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Lu Z, Lyu Z, Dong P, Liu Y, Huang L. N6-methyladenosine RNA modification in stomach carcinoma: Novel insights into mechanisms and implications for diagnosis and treatment. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167793. [PMID: 40088577 DOI: 10.1016/j.bbadis.2025.167793] [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: 11/21/2024] [Revised: 02/16/2025] [Accepted: 03/03/2025] [Indexed: 03/17/2025]
Abstract
N6-methyladenosine (m6A) RNA methylation is crucially involved in the genesis and advancement of gastric cancer (GC) by controlling various pathobiological aspects including gene expression, signal transduction, metabolism, cell death, epithelial-mesenchymal transition, angiogenesis, and exosome function. Despite its importance, the exact mechanisms by which m6A modification influences GC biology remain inadequately explored. This review consolidates the latest advances in uncovering the mechanisms and diverse roles of m6A in GC and proposes new research and translational directions. Key regulators (writers, readers, and erasers) of m6A, such as METTL3/14/16 and WTAP, significantly affect cancer progression, anticancer immune response, and treatment outcomes. m6A modification also impacts immune cell infiltration and the tumor microenvironment, highlighting its potential as a diagnostic and prognostic marker. Interactions between m6A methylation and non-coding RNAs offer further novel insights into GC development and therapeutic targets. Targeting m6A regulators could enhance immunotherapy response, overcome treatment resistance, and improve oncological and clinical outcomes. Models based on m6A can precisely predict treatment response and prognosis in GC. Additional investigation is needed to fully understand the mechanisms of m6A methylation and its potential clinical applications and relevance (e.g., as precise markers for early detection, prediction of outcome, and response to therapy and as therapeutic targets) in GC. Future research should focus on in vivo studies, potential clinical trials, and the examination of m6A modification in other types of cancers.
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Affiliation(s)
- Zhengmao Lu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Zhaojie Lyu
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Peixin Dong
- Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Yunmei Liu
- School of Cultural Heritage and Information Management, Shanghai University, Shanghai, China.
| | - Lei Huang
- Department of Gastroenterology, National Clinical Research Center for Digestive Diseases, Shanghai Institute of Pancreatic Diseases, The First Affiliated Hospital of Naval Medical University/Changhai Hospital, Naval Medical University, Shanghai 200433, China; National Key Laboratory of Immunity and Inflammation, Changhai Clinical Research Unit, The First Affiliated Hospital of Naval Medical University/Changhai Hospital, Naval Medical University, Shanghai 200433, China.
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Mohammad SI, Vasudevan A, Nadhim Mohammed S, Uthirapathy S, M M R, Kundlas M, Siva Prasad GV, Kumari M, Mustafa YF, Ali Hussein Z. Anti-metastatic potential of flavonoids for the treatment of cancers: focus on epithelial-mesenchymal transition (EMT) process. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04235-3. [PMID: 40434422 DOI: 10.1007/s00210-025-04235-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 04/26/2025] [Indexed: 05/29/2025]
Abstract
The leading factor contributing to patient mortality is the local invasion and metastasis of tumors, which are influenced by the malignant progression of tumor cells. The epithelial-mesenchymal transition (EMT) is key to understanding malignancy development. EMT is a critical regulatory mechanism for differentiating cell populations initially observed during the neural crest and embryonic gastrulation formation. This process is closely associated with tumor metastasis in cancer and is also related to the maintenance of cancer stem cells. Flavonoids, known for their antioxidant properties, have been widely studied for their anticancer potential to protect plants from harmful environmental conditions. They have attracted considerable attention and have been the focus of numerous experimental and epidemiological studies to evaluate their potential in cancer treatment. In vitro and in vivo research has demonstrated that flavonoids can significantly impact cancer-related EMT. They may inhibit the EMT process by reducing the levels of Twist1, N-cadherin, ZEB1, integrins, SNAI1/2, CD44, MMPs, and vimentin while increasing E-cadherin levels and targeting the PI3K/AKT, NF-κB p65, and JAK2/STAT3 signaling pathways. In order to suppress the transcription of the E-cadherin promoter, several Zn-finger transcription factors, such as SNAI2, ZEB1, and ZEB2, and basic helix-loop-helix (bHLH) factors, such as Twist, may directly bind to its E-boxes. Overall, clinical cancer research should integrate the anticancer properties of flavonoids, which address all phases of carcinogenesis, including EMT, to improve the prospects for targeted cancer therapies in patients suffering from aggressive forms of tumors.
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Affiliation(s)
- Suleiman Ibrahim Mohammad
- Electronic Marketing and Social Media, Economic and Administrative Sciences Zarqa University, Zarqa, Jordan
- INTI International University, 71800, Negeri Sembilan, Malaysia
| | - Asokan Vasudevan
- Faculty of Business and Communications, INTI International University, 71800, Negeri Sembilan, Malaysia
- Shinawatra University, 99 Moo 10, Bangtoey, Samkhok, Pathum Thani, 12160, Thailand
| | - Sumaya Nadhim Mohammed
- Medical Laboratory Techniques Department, College of Health and Medical Technology, University of Al-Maarif, Anbar, Iraq.
| | - Subasini Uthirapathy
- Pharmacy Department, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Rekha M M
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Mayank Kundlas
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - G V Siva Prasad
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, 531162, India
| | - Mukesh Kumari
- Department of Applied Sciences-Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, India
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Zainab Ali Hussein
- Radiological Techniques Department, College of Health and Medical Techniques, Al-Mustaqbal University, 51001, Babylon, Iraq
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Khalili-Tanha G, Radisky ES, Radisky DC, Shoari A. Matrix metalloproteinase-driven epithelial-mesenchymal transition: implications in health and disease. J Transl Med 2025; 23:436. [PMID: 40217300 PMCID: PMC11992850 DOI: 10.1186/s12967-025-06447-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] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Accepted: 03/30/2025] [Indexed: 04/14/2025] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a process in which epithelial cells, defined by apical-basal polarity and tight intercellular junctions, acquire migratory and invasive properties characteristic of mesenchymal cells. Under normal conditions, EMT directs essential morphogenetic events in embryogenesis and supports tissue repair. When dysregulated, EMT contributes to pathological processes such as organ fibrosis, chronic inflammation, and cancer progression and metastasis. Matrix metalloproteinases (MMPs)-a family of zinc-dependent proteases that degrade structural components of the extracellular matrix-sit at the nexus of this transition by dismantling basement membranes, activating pro-EMT signaling pathways, and cleaving adhesion molecules. When normally regulated, MMPs promote balanced ECM turnover and support the cyclical remodeling necessary for proper development, wound healing, and tissue homeostasis. When abnormally regulated, MMPs drive excessive ECM turnover, thereby promoting EMT-related pathologies, including tumor progression and fibrotic disease. This review provides an integrated overview of the molecular mechanisms by which MMPs both initiate and sustain EMT under physiological and disease conditions. It discusses how MMPs can potentiate EMT through TGF-β and Wnt/β-catenin signaling, disrupt cell-cell junction proteins, and potentiate the action of hypoxia-inducible factors in the tumor microenvironment. It discusses how these pathologic processes remodel tissues during fibrosis, and fuel cancer cell invasion, metastasis, and resistance to therapy. Finally, the review explores emerging therapeutic strategies that selectively target MMPs and EMT, ranging from CRISPR/Cas-mediated interventions to engineered tissue inhibitors of metalloproteinases (TIMPs), and demonstrates how such approaches may suppress pathological EMT without compromising its indispensable roles in normal biology.
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Affiliation(s)
- Ghazaleh Khalili-Tanha
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Evette S Radisky
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
| | - Derek C Radisky
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
| | - Alireza Shoari
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
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4
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Kulkarni AM, Gayam PKR, Baby BT, Aranjani JM. Epithelial-Mesenchymal Transition in Cancer: A Focus on Itraconazole, a Hedgehog Inhibitor. Biochim Biophys Acta Rev Cancer 2025; 1880:189279. [PMID: 39938662 DOI: 10.1016/j.bbcan.2025.189279] [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: 07/22/2024] [Revised: 01/24/2025] [Accepted: 02/04/2025] [Indexed: 02/14/2025]
Abstract
Cancer, and the resulting mortality from it, is an ever-increasing concern in global health. Cancer mortality stems from the metastatic progression of the disease, by dissemination of the tumor cells. Epithelial-Mesenchymal Transition, the major hypothesis purported to be the origin of metastasis, confers mesenchymal phenotype to epithelial cells in a variety of contexts, physiological and pathological. EMT in cancer leads to rise of cancer-stem-like cells, drug resistance, relapse, and progression of malignancy. Inhibition of EMT could potentially attenuate the mortality. While novel molecules for inhibiting EMT are underway, repurposing drugs is also being considered as a viable strategy. In this review, Itraconazole is focused upon, as a repurposed molecule to mitigate EMT. Itraconazole is known to inhibit Hedgehog signaling, and light is shed upon the existing evidence, as well as the questions remaining to be answered.
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Affiliation(s)
- Aniruddha Murahar Kulkarni
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka 576104, India.
| | - Prasanna Kumar Reddy Gayam
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka 576104, India.
| | - Beena Thazhackavayal Baby
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka 576104, India
| | - Jesil Mathew Aranjani
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka 576104, India.
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Bangarh R, Saini RV, Saini AK, Singh T, Joshi H, Ramniwas S, Shahwan M, Tuli HS. Dynamics of epithelial-mesenchymal plasticity driving cancer drug resistance. CANCER PATHOGENESIS AND THERAPY 2025; 3:120-128. [PMID: 40182126 PMCID: PMC11963173 DOI: 10.1016/j.cpt.2024.07.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 07/01/2024] [Accepted: 07/03/2024] [Indexed: 04/05/2025]
Abstract
Epithelial-mesenchymal transition (EMT) promotes several cancers by increasing tumor cell motility, disrupting epithelial cell phenotypes, apical-basal polarity, and intracellular connections, and enhancing tumor resistance to immunotherapy and chemotherapy. Mesenchymal-epithelial transition (MET), the opposite of EMT, causes tumor metastasis. EMT drives primary tumor cells, whereas MET inhibits them. Importantly, the complex network of EMT includes cell-cell interactions in the tumor microenvironment. Transcription factors, post-translational regulation, cytokine-mediated signaling, and microRNAs control EMT. In this review, we discussed how molecular mechanisms, signaling networks, and epithelial/mesenchymal states affect cancer treatment resistance and the tumor microenvironment. Research on immunotherapy and chemotherapy problems associated with EMT suggests that targeting EMT might be a potential cancer treatment resistance strategy.
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Affiliation(s)
- Rashmi Bangarh
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala 133207, India
| | - Reena V. Saini
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala 133207, India
| | - Adesh K. Saini
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala 133207, India
| | - Tejveer Singh
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi 110007, India
| | - Hemant Joshi
- School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India
| | - Seema Ramniwas
- University Centre for Research and Development, University Institute of Pharmaceutical Sciences, Chandigarh University, Mohali 140413, India
| | - Moyad Shahwan
- Department of Clinical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman 346, United Arab Emirates
- Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman 346, United Arab Emirates
| | - Hardeep Singh Tuli
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala 133207, India
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Doodmani SM, Safari MH, Akbari M, Farahani N, Alimohammadi M, Aref AR, Tajik F, Maghsoodlou A, Daneshi S, Tabari T, Taheriazam A, Entezari M, Nabavi N, Hashemi M. Metastasis and chemoresistance in breast cancer: Crucial function of ZEB1/2 proteins. Pathol Res Pract 2025; 267:155838. [PMID: 39954369 DOI: 10.1016/j.prp.2025.155838] [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: 10/14/2024] [Revised: 12/20/2024] [Accepted: 02/10/2025] [Indexed: 02/17/2025]
Abstract
Breast cancer remains one of the leading causes of mortality worldwide. While advancements in chemotherapy, immunotherapy, radiotherapy, and targeted therapies have significantly improved breast cancer treatment, many patients are diagnosed at advanced stages, where tumor cells exhibit aggressive behavior and therapy resistance. Understanding the mechanisms driving breast cancer progression is therefore critical. Metastasis is a major factor that drastically reduces patient prognosis and survival, accounting for most breast cancer-related deaths. ZEB proteins have emerged as key regulators of cancer metastasis. Beyond their role in metastasis, ZEB proteins also influence drug resistance. This review focuses on the role of ZEB1 and ZEB2 in regulating breast cancer metastasis. These proteins interact with components of the tumor microenvironment (TME) to drive cancer progression and metastasis. Additionally, ZEB proteins regulate angiogenesis through interactions with VEGF. Targeting ZEB proteins offers potential therapeutic benefits, particularly for aggressive breast cancer subtypes such as triple-negative breast cancer (TNBC), which often show poor therapeutic response. ZEB proteins also influence the sensitivity of breast cancer cells to chemotherapy, making them promising targets for enhancing treatment efficacy. Given their upregulation in breast cancer, ZEB proteins can serve as valuable diagnostic and prognostic markers.
