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Liang H, Zhou B, Li P, Zhang X, Zhang S, Zhang Y, Yao S, Qu S, Chen J. Stemness regulation in prostate cancer: prostate cancer stem cells and targeted therapy. Ann Med 2025; 57:2442067. [PMID: 39711287 DOI: 10.1080/07853890.2024.2442067] [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: 11/27/2023] [Revised: 11/07/2024] [Accepted: 11/22/2024] [Indexed: 12/24/2024] Open
Abstract
BACKGROUND Increasing evidence indicates that cancer stem cells (CSCs) and cancer stem-like cells form a special subpopulation of cells that are ubiquitous in tumors. These cells exhibit similar characteristics to those of normal stem cells in tissues; moreover, they are capable of self-renewal and differentiation, as well as high tumorigenicity and drug resistance. In prostate cancer (PCa), it is difficult to kill these cells using androgen signaling inhibitors and chemotherapy drugs. Consequently, the residual prostate cancer stem cells (PCSCs) mediate tumor recurrence and progression. OBJECTIVE This review aims to provide a comprehensive and up-to-date overview of PCSCs, with a particular emphasis on potential therapeutic strategies targeting these cells. METHODS After searching in PubMed and Embase databases using 'prostate cancer' and 'cancer stem cells' as keywords, studies related were compiled and examined. RESULTS In this review, we detail the origin and characteristics of PCSCs, introduce the regulatory pathways closely related to CSC survival and stemness maintenance, and discuss the link between epithelial-mesenchymal transition, tumor microenvironment and tumor stemness. Furthermore, we introduce the currently available therapeutic strategies targeting CSCs, including signaling pathway inhibitors, anti-apoptotic protein inhibitors, microRNAs, nanomedicine, and immunotherapy. Lastly, we summarize the limitations of current CSC research and mention future research directions. CONCLUSION A deeper understanding of the regulatory network and molecular markers of PCSCs could facilitate the development of novel therapeutic strategies targeting these cells. Previous preclinical studies have demonstrated the potential of this treatment approach. In the future, this may offer alternative treatment options for PCa patients.
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Affiliation(s)
- Hao Liang
- Department of Urology, Qilu Hospital of Shandong University (Qingdao), Qingdao, China
| | - Bin Zhou
- Department of Urology, Qilu Hospital of Shandong University, Jinan, China
| | - Peixin Li
- Department of Urology, Qilu Hospital of Shandong University, Jinan, China
| | - Xiaoyi Zhang
- Department of Urology, Qilu Hospital of Shandong University, Jinan, China
| | - Shijie Zhang
- Department of Urology, Qilu Hospital of Shandong University, Jinan, China
| | - Yaozhong Zhang
- Department of Urology, Qilu Hospital of Shandong University, Jinan, China
| | - Shengwen Yao
- Department of Urology, Qilu Hospital of Shandong University, Jinan, China
| | - Sifeng Qu
- Department of Urology, Qilu Hospital of Shandong University (Qingdao), Qingdao, China
| | - Jun Chen
- Department of Urology, Qilu Hospital of Shandong University (Qingdao), Qingdao, China
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2
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Zha W, Wang Z, Hu W, Ge C, Yuan W, Shen Q, Li W, Chen W, Tang J, Xiao Z, Meng Y, Huang L, Zhong Z, Li TS, Chen J, Cao Z. Bexarotene regulates zebrafish embryonic development by activating Wnt signaling pathway. Life Sci 2025; 373:123664. [PMID: 40288573 DOI: 10.1016/j.lfs.2025.123664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 04/10/2025] [Accepted: 04/21/2025] [Indexed: 04/29/2025]
Abstract
Bexarotene (Bex) is a selective retinoid X receptor (RXR) agonist and is commonly used as an anti-tumor drug in the clinic to treat patients with cutaneous T-cell lymphoma (CTCL). With the widespread use of this drug, people are increasingly concerned about its side effects and safety of use. At present, the effects of bexarotene drugs on the health of organisms remain uncertain, but retinoid drugs are generally biologically active and may pose potential risks to them. Therefore, in this study, we used a zebrafish model to evaluate the effects of Bex on embryonic development. Six hours after fertilization, we exposed zebrafish embryos to 3 μg/L, 6 μg/L, and 9 μg/L bexarotene. At 96 hpf, compared with the control group, zebrafish embryos exposed to bexarotene showed obvious heart and liver development defects, including reduced hatching rate, pericardial enlargement, heart rate disorder, yolk sac edema, small liver area and abnormal photo-optical motor responses. Transcriptome and qPCR results showed abnormal expression of genes related to heart and liver development was induced by Bexarotene. Mechanistically, bexarotene induced a significant upregulation of the transcriptional expression levels of genes related to the Wnt signaling pathway, and IWR-1 was able to effectively rescue the heart and liver developmental defects of zebrafish caused by bexarotene. Therefore, our study showed that bexarotene may cause zebrafish embryonic developmental defects by upregulating the Wnt signaling pathway, revealing the side effects and associated novel mechanisms of bexarotene, and providing a theoretical basis for its safe and effective use in the treatment of clinically related diseases.
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Affiliation(s)
- Wenwen Zha
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs and Epigenetics, Clinical Research Center of Affiliated Hospital of Jinggangshan University, Key Laboratory of Jiangxi Province for Biological Invasion and Biosecurity, College of Chinese Medicine, Jinggangshan University, Ji'an 343009, China
| | - Ziang Wang
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs and Epigenetics, Clinical Research Center of Affiliated Hospital of Jinggangshan University, Key Laboratory of Jiangxi Province for Biological Invasion and Biosecurity, College of Chinese Medicine, Jinggangshan University, Ji'an 343009, China
| | - Weitao Hu
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Development Biology of Organs and Epigenetics, Key Laboratory of Jiangxi Province for Biological Invasion and Biosecurity, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an 343009, China
| | - Chenkai Ge
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Development Biology of Organs and Epigenetics, Key Laboratory of Jiangxi Province for Biological Invasion and Biosecurity, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an 343009, China
| | - Wenbin Yuan
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Development Biology of Organs and Epigenetics, Key Laboratory of Jiangxi Province for Biological Invasion and Biosecurity, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an 343009, China
| | - Qinyuan Shen
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Development Biology of Organs and Epigenetics, Key Laboratory of Jiangxi Province for Biological Invasion and Biosecurity, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an 343009, China
| | - Weirong Li
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Development Biology of Organs and Epigenetics, Key Laboratory of Jiangxi Province for Biological Invasion and Biosecurity, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an 343009, China
| | - Wanqing Chen
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Development Biology of Organs and Epigenetics, Key Laboratory of Jiangxi Province for Biological Invasion and Biosecurity, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an 343009, China
| | - Jingrong Tang
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Development Biology of Organs and Epigenetics, Key Laboratory of Jiangxi Province for Biological Invasion and Biosecurity, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an 343009, China
| | - Zhonghao Xiao
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Development Biology of Organs and Epigenetics, Key Laboratory of Jiangxi Province for Biological Invasion and Biosecurity, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an 343009, China
| | - Yunlong Meng
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Department of Pediatrics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China; Institute of Medical Genetics, Department of Big Data in Health Science School of Public Health and General Medicine, Tongji University School of Medicine, Tongji University, Shanghai 200331, China
| | - Lirong Huang
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Department of Pediatrics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China; Institute of Medical Genetics, Department of Big Data in Health Science School of Public Health and General Medicine, Tongji University School of Medicine, Tongji University, Shanghai 200331, China
| | - Zilin Zhong
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Department of Pediatrics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China; Institute of Medical Genetics, Department of Big Data in Health Science School of Public Health and General Medicine, Tongji University School of Medicine, Tongji University, Shanghai 200331, China
| | - Tao-Sheng Li
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Jianjun Chen
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Department of Pediatrics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China; Institute of Medical Genetics, Department of Big Data in Health Science School of Public Health and General Medicine, Tongji University School of Medicine, Tongji University, Shanghai 200331, China.
| | - Zigang Cao
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Development Biology of Organs and Epigenetics, Key Laboratory of Jiangxi Province for Biological Invasion and Biosecurity, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an 343009, China.
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3
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Krishnamoorthy S, Mak JKL, Tan KCB, Li GHY, Cheung CL. Adult head circumference and the risk of cancer: a retrospective cohort study. Cancer Causes Control 2025; 36:683-689. [PMID: 39910021 PMCID: PMC12103361 DOI: 10.1007/s10552-025-01966-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 01/18/2025] [Indexed: 02/07/2025]
Abstract
PURPOSE Cancer-related genes and pathways have recently been implicated in a genome-wide meta-analysis of head size. In the current study, we aimed to evaluate the association between adult head circumference and the risk of cancer. METHODS This is a cohort study using data from the Hong Kong Osteoporosis Study, where 1,301 participants aged 27-96 years with head circumference measured between 2015 and 2019, and without a history of cancer, were followed up to 15 January 2024. Incident cancers were identified using electronic medical records from a territory-wide database. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression, adjusting for age, sex, height, weight, education, smoking, alcohol drinking, physical activity, and family history of cancer, as well as accounting for familial clustering. RESULTS The median head circumference was 53 cm (interquartile range [IQR]: 51-54) and 54 cm (IQR: 53-55) for women and men, respectively. During a median follow-up of 6.9 years, 66 individuals were diagnosed with cancer. In the adjusted model, a larger head circumference was associated with an increased risk of any cancer (HR per cm increase: 1.17; 95% CI 1.00-1.36). Results remained similar when adjusting for waist-to-hip ratio instead of weight or when additionally adjusting for serum calcium and phosphorus levels. When stratified by cancer sites, head circumference was most strongly associated with colorectal cancer (HR per cm increase: 1.81; 95% CI 1.14-2.90) and prostate cancer (HR per cm increase: 1.58; 95% CI 1.16-2.16). CONCLUSION Head circumference is positively associated with the risk of cancer independently of height, weight, and other cancer risk factors.
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Affiliation(s)
- Suhas Krishnamoorthy
- Department of Pharmacology and Pharmacy, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, SAR, China
| | - Jonathan K L Mak
- Department of Pharmacology and Pharmacy, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, SAR, China
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Kathryn C B Tan
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, SAR, China
| | - Gloria H Y Li
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, SAR, China
| | - Ching-Lung Cheung
- Department of Pharmacology and Pharmacy, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, SAR, China.
- Laboratory of Data Discovery for Health (D24H), Hong Kong Science Park, Pak Shek Kok, Hong Kong, SAR, China.
- Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, USA.
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4
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Danek V, Tureckova J, Huebner K, Erlenbach-Wuensch K, Baranova P, Dobes J, Balounova J, Simova M, Novosadova V, Madureira Trufen CE, Prochazkova M, Talacko P, Harant K, Barinka C, Beck IM, Schneider-Stock R, Sedlacek R, Prochazka J. CUL4A exhibits tumor-suppressing role via regulation of HUWE1-mediated SMAD3 intracellular shuttling. Cancer Lett 2025; 621:217663. [PMID: 40120800 DOI: 10.1016/j.canlet.2025.217663] [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: 12/23/2024] [Revised: 03/06/2025] [Accepted: 03/19/2025] [Indexed: 03/25/2025]
Abstract
Changes in cellular physiology and proteomic homeostasis accompanied the initiation and progression of colorectal cancer. Thus, ubiquitination represents a central regulatory mechanism in proteome dynamics. However, the complexity of the ubiquitinating network involved in carcinogenesis remains unclear. This study revealed the tumor-suppressive role of the ubiquitin ligase Cullin4A (CUL4A) in the intestine. We showed that simultaneous loss of CUL4A and hyperactivation of the Wnt pathway promotes tumor development in the distal colon. This tumor development is caused by an accumulation of the inactive SMAD3, a TGF-β pathway mediator. Depletion of CUL4A resulted in stabilization of HUWE1, which attenuated SMAD3 function. We showed a correlation between the intracellular localization of CUL4A and colorectal cancer progression, where nuclear CUL4A localization correlates with advanced colorectal cancer progression. In summary, we identified CUL4A as an important regulator of SMAD3 signal transduction competence in a HUWE1-dependent manner and demonstrated a critical role for the crosstalk between ubiquitination and the Wnt/TGF-β signaling pathways in gastrointestinal homeostasis.
