, Celestijnenlaan 200F, Bus 2404, 3001, Louvain, Belgium
| | - Zalua Rodríguez-Riera
- Instituto Superior de Tecnologías y Ciencias Aplicadas (InSTEC), Universidad de La Habana, La Habana, CP 10600, Cuba
| | - Idania Rodeiro Guerra
- Departamento de Farmacología, Instituto de Ciencias del Mar, Loma 14, Alturas del Vedado, Plaza de la Revolución, La Habana, CP 10600, Cuba
| | - Ulises J Jáuregui-Haza
- Instituto Tecnológico de Santo Domingo (INTEC), Avenida de los Próceres #49, Los Jardines del Norte, 10602, Santo Domingo, Dominican Republic.
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47
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Fanoodi A, Maharati A, Akhlaghipour I, Rahimi HR, Moghbeli M. MicroRNAs as the critical regulators of tumor angiogenesis in liver cancer. Pathol Res Pract 2023; 251:154913. [PMID: 37931431 DOI: 10.1016/j.prp.2023.154913] [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: 09/04/2023] [Revised: 10/25/2023] [Accepted: 10/26/2023] [Indexed: 11/08/2023]
Abstract
Liver cancer is one of the most common malignancies in human digestive system. Despite the recent therapeutic methods, there is a high rate of mortality among liver cancer patients. Late diagnosis in the advanced tumor stages can be one of the main reasons for the poor prognosis in these patients. Therefore, investigating the molecular mechanisms of liver cancer can be helpful for the early stage tumor detection and treatment. Vascular expansion in liver tumors can be one of the important reasons for poor prognosis and aggressiveness. Therefore, anti-angiogenic drugs are widely used in liver cancer patients. MicroRNAs (miRNAs) have key roles in the regulation of angiogenesis in liver tumors. Due to the high stability of miRNAs in body fluids, these factors are widely used as the non-invasive diagnostic and prognostic markers in cancer patients. Regarding, the importance of angiogenesis during liver tumor growth and invasion, in the present review, we discussed the role of miRNAs in regulation of angiogenesis in these tumors. It has been reported that miRNAs mainly exert an anti-angiogenic function by regulation of tumor microenvironment, transcription factors, and signaling pathways in liver tumors. This review can be an effective step to suggest the miRNAs for the non-invasive early detection of malignant and invasive liver tumors.
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Affiliation(s)
- Ali Fanoodi
- Student Research Committee, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Amirhosein Maharati
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Reza Rahimi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Chakraborty S, Banerjee S. Understanding crosstalk of organ tropism, tumor microenvironment and noncoding RNAs in breast cancer metastasis. Mol Biol Rep 2023; 50:9601-9623. [PMID: 37792172 DOI: 10.1007/s11033-023-08852-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 09/26/2023] [Indexed: 10/05/2023]
Abstract
Cancer metastasis is one of the major clinical challenges worldwide due to limited existing effective treatments. Metastasis roots from the host organ of origin and gradually migrates to different regional and distant organs. In different breast cancer subtypes, different organs like bones, liver, lungs and brain are targeted by the metastatic tumor cells. Cancer renders mortality to their respective metastasizing sites like bones, brain, liver, and lungs. Metastatic breast cancers are best treated and managed if detected at an early stage. Metastasis is regulated by various molecular activators and suppressors. The conventional theory of 'seed and soil' states that metastatic tumor cells move to tumor microenvironment that has favorable conditions like blood flow for them to grow just like seeds grows when planted in fertile land. Additionally, different coding as well as non-coding RNAs play a very significant role in the process of metastasis by modulating their expression levels leading to a crosstalk of various tumorigenic cascades. Treatments for metastasis is also very critical in controlling this lethal process. Detecting breast cancer metastasis at an early stage is crucial for managing and predicting metastatic progression. In this review, we have compiled several factors that can be targeted to manage the onset and gradual stages of breast cancer metastasis.
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Affiliation(s)
- Sohini Chakraborty
- Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India
| | - Satarupa Banerjee
- Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India.