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Affiliation(s)
- Seyed Mohammad Doodmani
- Department of Pathobiology, Faculty of Specialized Veterinary Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mohamad Hosein Safari
- Department of Internal Medicine, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
| | - Mohammadarian Akbari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences,Tehran, Iran
| | - Amir Reza Aref
- Department of Vitro Vision, DeepkinetiX, Inc, Boston, MA, USA
| | - Fatemeh Tajik
- Department of Surgery, University of California, Irvine Medical Center, Orange, CA, USA
| | - Amin Maghsoodlou
- Young Researchers and Elite Club, Damghan Branch, Islamic Azad University, Damghan, Iran
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Teimour Tabari
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia V8V 1P7, Canada
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Bai J, Yang G, Yu Q, Chi Q, Zeng X, Qi W. SATB1 in cancer progression and metastasis: mechanisms and therapeutic potential. Front Oncol 2025; 15:1535929. [PMID: 40071088 PMCID: PMC11893431 DOI: 10.3389/fonc.2025.1535929] [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: 11/28/2024] [Accepted: 02/06/2025] [Indexed: 03/14/2025] Open
Abstract
Cancer remains a major global health challenge, with prostate cancer, lung cancer, colorectal cancer, and breast cancer accounting for nearly half of all diagnoses. Despite advancements in cancer treatment, metastasis to distant organs continues to be the leading cause of cancer-related mortality. The progression of cancer involves the alteration of numerous genes, with dynamic changes in chromatin organization and histone modifications playing a critical role in regulating cancer-associated genes. Special AT-rich sequence-binding protein 1 (SATB1), a critical chromatin organizer, plays a pivotal role in cancer progression by regulating gene expression, chromatin remodeling, and cell signaling pathways. SATB1 binds to AT-rich DNA sequences, acting as a scaffold for chromatin-modifying enzymes and transcription factors, thus coordinating the regulation of extensive gene networks. Its overexpression has been implicated in a wide range of cancers and is associated with poor prognosis, aggressive tumor phenotypes, and enhanced epithelial-mesenchymal transition (EMT). Moreover, SATB1's activity is modulated by microRNAs (miRNAs) and post-translational modifications, further contributing to its complex regulatory functions. Given its crucial involvement in cancer progression and metastasis, SATB1 has emerged as a promising target for novel therapeutic strategies. This review delves into the molecular mechanisms of SATB1 in cancer and explores potential therapeutic approaches for targeting this key regulator in cancer treatment.
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Affiliation(s)
- Jinping Bai
- Department of Bioscience, Changchun Normal University, Changchun, China
| | - Gege Yang
- Department of Bioscience, Changchun Normal University, Changchun, China
| | - Qi Yu
- Department of Bioscience, Changchun Normal University, Changchun, China
| | - Qianya Chi
- Department of Bioscience, Changchun Normal University, Changchun, China
| | - Xianlu Zeng
- Key Laboratory of Molecular Epigenetics of Ministry of Education, College of Life Sciences, Northeast Normal University, Changchun, China
| | - Wenjing Qi
- Department of Bioscience, Changchun Normal University, Changchun, China
- Key Laboratory of Molecular Epigenetics of Ministry of Education, College of Life Sciences, Northeast Normal University, Changchun, China
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Atale N, Wells A. Statins as Secondary Preventive Agent to Limit Breast Cancer Metastatic Outgrowth. Int J Mol Sci 2025; 26:1300. [PMID: 39941069 PMCID: PMC11818786 DOI: 10.3390/ijms26031300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 01/27/2025] [Accepted: 01/31/2025] [Indexed: 02/16/2025] Open
Abstract
Metastasis is a leading cause of mortality in breast cancer, as metastatic disease is often aggressive and resistant to conventional treatments. Cancer cells that spread to distant organs can enter a dormant phase for extended periods, sometimes years or decades. During this dormant phase, cancer cells avoid immune and pharmacological response. Thus, new approaches are needed to prevent these disseminated cells from becoming lethal cancers. Statins are known inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase that have been extensively used in patients with cardiovascular diseases to lower cholesterol. However, recent research has demonstrated their potential in anticancer therapies. Epidemiological evidence suggests that statins are associated with a reduction in breast cancer-specific mortality, although they do not appear to affect the incidence of primary tumors. In this review, we discuss the role of statins in metastasis and dormancy, their cytocidal and cytostatic effects and their interactions with different cell types in the tumor microenvironment. The exact mechanisms by which statins reduce mortality without influencing primary tumor growth remain unclear, also warranting further investigation into their potential role in metastasis and tumor dormancy, which could ultimately help patients to improve survival and quality of life.
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Affiliation(s)
- Neha Atale
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA;
| | - Alan Wells
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA;
- Research and Development Service, Pittsburgh VA Health System, Pittsburgh, PA 15213, USA
- Cell Biology Program, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA
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Balakrishnan P, Thirunavukarasu K, Tamizhmani P, Michael AA, Velusamy T. Toxicological Impact of Chronic Chlorpyrifos Exposure: DNA Damage and Epigenetic Alterations Induces Neoplastic Transformation of Liver Cells. Biochem Biophys Res Commun 2025; 746:151287. [PMID: 39764911 DOI: 10.1016/j.bbrc.2025.151287] [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: 11/12/2024] [Revised: 12/26/2024] [Accepted: 01/01/2025] [Indexed: 01/15/2025]
Abstract
Organophosphate pesticides (OPPs) are widely used chemical pesticides in all the developed countries. Among the OPPs, Chlorpyrifos (CPF) is predominantly used and has been linked to various adverse health effects from acute to chronic exposure. Exposure to pesticides both occupationally and environmentally causes frequent human health problems including neurological disorders, liver, kidney dysfunctions and cancer. The acute and chronic effects of these environmental toxicants have been linked to epigenetic changes that appear shortly after exposure, but can last for a lifetime and possibly be passed down through generations. The present study investigates the effects of acute and chronic exposure to CPF, the predominantly used OPP globally on human liver cells, focusing on the induction of DNA damage and epigenetic alterations. Human normal liver cells (WRL-68) were acutely and chronically exposed to varying concentrations of CPF. The results revealed significant DNA damage, epigenetic changes and the onset of neoplastic transformation as evidenced by alterations in the DNA repair genes, DNA methyltransferases markers, cell cycle markers, epithelial to mesenchymal transition markers (EMT) and loss of apoptosis. Additionally, chronic CPF exposure led to increased colony formation, proliferation and migratory properties of normal liver cells indicating the neoplastic transformation of these cells. These findings highlight the potential of CPF to disrupt the cellular integrity and promote carcinogenesis in the liver cells. The present study underscores the impact of chronic CPF exposure in the initiation of cancer and also highlights the importance of continued research to fully understand the chronic health implications of CPF, for developing targeted interventions to mitigate its carcinogenic risks.
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Affiliation(s)
- Pavithra Balakrishnan
- Translational Genomics and Proteomics Laboratory, Department of Biotechnology, School of Biotechnology and Genetic Engineering, Bharathiar University, Coimbatore, 641046, India
| | - Kishore Thirunavukarasu
- Translational Genomics and Proteomics Laboratory, Department of Biotechnology, School of Biotechnology and Genetic Engineering, Bharathiar University, Coimbatore, 641046, India
| | - Priyadharshini Tamizhmani
- Translational Genomics and Proteomics Laboratory, Department of Biotechnology, School of Biotechnology and Genetic Engineering, Bharathiar University, Coimbatore, 641046, India
| | - Antony Anista Michael
- Translational Genomics and Proteomics Laboratory, Department of Biotechnology, School of Biotechnology and Genetic Engineering, Bharathiar University, Coimbatore, 641046, India
| | - Thirunavukkarasu Velusamy
- Translational Genomics and Proteomics Laboratory, Department of Biotechnology, School of Biotechnology and Genetic Engineering, Bharathiar University, Coimbatore, 641046, India.
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Elhosary E, Eldin Shibel PE, Eltoukhy M, Talaat R, Kamel M, Soliman NA. Downregulation of lncRNA-MALAT1, Altered Immunohistochemical Expression of Cyclin D1 Protein and E-Cadherin Protein in Correlation to Meningioma Grades. Asian Pac J Cancer Prev 2024; 25:4097-4107. [PMID: 39611935 PMCID: PMC11996092 DOI: 10.31557/apjcp.2024.25.11.4097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 11/13/2024] [Indexed: 11/30/2024] Open
Abstract
OBJECTIVES Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is known to be upregulated in the tumors with ability to metastasize. In contrast, long non-coding Ribonuclei acid (lncRNA) MALAT1 was reported by some studies to be downregulated in meningioma cells. E-cadherin and Cyclin D1 are prognostic indicators and possible attractive targets for the treatment of recurring and aggressive meningioma. This study aimed to evaluate the expression level of lncRNA MALAT1, as well as Cyclin D1 and E-cadherin immunohistochemical expression in meningiomas (Grade 1 and 2) and their association with the clinicopathological parameters of the studied cases. MATERIAL AND METHODS Quantitative determination of relative expression levels of lncRNA-MALAT1 in 64 cases of meningioma to 5 controls of normal dura mater was performed, in addition to evaluation of E-cadherin and Cyclin D1 immunohistochemical expression. The results were tested for association with the clinicopathological parameters. RESULTS lncRNA-MALAT1 expression were downregulated in 49/64 of the cases of meningioma (76%) in comparison to control. There were significant association of expression of lncRNA-MALAT1 with grade, brain invasion and increased mitosis (p=0.007, 0.04, 0.006 respectively). There were also significant associations of strong E-cadherin and negative Cyclin D1 proteins expression with grade 1 (p = 0.02, 0.004), low mitosis (p=0.03, and 0.04) and brain invasion (p=0.04, 0.03) respectively. Additionally, a significant weak negative correlation between E-cadherin and Cyclin D1 expression was fond, yet no significant correlation between lncRNA MALAT1 expression and either of E-cadherin or Cyclin D1 expression could be achieved. CONCLUSION lncRNA MALAT1 is downregulated in meningiomas and associated with increased aggressiveness. Overexpressed cyclin D1 and decreased E-cadherin expression are also associated with high grade meningioma.
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Affiliation(s)
- Enas Elhosary
- Department of Pathology, Faculty of Medicine, Helwan University, Helwan 11795, Egypt.
| | | | - Mohamed Eltoukhy
- Department of Neurosurgery, Faculty of Medicine, Cairo University, Cairo 12613, Egypt.
| | - Rania Talaat
- Department: Medical Microbiology and Immunology, Faculty of Medicine, Helwan University, Helwan 11795, Egypt.
| | - Marwa Kamel
- Department of Medical Biochemistry and Molecular biology, Faculty of Medicine, Helwan University, Helwan 11795, Egypt.
| | - Nahed Ahmed Soliman
- Department of Pathology, Faculty of Medicine, Helwan University, Helwan 11795, Egypt.
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Ni X, Wei Y, Li X, Pan J, Fang B, Zhang T, Lu Y, Ye D, Zhu Y. From biology to the clinic - exploring liver metastasis in prostate cancer. Nat Rev Urol 2024; 21:593-614. [PMID: 38671281 DOI: 10.1038/s41585-024-00875-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/22/2024] [Indexed: 04/28/2024]
Abstract
Liver metastases from prostate cancer are associated with an aggressive disease course and poor prognosis. Results from autopsy studies indicate a liver metastasis prevalence of up to 25% in patients with advanced prostate cancer. Population data estimate that ~3-10% of patients with metastatic castration-resistant prostate cancer harbour liver metastases at the baseline, rising to 20-30% in post-treatment cohorts, suggesting that selective pressure imposed by novel therapies might promote metastatic spread to the liver. Liver metastases are associated with more aggressive tumour biology than lung metastases. Molecular profiling of liver lesions showed an enrichment of low androgen receptor, neuroendocrine phenotypes and high genomic instability. Despite advancements in molecular imaging modalities such as prostate-specific membrane antigen PET-CT, and liquid biopsy markers such as circulating tumour DNA, early detection of liver metastases from prostate cancer remains challenging, as both approaches are hampered by false positive and false negative results, impeding the accurate identification of early liver lesions. Current therapeutic strategies showed limited efficacy in this patient population. Emerging targeted radionuclide therapies, metastasis-directed therapy, and novel systemic agents have shown preliminary activity against liver metastases, but require further validation. Treatment with various novel prostate cancer therapies might lead to an increase in the prevalence of liver metastasis, underscoring the urgent need for coordinated efforts across preclinical and clinical researchers to improve characterization, monitoring, and management of liver metastases from prostate cancer. Elucidating molecular drivers of liver tropism and interactions with the liver microenvironment might ultimately help to identify actionable targets to enhance survival in this high-risk patient group.
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Affiliation(s)
- Xudong Ni
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, China
| | - Yu Wei
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, China
| | - Xiaomeng Li
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, China
| | - Jian Pan
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, China
| | - Bangwei Fang
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, China
| | - Tingwei Zhang
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, China
| | - Ying Lu
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Dingwei Ye
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, China
| | - Yao Zhu
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Genitourinary Cancer Institute, Shanghai, China.
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12
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Phull AR, Arain SQ, Majid A, Fatima H, Ahmed M, Kim SJ. Oxidative stress-mediated epigenetic remodeling, metastatic progression and cell signaling in cancer. ONCOLOGIE 2024; 26:493-507. [DOI: 10.1515/oncologie-2024-0157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/16/2024]
Abstract
Abstract
Cancer is a serious public health issue and cases are rising at a high rate around the world. Altered production of reactive oxygen species (ROS) causes oxidative stress (OS) which plays a vital role in cancer development by disrupting signaling pathways and genomic integrity in the cellular microenvironment. In this study, we reviewed the regulation of noncoding RNAs, histone modifications, and DNA methylation which OS is involved in. These mechanisms promote cancer growth, metastasis, and resistance to chemotherapeutic agents. There is significant potential to improve patient outcomes through the development of customized medications and interventions that precisely address the role of OS in the onset and progression of cancer. Redox-modulating drugs, antioxidant-based therapies, and measures to restore regular cellular activity and OS-modulated signaling pathways are some examples of these strategies. One other hypothesis rationalizes the cancer-suppressing effect of OS, which acts as a two-edged condition that warns against the use of antioxidants for cancer treatment and management. The present study was executed to review the impact of OS on epigenetic machinery, the evolution of metastatic cancer, and how OS mediates cellular signaling. Along with, insights into the potential of targeting OS-mediated mechanisms for cancer therapy.