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Affiliation(s)
- Veronika Danek
- Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
| | - Jolana Tureckova
- Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
| | - Kerstin Huebner
- Experimental Tumorpathology, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, 91054, Erlangen, Germany
| | | | - Petra Baranova
- Laboratory of Structural Biology, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Vestec, 252 50, Czech Republic
| | - Jan Dobes
- Department of Cell Biology, Faculty of Science, Charles University, 128 00, Prague, Czech Republic
| | - Jana Balounova
- Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
| | - Michaela Simova
- Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
| | - Vendula Novosadova
- Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
| | - Carlos Eduardo Madureira Trufen
- Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
| | - Michaela Prochazkova
- Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
| | - Pavel Talacko
- BIOCEV Proteomics Core Facility, Faculty of Science, Charles University, Vestec, 252 50, Czech Republic
| | - Karel Harant
- BIOCEV Proteomics Core Facility, Faculty of Science, Charles University, Vestec, 252 50, Czech Republic
| | - Cyril Barinka
- Laboratory of Structural Biology, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Vestec, 252 50, Czech Republic
| | - Inken M Beck
- Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic; Animal Research Centre, Ulm University, Ulm, Germany
| | - Regine Schneider-Stock
- Experimental Tumorpathology, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, 91054, Erlangen, Germany; Institute of Pathology, FAU Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - Radislav Sedlacek
- Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic; Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic
| | - Jan Prochazka
- Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic; Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20, Prague, Czech Republic.
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5
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Altiparmak-Ulbegi G, Hasbal-Celikok G, Aksoy-Sagirli P. AKT1 and CTNNB1 mutations as drivers of paclitaxel resistance in breast cancer cells. Oncol Lett 2025; 30:324. [PMID: 40370645 PMCID: PMC12076040 DOI: 10.3892/ol.2025.15070] [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: 12/19/2024] [Accepted: 03/26/2025] [Indexed: 05/16/2025] Open
Abstract
Breast cancer (BC) is the most prevalent cancer type in the world, with increasing incidence rates. Drug resistance is a notable factor that limits the effectiveness of BC therapy. Paclitaxel (PTX), a chemotherapeutic agent belonging to the taxane class, is commonly used in BC; however, its efficacy is often compromised by drug resistance, which is primarily attributed to genetic alterations. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and wingless-type MMTV integration site family/β-catenin signaling pathways are involved in essential cellular processes, such as proliferation, apoptosis and maintenance of homeostasis. Dysregulated activation of these pathways is strongly associated with carcinogenesis and drug resistance. In the present study, the potential effects of AKT1 (E17K/E49K/L52R) and catenin β-1 (CTNNB1; S33P/T41A/S45F) mutations on PTX resistance in BC were investigated in vitro using site-directed mutagenesis, transient transfection, MTS assay and western blot analyses. The results of the present study indicated that AKT1-E17K/E49K and CTNNB1-S45F/T41A mutations induced PTX resistance compared with AKT1-wild-type (WT) and CTNNB1-WT in MCF-7 cells, respectively. In MDA-MB-231 cells, all three AKT1 mutations (E17K/E49K/L52R) triggered PTX resistance compared with AKT1-WT, while none of the CTNNB1 mutations exhibited such an effect. In conclusion, AKT1 mutations may serve as a biomarker for PTX resistance in both estrogen receptor (ER)(+)/progesterone receptor (PR)(+)/HER2(-) and triple negative BC, while CTNNB1 mutations may be a potential biomarker for PTX resistance in ER(+)/PR(+)/HER2(-) BC.
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Affiliation(s)
| | - Gozde Hasbal-Celikok
- Department of Biochemistry, Faculty of Pharmacy, Istanbul University, 34116 Istanbul, Türkiye
| | - Pinar Aksoy-Sagirli
- Department of Biochemistry, Faculty of Pharmacy, Istanbul University, 34116 Istanbul, Türkiye
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6
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Tiwari M, Dingankar M, Das J, R SS, Solanki A, Subramanyam D. CLCa mediates a novel cross-talk between Wnt secretion and actin organization. Life Sci Alliance 2025; 8:e202402962. [PMID: 40316417 PMCID: PMC12050421 DOI: 10.26508/lsa.202402962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 04/17/2025] [Accepted: 04/17/2025] [Indexed: 05/04/2025] Open
Abstract
Mammalian clathrin light chains (CLCa, CLCb) are critical players in clathrin-mediated endocytosis. However, their physiological role in contributing to specific cellular processes and early development remains elusive. To elucidate their individual functions, we generated CLC knockout mESCs. Loss of CLCa resulted in down-regulation of Wnt pathway genes along with altered secretion of Wnt3a because of impaired trafficking of its secretion mediator, WLS. Reduced Wnt signaling led to lower levels of Hip1R causing a reorganization of the actin cytoskeleton. CLCa knockout cells displayed actin patches enriched for Arp3 and cortactin, with activation of the Wnt pathway resulting in disassembly of these patches. Furthermore, we uncovered a bidirectional cross-talk between Wnt signaling and actin organization, with actin disruption resulting in lower Wnt signaling. Our data reveal a previously undiscovered role of CLCa in mediating molecular communication between actin organization and Wnt signaling.
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Affiliation(s)
- Mahak Tiwari
- National Centre for Cell Science, SP Pune University Campus, Pune, India
- SP Pune University, Pune, India
| | - Mihir Dingankar
- Indian Institute of Science Education and Research (IISER) Pune, Pune, India
| | - Jyoti Das
- National Centre for Cell Science, SP Pune University Campus, Pune, India
- SP Pune University, Pune, India
| | - Sreelekshmi S R
- National Centre for Cell Science, SP Pune University Campus, Pune, India
| | - Apurv Solanki
- National Centre for Cell Science, SP Pune University Campus, Pune, India
| | - Deepa Subramanyam
- National Centre for Cell Science, SP Pune University Campus, Pune, India
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Chen H, Huang M, Li J, Zhang S, Sun C, Luo W, Yu L. LncRNA APTR amplification serves as a potential glioma biomarker and promotes glioma progression via miR-6734-5p/ TCF7/LEF1 axis. Noncoding RNA Res 2025; 12:42-55. [PMID: 40103614 PMCID: PMC11914771 DOI: 10.1016/j.ncrna.2025.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 02/17/2025] [Accepted: 02/18/2025] [Indexed: 03/20/2025] Open
Abstract
Background Alu-mediated p21 transcriptional regulator (APTR) overexpression is detected in different human cancers; however, few reports have investigated APTR gene amplification conditions. Furthermore, whether APTR amplification is related to glioma malignancy and the underlying mechanism remain unknown. Methods APTR amplification and expression levels in 153 glioma samples were analyzed using qPCR. Correlations between APTR and patient prognosis were evaluated using Kaplan-Meier survival and COX regression analyses. Both in vitro and in vivo phenotypic assays were performed to confirm the carcinogenic effects of APTR in glioblastoma (GBM) cells. RNA-sequencing and RNA immunoprecipitation and luciferase reporter assays were performed to confirm APTR as a competing endogenous RNA (ceRNA) and to identify the downstream axis of APTR. Results Our results suggest that APTR amplification and overexpression are novel independent diagnostic biomarkers for predicting poor prognosis in patients with gliomas. APTR knockdown significantly repressed the proliferation and invasion of GBM cells, both in vitro and in vivo. APTR was demonstrated to absorb miR-6734-5p and upregulate TCF7 and LEF1 expression. Taken together, these results suggest that APTR promotes the malignant phenotypes of GBM by inducing TCF7 and LEF1 expression. Conclusion We identified APTR as a novel prognostic biomarker in patients with gliomas and confirmed that APTR is a ceRNA that promotes glioma progression via the APTR/miR-6734-5p/TCF7/LEF1 axis.
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Affiliation(s)
- Heng Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
- Laboratory of Molecular Immunology, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, 300070, China
- Tianjin Key Laboratory of Cellular and Molecular Immunology and Key Laboratory of the Educational Ministry of China, Tianjin Medical University, Tianjin, 300070, China
| | - Mengzhen Huang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
- Laboratory of Molecular Immunology, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, 300070, China
- Tianjin Key Laboratory of Cellular and Molecular Immunology and Key Laboratory of the Educational Ministry of China, Tianjin Medical University, Tianjin, 300070, China
| | - Jiayi Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
- Laboratory of Molecular Immunology, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, 300070, China
- Tianjin Key Laboratory of Cellular and Molecular Immunology and Key Laboratory of the Educational Ministry of China, Tianjin Medical University, Tianjin, 300070, China
| | - Shanshan Zhang
- Department of Radiology, Tianjin Medical University General Hospital, Tianjin, China
| | - Cuiyun Sun
- Department of Neuropathology, Tianjin Key Laboratory of Injuries, Variations and Regeneration of the Nervous System, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System of Education Ministry, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Wenjun Luo
- Department of Neuropathology, Tianjin Key Laboratory of Injuries, Variations and Regeneration of the Nervous System, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System of Education Ministry, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Lin Yu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
- Laboratory of Molecular Immunology, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, 300070, China
- Tianjin Key Laboratory of Cellular and Molecular Immunology and Key Laboratory of the Educational Ministry of China, Tianjin Medical University, Tianjin, 300070, China
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8
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Collinson R, Tanos B. Primary cilia and cancer: a tale of many faces. Oncogene 2025; 44:1551-1566. [PMID: 40301543 PMCID: PMC12095056 DOI: 10.1038/s41388-025-03416-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 04/04/2025] [Accepted: 04/10/2025] [Indexed: 05/01/2025]
Abstract
Cilia are microtubule-based sensory organelles which project from the cell surface, enabling detection of mechanical and chemical stimuli from the extracellular environment. It has been shown that cilia are lost in some cancers, while others depend on cilia or ciliary signaling. Several oncogenic molecules, including tyrosine kinases, G-protein coupled receptors, cytosolic kinases, and their downstream effectors localize to cilia. The Hedgehog pathway, one of the most studied ciliary-signaling pathways, is regulated at the cilium via an interplay between Smoothened (an oncogene) and Patched (a tumor suppressor), resulting in the activation of pro-survival programs. Interestingly, cilia loss can result in resistance to Smoothened-targeting drugs and increased cancer cell survival. On the other hand, kinase inhibitor-resistant and chemoresistant cancers have increased cilia and increased Hedgehog pathway activation, and suppressing cilia can overcome this resistance. How cilia regulate cancer is therefore context dependent. Defining the signaling output of cilia-localized oncogenic pathways could identify specific targets for cancer therapy, including the cilium itself. Increasing evidence implicates cilia in supporting several hallmarks of cancer, including migration, invasion, and metabolic rewiring. While cell cycle cues regulate the biogenesis of cilia, the absence of cilia has not been conclusively shown to affect the cell cycle. Thus, a complex interplay between molecular signals, phosphorylation events and spatial regulation renders this fascinating organelle an important new player in cancer through roles that we are only starting to uncover. In this review, we discuss recent advances in our understanding of cilia as signaling platforms in cancer and the influence this plays in tumor development.
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Affiliation(s)
- Rebecca Collinson
- Centre for Genome Engineering and Maintenance, Department of Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, London, UK
| | - Barbara Tanos
- Centre for Genome Engineering and Maintenance, Department of Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, London, UK.
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9
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Alvarado-Ortiz E, Castañeda-Patlán MC, Moreno-Londoño AP, Tinajero-Rodríguez JM, Briseño-Díaz P, Sarabia-Sánchez MA, Vargas M, Ortiz-Sánchez E, Robles-Flores M. Non-canonical Wnt co-receptors ROR1/ROR2 are differentially regulated by hypoxia in colon cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2025; 1872:119968. [PMID: 40268059 DOI: 10.1016/j.bbamcr.2025.119968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 04/16/2025] [Accepted: 04/18/2025] [Indexed: 04/25/2025]
Abstract
ROR1 and ROR2 co-receptors are transducers of non-canonical Wnt responses that promote an aggressive phenotype in several cancer types, including colon cancer. It has been demonstrated that hypoxia promotes tumor progression through the action of Hypoxia Inducible Factors (HIFs). An in silico analysis revealed that ROR2 is overexpressed in the advanced clinical stages of colon cancer. In line with this, ROR1 and ROR2 were found to be only expressed in malignant colon cells compared to non-malignant ones. The blockade of either ROR1 or ROR2 impaired colon cancer cells' colony formation abilities and the migration capacity of them. Additionally, the silencing of the ROR2 co-receptor blocked the metastatic ability of colon cancer cells in a xenografted mice model. We found that while silencing HIF-1α did not significantly reduce ROR1 or ROR2 expression, inhibiting HIF-2α and HIF-3α expression greatly decreased the protein levels of both co-receptors in colon cancer cells. The HIF-1α subunit expression is induced in acute hypoxia, whereas HIF-2α and HIF-3α show higher activity in chronic hypoxia, which may be functionally relevant since hypoxia induced a decrease in the constitutive active β-catenin transcriptional activity in SW480 cells. While both ROR1 and ROR2 stimulate proliferation and migration under normoxic conditions, the exposure of cells to hypoxia increased the expression of ROR1 or ROR2, depending on the Wnt cellular context, Thus, our results indicate that hypoxia partially represses β-catenin transcriptional activity and activates non-canonical Wnt signaling by regulating ROR1/ROR2 expression to induce an aggressive migrating and metastatic phenotype in colon cancer cells.