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49
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James A, Akash K, Sharma A, Bhattacharyya S, Sriamornsak P, Nagraik R, Kumar D. Himalayan flora: targeting various molecular pathways in lung cancer. Med Oncol 2023; 40:314. [PMID: 37787816 DOI: 10.1007/s12032-023-02171-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 08/21/2023] [Indexed: 10/04/2023]
Abstract
The fatal amplification of lung cancer across the globe and the limitations of current treatment strategies emphasize the necessity for substitute therapeutics. The incorporation of phyto-derived components in chemo treatment holds promise in addressing those challenges. Despite the significant progressions in lung cancer therapeutics, the complexities of molecular mechanism and pathways underlying this disease remain inadequately understood, necessitating novel biomarker targeting. The Himalayas, abundant in diverse plant varieties with established chemotherapeutic potential, presents a promising avenue for investigating potential cures for lung carcinoma. The vast diversity of phytocompounds herein can be explored for targeting the disease. This review delves into the multifaceted targets of lung cancer and explores the established phytochemicals with their specific molecular targets. It emphasizes comprehending the intricate pathways that govern effective therapeutic interventions for lung cancer. Through this exploration of Himalayan flora, this review seeks to illuminate potential breakthroughs in lung cancer management using natural compounds. The amalgamation of Himalayan plant-derived compounds with cautiously designed combined therapeutic approaches such as nanocarrier-mediated drug delivery and synergistic therapy offers an opportunity to redefine the boundaries of lung cancer treatment by reducing the drug resistance and side effects and enabling an effective targeted delivery of drugs. Furthermore, additional studies are obligatory to understand the possible derivation of natural compounds used in current lung cancer treatment from plant species within the Himalayan region.
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Affiliation(s)
- Abija James
- Faculty of Applied Sciences and Biotechnology, Shoolini University, Solan, Himachal Pradesh, 173229, India
| | - K Akash
- Faculty of Applied Sciences and Biotechnology, Shoolini University, Solan, Himachal Pradesh, 173229, India
| | - Avinash Sharma
- Faculty of Applied Sciences and Biotechnology, Shoolini University, Solan, Himachal Pradesh, 173229, India
| | - Sanjib Bhattacharyya
- Department of Pharmaceutical Sciences and Chinese Traditional Medicine, Southwest University, Beibei, 400715, Chongqing, People's Republic of China
- Department of Sciences, Nirma University, Ahmedabad, Gujarat, 382481, India
| | | | - Rupak Nagraik
- Faculty of Applied Sciences and Biotechnology, Shoolini University, Solan, Himachal Pradesh, 173229, India.
| | - Deepak Kumar
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, 173229, India.
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Ildiz ES, Gvozdenovic A, Kovacs WJ, Aceto N. Travelling under pressure - hypoxia and shear stress in the metastatic journey. Clin Exp Metastasis 2023; 40:375-394. [PMID: 37490147 PMCID: PMC10495280 DOI: 10.1007/s10585-023-10224-8] [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: 05/10/2023] [Accepted: 07/05/2023] [Indexed: 07/26/2023]
Abstract
Cancer cell invasion, intravasation and survival in the bloodstream are early steps of the metastatic process, pivotal to enabling the spread of cancer to distant tissues. Circulating tumor cells (CTCs) represent a highly selected subpopulation of cancer cells that tamed these critical steps, and a better understanding of their biology and driving molecular principles may facilitate the development of novel tools to prevent metastasis. Here, we describe key research advances in this field, aiming at describing early metastasis-related processes such as collective invasion, shedding, and survival of CTCs in the bloodstream, paying particular attention to microenvironmental factors like hypoxia and mechanical stress, considered as important influencers of the metastatic journey.
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Affiliation(s)
- Ece Su Ildiz
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich (ETH Zurich), Zurich, Switzerland
| | - Ana Gvozdenovic
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich (ETH Zurich), Zurich, Switzerland
| | - Werner J Kovacs
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich (ETH Zurich), Zurich, Switzerland
| | - Nicola Aceto
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich (ETH Zurich), Zurich, Switzerland.
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