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Affiliation(s)
- Abdul-Rehman Phull
- Department of Biochemistry , 66858 Shah Abdul Latif University , Khairpur , Sindh , Pakistan
| | - Sadia Qamar Arain
- Department of Biochemistry , 66858 Shah Abdul Latif University , Khairpur , Sindh , Pakistan
| | - Abdul Majid
- Department of Biochemistry , 66858 Shah Abdul Latif University , Khairpur , Sindh , Pakistan
| | - Humaira Fatima
- Department of Pharmacy , Quaid-i-Azam University , Islamabad , Pakistan
| | - Madiha Ahmed
- Shifa College of Pharmaceutical Sciences , Shifa Tameer-e-Millat University , Islamabad , Pakistan
| | - Song-Ja Kim
- Department of Biological Sciences, College of Natural Sciences , Kongju National University , Gongju , South Korea
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13
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Chen Y, Zhang Y, Duo S, Liu W, Luo B. Study on the regulatory mechanism of latent membrane protein 2A on GCNT3 expression in nasopharyngeal carcinoma. Virus Genes 2024; 60:347-356. [PMID: 38739247 DOI: 10.1007/s11262-024-02071-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] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 04/06/2024] [Indexed: 05/14/2024]
Abstract
O-Glycan synthesis enzyme glucosaminyl (N-acetyl) transferase 3 (GCNT3) is closely related to the occurrence and development of various cancers. However, the regulatory mechanism and function of GCNT3 in nasopharyngeal carcinoma (NPC) are still poorly understood. This study aims to explore the regulatory mechanism of EBV-encoded latent membrane protein 2A (LMP2A) on GCNT3 and the biological role of GCNT3 in NPC. The results show that LMP2A can activate GCNT3 through the mTORC1 pathway, and there is a positive feedback between the mTORC1 and GCNT3. GCNT3 regulates EMT progression by forming a complex with ZEB1 to promote cell migration. GCNT3 can also promote cell proliferation. These findings indicate that targeting the LMP2A-mTORC1-GCNT3 axis may represent a novel therapeutic target in NPC.
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Affiliation(s)
- Yijing Chen
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China
- Department of Clinical Laboratory, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, China
| | - Yan Zhang
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China
- Department of Clinical Laboratory, Central Hospital of Zibo, Zibo, China
| | - Shi Duo
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Wen Liu
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China.
| | - Bing Luo
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China.
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14
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Antonova L, Paramanthan P, Falls T, Wedge ME, Mayer J, Sekhon HS, McPherson J, Denroche RE, Gallinger S, Bell JC, Ilkow CS, Chatterjee A. Molecular Characterization and Xenotransplantation of Pancreatic Cancer Using Endoscopic Ultrasound-Guided Fine Needle Aspiration (EUS-FNA). Cancers (Basel) 2024; 16:2721. [PMID: 39123450 PMCID: PMC11311391 DOI: 10.3390/cancers16152721] [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: 06/28/2024] [Revised: 07/21/2024] [Accepted: 07/25/2024] [Indexed: 08/12/2024] Open
Abstract
Pancreatic cancer has one of the worst prognoses among all malignancies and few available treatment options. Patient-derived xenografts can be used to develop personalized therapy for pancreatic cancer. Endoscopic ultrasound fine-needle aspiration (EUS-FNA) may provide a powerful alternative to surgery for obtaining sufficient tissue for the establishment of patient-derived xenografts. In this study, EUS-FNA samples were obtained for 30 patients referred to the Ottawa Hospital, Ottawa, Ontario, Canada. These samples were used for xenotransplantation in NOD-SCID mice and for genetic analyses. The gene expression of pancreatic-cancer-relevant genes in xenograft tumors was examined by immunohistochemistry. Targeted sequencing of both the patient-derived tumors and xenograft tumors was performed. The xenografts' susceptibility to oncolytic virus infection was studied by infecting xenograft-derived cells with VSV∆51-GFP. The xenograft take rate was found to be 75.9% for passage 1 and 100% for passage 2. Eighty percent of patient tumor samples were successfully sequenced to a high depth for 42 cancer genes. Xenograft histological characteristics and marker expression were maintained between passages. All tested xenograft samples were susceptible to oncoviral infection. We found that EUS-FNA is an accessible, minimally invasive technique that can be used to acquire adequate pancreatic cancer tissue for the generation of patient-derived xenografts and for genetic sequencing.
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Affiliation(s)
- Lilia Antonova
- Department of Otolaryngology-Head and Neck Surgery, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | - Piriya Paramanthan
- Division of Gastroenterology, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada
| | - Theresa Falls
- Centre for Cancer Therapeutics, Ottawa Health Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Marie-Eve Wedge
- Centre for Cancer Therapeutics, Ottawa Health Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Justin Mayer
- Centre for Cancer Therapeutics, Ottawa Health Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Harman S. Sekhon
- Division of Anatomic Pathology, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada;
| | - John McPherson
- Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada
| | | | - Steven Gallinger
- Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada
| | - John Cameron Bell
- Centre for Cancer Therapeutics, Ottawa Health Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Carolina S. Ilkow
- Centre for Cancer Therapeutics, Ottawa Health Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Avijit Chatterjee
- Division of Gastroenterology, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada
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15
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Meng Y, Wang Y, Liu L, Wu R, Zhang Q, Chen Z, Yao Y, Li X, Gong Y, Li H, Wang Z, Liu H. Immunohistochemistry identifies E-cadherin, N-cadherin and focal adhesion kinase (FAK) as predictors of stage I non-small cell lung carcinoma spread through the air spaces (STAS), and the combinations as prognostic factors. Transl Lung Cancer Res 2024; 13:1450-1462. [PMID: 39118895 PMCID: PMC11304152 DOI: 10.21037/tlcr-24-247] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 06/11/2024] [Indexed: 08/10/2024]
Abstract
Background Spread through air spaces (STAS) is one of the multiple modes of lung cancer dissemination, yet its molecular and clinicopathological characterization remains poorly studied. This study aimed to investigate the effect of adhesion molecule expression levels on the incidence of STAS and postoperative recurrence in stage I lung cancer patients undergoing radical resection. Methods E-cadherin, P-cadherin, N-cadherin, focal adhesion kinase (FAK), epithelial cell adhesion molecule (EpCAM), neural cell adhesion molecule 1 (NCAM1), vascular cell adhesion molecule 1 (VCAM1), intercellular cell adhesion molecule-1 (ICAM-1) were analyzed retrospectively using immunohistochemistry in patients undergoing radical resection for stage I non-small cell lung cancer (NSCLC). Patients were categorized into four groups based on adhesion molecule expression levels: "low/low", "high/low", "low/high", and "high/high", and the group with the lowest recurrence-free probability (RFP) was defined as high risk. Associations between those adhesion molecules' expression levels and STAS were determined by using the Chi-squared test and logistic regression model. RFP was analyzed by using the log-rank test and Cox proportional risk model. Results As of January 1, 2024, 12 of 60 patients undergoing radical resection for stage I lung carcinoma had a disease recurrence. All 60 patients' tissue specimens were retrospectively analyzed, and there were no significant differences between patients with STAS-positive (n=30) and STAS-negative (n=30) in baseline clinicopathologic features, except for histological growth patterns. We found that low expression of E-cadherin, high expression of N-cadherin and FAK, and males were independent predictors of higher incidence of STAS. Multivariate Cox analysis showed that tumors with low E-cadherin/high N-cadherin, low E-cadherin/high FAK, and high N-cadherin/high FAK expression were important predictors of recurrence in patients with stage I lung carcinoma. In addition, females and high N-cadherin/high FAK were associated with a high risk of recurrence in patients with STAS. Conclusions E-cadherin, N-cadherin, and FAK are predictors of STAS occurrence in stage I NSCLC, and their combinations are prognostic factors. The discovery of these molecular markers provides clinicians with a reliable means that may help in the early identification of individuals with a higher risk of recurrence in lung cancer patients, targeting personalized treatment plans such as aggressive adjuvant therapy or closer follow-up.
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Affiliation(s)
- Yunchang Meng
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, China
| | - Yimin Wang
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, China
| | - Leilei Liu
- Department of Pathology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Ranpu Wu
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Southeast University School of Medicine, Nanjing, China
| | - Qingfeng Zhang
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Zhangxuan Chen
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yang Yao
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xinjing Li
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yanzhuo Gong
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing University of Chinese Medicine, Nanjing, China
| | - Huijuan Li
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Zhaofeng Wang
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Hongbing Liu
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, China
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
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16
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Aggeletopoulou I, Konstantakis C, Triantos C. Chronic Atrophic Autoimmune Gastritis: The Evolving Role of Vitamin D. FRONT BIOSCI-LANDMRK 2024; 29:252. [PMID: 39082343 DOI: 10.31083/j.fbl2907252] [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: 04/02/2024] [Revised: 05/20/2024] [Accepted: 05/24/2024] [Indexed: 01/06/2025]
Abstract
Vitamin D possesses a crucial role in preserving bone health, modulating the immune system responses, and supporting various physiological functions throughout the body. Chronic atrophic autoimmune gastritis (CAAG) constitutes an autoimmune condition marked by inflammation and damage to the stomach cells, often resulting in a decreased ability to absorb certain nutrients, including vitamin B12 and iron. Although, vitamin D is not directly affected by this condition, the sufficiency of this micronutrient seems to have important implications for overall health and management of the disease. The aim of the current review was to assess the incidence and related features of vitamin D deficiency in patients with CAAG and to elucidate the complex regulatory role of this nutrient, in an effort to improve patient outcomes. Vitamin D greatly contributes to the regulation of the immune system. In patients with CAAG, the immune system attacks the stomach lining; thus, the maintenance of a healthy and balanced immune response is important. In autoimmune conditions such as CAAG, where inflammation plays a decisive role in disease progression, vitamin D could potentially exert a role in managing and controlling the associated symptoms. Adequate vitamin D levels may help in regulating the immune response and reducing inflammation. In addition, patients with CAAG are at risk of nutrient deficiencies, including vitamin B12 and iron, which can lead to anemia and bone health issues. As vitamin D is critical for calcium absorption and bone health, assurance of sufficient levels of this micronutrient can be beneficial in preventing or mitigating bone-related complications. In conclusion, regular monitoring of vitamin D levels, among other nutrients, and appropriate supplementation, when necessary, can help improve overall health and well-being in these patients.
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Affiliation(s)
- Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece
| | - Christos Konstantakis
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece
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17
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Feng L, Tang X, You Z. Undifferentiated sarcomatoid carcinoma of the pancreas-a single-institution experience with 23 cases. BMC Cancer 2024; 24:250. [PMID: 38389041 PMCID: PMC10885366 DOI: 10.1186/s12885-024-11988-2] [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: 10/18/2023] [Accepted: 02/09/2024] [Indexed: 02/24/2024] Open
Abstract
BACKGROUND The clinical course and surgical outcomes of undifferentiated sarcomatoid carcinoma of the pancreas (USCP) remain poorly characterized owing to its rarity. This study aimed to describe the histology, clinicopathologic features, perioperative outcomes, and overall survival (OS) of 23 resected USCP patients. METHODS We retrospectively described the histology, clinicopathologic features, perioperative outcomes and OS of patients who underwent pancreatectomy with a final diagnosis of USCP in a single institution. RESULTS A total of 23 patients were included in this study. Twelve patients were male, the median age at diagnosis was 61.5 ± 13.0 years (range: 35-89). Patients with USCP had no specific symptoms and characteristic imaging findings. The R0 resection was achieved in 21 cases. The En bloc resection and reconstruction of mesenteric-portal axis was undertaken in 9 patients. There were no deaths attributed to perioperative complications in this study. The intraoperative tumor-draining lymph nodes (TDLNs) dissection was undergone in 14 patients. The 1-, 3- and 5-year survival rates were 43.5%, 4.8% and 4.8% in the whole study, the median survival was 9.0 months. Only 1 patient had survived more than 5 years and was still alive at last follow-up. The presence of distant metastasis (p = 0.004) and the presence of pathologically confirmed mesenteric-portal axis invasion (p = 0.007) was independently associated with poor OS. CONCLUSIONS USCP was a rare subgroup of pancreatic malignancies with a bleak prognosis. To make a diagnose of USCP by imaging was quite difficult because of the absence of specific manifestations. Accurate diagnosis depended on pathological biopsy, and the IHC profile of USCP was mainly characterized by co-expression of epithelial and mesenchymal markers. A large proportion of patients have an early demise, especially for patients with distant metastasis and pathologically confirmed mesenteric-portal axis invasion. Long-term survival after radical resection of USCPs remains rare.
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Affiliation(s)
- Lei Feng
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, No.37, Guoxue Lane, Wuhou District, Chengdu, Sichuan, China
| | - Xiaojuan Tang
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, No.37, Guoxue Lane, Wuhou District, Chengdu, Sichuan, China
| | - Zhen You
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, No.37, Guoxue Lane, Wuhou District, Chengdu, Sichuan, China.
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18
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Hussein MA, Valinezhad K, Adel E, Munirathinam G. MALAT-1 Is a Key Regulator of Epithelial-Mesenchymal Transition in Cancer: A Potential Therapeutic Target for Metastasis. Cancers (Basel) 2024; 16:234. [PMID: 38201661 PMCID: PMC10778055 DOI: 10.3390/cancers16010234] [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: 12/12/2023] [Revised: 12/29/2023] [Accepted: 01/01/2024] [Indexed: 01/12/2024] Open
Abstract
Metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1) is a long intergenic non-coding RNA (lncRNA) located on chr11q13. It is overexpressed in several cancers and controls gene expression through chromatin modification, transcriptional regulation, and post-transcriptional regulation. Importantly, MALAT-1 stimulates cell proliferation, migration, and metastasis and serves a vital role in driving the epithelial-to-mesenchymal transition (EMT), subsequently acquiring cancer stem cell-like properties and developing drug resistance. MALAT-1 modulates EMT by interacting with various intracellular signaling pathways, notably the phosphoinositide 3-kinase (PI3K)/Akt and Wnt/β-catenin pathways. It also behaves like a sponge for microRNAs, preventing their interaction with target genes and promoting EMT. In addition, we have used bioinformatics online tools to highlight the disparities in the expression of MALAT-1 between normal and cancer samples using data from The Cancer Genome Atlas (TCGA). Furthermore, the intricate interplay of MALAT-1 with several essential targets of cancer progression and metastasis renders it a good candidate for therapeutic interventions. Several innovative approaches have been exploited to target MALAT-1, such as short hairpin RNAs (shRNAs), antisense oligonucleotides (ASOs), and natural products. This review emphasizes the interplay between MALAT-1 and EMT in modulating cancer metastasis, stemness, and chemoresistance in different cancers.