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Affiliation(s)
- Eduardo Alvarado-Ortiz
- Programa de Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Mexico City, Mexico; Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | | | | | | | - Paola Briseño-Díaz
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Miguel Angel Sarabia-Sánchez
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Miguel Vargas
- Department of Molecular Biomedicine, Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV-IPN), Mexico
| | - Elizabeth Ortiz-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Mexico City, Mexico
| | - Martha Robles-Flores
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico.
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10
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Liu Z, Lei Y, Zuo J, Zhang R, Du H, Hu H, Zheng J, Yang P, Zhao D. Activated Notch1 promotes macrophage polarization and exacerbates sepsis-induced acute lung injury via β-catenin/NF-κB signaling. Biochem Pharmacol 2025; 236:116892. [PMID: 40127740 DOI: 10.1016/j.bcp.2025.116892] [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: 12/17/2024] [Revised: 02/26/2025] [Accepted: 03/21/2025] [Indexed: 03/26/2025]
Abstract
Sepsis-induced acute lung injury (ALI) is a critical condition characterized by excessive inflammation, with macrophage polarization playing a pivotal role in its pathogenesis. In this study, we constructed myeloid-specific Notch1 knockout mice, overexpressed the Notch intracellular domain (NICD), and inhibited β-catenin using XAV939 to investigate the impact and mechanisms of Notch1 regulation in macrophage polarization and inflammatory responses in cecal ligation and puncture (CLP)-induced septic mice. The results demonstrated that Notch1 knockout significantly reduced M1 macrophage polarization, alleviated systemic inflammation, mitigated lung injury, and improved survival in septic mice. In sepsis, Notch1 enhances β-catenin expression, which synergizes with the NF-κB pathway to promote M1 polarization and pro-inflammatory cytokine production. Specifically, NICD interacts with β-catenin in macrophages, amplifying NF-κB activation and its nuclear translocation. These results demonstrate that the Notch1 signaling pathway plays a pivotal role in regulating macrophage phenotypic switching, highlighting its potential as a therapeutic target for attenuating sepsis-associated ALI through immune homeostasis restoration.
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Affiliation(s)
- Zhi Liu
- Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Yuxi Lei
- Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Jing Zuo
- The Research Centre of Anesthesiology and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Ruiyu Zhang
- Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Hui Du
- Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Huizhi Hu
- Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Junwen Zheng
- Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Pu Yang
- Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Children's Digital Health and Data Center of Wuhan University, Wuhan 430071, China.
| | - Dongchi Zhao
- Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Children's Digital Health and Data Center of Wuhan University, Wuhan 430071, China.
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11
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Cetiz MV, Ahmed S, Zengin G, Sinan KI, Emre G, Dolina K, Kalyniukova A, Uba AI, Koyuncu I, Yuksekdag O, Li MY. Bioinformatic and experimental approaches to uncover the bio-potential of Mercurialis annua extracts based on chemical constituents. J Mol Liq 2025; 427:127390. [DOI: 10.1016/j.molliq.2025.127390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/04/2025]
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12
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Clune S, Awolade P, Esquer H, Zhou Q, LaBarbera DV. CHD1L in cancer and beyond: structure, oncogenic functions, and therapeutic potential. J Exp Clin Cancer Res 2025; 44:167. [PMID: 40442742 PMCID: PMC12123854 DOI: 10.1186/s13046-025-03428-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2025] [Accepted: 05/25/2025] [Indexed: 06/02/2025] Open
Abstract
Chromodomain Helicase DNA-binding protein 1-Like (CHD1L) is a chromatin remodeling enzyme increasingly recognized as an oncogenic factor promoting tumor progression and metastatic potential by orchestrating transcriptional programs that drive epithelial-mesenchymal transition (EMT), cytoskeletal remodeling, and metastatic dissemination. In parallel, CHD1L has emerged as a master regulator of tumor cell survival by regulating DNA damage response and repair and enforcing G1 cell cycle progression. Furthermore, CHD1L plays a key role in immune evasion pathways by regulating signaling cascades and by suppressing both apoptotic and non-apoptotic cell death. In particular, CHD1L is a key suppressor of PARthanatos, a caspase-independent mechanism triggered by poly(ADP-ribose) (PAR) polymer fragmentation and apoptosis-inducing factor (AIF) activation. By regulating SPOCK1, MDM2, and TCTP, CHD1L further supports survival under cellular stress. Its overexpression correlates with metastasis, therapy resistance, and poor prognosis across many solid tumors. This review covers CHD1L's structure, oncogenic functions, and developmental origins, and highlights emerging therapeutic strategies that target CHD1L as a druggable vulnerability in cancer.
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Affiliation(s)
- Sophia Clune
- Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Paul Awolade
- Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Center for Drug Discovery, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Hector Esquer
- Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Center for Drug Discovery, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Qiong Zhou
- Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Center for Drug Discovery, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Daniel V LaBarbera
- Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
- Center for Drug Discovery, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
- University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
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13
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Szopa IM, Majchrzak-Kuligowska K, Pingwara R, Kulka M, Taşdemir M, Gajewska M. A New Method of Canine CD4 + T Lymphocyte Differentiation Towards the Th17 Phenotype with Analysis of Properties and Mitochondrial Activity. Int J Mol Sci 2025; 26:4946. [PMID: 40430086 PMCID: PMC12112516 DOI: 10.3390/ijms26104946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Revised: 05/15/2025] [Accepted: 05/19/2025] [Indexed: 05/29/2025] Open
Abstract
Th17 lymphocytes are a distinct subpopulation of T cells that are characterized by the production of interleukins IL-17, IL-21, IL-22, and IL-26, and high expression of RORγt. These cells play an important role in inflammation and autoimmune diseases. Recent studies using rodent and human models have also highlighted their promising properties as agents in cellular immunotherapy for cancer. However, much less is known about the properties of canine Th17 lymphocytes, despite the domestic dog being an important model used in comparative medicine. In this study, we developed methods of activation and differentiation of canine CD4+ T lymphocytes towards the Th17 phenotype. Additionally, we targeted the Wnt/β-catenin signaling pathway to modulate the efficiency of Th17 cells differentiation. CD4+ T cells were successfully activated with magnetic EpoxyBeads, and in combination with the appropriate programming medium, they acquired the Th17 phenotype. Furthermore, indomethacin, an inhibitor of the Wnt/β-catenin pathway, significantly increased the efficiency of differentiation, causing elevated production of IL-17 and changed T cell metabolism by promoting oxidative phosphorylation. The protocol elaborated in our study provides an efficient method of canine Th17 lymphocyte differentiation. Our findings also suggested that the modification of the Wnt/β-catenin signaling pathway could be a valuable strategy for optimizing canine Th17 cell differentiation and advancing cell-based immunotherapy.
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Affiliation(s)
- Iwona Monika Szopa
- Department of Physiological Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 02-776 Warsaw, Poland; (K.M.-K.); (R.P.); (M.G.)
| | - Kinga Majchrzak-Kuligowska
- Department of Physiological Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 02-776 Warsaw, Poland; (K.M.-K.); (R.P.); (M.G.)
| | - Rafał Pingwara
- Department of Physiological Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 02-776 Warsaw, Poland; (K.M.-K.); (R.P.); (M.G.)
| | - Marek Kulka
- Department of Pathology and Veterinary Diagnostics, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 02-776 Warsaw, Poland;
| | - Monika Taşdemir
- Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland;
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Małgorzata Gajewska
- Department of Physiological Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 02-776 Warsaw, Poland; (K.M.-K.); (R.P.); (M.G.)
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14
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Shinkai N, Asada K, Machino H, Takasawa K, Takahashi S, Kouno N, Komatsu M, Hamamoto R, Kaneko S. SEgene identifies links between super enhancers and gene expression across cell types. NPJ Syst Biol Appl 2025; 11:49. [PMID: 40389443 PMCID: PMC12089303 DOI: 10.1038/s41540-025-00533-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 05/11/2025] [Indexed: 05/21/2025] Open
Abstract
Enhancers are non-coding DNA regions that facilitate gene transcription, with a specialized subset, super-enhancers, known to exert exceptionally strong transcriptional activation effects. Super-enhancers have been implicated in oncogenesis, and their identification is achievable through histone mark chromatin immunoprecipitation followed by sequencing data using existing analytical tools. However, conventional super-enhancer detection methodologies often do not accurately reflect actual gene expression levels, and the large volume of identified super-enhancers complicates comprehensive analysis. To address these limitations, we developed the super-enhancer to gene links (SE-to-gene Links) analysis, a platform named "SEgene" which incorporates the peak-to-gene links approach-a statistical method designed to reveal correlations between genes and peak regions ( https://github.com/hamamoto-lab/SEgene ). This platform enables a targeted evaluation of super-enhancer regions in relation to gene expression, facilitating the identification of super-enhancers that are functionally linked to transcriptional activity. Here, we demonstrate the application of SE-to-gene Links analysis to public datasets, confirming its efficacy in accurately detecting super-enhancers and identifying functionally associated genes. Additionally, SE-to-gene Links analysis identified ERBB2 as a significant gene of interest in the lung adenocarcinoma dataset from the National Cancer Center Japan cohort, suggesting a potential impact across multiple patient samples. Thus, the SE-to-gene Links analysis provides an analytical tool for evaluating super-enhancers as potential therapeutic targets, supporting the identification of clinically significant super-enhancer regions and their functionally associated genes.
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Affiliation(s)
- Norio Shinkai
- Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan
- Department of NCC Cancer Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ken Asada
- Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan
| | - Hidenori Machino
- Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan
| | - Ken Takasawa
- Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan
| | - Satoshi Takahashi
- Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan
| | - Nobuji Kouno
- Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan
| | - Masaaki Komatsu
- Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan
| | - Ryuji Hamamoto
- Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan.
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan.
- Department of NCC Cancer Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
| | - Syuzo Kaneko
- Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan.
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan.
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15
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Zhou YF, Zhu YW, Wang YW, Liang XY, Jiang QY, Wu DD. Diallyl disulfide in oncotherapy: molecular mechanisms and therapeutic potentials. Apoptosis 2025:10.1007/s10495-025-02105-0. [PMID: 40375038 DOI: 10.1007/s10495-025-02105-0] [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] [Accepted: 03/16/2025] [Indexed: 05/18/2025]
Abstract
Garlic possesses a broad spectrum of medicinal properties, such as anti-cancer, antioxidant, anti-diabetic effects, and protective effects on the heart, nervous system, and liver. Diallyl disulfide (DADS), an oil-soluble organic sulfur-containing compound in garlic, has garnered attention in recent years for its demonstrated anti-cancer efficacy in various cancer types such as leukemia, breast cancer, hepatocellular carcinoma, stomach cancer, and prostate cancer. The anticancer properties of DADS are attributed to its ability to suppress cancer cell proliferation, impede invasion and metastasis, as well as induce apoptosis, promote differentiation, and facilitate cell cycle arrest. Although many literatures have reviewed the pharmacokinetics, molecular mechanisms of anti-cancer effects and some clinical trials of DADS, the specific mechanisms and clinical-translational therapeutic potentials have not been elucidated. This comprehensive review focuses on delineating the molecular mechanisms underlying the anticancer effects of DADS, with a particular emphasis on its potential utility as a therapeutic intervention in the clinical management of cancer, and analyzes the challenges and coping strategies faced in the application of DADS as an anti-cancer drug, pointing out the directions for scientific research.