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Affiliation(s)
- Mohamed Ali Hussein
- Department of Pharmaceutical Services, Children’s Cancer Hospital Egypt, Cairo 57357, Egypt;
- Department of Biology, School of Sciences and Engineering, American University in Cairo, New Cairo 11835, Egypt;
| | - Kamyab Valinezhad
- Department of Biomedical Sciences, College of Medicine, University of Illinois, Rockford, IL 61107, USA;
| | - Eman Adel
- Department of Biology, School of Sciences and Engineering, American University in Cairo, New Cairo 11835, Egypt;
| | - Gnanasekar Munirathinam
- Department of Biomedical Sciences, College of Medicine, University of Illinois, Rockford, IL 61107, USA;
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Shi L, Zhang D, Han H, Zhang L, Li S, Yang F, He C. HOTAIR knockdown impairs metastasis of cervical cancer cells by down-regulating metastasis-related genes. J OBSTET GYNAECOL 2023; 43:2181060. [PMID: 36972141 DOI: 10.1080/01443615.2023.2181060] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
Abstract
This study investigated the role of LncRNA HOTAIR knockdown in the biological impacts on cervical cancer cells. The HOTAIR gene in two human cervical cancer cell lines was silenced with small interfering (si) RNA siHOTAIR. Proliferation, apoptosis, migration and invasion of cells were assessed following the knockdown. The expressions of Notch1, EpCAM, E-cadherin, vimentin and STAT3 were assessed using qRT-PCR and Western blotting analysis. Compared with controls, HOTAIR levels were reduced significantly, the OD values of cells were significantly decreased in proliferation assays, cell apoptosis was significantly increased, cell migration and invasion were significantly reduced after HOTAIR knockdown. Molecular analysis showed that Notch1, EpCAM, vimentin and STAT3 expressions were decreased significantly, while the expression of E-cadherin was significantly increased after HOTAIR knockdown. Rescue experiments further confirmed that Notch1 and STAT3 were involved in siHOTAIR-mediated reduction of migration and invasion of cervical cancer cells.IMPACT STATEMENTWhat is already known on this subject? Long non-coding RNAs including HOTAIR, is implicated in occurrence and development of cancer and have been explored to develop new therapeutic options for cancer.What do the results of this study add? HOTAIR silencing significantly reduces the viability and migration ability of cells and induces cell apoptosis, adding experimental data supporting the potential use of HOTAIR specific-siRNA as a therapeutic avenue for the cancer.What are the implications of these findings for clinical practice and/or further research? The finding from this study would help develop clinically applicable therapeutic avenues for the cancer and identify new treatment targets in the relevant pathways leading to new drugs or treatments.
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Affiliation(s)
- Lei Shi
- Department of Obstetrics and Gynecology, Daqing Oilfield General Hospital, Daqing, P.R. China
| | - Dehui Zhang
- Department of Oncology, Daqing Oilfield General Hospital and Huiren Cancer Hospital, Daqing, P.R. China
| | - Huijuan Han
- Department of Obstetrics and Gynecology, the 962 Hospital, Joint Logistics Support of the Chinese People's Liberation Army, Harbin, P.R. China
| | - Liangyu Zhang
- Department of Obstetrics and Gynecology, Daqing Oilfield General Hospital, Daqing, P.R. China
| | - Sirui Li
- Department of Obstetrics and Gynecology, Daqing Oilfield General Hospital, Daqing, P.R. China
| | - Fang Yang
- Department of Obstetrics and Gynecology, Daqing Oilfield General Hospital, Daqing, P.R. China
| | - Caijun He
- Department of Obstetrics and Gynecology, the 962 Hospital, Joint Logistics Support of the Chinese People's Liberation Army, Harbin, P.R. China
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20
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Schito L, Rey-Keim S. Hypoxia signaling and metastatic progression. Semin Cancer Biol 2023; 97:42-49. [PMID: 37926346 DOI: 10.1016/j.semcancer.2023.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 10/30/2023] [Accepted: 11/01/2023] [Indexed: 11/07/2023]
Abstract
Disruption of oxygen homeostasis, resulting from an imbalance between O2 supply and demand during malignant proliferation, leads to the development of hypoxic tumor microenvironments that promote the acquisition of aggressive cancer cell phenotypes linked to metastasis and patient mortality. In this review, the mechanistic links between tumor hypoxia and metastatic progression are presented. Current status and perspectives of targeting hypoxia signaling pathways as a strategy to halt cancer cell metastatic activities are emphasized.
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Affiliation(s)
- Luana Schito
- UCD School of Medicine, Belfield, Dublin D04 C7X2, Ireland; UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin D04 C7X2, Ireland.
| | - Sergio Rey-Keim
- UCD School of Medicine, Belfield, Dublin D04 C7X2, Ireland; UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin D04 C7X2, Ireland.
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21
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San-Millan I, Martinez JL, Pickard SL, Yu H, Hirsch FR, Rivard CJ, Brooks GA. Role of Lactate in the Regulation of Transcriptional Activity of Breast Cancer-Related Genes and Epithelial-to-Mesenchymal Transition Proteins: A Compassion of MCF7 and MDA-MB-231 Cancer Cell Lines. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.23.533060. [PMID: 36993762 PMCID: PMC10055400 DOI: 10.1101/2023.03.23.533060] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
Abstract
The Warburg Effect is characterized by accelerated glycolytic metabolism and lactate production and under fully aerobic conditions is a hallmark of cancer cells. Recently, we have demonstrated the role of endogenous, glucose-derived lactate as an oncometabolite which regulates gene expression in the estrogen receptor positive (ER+) MCF7 cell line cultivated in glucose media. Presently, with the addition of a triple negative breast cancer (TNBC) cell line, MDA-MB-231, we further confirm the effect of lactate on gene expression patterns and extend results to include lactate effects on protein expression. As well, we report effects of lactate on the expression of E-cadherin and vimentin, proteins associated with epithelial-to-mesenchymal transition (EMT). Endogenous lactate regulates the expression of multiple genes involved in carcinogenesis. In MCF7 cells, lactate increased the expression of EGFR, VEGF, HIF-1a, KRAS, MIF, mTOR, PIK3CA, TP53, and CDK4 as well as decreased the expression of ATM, BRCA1, BRCA2, E2F1, MET, MYC, and RAF mainly after 48h of exposure. On the other hand, in the MDA-MB-231 cell line, lactate increased the expressions of PIK3CA, VEGF, EGFR, mTOR, HIF-1α, ATM, E2F1, TP53 and decreased the expressions of BRCA1, BRCA2, CDK4, CDK6, MET, MIF, MYC, and RAF after 48h of exposure. In response to endogenous lactate, changes in protein expression of representative genes corroborated changes in mRNA expressions. Finally, lactate exposure decreased E-cadherin protein expression in MCF7 cells and increased vimentin expression in MDA-MB-231 cells. Furthermore, by genetically silencing LDHA in MCF7 cells, we show suppression of protein expression of EGFR and HIF-1α, while full protein expression occurred under glucose and glucose + exogenous lactate exposure. Hence, endogenous, glucose-derived lactate, and not glucose, elicited changes in gene and protein expression levels. In this study, we demonstrate that endogenous lactate produced under aerobic conditions (Warburg Effect) elicits important changes in gene and protein expression in both ER+ and TNBC cell lines. The widespread regulation of multiple genes by lactate and involves those involved in carcinogenesis including DNA repair, cell growth, proliferation, angiogenesis, and metastasis. Furthermore, lactate affected the expression of two relevant EMT biomarkers, E-cadherin and vimentin, which could contribute to the complex process of EMT and a shift towards a more mesenchymal phenotype in the two cancer cell lines studied.
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Affiliation(s)
- Inigo San-Millan
- Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Department of Human Physiology and Nutrition, University of Colorado, Colorado Springs, CO, USA
| | - Janel L. Martinez
- Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Shivaun Lueke Pickard
- Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Hui Yu
- Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Fred R. Hirsch
- Tisch Cancer Institute, Center for Thoracic Oncology, Mount Sinai Health System, New York, NY, USA
| | - Christopher J. Rivard
- Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - George A. Brooks
- Department of Integrative Biology, University of California, Berkeley, Berkeley, CA, USA
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22
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Karjula T, Kemi N, Niskakangas A, Mustonen O, Puro I, Pohjanen VM, Kuopio T, Elomaa H, Ahtiainen M, Mecklin JP, Seppälä TT, Wirta EV, Sihvo E, Väyrynen JP, Yannopoulos F, Helminen O. The prognostic role of tumor budding and tumor-stroma ratio in pulmonary metastasis of colorectal carcinoma. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2023; 49:1298-1306. [PMID: 36841693 DOI: 10.1016/j.ejso.2023.02.009] [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: 12/07/2022] [Revised: 01/25/2023] [Accepted: 02/14/2023] [Indexed: 02/25/2023]
Abstract
OBJECTIVE To evaluate the prognostic value of tumor budding and tumor-stroma ratio (TSR) in resected pulmonary metastases of colorectal carcinoma (CRC). METHODS In total, 106 pulmonary metastasectomies were performed to 74 patients in two study hospitals during 2000-2020. All relevant clinical data were retrospectively collected. Tumor budding based on the International Tumor Budding Consensus Conference recommendations and TSR in the first resected pulmonary metastases and primary tumors were evaluated from diagnostic hematoxylin-eosin-stained histopathological slides. RESULTS 60 patients (85.7%) had low tumor budding (≤5 buds/field) and 10 patients (14.3%) had high tumor budding (>5 buds/field) in their first pulmonary metastases of CRC. 5-year overall survival rates of pulmonary metastasectomy in low and high total tumor budding were 28.3% and 37.3% (p = 0.387), respectively. 19 patients (27.1%) had low TSR and 51 patients (72.9%) had high TSR. The 5-year overall survival rates were 32.9% in low and 28.6% in high TSR of first pulmonary metastases (p = 0.746). Tumor budding and TSR did not provide prognostic value in Cox multivariate analysis. Tumor budding and TSR in resected pulmonary metastases were not associated with those of the primary tumor. CONCLUSION Tumor budding and TSR in the resected pulmonary metastases of CRC showed no statistically significant prognostic value, however, additional well-powered confirmatory studies are needed.
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Affiliation(s)
- Topias Karjula
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
| | - Niko Kemi
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Anne Niskakangas
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Olli Mustonen
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Iiris Puro
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Vesa-Matti Pohjanen
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Teijo Kuopio
- Department of Biological and Environmental Science, University of Jyväskylä, 40014, Jyväskylä, Finland; Department of Pathology, Central Finland Health Care District, 40620, Jyväskylä, Finland
| | - Hanna Elomaa
- Department of Biological and Environmental Science, University of Jyväskylä, 40014, Jyväskylä, Finland; Department of Education and Research, Central Finland Health Care District, 40620, Jyväskylä, Finland
| | - Maarit Ahtiainen
- Department of Pathology, Central Finland Health Care District, 40620, Jyväskylä, Finland
| | - Jukka-Pekka Mecklin
- Department of Education and Research, Central Finland Health Care District, 40620, Jyväskylä, Finland; Faculty of Sport and Health Sciences, University of Jyväskylä, 40014, Jyväskylä, Finland
| | - Toni T Seppälä
- Faculty of Medicine and Health Technology, Tampere University and TAYS Cancer Center, Tampere University Hospital, 33520, Tampere, Finland; Department of Gastrointestinal Surgery, Helsinki University Central Hospital, University of Helsinki, 00290, Helsinki, Finland; Applied Tumor Genomics, Research Program Unit, University of Helsinki, 00290, Helsinki, Finland
| | - Erkki-Ville Wirta
- Faculty of Medicine and Health Technology, Tampere University and TAYS Cancer Center, Tampere University Hospital, 33520, Tampere, Finland; Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, 33520, Tampere, Finland
| | - Eero Sihvo
- Central Hospital of Central Finland, 40014, Jyväskylä, Finland
| | - Juha P Väyrynen
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Fredrik Yannopoulos
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland; Department of Cardiothoracic Surgery, Oulu University Hospital, Oulu, Finland; University Hospital and University of Oulu, 90014, Oulu, Finland
| | - Olli Helminen
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
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23
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Omar Osman I, Mezouar S, Brahim-Belhaouari D, Mege JL, Devaux CA. Modulation of the E-cadherin in human cells infected in vitro with Coxiella burnetii. PLoS One 2023; 18:e0285577. [PMID: 37285354 PMCID: PMC10246793 DOI: 10.1371/journal.pone.0285577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 04/25/2023] [Indexed: 06/09/2023] Open
Abstract
High concentration of soluble E-cadherin (E-cad) was previously found in sera from Q fever patients. Here, BeWo cells which express a high concentration of E-cad were used as an in vitro model to investigate the expression and function of E-cad in response to infection by Coxiella burnetii, the etiological agent of Q fever. Infection of BeWo cells with C. burnetii leads to a decrease in the number of BeWo cells expressing E-cad at their membrane. A shedding of soluble E-cad was associated with the post-infection decrease of membrane-bound E-cad. The modulation of E-cad expression requires bacterial viability and was not found with heat-inactivated C. burnetii. Moreover, the intracytoplasmic cell concentration of β-catenin (β-cat), a ligand of E-cad, was reduced after bacterial infection, suggesting that the bacterium induces modulation of the E-cad/β-cat signaling pathway and CDH1 and CTNNB1 genes transcription. Finally, several genes operating the canonical Wnt-Frizzled/β-cat pathway were overexpressed in cells infected with C. burnetii. This was particularly evident with the highly virulent strain of C. burnetii, Guiana. Our data demonstrate that infection of BeWo cells by live C. burnetii modulates the E-cad/β-cat signaling pathway.
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Affiliation(s)
- Ikram Omar Osman
- Aix-Marseille Univ, IRD, APHM, MEPHI, Marseille, France
- IHU-Méditerranée Infection, Marseille, France
| | - Soraya Mezouar
- Aix-Marseille Univ, IRD, APHM, MEPHI, Marseille, France
- IHU-Méditerranée Infection, Marseille, France
| | - Djamal Brahim-Belhaouari
- Aix-Marseille Univ, IRD, APHM, MEPHI, Marseille, France
- IHU-Méditerranée Infection, Marseille, France
| | - Jean-Louis Mege
- Aix-Marseille Univ, IRD, APHM, MEPHI, Marseille, France
- IHU-Méditerranée Infection, Marseille, France
| | - Christian Albert Devaux
- Aix-Marseille Univ, IRD, APHM, MEPHI, Marseille, France
- IHU-Méditerranée Infection, Marseille, France
- CNRS, Marseille, France
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24
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Yetkin S, Alotaibi H. Selection and validation of novel stable reference genes for qPCR analysis in EMT and MET. Exp Cell Res 2023; 428:113619. [PMID: 37146958 DOI: 10.1016/j.yexcr.2023.113619] [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: 02/25/2023] [Revised: 04/18/2023] [Accepted: 04/29/2023] [Indexed: 05/07/2023]
Abstract
Quantitative real-time polymerase chain reaction is a powerful tool for quantifying gene expression. The relative quantification relies on normalizing the data to reference genes or internal controls not modulated by the experimental conditions. The most widely used internal controls occasionally show changed expression patterns in different experimental settings, such as the mesenchymal to epithelial transition. Thus, identifying appropriate internal controls is of utmost importance. We analyzed multiple RNA-Seq datasets using a combination of statistical approaches such as percent relative range and coefficient of variance to define a list of candidate internal control genes, which was then validated experimentally and by using in silico analyses as well. We identified a group of genes as strong internal control candidates with high stability compared to the classical ones. We also presented evidence for the superiority of the percent relative range method for calculating expression stability in data sets with larger sample sizes. We used multiple methods to analyze data collected from several RNA-Seq datasets; we identified Rbm17 and Katna1 as the most stable reference genes in EMT/MET studies. The percent relative range approach surpasses other methods when analyzing datasets of larger sample sizes.
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Affiliation(s)
- Seray Yetkin
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University Health Campus, 35340, Balçova, İzmir, Turkey
| | - Hani Alotaibi
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University Health Campus, 35340, Balçova, İzmir, Turkey; Izmir Biomedicine and Genome Center, Dokuz Eylül University Health Campus, 35340, Balçova, İzmir, Turkey.
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25
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Dytrych P, Kejík Z, Hajduch J, Kaplánek R, Veselá K, Kučnirová K, Skaličková M, Venhauerová A, Hoskovec D, Martásek P, Jakubek M. Therapeutic potential and limitations of curcumin as antimetastatic agent. Biomed Pharmacother 2023; 163:114758. [PMID: 37141738 DOI: 10.1016/j.biopha.2023.114758] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/18/2023] [Accepted: 04/20/2023] [Indexed: 05/06/2023] Open
Abstract
Treatment of metastatic cancer is one of the biggest challenges in anticancer therapy. Curcumin is interesting nature polyphenolic compound with unique biological and medicinal effects, including repression of metastases. High impact studies imply that curcumin can modulate the immune system, independently target various metastatic signalling pathways, and repress migration and invasiveness of cancer cells. This review discusses the potential of curcumin as an antimetastatic agent and describes potential mechanisms of its antimetastatic activity. In addition, possible strategies (curcumin formulation, optimization of the method of administration and modification of its structure motif) to overcome its limitation such as low solubility and bioactivity are also presented. These strategies are discussed in the context of clinical trials and relevant biological studies.
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Affiliation(s)
- Petr Dytrych
- 1st Department of Surgery-Department of Abdominal, Thoracic Surgery and Traumatology, First Faculty of Medicine, Charles University and General University Hospital, U Nemocnice 2, 121 08 Prague, Czech Republic
| | - Zdeněk Kejík
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - Jan Hajduch
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic
| | - Robert Kaplánek
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic
| | - Kateřina Veselá
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - Kateřina Kučnirová
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - Markéta Skaličková
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - Anna Venhauerová
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - David Hoskovec
- 1st Department of Surgery-Department of Abdominal, Thoracic Surgery and Traumatology, First Faculty of Medicine, Charles University and General University Hospital, U Nemocnice 2, 121 08 Prague, Czech Republic
| | - Pavel Martásek
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic.
| | - Milan Jakubek
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic.
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26
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Aida T, Iwase R, Usuba T, Kumagai Y, Furukawa K, Onda S, Ogawa M, Ikegami T. Successful resection of port site recurrence of pancreatic ductal adenocarcinoma after laparoscopic distal pancreatectomy. Surg Case Rep 2023; 9:35. [PMID: 36867254 PMCID: PMC9984651 DOI: 10.1186/s40792-023-01607-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 02/10/2023] [Indexed: 03/04/2023] Open
Abstract
BACKGROUND There are many reports of port site recurrence after laparoscopic surgery for various types of cancer. However, only two cases of port site recurrence after laparoscopic pancreatectomy have been reported to date. We herein report a case of port site recurrence after laparoscopic distal pancreatectomy. CASE PRESENTATION A 73-year-old woman was diagnosed with pancreatic tail cancer and underwent laparoscopic distal pancreatectomy with splenectomy. Histopathological examination revealed pancreatic ductal carcinoma (pT1N0M0 pStage I). The patient was discharged on postoperative day 14 with no complications. However, 5 months after surgery, computed tomography showed a small tumor at the right abdominal wall. No distant metastasis had appeared after 7 months of follow-up. Under the diagnosis of port site recurrence without any other metastases, we resected this abdominal tumor. Histopathological examination showed port site recurrence of pancreatic ductal carcinoma. No recurrence was observed 15 months postoperatively. CONCLUSIONS This is the report of successful resection of port site recurrence of pancreatic cancer.
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Affiliation(s)
- Takashi Aida
- grid.411898.d0000 0001 0661 2073Department of Surgery, The Jikei University Katsushika Medical Center, 6-41-2, Aoto, Katsushika-Ku, Tokyo, 125-8506 Japan
| | - Ryota Iwase
- grid.411898.d0000 0001 0661 2073Department of Surgery, The Jikei University Katsushika Medical Center, 6-41-2, Aoto, Katsushika-Ku, Tokyo, 125-8506 Japan
| | - Teruyuki Usuba
- grid.411898.d0000 0001 0661 2073Department of Surgery, The Jikei University Katsushika Medical Center, 6-41-2, Aoto, Katsushika-Ku, Tokyo, 125-8506 Japan
| | - Yu Kumagai
- grid.411898.d0000 0001 0661 2073Department of Surgery, The Jikei University Katsushika Medical Center, 6-41-2, Aoto, Katsushika-Ku, Tokyo, 125-8506 Japan
| | - Kenei Furukawa
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan.
| | - Shinji Onda
- grid.411898.d0000 0001 0661 2073Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461 Japan
| | - Masaichi Ogawa
- grid.411898.d0000 0001 0661 2073Department of Surgery, The Jikei University Katsushika Medical Center, 6-41-2, Aoto, Katsushika-Ku, Tokyo, 125-8506 Japan
| | - Toru Ikegami
- grid.411898.d0000 0001 0661 2073Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461 Japan
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Guo M, Niu Y, Xie M, Liu X, Li X. Notch signaling, hypoxia, and cancer. Front Oncol 2023; 13:1078768. [PMID: 36798826 PMCID: PMC9927648 DOI: 10.3389/fonc.2023.1078768] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 01/19/2023] [Indexed: 02/04/2023] Open
Abstract
Notch signaling is involved in cell fate determination and deregulated in human solid tumors. Hypoxia is an important feature in many solid tumors, which activates hypoxia-induced factors (HIFs) and their downstream targets to promote tumorigenesis and cancer development. Recently, HIFs have been shown to trigger the Notch signaling pathway in a variety of organisms and tissues. In this review, we focus on the pro- and anti-tumorigenic functions of Notch signaling and discuss the crosstalk between Notch signaling and cellular hypoxic response in cancer pathogenesis, including epithelia-mesenchymal transition, angiogenesis, and the maintenance of cancer stem cells. The pharmacological strategies targeting Notch signaling and hypoxia in cancer are also discussed in this review.
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Affiliation(s)
- Mingzhou Guo
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Yang Niu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Min Xie
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Xiansheng Liu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Xiaochen Li
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China,*Correspondence: Xiaochen Li,
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28
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Dos Santos JF, Freitas-Marchi BL, Reigado GR, de Assis SR, Maria Engler SS, Chambergo Alcalde FS, Nunes VA. Mesenchymal stem cells express epidermal markers in an in vitro reconstructed human skin model. Front Cell Dev Biol 2023; 10:1012637. [PMID: 36712971 PMCID: PMC9878690 DOI: 10.3389/fcell.2022.1012637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 12/28/2022] [Indexed: 01/13/2023] Open
Abstract
Introduction: In skin traumas, such as burns, epidermal homeostasis is affected, often requiring clinical approaches. Different therapeutic strategies can be used including transplantation, besides the use of synthetic or natural materials with allogeneic cells. In this context, tissue engineering is an essential tool for skin regeneration, and using mesenchymal stem cells (MSC) from the umbilical cord appears to be a promising strategy in regenerative medicine due to its renewal and differentiation potential and hypo immunogenicity. We evaluated the transdifferentiation of MSC from umbilical cord into keratinocytes in three-dimensional (3D) in vitro skin models, using dermal equivalents composed by type I collagen with dermal fibroblasts and a commercial porcine skin decellularized matrix, both cultured at air-liquid interface (ALI). Methods: The expression of epidermal proteins cytokeratins (CK) 5, 14 and 10, involucrin and filaggrin was investigated by real-time PCR and immunofluorescence, in addition to the activity of epidermal kallikreins (KLK) on the hydrolysis of fluorogenic substrates. Results and discussion: The cultivation of MSCs with differentiation medium on these dermal supports resulted in organotypic cultures characterized by the expression of the epidermal markers CK5, CK14, CK10 and involucrin, mainly on the 7th day of culture, and filaggrin at 10th day in ALI. Also, there was a 3-fold increase in the KLK activity in the epidermal equivalents composed by MSC induced to differentiate into keratinocytes compared to the control (MSC cultivated in the proliferation medium). Specifically, the use of collagen and fibroblasts resulted in a more organized MSC-based organotypic culture in comparison to the decellularized matrix. Despite the non-typical epithelium structure formed by MSC onto dermal equivalents, the expression of important epidermal markers in addition to the paracrine effects of these cells in skin may indicate its potential use to produce skin-based substitutes.
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Affiliation(s)
- Jeniffer Farias Dos Santos
- Laboratory of Skin Physiology and Tissue Bioengineering, School of Arts, Sciences and Humanities, University of Sao Paulo (EACH-USP), São Paulo, São Paulo, Brazil
| | - Bruna Letícia Freitas-Marchi
- Laboratory of Skin Physiology and Tissue Bioengineering, School of Arts, Sciences and Humanities, University of Sao Paulo (EACH-USP), São Paulo, São Paulo, Brazil
| | - Gustavo Roncoli Reigado
- Laboratory of Skin Physiology and Tissue Bioengineering, School of Arts, Sciences and Humanities, University of Sao Paulo (EACH-USP), São Paulo, São Paulo, Brazil
| | - Silvia Romano de Assis
- Skin Biology Group, iNOVA Pele, School of Pharmaceutical Sciences (FCF), University of São Paulo, São Paulo, São Paulo, Brazil
| | - Silvya Stuchi Maria Engler
- Skin Biology Group, iNOVA Pele, School of Pharmaceutical Sciences (FCF), University of São Paulo, São Paulo, São Paulo, Brazil
| | - Felipe Santiago Chambergo Alcalde
- Laboratory of Skin Physiology and Tissue Bioengineering, School of Arts, Sciences and Humanities, University of Sao Paulo (EACH-USP), São Paulo, São Paulo, Brazil
| | - Viviane Abreu Nunes
- Laboratory of Skin Physiology and Tissue Bioengineering, School of Arts, Sciences and Humanities, University of Sao Paulo (EACH-USP), São Paulo, São Paulo, Brazil,*Correspondence: Viviane Abreu Nunes,
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29
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Chaudhary A, Raza SS, Haque R. Transcriptional factors targeting in cancer stem cells for tumor modulation. Semin Cancer Biol 2023; 88:123-137. [PMID: 36603792 DOI: 10.1016/j.semcancer.2022.12.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 12/29/2022] [Accepted: 12/30/2022] [Indexed: 01/03/2023]
Abstract
Cancer Stem Cells (CSCs) are now considered the primary "seeds" for the onset, development, metastasis, and recurrence of tumors. Despite therapeutic breakthroughs, cancer remains the leading cause of death worldwide. This is because the tumor microenvironment contains a key population of cells known as CSCs, which promote tumor aggression. CSCs are self-renewing cells that aid tumor recurrence by promoting tumor growth and persisting in patients after many traditional cancer treatments. According to reports, numerous transcription factors (TF) play a key role in maintaining CSC pluripotency and its self-renewal property. The understanding of the functions, structures, and interactional dynamics of these transcription factors with DNA has modified the hypothesis, paving the way for novel transcription factor-targeted therapies. These TFs, which are crucial and are required by cancer cells, play a vital function in the etiology of human cancer. Such CSC TFs will help with gene expression profiling, which provides crucial data for predicting the prognosis of patients. To overcome anti-cancer medication resistance and completely eradicate cancer, a potent therapy combining TFs-based CSC targets with traditional chemotherapy may be developed. In order to develop therapies that could eliminate CSCs, we here concentrated on the effect of TFs and other components of signalling pathways on cancer stemness.
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Affiliation(s)
- Archana Chaudhary
- Department of Biotechnology, School of Earth Biological and Environmental Sciences, Central University of South Bihar, Gaya, Bihar, India
| | - Syed Shadab Raza
- Laboratory for Stem Cell & Restorative Neurology, Era's Lucknow Medical College and Hospital, Era University, Lucknow, India
| | - Rizwanul Haque
- Department of Biotechnology, School of Earth Biological and Environmental Sciences, Central University of South Bihar, Gaya, Bihar, India.