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Affiliation(s)
- Yun-Fei Zhou
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, 475004, Henan, China
- School of Clinical Medicine, Henan University, Kaifeng, 475004, Henan, China
| | - Yi-Wen Zhu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, 475004, Henan, China
- School of Clinical Medicine, Henan University, Kaifeng, 475004, Henan, China
| | - Yan-Wen Wang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, 475004, Henan, China
| | - Xiao-Yi Liang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, 475004, Henan, China
| | - Qi-Ying Jiang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, 475004, Henan, China.
| | - Dong-Dong Wu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, 475004, Henan, China.
- Department of Stomatology, Huaihe Hospital of Henan University, School of Stomatology, Henan University, Kaifeng, 475004, Henan, China.
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16
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Maurice MM, Angers S. Mechanistic insights into Wnt-β-catenin pathway activation and signal transduction. Nat Rev Mol Cell Biol 2025; 26:371-388. [PMID: 39856369 DOI: 10.1038/s41580-024-00823-y] [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: 12/12/2024] [Indexed: 01/27/2025]
Abstract
In multicellular organisms, Wnt proteins govern stem and progenitor cell renewal and differentiation to regulate embryonic development, adult tissue homeostasis and tissue regeneration. Defects in canonical Wnt signalling, which is transduced intracellularly by β-catenin, have been associated with developmental disorders, degenerative diseases and cancers. Although a simple model describing Wnt-β-catenin signalling is widely used to introduce this pathway and has largely remained unchanged over the past 30 years, in this Review we discuss recent studies that have provided important new insights into the mechanisms of Wnt production, receptor activation and intracellular signalling that advance our understanding of the molecular mechanisms that underlie this important cell-cell communication system. In addition, we review the recent development of molecules capable of activating the Wnt-β-catenin pathway with selectivity in vitro and in vivo that is enabling new lines of study to pave the way for the development of Wnt therapies for the treatment of human diseases.
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Affiliation(s)
- Madelon M Maurice
- Center for Molecular Medicine, University Medical Center, Utrecht, Netherlands.
- Oncode Institute, Utrecht, Netherlands.
| | - Stephane Angers
- Donnelly Centre for Cellular and Biomolecular Research and Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
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17
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Guo S, Ding R, Zhao Q, Wang X, Lv S, Ji XY. Recent Insights into the Roles of PEST-Containing Nuclear Protein. Mol Biotechnol 2025; 67:1800-1813. [PMID: 38762838 DOI: 10.1007/s12033-024-01188-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 04/26/2024] [Indexed: 05/20/2024]
Abstract
PEST-containing nuclear protein (PCNP), a short-lived small nuclear protein with 178 amino acids, is a nuclear protein containing two PEST sequences. PCNP is highly expressed in several malignant tumors such as cervical cancer, rectal cancer, and lung cancer. It is also associated with cell cycle regulation and the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and Wnt signaling pathways during tumor growth. The present article discuss how PCNP regulates the PI3K/AKT/mTOR and Wnt signaling pathways and related proteins, and the ubiquitination of PCNP regulates tumor cell cycle as well as the progress of the application of PCNP in the pathophysiology and treatment of colon cancer, human ovarian cancer, thyroid cancer, lung adenocarcinoma and oral squamous cell carcinoma. The main relevant articles were retrieved from PubMed, with keywords such as PEST-containing nuclear protein (PCNP), cancer (tumor), and signaling pathways as inclusion/exclusion criteria. Relevant references has been included and cited in the manuscript.
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Affiliation(s)
- Shiyun Guo
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, Henan, China
| | - Ruidong Ding
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, Henan, China
| | - Qian Zhao
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, Henan, China
| | - Xu Wang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, Henan, China
| | - Shuangyu Lv
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, Henan, China.
| | - Xin-Ying Ji
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, Henan, China.
- Kaifeng Key Laboratory for Infectious Diseases and Biosafety, Kaifeng, 475004, Henan, China.
- Faculty of Basic Medical Subjects, Shu-Qing Medical College of Zhengzhou, Mazhai, Erqi District, Zhengzhou, 450064, Henan, China.
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18
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Cheng J, Yang L, Wang S, Luo K, Luo S, Dong Y, Ning Y, Wang W. Phylogenetic Insights into the Evolutionary History of the RSPO Gene Family in Metazoa. Genes (Basel) 2025; 16:477. [PMID: 40428299 PMCID: PMC12111769 DOI: 10.3390/genes16050477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 04/21/2025] [Accepted: 04/22/2025] [Indexed: 05/29/2025] Open
Abstract
Background: The RSPO gene family encodes secreted glycoproteins that are rich in cysteine, which generally serve as activators of the Wnt signaling pathway in animals. Four types of this family have been identified in a few model species. However, the evolution of the family remains unclear. Methods: In this study, we identified a total of 1496 RSPO homologs through an extensive survey of the RSPO genes in 430 animals. Gene family clustering and phylogenetic analysis identified four major subtypes of the family (RSPO1-RSPO4) and clarified their distribution of copy number in different species. Results and Conclusions: Members of the RSPO4 subfamily that were closest to ancestral forms existed in both Deuterostomes and Protostomates, and we speculate that representatives of this subfamily already existed in Urbilatera, the last common ancestor of Deuterostomes. Particularly, in some RSPO3 subtypes of Actinopterygii (ray-finned fishes), an FU repeated motif with three conserved cysteines was identified. Further conservative analysis of amino acids and alignment of tertiary protein structure revealed the potential functional sites for each subgroup. The results provide insight into the phylogenetic relationships and evolutionary patterns of conserved motifs of RSPO family genes in animal kingdoms, which will guide further studies on the biological functions of RSPO in other non-model species.
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Affiliation(s)
- Jia Cheng
- College of Food Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (J.C.); (K.L.); (S.L.)
- Yunnan Provincial Key Laboratory of Biological Big Data, Yunnan Agricultural University, Kunming 650201, China;
| | - Ling Yang
- Institute of Agro-Products of Processing and Design, Hainan Academy of Agricultural Sciences, Haikou 571100, China;
| | - Shiping Wang
- Yunnan Provincial Key Laboratory of Biological Big Data, Yunnan Agricultural University, Kunming 650201, China;
- Institute of Agro-Products of Processing and Design, Hainan Academy of Agricultural Sciences, Haikou 571100, China;
| | - Kaiyong Luo
- College of Food Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (J.C.); (K.L.); (S.L.)
- Yunnan Provincial Key Laboratory of Biological Big Data, Yunnan Agricultural University, Kunming 650201, China;
| | - Senlin Luo
- College of Food Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (J.C.); (K.L.); (S.L.)
- Yunnan Provincial Key Laboratory of Biological Big Data, Yunnan Agricultural University, Kunming 650201, China;
| | - Yang Dong
- Yunnan Provincial Key Laboratory of Biological Big Data, Yunnan Agricultural University, Kunming 650201, China;
| | - Ya Ning
- College of Science, Yunnan Agricultural University, Kunming 650201, China;
| | - Weibin Wang
- Yunnan Provincial Key Laboratory of Biological Big Data, Yunnan Agricultural University, Kunming 650201, China;
- College of Science, Yunnan Agricultural University, Kunming 650201, China;
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19
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Joo JE, Viana-Errasti J, Buchanan DD, Valle L. Genetics, genomics and clinical features of adenomatous polyposis. Fam Cancer 2025; 24:38. [PMID: 40237887 PMCID: PMC12003455 DOI: 10.1007/s10689-025-00460-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Accepted: 03/16/2025] [Indexed: 04/18/2025]
Abstract
Adenomatous polyposis syndromes are hereditary conditions characterised by the development of multiple adenomas in the gastrointestinal tract, particularly in the colon and rectum, significantly increasing the risk of colorectal cancer and, in some cases, extra-colonic malignancies. These syndromes are caused by germline pathogenic variants (PVs) in genes involved in Wnt signalling and DNA repair. The main autosomal dominant adenomatous polyposis syndromes include familial adenomatous polyposis (FAP) and polymerase proofreading-associated polyposis (PPAP), caused by germline PVs in APC and the POLE and POLD1 genes, respectively. Autosomal recessive syndromes include those caused by biallelic PVs in the DNA mismatch repair genes MLH1, MSH2, MSH6, PMS2, MSH3 and probably MLH3, and in the base excision repair genes MUTYH, NTHL1 and MBD4. This review provides an in-depth discussion of the genetic and molecular mechanisms underlying hereditary adenomatous polyposis syndromes, their clinical presentations, tumour mutational signatures, and emerging approaches for the treatment of the associated cancers. Considerations for genetic testing are described, including post-zygotic mosaicism, non-coding PVs, the interpretation of variants of unknown significance and cancer risks associated with monoallelic variants in the recessive genes. Despite advances in genetic testing and the recent identification of new adenomatous polyposis genes, many cases of multiple adenomas remain genetically unexplained. Non-genetic factors, including environmental risk factors, prior oncologic treatments, and bacterial genotoxins colonising the intestine - particularly colibactin-producing Escherichia coli - have emerged as alternative pathogenic mechanisms.
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Affiliation(s)
- Jihoon E Joo
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, Australia
- Collaborative Centre for Genomic Cancer Medicine, Victorian Comprehensive Cancer Centre, Parkville, VIC, Australia
| | - Julen Viana-Errasti
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Av. Gran Via 199- 203, Hospitalet de Llobregat, 08908, Spain
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Doctoral Program in Biomedicine, University of Barcelona, Hospitalet de Llobregat, Barcelona, Spain
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, Australia.
- Collaborative Centre for Genomic Cancer Medicine, Victorian Comprehensive Cancer Centre, Parkville, VIC, Australia.
- Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, Australia.
| | - Laura Valle
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Av. Gran Via 199- 203, Hospitalet de Llobregat, 08908, Spain.
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
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20
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Canak HN, Bas K, Yağmur EA, Karakurt S. Mesobuthus eupeus venom modulates colorectal carcinoma signaling pathways and induces apoptosis. Med Oncol 2025; 42:163. [PMID: 40229568 PMCID: PMC11996983 DOI: 10.1007/s12032-025-02689-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 03/13/2025] [Indexed: 04/16/2025]
Abstract
Colorectal cancer (CRC) is a significant global health concern, often challenging to treat effectively with conventional methods and burdened by adverse effects. Scorpion venoms offer a unique avenue for exploration, given their ability to disrupt the cell cycle, inhibit growth, and trigger apoptosis. This study delves into the impact of Mesobuthus eupeus (M. eupeus) scorpion venom on the proliferation and progression of colorectal cancer at the molecular level. The total protein concentration in the venom (607.5 µg/mL) also emphasized the rich composition and potential for therapeutic applications. The study reveals that M. eupeus venom effectively reduced the proliferation of DLD-1 and HT-29 colorectal cancer cells in a dose-dependent manner with IC50 values of 4.32 and 7.61 µg/mL, respectively. The venom also impedes cell migration, diminishes colony formation, and triggers apoptosis in the cancer cells. The venom also induced early and late apoptosis in the two cancer cell lines. The human colorectal cancer and apoptotic pathways were clarified at the molecular level using pathway panels, which revealed that 16 genes involved in colorectal cancer increased while 23 decreased. In the HT-29 cell line, 57 genes increased, and 1 decreased following venom treatment. Besides, the mRNA expression of 19 genes involved in the apoptotic pathway was increased, while 22 were reduced in DLD-1 cells. This study underscores the potential of M. eupeus venom as a natural therapeutic approach in the quest for cancer treatments.
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Affiliation(s)
- Havva Nur Canak
- Faculty of Science, Department of Biochemistry, Selcuk University, Konya, Türkiye
| | - Kemal Bas
- Faculty of Science, Department of Biochemistry, Selcuk University, Konya, Türkiye
| | - Ersen Aydın Yağmur
- Department of Plant and Animal Production, Alasehir Vocational High School, Manisa Celal Bayar University, Manisa, Türkiye
| | - Serdar Karakurt
- Faculty of Science, Department of Biochemistry, Selcuk University, Konya, Türkiye.