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Medina S, Ihrie RA, Irish JM. Learning cell identity in immunology, neuroscience, and cancer. Semin Immunopathol 2023; 45:3-16. [PMID: 36534139 PMCID: PMC9762661 DOI: 10.1007/s00281-022-00976-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 11/19/2022] [Indexed: 12/23/2022]
Abstract
Suspension and imaging cytometry techniques that simultaneously measure hundreds of cellular features are powering a new era of cell biology and transforming our understanding of human tissues and tumors. However, a central challenge remains in learning the identities of unexpected or novel cell types. Cell identification rubrics that could assist trainees, whether human or machine, are not always rigorously defined, vary greatly by field, and differentially rely on cell intrinsic measurements, cell extrinsic tissue measurements, or external contextual information such as clinical outcomes. This challenge is especially acute in the context of tumors, where cells aberrantly express developmental programs that are normally time, location, or cell-type restricted. Well-established fields have contrasting practices for cell identity that have emerged from convention and convenience as much as design. For example, early immunology focused on identifying minimal sets of protein features that mark individual, functionally distinct cells. In neuroscience, features including morphology, development, and anatomical location were typical starting points for defining cell types. Both immunology and neuroscience now aim to link standardized measurements of protein or RNA to informative cell functions such as electrophysiology, connectivity, lineage potential, phospho-protein signaling, cell suppression, and tumor cell killing ability. The expansion of automated, machine-driven methods for learning cell identity has further created an urgent need for a harmonized framework for distinguishing cell identity across fields and technology platforms. Here, we compare practices in the fields of immunology and neuroscience, highlight concepts from each that might work well in the other, and propose ways to implement these ideas to study neural and immune cell interactions in brain tumors and associated model systems.
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Affiliation(s)
- Stephanie Medina
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Rebecca A Ihrie
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
- Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jonathan M Irish
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
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An Overview of Epithelial-to-Mesenchymal Transition and Mesenchymal-to-Epithelial Transition in Canine Tumors: How Far Have We Come? Vet Sci 2022; 10:vetsci10010019. [PMID: 36669020 PMCID: PMC9865109 DOI: 10.3390/vetsci10010019] [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: 11/18/2022] [Revised: 12/23/2022] [Accepted: 12/24/2022] [Indexed: 12/31/2022] Open
Abstract
Historically, pre-clinical and clinical studies in human medicine have provided new insights, pushing forward the contemporary knowledge. The new results represented a motivation for investigators in specific fields of veterinary medicine, who addressed the same research topics from different perspectives in studies based on experimental and spontaneous animal disease models. The study of different pheno-genotypic contexts contributes to the confirmation of translational models of pathologic mechanisms. This review provides an overview of EMT and MET processes in both human and canine species. While human medicine rapidly advances, having a large amount of information available, veterinary medicine is not at the same level. This situation should provide motivation for the veterinary medicine research field, to apply the knowledge on humans to research in pets. By merging the knowledge of these two disciplines, better and faster results can be achieved, thus improving human and canine health.
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Li G, Fu Q, Liu C, Peng Y, Gong J, Li S, Huang Y, Zhang H. The regulatory role of N6-methyladenosine RNA modification in gastric cancer: Molecular mechanisms and potential therapeutic targets. Front Oncol 2022; 12:1074307. [PMID: 36561529 PMCID: PMC9763625 DOI: 10.3389/fonc.2022.1074307] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 11/16/2022] [Indexed: 12/12/2022] Open
Abstract
N6-methyladenosinen (m6A) methylation is a frequent RNA methylation modification that is regulated by three proteins: "writers", "erasers", and "readers". The m6A modification regulates RNA stability and other mechanisms, including translation, cleavage, and degradation. Interestingly, recent research has linked m6A RNA modification to the occurrence and development of cancers, such as hepatocellular carcinoma and non-small cell lung cancer. This review summarizes the regulatory role of m6A RNA modification in gastric cancer (GC), including targets, the mechanisms of action, and the potential signaling pathways. Our present findings can facilitate our understanding of the significance of m6A RNA modification in GC.
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Affiliation(s)
- Gaofeng Li
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China
| | - Qiru Fu
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China
| | - Cong Liu
- Editorial Department of Journal of Hubei University of Science and Technology, Xianning, Hubei, China
| | - Yuxi Peng
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China
| | - Jun Gong
- Department of Abdominal and Pelvic Medical Oncology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, Hubei, China
| | - Shilan Li
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China
| | - Yan Huang
- Department of Clinical Laboratory, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, Hubei, China,*Correspondence: Haiyuan Zhang, ; Yan Huang,
| | - Haiyuan Zhang
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China,*Correspondence: Haiyuan Zhang, ; Yan Huang,
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Guo Y, Jiang Y, Rose JB, Nagaraju GP, Jaskula-Sztul R, Hjelmeland AB, Beck AW, Chen H, Ren B. Protein Kinase D1 Signaling in Cancer Stem Cells with Epithelial-Mesenchymal Plasticity. Cells 2022; 11:3885. [PMID: 36497140 PMCID: PMC9739736 DOI: 10.3390/cells11233885] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/10/2022] [Accepted: 11/20/2022] [Indexed: 12/05/2022] Open
Abstract
Pancreatic neuroendocrine tumors (pNETs) are extremely diverse and highly vascularized neoplasms that arise from endocrine cells in the pancreas. The pNETs harbor a subpopulation of stem cell-like malignant cells, known as cancer stem cells (CSCs), which contribute to intratumoral heterogeneity and promote tumor maintenance and recurrence. In this study, we demonstrate that CSCs in human pNETs co-express protein kinase PKD1 and CD44. We further identify PKD1 signaling as a critical pathway in the control of CSC maintenance in pNET cells. PKD1 signaling regulates the expression of a CSC- and EMT-related gene signature and promotes CSC self-renewal, likely leading to the preservation of a subpopulation of CSCs at an intermediate EMT state. This suggests that the PKD1 signaling pathway may be required for the development of a unique CSC phenotype with plasticity and partial EMT. Given that the signaling networks connected with CSC maintenance and EMT are complex, and extend through multiple levels of regulation, this study provides insight into signaling regulation of CSC plasticity and partial EMT in determining the fate of CSCs. Inhibition of the PKD1 pathway may facilitate the elimination of specific CSC subsets, thereby curbing tumor progression and metastasis.
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Affiliation(s)
- Yichen Guo
- Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Yinan Jiang
- Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - J. Bart Rose
- Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- O’Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Ganji Purnachandra Nagaraju
- Department of Medicine, Division of Hematology and Oncology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Renata Jaskula-Sztul
- Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- O’Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Anita B. Hjelmeland
- O’Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Department of Cell Developmental and Integrative Biology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Adam W. Beck
- Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Herbert Chen
- Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- O’Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Bin Ren
- Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- O’Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- GBS Biomedical Engineering Program, Graduate School, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Liu C, Mohan SC, Wei J, Seki E, Liu M, Basho R, Giuliano AE, Zhao Y, Cui X. Breast cancer liver metastasis: Pathogenesis and clinical implications. Front Oncol 2022; 12:1043771. [PMID: 36387238 PMCID: PMC9641291 DOI: 10.3389/fonc.2022.1043771] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 10/04/2022] [Indexed: 09/30/2023] Open
Abstract
Breast cancer is the most common malignant disease in female patients worldwide and can spread to almost every place in the human body, most frequently metastasizing to lymph nodes, bones, lungs, liver and brain. The liver is a common metastatic location for solid cancers as a whole, and it is also the third most common metastatic site for breast cancer. Breast cancer liver metastasis (BCLM) is a complex process. Although the hepatic microenvironment and liver sinusoidal structure are crucial factors for the initial arrest of breast cancer and progression within the liver, the biological basis of BCLM remains to be elucidated. Importantly, further understanding of the interaction between breast cancer cells and hepatic microenvironment in the liver metastasis of breast cancer will suggest ways for the development of effective therapy and prevention strategies for BCLM. In this review, we provide an overview of the recent advances in the understanding of the molecular mechanisms of the hepatic microenvironment in BCLM formation and discuss current systemic therapies for treating patients with BCLM as well as potential therapeutic development based on the liver microenvironment-associated signaling proteins governing BCLM.
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Affiliation(s)
- Cuiwei Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Srivarshini C. Mohan
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Jielin Wei
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ekihiro Seki
- Department of Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Manran Liu
- Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Reva Basho
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- The Lawrence J. Ellison Institute for Transformative Medicine, Los Angeles, CA, United States
| | - Armando E. Giuliano
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Yanxia Zhao
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaojiang Cui
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
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35
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Li Y, Zhang L, Xiong W, Gao X, Xiong Y, Sun W. A Molecular Mechanism Study to Reveal Hirudin's Downregulation to PI3K/AKT Signaling Pathway through Decreasing PDGFR β in Renal Fibrosis Treatment. BIOMED RESEARCH INTERNATIONAL 2022; 2022:5481552. [PMID: 36119923 PMCID: PMC9473867 DOI: 10.1155/2022/5481552] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 07/26/2022] [Accepted: 08/05/2022] [Indexed: 11/29/2022]
Abstract
Chronic kidney disease (CKD) is identified as a widespread chronic progressive disease jeopardizing public health which characterized by gradually loss of renal function. However, there is no efficient therapy to prevail over this disease. Our study was attempting to reveal hirudin's regulation to renal fibrosis as well as the molecular mechanism. We built renal fibrosis models on both cell and animal levels, which were subsequently given with hirudin disposal; then, we performed the transwell assay to estimate the cells' migration and had our detection to relevant proteins with western blot and immunofluorescence. Finally, we commenced both the identification and the determination to the hirudin targeted proteins and its downstream signaling pathways with the methods of network pharmacology. And the results turned out that when it was compared with the model group, the group with hirudin addition came with the suppression in the migration of renal tubular epithelial cells NRK-52E and with a conspicuous decline in the expressions of fibronectin, N-cadherin, vimentin, TGF-β, and snail. After that, we predicted that there were 17 hirudin target points mainly involving in the PI3K-AKT signaling pathway. Our outcomes of the animal level demonstrated that the conditions of interstitial fibrosis, severe tubular dilatation or atrophy, inflammatory cell infiltration, and massive accumulation of interstitial collagen in the model group were withdrawn after the addition of hirudin. In addition, p-PDGFRβ, p-PI3K, and p-AKT protein expressions were significantly reduced, and the PI3K/AKT pathway was downregulated after hirudin treatment in the model group of NRK-52E cells and animals. Therefore, we had our conclusion that hirudin is capable of suppressing the PI3K-AKT signaling pathway as well as the EMT by decreasing PDGFRβ phosphorylation.
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Affiliation(s)
- Ying Li
- Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Ling Zhang
- Department of Nephrology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400021, China
| | - Weijian Xiong
- Department of Nephrology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400021, China
| | - Xuan Gao
- Department of Nephrology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400021, China
| | - Yanying Xiong
- Department of Nephrology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400021, China
| | - Wei Sun
- Nanjing University of Chinese Medicine, Nanjing 210023, China
- Department of Nephrology, Jiangsu Province Hospital of Chinese Medicine (Affiliated Hospital of Nanjing University of Chinese Medicine), 210029, China
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36
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The Pleiotropy of PAX5 Gene Products and Function. Int J Mol Sci 2022; 23:ijms231710095. [PMID: 36077495 PMCID: PMC9456430 DOI: 10.3390/ijms231710095] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/23/2022] [Accepted: 08/26/2022] [Indexed: 11/17/2022] Open
Abstract
PAX5, a member of the Paired Box (PAX) transcription factor family, is an essential factor for B-lineage identity during lymphoid differentiation. Mechanistically, PAX5 controls gene expression profiles, which are pivotal to cellular processes such as viability, proliferation, and differentiation. Given its crucial function in B-cell development, PAX5 aberrant expression also correlates with hallmark cancer processes leading to hematological and other types of cancer lesions. Despite the well-established association of PAX5 in the development, maintenance, and progression of cancer disease, the use of PAX5 as a cancer biomarker or therapeutic target has yet to be implemented. This may be partly due to the assortment of PAX5 expressed products, which layers the complexity of their function and role in various regulatory networks and biological processes. In this review, we provide an overview of the reported data describing PAX5 products, their regulation, and function in cellular processes, cellular biology, and neoplasm.
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37
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Lv X, Zhao Q, Dong Y, Yang L, Gong J, Zheng Y, Yang T. IMB5036, a novel pyridazinone compound, inhibits hepatocellular carcinoma growth and metastasis. Invest New Drugs 2022; 40:487-496. [PMID: 35020067 DOI: 10.1007/s10637-021-01210-6] [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: 10/26/2021] [Accepted: 12/28/2021] [Indexed: 12/24/2022]
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most common cancers with a high mortality rate due to metastasis and relapse. Purpose Here, we reported a small-molecule pyridazinone compound, designated as IMB5036. Its antitumor activity against HCC and underlying mechanism were studied. Methods In vitro cytotoxicity, apoptosis, DNA breaks, and cell motility assays were performed. Protein expression was analyzed by Western blot and microarray analysis. A xenograft tumor model in athymic mice was used to evaluate the antitumor activity. Results IMB5036 displayed potent cytotoxicity against various HCC cell lines. It caused double DNA breakages and induced cell death via apoptosis. It also significantly inhibited the motility of HCC cells. Western blot showed that IMB5036 induced the up-regulation of E-cadherin, while down-regulation of N-cadherin. The gene expression profile analysis and Western blot assay revealed that IMB5036 down-regulated the expression of Tau protein. Analysis of the TCGA dataset revealed that high expression of Tau decreased the survival rate of HCC patients. In vivo experiments proved that IMB5036 significantly inhibited the growth of HCC xenografts in athymic mice. Conclusions These results collectively demonstrate IMB5036 can be a promising therapeutic candidate for patients with HCC.
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Affiliation(s)
- Xing Lv
- Department of Biochemistry & Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi, China
- Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, Taiyuan, Shanxi, China
| | - Qi Zhao
- Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, Taiyuan, Shanxi, China
- Department of Pharmacology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yanqun Dong
- Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lijun Yang
- Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, Taiyuan, Shanxi, China
- Department of Pharmacology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jianhua Gong
- Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Yanbo Zheng
- Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Tao Yang
- Department of Biochemistry & Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi, China.
- Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, Taiyuan, Shanxi, China.