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21
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Dalle Carbonare L, Cominacini M, Trabetti E, Bombieri C, Pessoa J, Romanelli MG, Valenti MT. The bone microenvironment: new insights into the role of stem cells and cell communication in bone regeneration. Stem Cell Res Ther 2025; 16:169. [PMID: 40221779 PMCID: PMC11993959 DOI: 10.1186/s13287-025-04288-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 03/19/2025] [Indexed: 04/14/2025] Open
Abstract
Mesenchymal stem cells (MSCs) play a crucial role in bone formation and remodeling. Intrinsic genetic factors and extrinsic environmental cues regulate their differentiation into osteoblasts. Within the bone microenvironment, a complex network of biochemical and biomechanical signals orchestrates bone homeostasis and regeneration. In addition, the crosstalk among MSCs, immune cells, and neighboring cells-mediated by extracellular vesicles and non-coding RNAs (such as circular RNAs and micro RNAs) -profoundly influences osteogenic differentiation and bone remodeling. Recent studies have explored specific signaling pathways that contribute to effective bone regeneration, highlighting the potential of manipulating the bone microenvironment to enhance MSC functionality. The integration of advanced biomaterials, gene editing techniques, and controlled delivery systems is paving the way for more targeted and efficient regenerative therapies. Furthermore, artificial intelligence could improve bone tissue engineering, optimize biomaterial design, and enable personalized treatment strategies. This review explores the latest advancements in bone regeneration, emphasizing the intricate interplay among stem cells, immune cells, and signaling molecules. By providing a comprehensive overview of these mechanisms and their clinical implications, we aim to shed light on future research directions in this rapidly evolving field.
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Affiliation(s)
- L Dalle Carbonare
- Department of Engineering for the Innovation Medicine, University of Verona, 37100, Verona, Italy
| | - M Cominacini
- Department of Engineering for the Innovation Medicine, University of Verona, 37100, Verona, Italy
| | - E Trabetti
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37100, Verona, Italy
| | - C Bombieri
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37100, Verona, Italy
| | - J Pessoa
- Department of Medical Sciences and Institute of Biomedicine-Ibimed, University of Aveiro, 3810 - 193, Aveiro, Portugal
| | - M G Romanelli
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37100, Verona, Italy
| | - M T Valenti
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37100, Verona, Italy.
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22
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Ayala I, Hebbale SK, Mononen J, Brearley-Sholto MC, Shannon CE, Valdez I, Fourcaudot M, Bakewell TM, Zagorska A, Romero G, Asmis M, Musa FA, Sily JT, Smelter AA, Hinostroza EA, Freitas Lima LC, de Aguiar Vallim TQ, Heikkinen S, Norton L. The Spatial Transcriptional Activity of Hepatic TCF7L2 Regulates Zonated Metabolic Pathways that Contribute to Liver Fibrosis. Nat Commun 2025; 16:3408. [PMID: 40210847 PMCID: PMC11986045 DOI: 10.1038/s41467-025-58714-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 03/20/2025] [Indexed: 04/12/2025] Open
Abstract
The molecular mechanisms regulating the zonal distribution of metabolism in liver are incompletely understood. Here we use single nuclei genomics techniques to examine the spatial transcriptional function of transcription factor 7-like 2 (TCF7L2) in mouse liver, and determine the consequences of TCF7L2 transcriptional inactivation on the metabolic architecture of the liver and the function of zonated metabolic pathways. We report that while Tcf7l2 mRNA expression is ubiquitous across the liver lobule, accessibility of the consensus TCF/LEF DNA binding motif is restricted to pericentral (PC) hepatocytes in zone 3. In mice expressing functionally inactive TCF7L2 in liver, PC hepatocyte-specific gene expression is absent, which we demonstrate promotes hepatic cholesterol accumulation, impaired bile acid synthesis, disruption to glutamine/glutamate homeostasis and pronounced dietary-induced hepatic fibrosis. In summary, TCF7L2 is a key regulator of hepatic zonal gene expression and regulates several zonated metabolic pathways that may contribute to the development of fibrotic liver disease.
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Affiliation(s)
- Iriscilla Ayala
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Skanda K Hebbale
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Juho Mononen
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland
| | | | - Christopher E Shannon
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Ivan Valdez
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Marcel Fourcaudot
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Terry M Bakewell
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | | | - Giovanna Romero
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Mara Asmis
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Fatima A Musa
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Jonah T Sily
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Annie A Smelter
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Edgar A Hinostroza
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Leandro C Freitas Lima
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Thomas Q de Aguiar Vallim
- Department of Cardiology, School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Sami Heikkinen
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland
| | - Luke Norton
- Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
- Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, TX, USA.
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23
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Hosseini N, Forghanifard MM. MEIS1 knockdown upregulates WNT signaling pathway genes in esophageal squamous cell carcinoma. BMC Med Genomics 2025; 18:69. [PMID: 40211274 PMCID: PMC11983858 DOI: 10.1186/s12920-025-02134-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Accepted: 03/27/2025] [Indexed: 04/12/2025] Open
Abstract
BACKGROUND The transcription factor MEIS1 belongs to the 3-amino acid loop extension (TALE) family of homeodomain proteins which plays various functions in normal and tumor cell progression. The canonical WNT/β-catenin pathway governs a plethora of biological processes including cell proliferation, differentiation, and tumor development. In the present study, the effect of MEIS1 gene silencing was assessed on WNT pathway genes in esophageal squamous cell carcinoma (ESCC) cells. MATERIALS AND METHODS Along with the packaging plasmids, the pLKO.1-MEIS1 plasmid was cotransfected into HEK293T to generate lentiviral particles, followed by transduction of a semi-confluent KYSE-30 cell culture. After total RNA extraction and cDNA synthesis, comparative real-time PCR was applied to assess the efficiency of MEIS1 knockdown and the expression of genes related to the WNT signaling pathway. RESULTS The results revealed effective downregulation of MEIS1 in KYSE-30 cells. Interestingly, MEIS1 silencing led to a substantial overexpression of WNT pathway key components while the expression of negative regulators of this pathway was substantially decreased. CONCLUSIONS Our data suggest that MEIS1 gene probably induces WNT/β-catenin pathway deactivation in ESCC cells. Consequently, the inverse correlation of MEIS1 expression and WNT signaling pathway activation may introduce a new molecular linkage through ESCC progression and aggressiveness.
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Affiliation(s)
- Nayyerehalsadat Hosseini
- Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Mahdi Forghanifard
- Department of Biology, Da.C., Islamic Azad University, Cheshmeh-Ali Boulevard, Sa'dei square, P.O.Box: 3671639998, Damghan, Iran.
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24
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Pirvu LC, Stefaniu A, Nita S, Radu N, Neagu G. In Silico and In Vitro Analyses of Strawberry-Derived Extracts in Relation to Key Compounds' Metabolic and Anti-Tumor Effects. Int J Mol Sci 2025; 26:3492. [PMID: 40331930 PMCID: PMC12026510 DOI: 10.3390/ijms26083492] [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: 02/23/2025] [Revised: 04/04/2025] [Accepted: 04/05/2025] [Indexed: 05/08/2025] Open
Abstract
Plant extracts contain many small molecules that are less investigated. The present paper aims to study in silico physical-chemical, pharmacokinetic, medicinal chemistry and lead/drug-likeness properties and the ability to interfere with the activity of P-glycoprotein (P-gp) transporter and cytochrome P450 (CYP) oxidase system in humans of phloridzin, phloretin, 4-methylchalcone metabolic series alongside the top three compounds found in the ethanolic extract from strawberries (S), namely 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one, 2-pyrrolidinone 5-(cyclohexylmethyl) and hexadecanoic acid. The phloridzin derivatives also were studied for their inhibitory potential upon Bcl-2, TNKS1 and COX-2 molecular targets. In vitro, Caco-2 studies analyzed the cytoprotective and anti-proliferative activity of S and the three phloridzin derivatives (pure compounds) in comparison with their combination 1:1 (GAE/pure compound, w/w), in the range 1 to 50 µg active compounds per test sample. Altogether, it was concluded that phloretin (Phl) can be used alone or in combination with S to support intestinal cell health in humans. Phloridzin (Phd) and phloridzin combined with S were proven ineffective. 4-methylchalcone (4-MeCh) combined with S indicated no advantages, while the pure compound exhibited augmented inhibitory effects, becoming a candidate for combinations with anticancer drugs. Overall, in silico studies revealed possible limitations in the practical use of phloridzin derivatives due to their potential to interfere with the activity of several major CYP enzymes.
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Affiliation(s)
- Lucia Camelia Pirvu
- Department of Pharmaceutical Biotechnologies, National Institute for Chemical Pharmaceutical Research and Development (INCDCF-ICCF), 112 Vitan, 031299 Bucharest, Romania;
| | - Amalia Stefaniu
- Department of Pharmaceutical Biotechnologies, National Institute for Chemical Pharmaceutical Research and Development (INCDCF-ICCF), 112 Vitan, 031299 Bucharest, Romania;
| | - Sultana Nita
- Department of Physical-Chemical Analysis and Quality Control, National Institute for Chemical Pharmaceutical Research and Development (INCDCF-ICCF), 112 Vitan, 031299 Bucharest, Romania;
| | - Nicoleta Radu
- Biotechnology Faculty, University of Agronomic Sciences and Veterinary Medicine of Bucharest, 59 Marasti, District 1, 011464 Bucharest, Romania;
- Department of Biotechnology, National Institute of Chemistry and Petrochemistry Research and Development, 202 Splaiul Independentei, 060021 Bucharest, Romania
| | - Georgeta Neagu
- Department of Pharmacology, National Institute for Chemical Pharmaceutical Research and Development (INCDCF-ICCF), 112 Vitan, 031299 Bucharest, Romania
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25
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Tetè G, Trofimov A, Vinskid NC, Tafuri G, Profili F, Sinjari B. How short peptides interact with oral cells? A systematic review. BMC Oral Health 2025; 25:494. [PMID: 40197322 PMCID: PMC11974078 DOI: 10.1186/s12903-025-05856-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 03/20/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND The study of short peptides in dentistry is a particularly promising area, due to their unique biological properties, such as antibacterial and antitumor activity, the ability to modulate immune responses, tissue regeneration processes, and their potential to stimulate stem cell differentiation. This study provides a systematic review aimed at analyzing the role of short peptides in the pathogenesis and treatment of oral diseases. METHODS A systematic search was performed according to the PRISMA statement and employed the PICO(S) approach. The search was limited to English-language articles, and in vitro study were included in the electronic search. A comprehensive search was conducted across PubMed, Embase, Web of Science and Cochrane Library databases, without timeframe limits, resulting in a total of 1085 scientific articles. After duplicate removal, 563 unique papers remained for further analysis. Following this screening process, 19 studies were identified as relevant to the topic. A final selection of 9 scientific papers was made based on their study type and the specific peptide examined. One last article was eliminated in final analysis because the laboratory methodology is now refuted by more recent scientific evidence. RESULTS 8 in vitro studies dealing with different short peptides with different biological functions against oral cavity cells and tissues were included. 4 articles highlighted the ability of short peptides to positively influence the proliferation of cells in the oral cavity. 2 articles highlighted the antitumour activity of short peptides. 1 article highlighted the antimicrobial activity of the peptide DJK-15. The last paper showed that Pep-B has anti-inflammatory properties towards the cells of the oral cavity. CONCLUSIONS However, the main short peptides that have been tested in vitro and that act on cells and tissues of the oral cavity are the focus of this systematic review. It can therefore be used as a basis for a possible hypothesis of new in vitro studies to compare the different molecules, for new in vivo studies and for the investigation of potential action mechanisms and applications for new drugs to combat diseases of the oral cavity. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Giulia Tetè
- Department of Human Sciences, "Sustainable Blue Economy and One Health"-XL Cycle, Law, and Economics "Leonardo da Vinci", UNIDAV, Telematic University, Chieti, Torrevecchia Teatina, 66100, Italy.