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Interferon-γ increases sensitivity to chemotherapy and provides immunotherapy targets in models of metastatic castration-resistant prostate cancer. Sci Rep 2022; 12:6657. [PMID: 35459800 PMCID: PMC9033763 DOI: 10.1038/s41598-022-10724-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 04/12/2022] [Indexed: 01/26/2023] Open
Abstract
Interferon-γ (IFNγ) is a cytokine with limited evidence of benefit in cancer clinical trials to date. However, it could potentially play a role in potentiating anti-tumor immunity in the immunologically "cold" metastatic castration-resistant prostate cancer (mCRPC) by inducing antigen presentation pathways and concurrently providing targets for immune checkpoint blockade therapy. Moreover, it could additionally increase sensitivity to chemotherapy based on its pleiotropic effects on cell phenotype. Here, we show that IFNγ treatment induced expression of major histocompatibility class-I (MHC-I) genes and PD-L1 in prostate cancer cells in vitro. Furthermore, IFNγ treatment led to a decrease in E-cadherin expression with a consequent increase in sensitivity to chemotherapy in vitro. In an in vivo murine tumor model of spontaneous metastatic prostate cancer, IFNγ systemic pretreatment upregulated the expression of HLA-A and decreased E-cadherin expression in the primary tumor, and more importantly in the metastatic site led to increased apoptosis and limited micrometastases in combination with paclitaxel treatment compared to diffuse metastatic disease in control and monotherapy treatment groups. These findings suggest that IFNγ may be useful in combinatorial regimens to induce sensitivity to immunotherapy and chemotherapy in hepatic metastases of mCRPC.
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Transcriptome Profile of Membrane and Extracellular Matrix Components in Ligament-Fibroblastic Progenitors and Cementoblasts Differentiated from Human Periodontal Ligament Cells. Genes (Basel) 2022; 13:genes13040659. [PMID: 35456465 PMCID: PMC9031187 DOI: 10.3390/genes13040659] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/05/2022] [Accepted: 04/06/2022] [Indexed: 02/04/2023] Open
Abstract
Ligament-fibroblastic cells and cementoblasts, two types of progenitor cells that differentiate from periodontal ligament stem cells (hPDLSCs), are responsible for the formation of the adhesive tissues in the tooth root. Since one of the factors that determines the fate of stem cell differentiation is the change in the microenvironment of the stem/progenitor cells, this study attempted to compare and analyze the molecular differences in the membrane and ECM of the two progenitor cells. Single cells derived from hPDLSCs were treated with TGF-β1 and BMP7 to obtain ligament-fibroblastic and cementoblastic cells, respectively. The transcriptome profiles of three independent replicates of each progenitor were evaluated using next-generation sequencing. The representative differentially expressed genes (DEGs) were verified by qRT-PCR, Western blot analysis, and immunohistochemistry. Among a total of 2245 DEGs identified, 142 and 114 DEGs related to ECM and cell membrane molecules were upregulated in ligament-fibroblastic and cementoblast-like cells, respectively. The major types of integrin and cadherin were found to be different between the two progenitor cells. In addition, the representative core proteins for each glycosaminoglycan-specific proteoglycan class were different between the two progenitors. This study provides a detailed understanding of cell–cell and cell–ECM interactions through the specific components of the membrane and ECM for ligament-fibroblastic and cementoblastic differentiation of hPDLSCs.
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40
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Bai S, Wang Z, Wang M, Li J, Wei Y, Xu R, Du J. Tumor-Derived Exosomes Modulate Primary Site Tumor Metastasis. Front Cell Dev Biol 2022; 10:752818. [PMID: 35309949 PMCID: PMC8924426 DOI: 10.3389/fcell.2022.752818] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 02/10/2022] [Indexed: 12/12/2022] Open
Abstract
Tumor-derived exosomes (TDEs) are actively produced and released by tumor cells and carry messages from tumor cells to healthy cells or abnormal cells, and they participate in tumor metastasis. In this review, we explore the underlying mechanism of action of TDEs in tumor metastasis. TDEs transport tumor-derived proteins and non-coding RNA to tumor cells and promote migration. Transport to normal cells, such as vascular endothelial cells and immune cells, promotes angiogenesis, inhibits immune cell activation, and improves chances of tumor implantation. Thus, TDEs contribute to tumor metastasis. We summarize the function of TDEs and their components in tumor metastasis and illuminate shortcomings for advancing research on TDEs in tumor metastasis.
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Affiliation(s)
- Suwen Bai
- Longgang District People´s Hospital of Shenzhen, The Second Affiliated Hospital of The Chinese University of Hong Kong, Shenzhen, China.,School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Zunyun Wang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Minghua Wang
- Longgang District People´s Hospital of Shenzhen, The Second Affiliated Hospital of The Chinese University of Hong Kong, Shenzhen, China
| | - Junai Li
- Longgang District People´s Hospital of Shenzhen, The Second Affiliated Hospital of The Chinese University of Hong Kong, Shenzhen, China
| | - Yuan Wei
- Longgang District People´s Hospital of Shenzhen, The Second Affiliated Hospital of The Chinese University of Hong Kong, Shenzhen, China
| | - Ruihuan Xu
- Longgang District People´s Hospital of Shenzhen, The Second Affiliated Hospital of The Chinese University of Hong Kong, Shenzhen, China
| | - Juan Du
- Longgang District People´s Hospital of Shenzhen, The Second Affiliated Hospital of The Chinese University of Hong Kong, Shenzhen, China
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41
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Circulating tumour cells in the -omics era: how far are we from achieving the 'singularity'? Br J Cancer 2022; 127:173-184. [PMID: 35273384 PMCID: PMC9296521 DOI: 10.1038/s41416-022-01768-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 01/27/2022] [Accepted: 02/17/2022] [Indexed: 12/22/2022] Open
Abstract
Over the past decade, cancer diagnosis has expanded to include liquid biopsies in addition to tissue biopsies. Liquid biopsies can result in earlier and more accurate diagnosis and more effective monitoring of disease progression than tissue biopsies as samples can be collected frequently. Because of these advantages, liquid biopsies are now used extensively in clinical care. Liquid biopsy samples are analysed for circulating tumour cells (CTCs), cell-free DNA, RNA, proteins and exosomes. CTCs originate from the tumour, play crucial roles in metastasis and carry information on tumour heterogeneity. Multiple single-cell omics approaches allow the characterisation of the molecular makeup of CTCs. It has become evident that CTCs are robust biomarkers for predicting therapy response, clinical development of metastasis and disease progression. This review describes CTC biology, molecular heterogeneity within CTCs and the involvement of EMT in CTC dynamics. In addition, we describe the single-cell multi-omics technologies that have provided insights into the molecular features within therapy-resistant and metastasis-prone CTC populations. Functional studies coupled with integrated multi-omics analyses have the potential to identify therapies that can intervene the functions of CTCs.
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Tanimura K, Yamada T, Okada K, Nakai K, Horinaka M, Katayama Y, Morimoto K, Ogura Y, Takeda T, Shiotsu S, Ichikawa K, Watanabe S, Morimoto Y, Iwasaku M, Kaneko Y, Uchino J, Taniguchi H, Yoneda K, Matoba S, Sakai T, Uehara H, Yano S, Kusaba T, Katayama R, Takayama K. HER3 activation contributes toward the emergence of ALK inhibitor-tolerant cells in ALK-rearranged lung cancer with mesenchymal features. NPJ Precis Oncol 2022; 6:5. [PMID: 35042943 PMCID: PMC8766605 DOI: 10.1038/s41698-021-00250-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 12/16/2021] [Indexed: 01/22/2023] Open
Abstract
Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have shown dramatic efficacy in patients with ALK-rearranged lung cancer; however, complete response in these patients is rare. Here, we investigated the molecular mechanisms underlying the emergence and maintenance of drug-tolerant cells in ALK-rearranged lung cancer. Cell based-assays demonstrated that HER3 activation and mesenchymal-to-epithelial transition, mediated through ZEB1 proteins, help maintain cell survival and induce the emergence of ALK-TKI-tolerant cells. Compared with ALK-TKIs alone, cotreatment with pan-HER inhibitor afatinib and ALK-TKIs prevented tumor regrowth, leading to the eradication of tumors in ALK-rearranged tumors with mesenchymal features. Moreover, pre-treatment vimentin expression in clinical specimens obtained from patients with ALK-rearranged lung cancer was associated with poor ALK-TKI treatment outcomes. These results demonstrated that HER3 activation plays a pivotal role in the emergence of ALK-TKI-tolerant cells. Furthermore, the inhibition of HER3 signals combined with ALK-TKIs dramatically improves treatment outcomes for ALK-rearranged lung cancer with mesenchymal features.
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Affiliation(s)
- Keiko Tanimura
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-Cho Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan
| | - Tadaaki Yamada
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-Cho Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan.
| | - Koutaroh Okada
- Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto, Tokyo, 135-8550, Japan
| | - Kunihiro Nakai
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-Cho Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan
| | - Mano Horinaka
- Department of Drug Discovery Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-Cho Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan
| | - Yuki Katayama
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-Cho Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan
| | - Kenji Morimoto
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-Cho Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan
| | - Yuri Ogura
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, 355-5 Haruobi-Cho, Kamigyo-Ku, Kyoto, 602-8026, Japan
| | - Takayuki Takeda
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, 355-5 Haruobi-Cho, Kamigyo-Ku, Kyoto, 602-8026, Japan
| | - Shinsuke Shiotsu
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daiichi Hospital, 15-749, Honmachi, Higashiyama-Ku, Kyoto, 605-0981, Japan
| | - Kosuke Ichikawa
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, 2-5274, Gakkocho-Dori, Niigata, 951-8514, Japan
| | - Satoshi Watanabe
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, 2-5274, Gakkocho-Dori, Niigata, 951-8514, Japan
| | - Yoshie Morimoto
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-Cho Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan
| | - Masahiro Iwasaku
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-Cho Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan
| | - Yoshiko Kaneko
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-Cho Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan
| | - Junji Uchino
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-Cho Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan
| | - Hirokazu Taniguchi
- Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4, Sakamoto, Nagasaki, 852-8523, Japan
| | - Kazue Yoneda
- University of Occupational and Environmental Health, Second Department of Surgery, 1-1, Iseigaoka, Kitakyushu, Fukuoka, 807-8556, Japan
| | - Satoaki Matoba
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-Cho Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan
| | - Toshiyuki Sakai
- Department of Drug Discovery Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-Cho Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan
| | - Hisanori Uehara
- Division of Pathology, Tokushima University Hospital, 2-50-1 Kuramotocho, Tokushima City, Tokushima, 770-8503, Japan
| | - Seiji Yano
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kakuma-Machi, Kanazawa, Ishikaswa, 920-1192, Japan
| | - Tetsuro Kusaba
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-Cho Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan
| | - Ryohei Katayama
- Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto, Tokyo, 135-8550, Japan
| | - Koichi Takayama
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-Cho Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan
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Circulating Tumour Cells (CTCs) in NSCLC: From Prognosis to Therapy Design. Pharmaceutics 2021; 13:pharmaceutics13111879. [PMID: 34834295 PMCID: PMC8619417 DOI: 10.3390/pharmaceutics13111879] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/27/2021] [Accepted: 10/30/2021] [Indexed: 02/08/2023] Open
Abstract
Designing optimal (neo)adjuvant therapy is a crucial aspect of the treatment of non-small-cell lung carcinoma (NSCLC). Standard methods of chemotherapy, radiotherapy, and immunotherapy represent effective strategies for treatment. However, in some cases with high metastatic activity and high levels of circulating tumour cells (CTCs), the efficacy of standard treatment methods is insufficient and results in treatment failure and reduced patient survival. CTCs are seen not only as an isolated phenomenon but also a key inherent part of the formation of metastasis and a key factor in cancer death. This review discusses the impact of NSCLC therapy strategies based on a meta-analysis of clinical studies. In addition, possible therapeutic strategies for repression when standard methods fail, such as the administration of low-toxicity natural anticancer agents targeting these phenomena (curcumin and flavonoids), are also discussed. These strategies are presented in the context of key mechanisms of tumour biology with a strong influence on CTC spread and metastasis (mechanisms related to tumour-associated and -infiltrating cells, epithelial–mesenchymal transition, and migration of cancer cells).
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Dombroski JA, Hope JM, Sarna NS, King MR. Channeling the Force: Piezo1 Mechanotransduction in Cancer Metastasis. Cells 2021; 10:2815. [PMID: 34831037 PMCID: PMC8616475 DOI: 10.3390/cells10112815] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/08/2021] [Accepted: 10/12/2021] [Indexed: 12/25/2022] Open
Abstract
Cancer metastasis is one of the leading causes of death worldwide, motivating research into identifying new methods of preventing cancer metastasis. Recently there has been increasing interest in understanding how cancer cells transduce mechanical forces into biochemical signals, as metastasis is a process that consists of a wide range of physical forces. For instance, the circulatory system through which disseminating cancer cells must transit is an environment characterized by variable fluid shear stress due to blood flow. Cancer cells and other cells can transduce physical stimuli into biochemical responses using the mechanosensitive ion channel Piezo1, which is activated by membrane deformations that occur when cells are exposed to physical forces. When active, Piezo1 opens, allowing for calcium flux into the cell. Calcium, as a ubiquitous second-messenger cation, is associated with many signaling pathways involved in cancer metastasis, such as angiogenesis, cell migration, intravasation, and proliferation. In this review, we discuss the roles of Piezo1 in each stage of cancer metastasis in addition to its roles in immune cell activation and cancer cell death.
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Affiliation(s)
| | | | | | - Michael R. King
- King Lab, Department of Biomedical Engineering, Vanderbilt University, 5824 Stevenson Center, Nashville, TN 37235, USA; (J.A.D.); (J.M.H.); (N.S.S.)