| | - Aleksandr Trofimov
- Department of Innovative Technologies in Medicine and Dentistry, Unit of Prosthodontics, University "G. d'Annunzio" of Chieti-Pescara, Chieti, 66100, Italy
- Department of Innovative Technologies in Medicine and Dentistry, Hi-Tech Dental Materials Laboratory, University "G. d'Annunzio" of Chieti-Pescara, Chieti, 66100, Italy
| | - Natasha Cinta Vinskid
- Unit of Biomedical Science, Department of Biomedical Engineering, Hasanuddin University, Makassar, Indonesia
| | - Giuseppe Tafuri
- Department of Innovative Technologies in Medicine and Dentistry, Unit of Prosthodontics, University "G. d'Annunzio" of Chieti-Pescara, Chieti, 66100, Italy
- Department of Innovative Technologies in Medicine and Dentistry, Hi-Tech Dental Materials Laboratory, University "G. d'Annunzio" of Chieti-Pescara, Chieti, 66100, Italy
| | - Fabia Profili
- Department of Innovative Technologies in Medicine and Dentistry, Unit of Prosthodontics, University "G. d'Annunzio" of Chieti-Pescara, Chieti, 66100, Italy
- Department of Innovative Technologies in Medicine and Dentistry, Hi-Tech Dental Materials Laboratory, University "G. d'Annunzio" of Chieti-Pescara, Chieti, 66100, Italy
| | - Bruna Sinjari
- Department of Innovative Technologies in Medicine and Dentistry, Unit of Prosthodontics, University "G. d'Annunzio" of Chieti-Pescara, Chieti, 66100, Italy
- Department of Innovative Technologies in Medicine and Dentistry, Hi-Tech Dental Materials Laboratory, University "G. d'Annunzio" of Chieti-Pescara, Chieti, 66100, Italy
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26
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Luo Q, Teschendorff AE. Cell-type-specific subtyping of epigenomes improves prognostic stratification of cancer. Genome Med 2025; 17:34. [PMID: 40181447 PMCID: PMC11967111 DOI: 10.1186/s13073-025-01453-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 03/10/2025] [Indexed: 04/05/2025] Open
Abstract
BACKGROUND Most molecular classifications of cancer are based on bulk-tissue profiles that measure an average over many distinct cell types. As such, cancer subtypes inferred from transcriptomic or epigenetic data are strongly influenced by cell-type composition and do not necessarily reflect subtypes defined by cell-type-specific cancer-associated alterations, which could lead to suboptimal cancer classifications. METHODS To address this problem, we here propose the novel concept of cell-type-specific combinatorial clustering (CELTYC), which aims to group cancer samples by the molecular alterations they display in specific cell types. We illustrate this concept in the context of DNA methylation data of liver and kidney cancer, deriving in each case novel cancer subtypes and assessing their prognostic relevance against current state-of-the-art prognostic models. RESULTS In both liver and kidney cancer, we reveal improved cell-type-specific prognostic models, not discoverable using standard methods. In the case of kidney cancer, we show how combinatorial indexing of epithelial and immune-cell clusters define improved prognostic models driven by synergy of high mitotic age and altered cytokine signaling. We validate the improved prognostic models in independent datasets and identify underlying cytokine-immune-cell signatures driving poor outcome. CONCLUSIONS In summary, cell-type-specific combinatorial clustering is a valuable strategy to help dissect and improve current prognostic classifications of cancer in terms of the underlying cell-type-specific epigenetic and transcriptomic alterations.
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Affiliation(s)
- Qi Luo
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China
| | - Andrew E Teschendorff
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China.
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27
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Zhao S, Wang J, Liu H, Liu S, Sun L, Wang Y, Gao S, Sun Y. Analyses of CTNNB1 mutation and expression and clinicopathological characteristics in 179 cases of solid-pseudopapillary neoplasm of the pancreas. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2025; 32:327-338. [PMID: 39991945 DOI: 10.1002/jhbp.12123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2025]
Abstract
BACKGROUND Nuclear expression of CTNNB1 is occasionally negative in solid-pseudopapillary neoplasm (SPN) of the pancreas, leading to a missed diagnosis. In the present study, we aimed to investigate the clinical significance of CTNNB1 mutation detection for diagnosing SPN and explore the difference in clinicopathological characteristics at different ages and sex. METHODS Patients who underwent surgery for a pathologically confirmed SPN in our institution between 2011 and 2020 were collected. Their clinicopathological data were analyzed. RESULTS The median age of the 179 patients was 31 years (6-64 years), including 34 pediatric patients (19.0%), and 32 patients were male (17.9%). We detected point mutations in exon 3 of CTNNB1 in 74.3% (133/179) of SPNs by Sanger sequencing. The main mutation sites were D32, S33, S37, G34 and T41. In the three SPNs without nuclear expression of CTNNB1, Sanger sequencing showed point mutations of CTNNB1. NGS did not detect any consistent mutation except CTNNB1 in the three cases. The tumor size, Ki-67 index, and the negative rates of CTNNB1 nuclear expression and synaptophysin expression in the pediatric group were higher than those in other groups (p < .05). CONCLUSIONS For atypical cases, testing for CTNNB1 mutations can help in the accurate diagnosis of SPN. Compared with adult patients, pediatrics with SPN may be more prone to recurrence, and their immunohistochemical phenotype is more complex, requiring additional care in the diagnosis and postoperative follow-up.
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Affiliation(s)
- Shuai Zhao
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jian Wang
- Department of Pancreatic Carcinoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin, China
| | - Huimin Liu
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Shasha Liu
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Lin Sun
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Ying Wang
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Song Gao
- Department of Pancreatic Carcinoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin, China
| | - Yan Sun
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China
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28
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Yuan M, Li Q, Wang Z, Liu L, Wen C, Liu G, Yu F, Feng L, Yang L. TRPV4 Promotes Vascular Calcification by Directly Associating With and Activating β-Catenin. Arterioscler Thromb Vasc Biol 2025; 45:e101-e117. [PMID: 39973749 DOI: 10.1161/atvbaha.124.321793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 02/07/2025] [Indexed: 02/21/2025]
Abstract
BACKGROUND Vascular calcification contributes to increased cardiovascular morbidity and mortality in patients with chronic kidney disease, diabetes, and atherosclerosis. Currently, there are no effective therapeutic strategies to prevent or reverse vascular calcification. TRPV4 (transient receptor potential channel V4), a key Ca2+-permeable channel, plays an important role in various diseases. However, the role and mechanism of TRPV4 in vascular calcification have not yet been elucidated. METHODS The effects of TRPV4 on vascular calcification were explored in vitro and in vivo. TRPV4 interactome assessment and molecular docking were performed to investigate the mechanism and specific therapeutic strategy for vascular calcification. RESULTS TRPV4 was substantially upregulated in high inorganic phosphate-induced calcified vascular smooth muscle cells (SMCs) and calcified aortas from cholecalciferol (vitamin D3)-overloaded mice. TRPV4 overexpression increased the expression of the osteochondrogenic markers Runx2 (runt-related transcription factor 2), Msx2 (Msh homeobox 2), and Sox9 (SRY-box transcription factor 9) and exacerbated high inorganic phosphate-induced vascular SMC calcification in a Ca2+ influx-dependent manner. In contrast, TRPV4 deficiency or inactivation significantly inhibited vascular SMC calcification under high inorganic phosphate conditions. Moreover, compared with that in control littermates, SMC-specific TRPV4 deficiency in mice alleviated vitamin D3-induced and 5/6 nephrectomy-induced vascular calcification. Mechanistically, TRPV4 interacted with β-catenin and activated β-catenin/TCF (T-cell factor) transcriptional activity via Ca2+/ASK1 (apoptosis signal regulating kinase 1)/p38 signaling. β-Catenin knockdown abolished the effects of TRPV4 overexpression on vascular SMC calcification. TRPV4/β-catenin interaction is pivotal for maintaining TRPV4/Ca2+-induced ASK1/p38/β-catenin activation. Hesperidin, a natural product found in citrus fruits, effectively disrupted TRPV4/β-catenin interaction, thereby inhibiting ASK1/p38/β-catenin activity and preventing vascular calcification. CONCLUSIONS Our study identified TRPV4 as a new pathogenic factor for vascular calcification that directly associates with and activates β-catenin. Blocking the TRPV4/β-catenin interaction through hesperidin suppressed the progression of vascular calcification and may be an effective precision strategy to address vascular calcification.
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MESH Headings
- Animals
- TRPV Cation Channels/metabolism
- TRPV Cation Channels/genetics
- TRPV Cation Channels/deficiency
- Vascular Calcification/metabolism
- Vascular Calcification/pathology
- Vascular Calcification/genetics
- Vascular Calcification/prevention & control
- Vascular Calcification/chemically induced
- beta Catenin/metabolism
- beta Catenin/genetics
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/drug effects
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Myocytes, Smooth Muscle/drug effects
- Humans
- Mice, Inbred C57BL
- Disease Models, Animal
- Male
- Cells, Cultured
- Signal Transduction
- Mice, Knockout
- Phosphates
- Mice
- Aortic Diseases/pathology
- Aortic Diseases/metabolism
- Aortic Diseases/genetics
- Aortic Diseases/prevention & control
- Cholecalciferol
- Molecular Docking Simulation
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Affiliation(s)
- Menglu Yuan
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, China. MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, China
| | - Qi Li
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, China. MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, China
| | - Zhiwei Wang
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, China. MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, China
| | - Liangju Liu
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, China. MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, China
| | - Chengyuan Wen
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, China. MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, China
| | - Guizhu Liu
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, China. MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, China
| | - Fan Yu
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, China. MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, China
| | - Lei Feng
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, China. MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, China
| | - Liu Yang
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, China. MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, China
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Mao M, Lei Y, Ma X, Xie HY. Challenges and Emerging Strategies of Immunotherapy for Glioblastoma. Chembiochem 2025; 26:e202400848. [PMID: 39945240 DOI: 10.1002/cbic.202400848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/31/2025] [Accepted: 02/13/2025] [Indexed: 03/05/2025]
Abstract
Glioblastoma (GBM) is recognized as the most lethal primary malignant tumor of the central nervous system. Although traditional treatments can somewhat prolong patient survival, the overall prognosis remains grim. Immunotherapy has become an effective method for GBM treatment. Oncolytic virus, checkpoint inhibitors, CAR T cells and tumor vaccines have all been applied in this field. Moreover, the combining of immunotherapy with traditional radiotherapy, chemotherapy, or gene therapy can further improve the treatment outcome. This review systematically summarizes the features of GBM, the recent progress of immunotherapy in overcoming GBM.
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Affiliation(s)
- Mingchuan Mao
- School of Medical Technology, Beijing Institute of Technology, Beijing, 100081, China
| | - Yao Lei
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Xianbin Ma
- School of Medical Technology, Beijing Institute of Technology, Beijing, 100081, China
| | - Hai-Yan Xie
- Chemical Biology Center, Peking University, Beijing, 100191, China
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
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30
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Shameem M, Olson SL, Marron Fernandez de Velasco E, Kumar A, Singh BN. Cardiac Fibroblasts: Helping or Hurting. Genes (Basel) 2025; 16:381. [PMID: 40282342 PMCID: PMC12026832 DOI: 10.3390/genes16040381] [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: 02/28/2025] [Revised: 03/22/2025] [Accepted: 03/25/2025] [Indexed: 04/29/2025] Open
Abstract
Cardiac fibroblasts (CFs) are the essential cell type for heart morphogenesis and homeostasis. In addition to maintaining the structural integrity of the heart tissue, muscle fibroblasts are involved in complex signaling cascades that regulate cardiomyocyte proliferation, migration, and maturation. While CFs serve as the primary source of extracellular matrix proteins (ECM), tissue repair, and paracrine signaling, they are also responsible for adverse pathological changes associated with cardiovascular disease. Following activation, fibroblasts produce excessive ECM components that ultimately lead to fibrosis and cardiac dysfunction. Decades of research have led to a much deeper understanding of the role of CFs in cardiogenesis. Recent studies using the single-cell genomic approach have focused on advancing the role of CFs in cellular interactions, and the mechanistic implications involved during cardiovascular development and disease. Arguably, the unique role of fibroblasts in development, tissue repair, and disease progression categorizes them into the friend or foe category. This brief review summarizes the current understanding of cardiac fibroblast biology and discusses the key findings in the context of development and pathophysiological conditions.
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Affiliation(s)
- Mohammad Shameem
- Department of Rehabilitation Medicine, University of Minnesota, Minneapolis, MN 55455, USA;
| | - Shelby L. Olson
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA;
| | | | - Akhilesh Kumar
- Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA;
- Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA
| | - Bhairab N. Singh
- Department of Rehabilitation Medicine, University of Minnesota, Minneapolis, MN 55455, USA;
- Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA
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31
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Teng C, Chen JW, Shen LS, Chen S, Chen GQ. Research advances in natural sesquiterpene lactones: overcoming cancer drug resistance through modulation of key signaling pathways. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2025; 8:13. [PMID: 40201307 PMCID: PMC11977367 DOI: 10.20517/cdr.2024.178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 03/04/2025] [Accepted: 03/04/2025] [Indexed: 04/10/2025]
Abstract
Cancer remains a significant global health challenge, with current chemotherapeutic strategies frequently limited by the emergence of resistance. In this context, natural compounds with the potential to overcome resistance have garnered considerable attention. Among these, sesquiterpene lactones, primarily derived from plants in the Asteraceae family, stand out for their potential anticancer properties. This review specifically focuses on five key signaling pathways: PI3K/Akt/mTOR, NF-κB, Wnt/β-catenin, MAPK/ERK, and STAT3, which play central roles in the mechanisms of cancer resistance. For each of these pathways, we detail their involvement in both cancer development and the emergence of drug resistance. Additionally, we investigate how sesquiterpene lactones modulate these pathways to overcome resistance across diverse cancer types. These insights highlight the potential of sesquiterpene lactones to drive the advancement of novel therapies that can effectively combat both cancer progression and drug resistance.
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Affiliation(s)
- Chi Teng
- College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, Guangdong, China
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, Guangdong, China
- Authors contributed equally
| | - Jia-Wen Chen
- College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, Guangdong, China
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, Guangdong, China
- Authors contributed equally
| | - Li-Sha Shen
- Chongqing Academy of Chinese Materia Medica, Chongqing 400065, China
| | - Sibao Chen
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, Guangdong, China
- Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong 999077, China
- Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hong Kong 999077, China
| | - Guo-Qing Chen
- College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, Guangdong, China
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, Guangdong, China
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Terra ML, Sant’Anna TBF, de Barros JJF, de Araujo NM. Geographic and Viral Etiology Patterns of TERT Promoter and CTNNB1 Exon 3 Mutations in Hepatocellular Carcinoma: A Comprehensive Review. Int J Mol Sci 2025; 26:2889. [PMID: 40243493 PMCID: PMC11988703 DOI: 10.3390/ijms26072889] [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: 02/23/2025] [Revised: 03/19/2025] [Accepted: 03/20/2025] [Indexed: 04/18/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a leading cause of cancer-related mortality worldwide. Genetic alterations play a critical role in hepatocarcinogenesis, with mutations in the telomerase reverse transcriptase promoter (TERTp) and CTNNB1 exon 3 representing two of the most frequently reported somatic events in HCC. However, the frequency and distribution of these mutations vary across geographic regions and viral etiologies, particularly hepatitis B virus (HBV) and hepatitis C virus (HCV). This study aimed to assess the global distribution and etiological associations of TERTp and CTNNB1 exon 3 mutations in HCC through a comprehensive literature review. Our analysis, encompassing over 4000 HCC cases, revealed that TERTp mutations were present in 49.2% of tumors, with C228T being the predominant variant (93.3% among mutated cases). A striking contrast was observed between viral etiologies: TERTp mutations were detected in 31.6% of HBV-related HCCs, compared to 66.2% in HCV-related cases. CTNNB1 exon 3 mutations were identified in 23.1% of HCCs, showing a similar association with viral etiology, being more common in HCV-related cases (30.7%) than in HBV-related tumors (12.8%). Geographically, both mutations exhibited comparable patterns, with higher frequencies in Europe, Japan, and the USA, while lower rates were observed in China, Taiwan, and South Korea. Our findings underscore the distinct molecular profiles of HCC according to viral etiology and geographic origin, highlighting the need for region- and etiology-specific approaches to HCC prevention, diagnosis, and targeted therapy.
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Affiliation(s)
| | | | | | - Natalia Motta de Araujo
- Laboratory of Molecular Virology and Parasitology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21040-900, Brazil; (M.L.T.); (T.B.F.S.); (J.J.F.d.B.)
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Pun R, Thapa A, Takafuji SR, Suzuki RM, Kay GF, Howard TD, Kim MH, North BJ. BubR1 Controls Heart Development by Promoting Expression of Cardiogenesis Regulators. J Am Heart Assoc 2025; 14:e038286. [PMID: 40055864 DOI: 10.1161/jaha.124.038286] [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: 11/16/2024] [Accepted: 01/22/2025] [Indexed: 03/19/2025]
Abstract
BACKGROUND Congenital heart defects are structural anomalies present at birth that can affect the function of the heart. Aneuploidy is a significant risk factor for congenital heart defects. Mosaic variegated aneuploidy syndrome, caused by mutations in Bub1b (encoding BubR1, a mitotic checkpoint protein), leads to congenital heart defects such as septal defects. However, the molecular rationale for how Bub1b mutations promote congenital heart defects associated with mosaic variegated aneuploidy syndrome remains unresolved. METHODS To study morphological, structural, and cellular consequences of BubR1 deletion in the heart, we crossed mice carrying conditional alleles of Bub1b with Nkx2.5-cre mice. Single-cell RNA sequencing was carried out to determine differentially expressed genes and biological processes in various cell types present in the developing heart. Trajectory analysis was carried out to determine the differentiation trajectory of BubR1 knockout embryonic hearts. Finally, CellChat analysis provided details on the major signaling interactions that were either absent or hyperactive in the BubR1 knockout heart. RESULTS Here, we show that cardiac-specific BubR1 deletion causes embryonic lethality due to developmental stalling after cardiac looping with defects in cardiac maturation including chamber wall thickness, septation, and trabeculation. Single-cell transcriptomic profiling further revealed that the differentiation trajectory of cardiomyocytes is severely impacted with suppression of critical cardiogenesis genes. Hyperactivation of Wnt signaling in BubR1 knockout hearts indicated a disturbed homeostasis in cellular pathways essential for proper tissue morphogenesis of the heart. CONCLUSIONS Taken together, these findings reveal that BubR1 is a crucial regulator of cardiac development in vivo, which ensures the proper timing of heart morphogenesis.
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Affiliation(s)
- Renju Pun
- Biomedical Sciences Department Creighton University School of Medicine Omaha NE USA
| | - Aradhana Thapa
- Biomedical Sciences Department Creighton University School of Medicine Omaha NE USA
| | - Sylar R Takafuji
- Biomedical Sciences Department Creighton University School of Medicine Omaha NE USA
| | - Rexton M Suzuki
- Biomedical Sciences Department Creighton University School of Medicine Omaha NE USA
| | - Gabrielle F Kay
- Biomedical Sciences Department Creighton University School of Medicine Omaha NE USA
| | - Toni D Howard
- Biomedical Sciences Department Creighton University School of Medicine Omaha NE USA
| | - Michael H Kim
- CHI Heart Institute and Department of Medicine Creighton University School of Medicine Omaha NE USA
| | - Brian J North
- Biomedical Sciences Department Creighton University School of Medicine Omaha NE USA
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Matsumoto K, Matsumoto Y, Wada J. PARylation-mediated post-transcriptional modifications in cancer immunity and immunotherapy. Front Immunol 2025; 16:1537615. [PMID: 40134437 PMCID: PMC11933034 DOI: 10.3389/fimmu.2025.1537615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Accepted: 02/17/2025] [Indexed: 03/27/2025] Open
Abstract
Poly-ADP-ribosylation (PARylation) is a post-translational modification in which ADP-ribose is added to substrate proteins. PARylation is mediated by a superfamily of ADP-ribosyl transferases known as PARPs and influences a wide range of cellular functions, including genome integrity maintenance, and the regulation of proliferation and differentiation. We and others have recently reported that PARylation of SH3 domain-binding protein 2 (3BP2) plays a role in bone metabolism, immune system regulation, and cytokine production. Additionally, PARylation has recently gained attention as a target for cancer treatment. In this review, we provide an overview of PARylation, its involvement in several signaling pathways related to cancer immunity, and the potential of combination therapies with PARP inhibitors and immune checkpoint inhibitors.
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Affiliation(s)
| | - Yoshinori Matsumoto
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of
Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
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Schwarzmueller LJ, Adam RS, Moreno LF, Nijman LE, Logiantara A, Eleonora S, Bril O, Vromans S, de Groot NE, Giugliano FP, Stepanova E, Muncan V, Elbers CC, Lenos KJ, Zwijnenburg DA, van Eijndhoven MAJ, Pegtel DM, van Neerven SM, Loayza-Puch F, Dadali T, Broom WJ, Maier MA, Koster J, Vermeulen L, Léveillé N. Identifying colorectal cancer-specific vulnerabilities in the Wnt-driven long non-coding transcriptome. Gut 2025; 74:571-585. [PMID: 39562049 PMCID: PMC12013597 DOI: 10.1136/gutjnl-2024-332752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 10/31/2024] [Indexed: 11/21/2024]
Abstract
BACKGROUND Aberrant Wnt pathway activation is a key driver of colorectal cancer (CRC) and is essential to sustain tumour growth and progression. Although the downstream protein-coding target genes of the Wnt cascade are well known, the long non-coding transcriptome has not yet been fully resolved. OBJECTIVE In this study, we aim to comprehensively reveal the Wnt-regulated long non-coding transcriptome and exploit essential molecules as novel therapeutic targets. DESIGN We used global run-on sequencing to define β-catenin-regulated long non-coding RNAs (lncRNAs) in CRC. CRISPRi dropout screens were subsequently used to establish the functional relevance of a subset of these lncRNAs for long-term expansion of CRC. RESULTS We uncovered that LINC02418 is essential for cancer cell clonogenic outgrowth. Mechanistically, LINC02418 regulates MYC expression levels to promote CRC stem cell functionality and prevent terminal differentiation. Furthermore, we developed effective small interfering RNA (siRNA)-based therapeutics to target LINC02418 RNA in vivo. CONCLUSION We propose that cancer-specific Wnt-regulated lncRNAs provide novel therapeutic opportunities to interfere with the Wnt pathway, which has so far defied effective pharmacological inhibition.
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Affiliation(s)
- Laura J Schwarzmueller
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam, The Netherlands
| | - Ronja S Adam
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam, The Netherlands
| | - Leandro F Moreno
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam, The Netherlands
| | - Lisanne E Nijman
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam, The Netherlands
| | - Adrian Logiantara
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam, The Netherlands
| | - Steven Eleonora
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam, The Netherlands
| | - Oscar Bril
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam, The Netherlands
| | - Sophie Vromans
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam, The Netherlands
| | - Nina E de Groot
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam, The Netherlands
| | - Francesca Paola Giugliano
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Ekaterina Stepanova
- Translational Control and Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Vanesa Muncan
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Clara C Elbers
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam, The Netherlands
| | - Kristiaan J Lenos
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam, The Netherlands
| | - Danny A Zwijnenburg
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
| | | | - Dirk Michiel Pegtel
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
| | - Sanne M van Neerven
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam, The Netherlands
| | - Fabricio Loayza-Puch
- Translational Control and Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Tulin Dadali
- Alnylam Pharmaceuticals Inc, Cambridge, Massachusetts, USA
| | - Wendy J Broom
- Alnylam Pharmaceuticals Inc, Cambridge, Massachusetts, USA
| | - Martin A Maier
- Alnylam Pharmaceuticals Inc, Cambridge, Massachusetts, USA
| | - Jan Koster
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
| | - Louis Vermeulen
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam, The Netherlands
| | - Nicolas Léveillé
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam, The Netherlands
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Shaham SH, Vij P, Tripathi MK. Advances in Targeted and Chemotherapeutic Strategies for Colorectal Cancer: Current Insights and Future Directions. Biomedicines 2025; 13:642. [PMID: 40149618 PMCID: PMC11940796 DOI: 10.3390/biomedicines13030642] [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: 01/30/2025] [Revised: 02/22/2025] [Accepted: 02/25/2025] [Indexed: 03/29/2025] Open
Abstract
Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, necessitating the continuous evolution of therapeutic approaches. Despite advancements in early detection and localized treatments, metastatic colorectal cancer (mCRC) poses significant challenges due to low survival rates and resistance to conventional therapies. This review highlights the current landscape of CRC treatment, focusing on chemotherapy and targeted therapies. Chemotherapeutic agents, including 5-fluorouracil, irinotecan, and oxaliplatin, have significantly improved survival but face limitations such as systemic toxicity and resistance. Targeted therapies, leveraging mechanisms like VEGF, EGFR, and Hedgehog pathway inhibition, offer promising alternatives, minimizing damage to healthy tissues while enhancing therapeutic precision. Furthermore, future directions in CRC treatment include exploring innovative targets such as Wnt/β-catenin, Notch, and TGF-β pathways, alongside IGF/IGF1R inhibition. These emerging strategies aim to address drug resistance and improve patient outcomes. This review emphasizes the importance of integrating molecular insights into drug development, advocating for a more personalized approach to combat CRC's complexity and heterogeneity.