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Ikezaki M, Nishitsuji K, Matsumura K, Manabe S, Shibukawa Y, Wada Y, Ito Y, Ihara Y. C-Mannosylated tryptophan-containing WSPW peptide binds to actinin-4 and alters E-cadherin subcellular localization in lung epithelial-like A549 cells. Biochimie 2021; 192:136-146. [PMID: 34673139 DOI: 10.1016/j.biochi.2021.10.007] [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: 04/12/2021] [Revised: 10/08/2021] [Accepted: 10/14/2021] [Indexed: 11/18/2022]
Abstract
The Trp-x-x-Trp (W-x-x-W) peptide motif, a consensus site for C-mannosylation, is the functional motif in cytokine type I receptors or thrombospondin type I repeat (TSR) superfamily proteins. W-x-x-W motifs are important for physiological and pathological functions of their parental proteins, but effects of C-mannosylation on protein functions remain to be elucidated. By using chemically synthesized WSPW peptides and C-mannosylated WSPW peptides (C-Man-WSPW), we herein investigated whether C-mannosylation of WSPW peptides confer additional biological functions to WSPW peptides. C-Man-WSPW peptide, but not non-mannosylated WSPW, reduced E-cadherin levels in A549 cells. Via peptide mass fingerprinting analysis, we identified actinin-4 as a C-Man-WSPW-binding protein in A549 cells. Actinin-4 partly co-localized with E-cadherin or β-catenin, despite no direct interaction between actinin-4 and E-cadherin. C-Man-WSPW reduced co-localization of E-cadherin and actinin-4; non-mannosylated WSPW had no effect on localization. In actinin-4-knockdown cells, E-cadherin was upregulated and demonstrated a punctate staining pattern in the cytoplasm, which suggests that actinin-4 regulated cell-surface E-cadherin localization. Thus, C-mannosylation of WSPW peptides is required for interaction with actinin-4 that subsequently alters expression and subcellular localization of E-cadherin and morphology of epithelial-like cells. Our results therefore suggest a regulatory role of C-mannosylation of the W-x-x-W motif in interactions between the motif and its binding partner and will thereby enhance understanding of protein C-mannosylation.
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Affiliation(s)
- Midori Ikezaki
- Department of Biochemistry, School of Medicine, Wakayama Medical University, Wakayama, 641-8509, Japan
| | - Kazuchika Nishitsuji
- Department of Biochemistry, School of Medicine, Wakayama Medical University, Wakayama, 641-8509, Japan.
| | - Ko Matsumura
- Department of Biochemistry, School of Medicine, Wakayama Medical University, Wakayama, 641-8509, Japan
| | - Shino Manabe
- Laboratory of Functional Molecule Chemistry, Pharmaceutical Department and Institute of Medicinal Chemistry, Hoshi University, Tokyo, 142-8501, Japan; Research Center for Pharmaceutical Development, Graduate School of Pharmaceutical Sciences & Faculty of Pharmaceutical Sciences, Tohoku University, Miyagi, 980-8578, Japan
| | - Yukinao Shibukawa
- Department of Molecular Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, 594-1101, Japan
| | - Yoshinao Wada
- Department of Molecular Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, 594-1101, Japan
| | - Yukishige Ito
- RIKEN Cluster for Pioneering Research, Saitama, 351-0198, Japan; Graduate School of Science, Osaka University, Osaka, 560-0043, Japan
| | - Yoshito Ihara
- Department of Biochemistry, School of Medicine, Wakayama Medical University, Wakayama, 641-8509, Japan.
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de Moura NA, Caetano BFR, Bidinotto LT, Rodrigues MAM, Barbisan LF. Synbiotic supplementation attenuates the promoting effect of indole-3-carbinol on colon tumorigenesis. Benef Microbes 2021; 12:493-501. [PMID: 34463193 DOI: 10.3920/bm2020.0209] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Indole-3 carbinol (I3C) has shown dual effects on the promotion and progression stages of colon carcinogenesis while synbiotics (Syn) have exerted anti-carcinogenic activities in most rodent studies. This study aimed to investigate the effects of I3C given alone or together with a Syn intervention on 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis. All animals were given four subcutaneous DMH injections (4×40 mg/kg bodyweight, twice a week for two weeks) and then received either basal diet (G1), basal diet containing I3C (1g/kg chow) (G2) or basal diet containing I3C+Syn (I3C + inulin 50g/kg chow + Bifidobacterium lactis BB-12®), 2.5×1010 cfu/g of basal diet), (G3) for 21 weeks. Dietary I3C (G2) significantly increased tumour volume and cell proliferation when compared to the DMH control group (G1). Syn intervention (G3) significantly reduced tumour volume and cell proliferation when compared to I3C (G2). The colon tumours found were classified into well-differentiated tubular adenomas or adenocarcinomas. Dietary I3C or I3C+Syn did not significantly affect the incidence and the multiplicity of tumours in comparison with the DMH control group. Furthermore, Syn intervention (G3) increased Gstm1 and reduced Mapk9 gene expression in colonic tumours. The findings of the present study show that the dietary I3C shows a weak promoting activity, while the combination with Syn ameliorates I3C effects.
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Affiliation(s)
- N A de Moura
- Department of Structural and Functional Biology, Institute of Biosciences, Sao Paulo State University (UNESP), Prof. Dr. Antônio Celso Wagner Zanin 250, Distrito de Rubião Junior, Botucatu, SP, Brazil
| | - B F R Caetano
- Department of Pathology, School of Medicine, Sao Paulo State University (UNESP), Botucatu, SP, Brazil
| | - L T Bidinotto
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil.,Barretos School of Health Sciences, Dr. Paulo Prata - FACISB, Barretos, SP, Brazil.,Department of Pathology, School of Medicine, Sao Paulo State University (UNESP), Botucatu, SP, Brazil
| | - M A M Rodrigues
- Department of Pathology, School of Medicine, Sao Paulo State University (UNESP), Botucatu, SP, Brazil
| | - L F Barbisan
- Department of Structural and Functional Biology, Institute of Biosciences, Sao Paulo State University (UNESP), Prof. Dr. Antônio Celso Wagner Zanin 250, Distrito de Rubião Junior, Botucatu, SP, Brazil
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Atorvastatin facilitates chemotherapy effects in metastatic triple-negative breast cancer. Br J Cancer 2021; 125:1285-1298. [PMID: 34462586 DOI: 10.1038/s41416-021-01529-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 07/12/2021] [Accepted: 08/12/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Metastatic triple-negative breast cancer (mTNBC) is treated mainly with chemotherapy. However, resistance frequently occurs as tumours enter dormancy. Statins have been suggested as effective against cancer but as they prolong and promote dormancy, it is an open question of whether the concomitant use would interfere with chemotherapy in primary and mTNBC. We examined this question in animal models and clinical correlations. METHODS We used a xenograft model of spontaneous metastasis to the liver from an ectopic tumour employing a mTNBC cell line. Atorvastatin was provided to sensitise metastatic cells, followed by chemotherapy. The effects of statin usage on outcomes in women with metastatic breast cancer was assessed respectively by querying a database of those diagnosed from 1999 to 2019. RESULTS Atorvastatin had limited influence on tumour growth or chemotherapy effects in ectopic primary tumours. Interestingly, atorvastatin was additive with doxorubicin (but not paclitaxel) when targeting liver metastases. E-cadherin-expressing, dormant, breast cancer cells were resistant to the use of either statins or chemotherapy as compared to wild-type cells; however, the combination of both did lead to increased cell death. Although prospective randomised studies are needed for validation, our retrospective clinical analysis suggested that patients on statin treatment could experience prolonged dormancy and overall survival; still once the tumour recurred progression was not affected by statin use. CONCLUSION Atorvastatin could be used during adjuvant chemotherapy and also in conjunction with metastatic chemotherapy to reduce mTNBC cancer progression. These preclinical data establish a rationale for the development of randomised studies.
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Differences in Extracellular Vesicle Protein Cargo Are Dependent on Head and Neck Squamous Cell Carcinoma Cell of Origin and Human Papillomavirus Status. Cancers (Basel) 2021; 13:cancers13153714. [PMID: 34359613 PMCID: PMC8345072 DOI: 10.3390/cancers13153714] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 07/20/2021] [Indexed: 12/12/2022] Open
Abstract
To identify potential extracellular vesicle (EV) biomarkers in head and neck squamous cell carcinoma (HNSCC), we evaluated EV protein cargo and whole cell lysates (WCL) from HPV-positive and -negative HNSCC cell lines, as well as normal oral keratinocytes and HPV16-transformed cells. EVs were isolated from serum-depleted, conditioned cell culture media by polyethylene glycol (PEG) precipitation/ultracentrifugation. EV and WCL preparations were analyzed by LC-MS/MS. Candidate proteins detected at significantly higher levels in EV compared with WCL, or compared with EV from normal oral keratinocytes, were identified and confirmed by Wes Simple Western protein analysis. Our findings suggest that these proteins may be potential HNSCC EV markers as proteins that may be (1) selectively included in EV cargo for export from the cell as a strategy for metastasis, tumor cell survival, or modification of tumor microenvironment, or (2) representative of originating cell composition, which may be developed for diagnostic or prognostic use in clinical liquid biopsy applications. This work demonstrates that our method can be used to reliably detect EV proteins from HNSCC, normal keratinocyte, and transformed cell lines. Furthermore, this work has identified HNSCC EV protein candidates for continued evaluation, specifically tenascin-C, HLA-A, E-cadherin, EGFR, EPHA2, and cytokeratin 19.
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Liu C, Barger CJ, Karpf AR. FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer. Cancers (Basel) 2021; 13:3065. [PMID: 34205406 PMCID: PMC8235333 DOI: 10.3390/cancers13123065] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/11/2021] [Accepted: 06/16/2021] [Indexed: 02/08/2023] Open
Abstract
Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. In this review article, we address the current knowledge regarding the mechanisms of regulation and oncogenic functions of FOXM1, particularly in the context of ovarian cancer. FOXM1 and its associated oncogenic transcriptional signature are enriched in >85% of ovarian cancer cases and FOXM1 expression and activity can be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes in ovarian cancer, including: (1) cell proliferation, (2) invasion and metastasis, (3) chemotherapy resistance, (4) cancer stem cell (CSC) properties, (5) genomic instability, and (6) altered cellular metabolism. We additionally discuss the evidence for FOXM1 as a cancer biomarker, describe the rationale for FOXM1 as a cancer therapeutic target, and provide an overview of therapeutic strategies used to target FOXM1 for cancer treatment.
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Affiliation(s)
| | | | - Adam R. Karpf
- Eppley Institute and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68918-6805, USA; (C.L.); (C.J.B.)
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Soukup J, Cesak T, Hornychova H, Manethova M, Michnova L, Netuka D, Vitovcova B, Cap J, Ryska A, Gabalec F. Cytokeratin 8/18-negative somatotroph pituitary neuroendocrine tumours (PitNETs, adenomas) show variable morphological features and do not represent a clinicopathologically distinct entity. Histopathology 2021; 79:406-415. [PMID: 33738859 DOI: 10.1111/his.14366] [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: 02/08/2021] [Revised: 03/02/2021] [Accepted: 03/16/2021] [Indexed: 11/30/2022]
Abstract
AIMS In somatotroph pituitary neuroendocrine tumours (adenomas), a pattern of cytokeratin (CK) 18 expression is used for tumour subclassification, with possible clinical implications. Rare somatotroph tumours do not express CK 18. We aimed to characterise this subset clinically and histologically. METHODS AND RESULTS Clinical and pathological data for the study were derived from a previously published data set of a cohort of 110 patients with acromegaly. Data included serum levels of insulin-like growth factor 1 (IGF1), growth hormone (GH), prolactin and thyroid-stimulating hormone (TSH), tumour diameter, tumour invasion defined by Knosp grade and immunohistochemical data concerning the expression of Ki67, p53, E-cadherin, somatostatin receptor (SSTR)1, SSTR2A, SSTR3, SSTR5 and D2 dopamine receptor. Additional immunohistochemical analysis (AE1/3, CK 8/18, vimentin, neurofilament light chain, internexin-α) was performed. CK 18 was negative in 10 of 110 (9.1%) tumours. One of these tumours was immunoreactive with CK 8/18 antibody, while the remainder expressed only internexin-α intermediate filament in patterns similar to CK 18 (perinuclear fibrous bodies). CK-negative tumours showed no significant differences with respect to biochemical, radiological or pathological features. They showed significantly higher expression of SSTR2A compared to the sparsely granulated subtype and significantly lower expression of E-cadherin compared to the non-sparsely granulated subtypes of tumours. The tumours showed divergent morphology and hormonal expression: two corresponded to densely granulated tumours and three showed co-expression of prolactin and morphology of either mammosomatotroph or somatotroph-lactotroph tumours. Four tumours showed morphology and immunoprofile compatible with plurihormonal Pit1-positive tumours. CONCLUSIONS CK-negative somatotroph tumours do not represent a distinct subtype of somatotroph tumours, and can be further subdivided according to their morphology and immunoprofile.
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Affiliation(s)
- Jiri Soukup
- The Fingerland Department of Pathology, Faculty of Medicine Hradec Kralove, University Hospital, Charles University, Hradec Kralove, Czech Republic
| | - Tomas Cesak
- Department of Neurosurgery, Faculty of Medicine Hradec Kralove, University Hospital, Charles University, Hradec Kralove, Czech Republic
| | - Helena Hornychova
- The Fingerland Department of Pathology, Faculty of Medicine Hradec Kralove, University Hospital, Charles University, Hradec Kralove, Czech Republic
| | - Monika Manethova
- The Fingerland Department of Pathology, Faculty of Medicine Hradec Kralove, University Hospital, Charles University, Hradec Kralove, Czech Republic
| | - Ludmila Michnova
- Department of Pathology, Military University Hospital Prague, Praha, Czech Republic
| | - David Netuka
- Department of Neurosurgery and Neurooncology, 1st Medical Faculty, Charles University, Military University Hospital Prague, Prague, Czech Republic
| | - Barbora Vitovcova
- Department of Medical Biology and Genetics, Faculty of Medicine Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| | - Jan Cap
- 4th Department of Internal Medicine, Faculty of Medicine Hradec Kralove, University Hospital, Charles University, Hradec Kralove, Czech Republic
| | - Ales Ryska
- The Fingerland Department of Pathology, Faculty of Medicine Hradec Kralove, University Hospital, Charles University, Hradec Kralove, Czech Republic
| | - Filip Gabalec
- 4th Department of Internal Medicine, Faculty of Medicine Hradec Kralove, University Hospital, Charles University, Hradec Kralove, Czech Republic
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