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Affiliation(s)
- Salique H. Shaham
- Medicine and Oncology ISU, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA;
- South Texas Center of Excellence in Cancer Research, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Puneet Vij
- Department of Pharmaceutical Sciences, St. John’s University, 8000 Utopia Parkway, Queens, New York, NY 11439, USA;
| | - Manish K. Tripathi
- Medicine and Oncology ISU, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA;
- South Texas Center of Excellence in Cancer Research, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
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Sui Y, Hoshi N, Okamoto N, Inoue Y, Funatsu T, Ku Y, Ooi M, Watanabe D, Miyazaki H, Agawa M, Nakamura H, Ohgaki R, Kanai Y, Yang H, Kodama Y. The role of LAT1 in AOM/DSS-induced colorectal tumorigenesis. Biochem Biophys Res Commun 2025; 751:151446. [PMID: 39922055 DOI: 10.1016/j.bbrc.2025.151446] [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: 11/14/2024] [Revised: 01/25/2025] [Accepted: 02/03/2025] [Indexed: 02/10/2025]
Abstract
Amino acid transporters are essential for supplying nutrients to cells and are implicated in tumor progression. L-type amino acid transporter 1 (LAT1) is reported to be overexpressed in various cancers, affecting tumor development. However, the exact mechanisms by which LAT1 affects colorectal cancer (CRC) arising from a chronic inflammatory background are not yet fully understood. This study aimed to explore the role of LAT1 in CRC. Mice with intestinal epithelium-specific deletions of LAT1 (LAT1fl/fl; vil-cre) were treated with azoxymethane (AOM)/dextran sulfate sodium (DSS) in a colitis-associated cancer (CAC) model. Our results demonstrated that LAT1 was detected in normal colon crypts and highly expressed in AOM/DSS-induced tumor tissue. During the chronic colitis phase, weight loss was more prominent in LAT1fl/fl; vil-cre mice, compared with that in LAT1fl/fl mice. IL-1β and IL-6 expressions significantly increased in LAT1-deleted tumors; however, no overall difference in colon tumor number or size was observed between LAT1fl/fl and LAT1fl/fl; vil-cre mice. Accordingly, cell proliferation and apoptotic cell number were similar when comparing LAT1-deleted tumors with those with sufficient LAT1. Our findings indicated that LAT1 might not phenotypically affect overall colonic tumor development in this model; however, it affected the chronic colitis phase and inflammatory status within the tumors. These findings suggest that severe inflammation in tumors might have compensated for tumor growth in defects of amino acid supplementation through LAT1 deficiency, and provide insights into the potential of LAT1-targeted therapies for clinical CRC treatment.
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Affiliation(s)
- Yunlong Sui
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, China; Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, 650-0017, Japan
| | - Namiko Hoshi
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, 650-0017, Japan; Division of Integrated Analyses of Bioresource and Health Care, Kobe University Graduate School of Medicine, Hyogo, 650-0047, Japan.
| | - Norihiro Okamoto
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, 650-0017, Japan
| | - Yuta Inoue
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, 650-0017, Japan
| | - Takumi Funatsu
- Division of Integrated Analyses of Bioresource and Health Care, Kobe University Graduate School of Medicine, Hyogo, 650-0047, Japan
| | - Yuna Ku
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, 650-0017, Japan
| | - Makoto Ooi
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, 650-0017, Japan
| | - Daisuke Watanabe
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, 650-0017, Japan
| | - Haruka Miyazaki
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, 650-0017, Japan
| | - Misaki Agawa
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, 650-0017, Japan
| | - Hirotaka Nakamura
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, 650-0017, Japan
| | - Ryuichi Ohgaki
- Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, 565-0871, Japan
| | - Yoshikatsu Kanai
- Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, 565-0871, Japan; Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), Osaka University, Osaka, 565-0871, Japan
| | - Hui Yang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, China
| | - Yuzo Kodama
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, 650-0017, Japan
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Hushmandi K, Alimohammadi M, Heiat M, Hashemi M, Nabavi N, Tabari T, Raei M, Aref AR, Farahani N, Daneshi S, Taheriazam A. Targeting Wnt signaling in cancer drug resistance: Insights from pre-clinical and clinical research. Pathol Res Pract 2025; 267:155837. [PMID: 39954370 DOI: 10.1016/j.prp.2025.155837] [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: 08/08/2024] [Revised: 12/22/2024] [Accepted: 02/10/2025] [Indexed: 02/17/2025]
Abstract
Cancer drug resistance, encompassing both acquired and intrinsic chemoresistance, remains a significant challenge in the clinical management of tumors. While advancements in drug discovery and the development of various small molecules and anti-cancer compounds have improved patient responses to chemotherapy, the frequent and prolonged use of these drugs continues to pose a high risk of developing chemoresistance. Therefore, understanding the primary mechanisms underlying drug resistance is crucial. Wnt proteins, as secreted signaling molecules, play a pivotal role in transmitting signals from the cell surface to the nucleus. Aberrant expression of Wnt proteins has been observed in a variety of solid and hematological tumors, where they contribute to key processes such as proliferation, metastasis, stemness, and immune evasion, often acting in an oncogenic manner. Notably, the role of the Wnt signaling pathway in modulating chemotherapy response in human cancers has garnered significant attention. This review focuses on the involvement of Wnt signaling and its related molecular pathways in drug resistance, highlighting their associations with cancer hallmarks, stemness, and tumorigenesis linked to chemoresistance. Additionally, the overexpression of Wnt proteins has been shown to accelerate cancer drug resistance, with regulation mediated by non-coding RNAs. Elevated Wnt activity reduces cell death in cancers, particularly by affecting mechanisms like apoptosis, autophagy, and ferroptosis. Furthermore, pharmacological compounds and small molecules have demonstrated the potential to modulate Wnt signaling in cancer therapy. Given its impact, Wnt expression can also serve as a prognostic marker and a factor influencing survival outcomes in human cancers.
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Affiliation(s)
- Kiavash Hushmandi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Heiat
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - 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
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia V8V 1P7, Canada
| | - Teimour Tabari
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Mehdi Raei
- Health Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Amir Reza Aref
- Department of Vitro Vision, DeepkinetiX, Inc, Boston, MA, USA
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University of Medical Sciences, Jiroft, 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.
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39
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Kim KT, Kim SM, Cha HJ. Crosstalk between Signaling Pathways and Energy Metabolism in Pluripotency. Int J Stem Cells 2025; 18:12-20. [PMID: 38494425 PMCID: PMC11867904 DOI: 10.15283/ijsc23173] [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: 11/03/2023] [Revised: 01/08/2024] [Accepted: 02/14/2024] [Indexed: 03/19/2024] Open
Abstract
The sequential change from totipotency to multipotency occurs during early mammalian embryo development. However, due to the lack of cellular models to recapitulate the distinct potency of stem cells at each stage, their molecular and cellular characteristics remain ambiguous. The establishment of isogenic naïve and primed pluripotent stem cells to represent the pluripotency in the inner cell mass of the pre-implantation blastocyst and in the epiblast from the post-implantation embryo allows the understanding of the distinctive characteristics of two different states of pluripotent stem cells. This review discusses the prominent disparities between naïve and primed pluripotency, including signaling pathways, metabolism, and epigenetic status, ultimately facilitating a comprehensive understanding of their significance during early mammalian embryonic development.
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Affiliation(s)
- Keun-Tae Kim
- Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan
| | - Seong-Min Kim
- College of Pharmacy, Seoul National University, Seoul, Korea
| | - Hyuk-Jin Cha
- College of Pharmacy, Seoul National University, Seoul, Korea
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40
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Walters BM, Guttieres LJ, Goëb M, Marjenberg SJ, Martindale MQ, Wikramanayake AH. β-Catenin localization in the ctenophore Mnemiopsis leidyi suggests an ancestral role in cell adhesion and nuclear function. Dev Dyn 2025. [PMID: 39976308 DOI: 10.1002/dvdy.70004] [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: 11/06/2024] [Revised: 01/08/2025] [Accepted: 01/12/2025] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND The emergence of multicellularity in animals marks a pivotal evolutionary event, which was likely enabled by molecular innovations in the way cells adhere and communicate with one another. β-Catenin is significant to this transition due to its dual role as both a structural component in the cadherin-catenin complex and as a transcriptional coactivator involved in the Wnt/β-catenin signaling pathway. However, our knowledge of how this protein functions in ctenophores, one of the earliest diverging metazoans, is limited. RESULTS To study β-catenin function in the ctenophore Mnemiopsis leidyi, we generated affinity-purified polyclonal antibodies targeting Mlβ-catenin. We then used this tool to observe β-catenin protein localization in developing Mnemiopsis embryos. In this article, we provide evidence of consistent β-catenin protein enrichment at cell-cell interfaces in Mnemiopsis embryos. Additionally, we found β-catenin enrichment in some nuclei, particularly restricted to the oral pole around the time of gastrulation. The Mlβ-catenin affinity-purified antibodies now provide us with a powerful reagent to study the ancestral functions of β-catenin in cell adhesion and transcriptional regulation. CONCLUSIONS The localization pattern of embryonic Mlβ-catenin suggests that this protein had an ancestral role in cell adhesion and may have a nuclear function as well.
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Affiliation(s)
- Brian M Walters
- Department of Biology, University of Miami, Coral Gables, Florida, USA
| | - Lucas J Guttieres
- The Whitney Laboratory for Marine Bioscience, Department of Biology, University of Florida, Saint Augustine, Florida, USA
| | - Mayline Goëb
- The Whitney Laboratory for Marine Bioscience, Department of Biology, University of Florida, Saint Augustine, Florida, USA
| | | | - Mark Q Martindale
- The Whitney Laboratory for Marine Bioscience, Department of Biology, University of Florida, Saint Augustine, Florida, USA
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Rothstein M, Azambuja AP, Kanno TY, Breen C, Simoes-Costa M. TGF-β signaling controls neural crest developmental plasticity via SMAD2/3. Dev Cell 2025:S1534-5807(25)00059-0. [PMID: 39983721 DOI: 10.1016/j.devcel.2025.01.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/25/2024] [Accepted: 01/28/2025] [Indexed: 02/23/2025]
Abstract
The neural crest is a highly plastic stem cell population that represents an exception to the germ layer theory. Despite being of ectodermal origin, cranial neural crest cells can differentiate into skeletal derivatives typically formed by mesoderm. Here, we report that SMAD2/3-mediated transforming growth factor β (TGF-β) signaling enhances neural crest developmental potential in the chicken embryo. Our results show that TGF-β signaling modulates neural crest axial identity and directly controls the gene circuits that support skeletal differentiation. Cooperation between TGF-β and low levels of WNT signaling in the embryonic head activates cranial-specific cis-regulatory elements. Activation of TGF-β signaling reprogrammed trunk neural crest cells into adopting an anterior identity and led to the development of an improved protocol for the generation of human cranial neural crest cells. Our findings indicate TGF-β signaling is required for the specification of cranial neural crest cells, endowing them with the potential to give rise to the craniofacial skeleton.
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Affiliation(s)
- Megan Rothstein
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
| | - Ana Paula Azambuja
- Department of Systems Biology, Harvard Medical School, Boston, MA, USA; Department of Pathology, Boston Children's Hospital, Boston, MA, USA; Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
| | - Tatiane Y Kanno
- Department of Systems Biology, Harvard Medical School, Boston, MA, USA; Department of Pathology, Boston Children's Hospital, Boston, MA, USA; Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
| | - Catriona Breen
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
| | - Marcos Simoes-Costa
- Department of Systems Biology, Harvard Medical School, Boston, MA, USA; Department of Pathology, Boston Children's Hospital, Boston, MA, USA; Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA.
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42
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Sangsuwan R, Thuamsang B, Pacifici N, Tachachartvanich P, Murphy D, Ram A, Albeck J, Lewis JS. Identification of signaling networks associated with lactate modulation of macrophages and dendritic cells. Heliyon 2025; 11:e42098. [PMID: 39975831 PMCID: PMC11835580 DOI: 10.1016/j.heliyon.2025.e42098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 01/16/2025] [Accepted: 01/17/2025] [Indexed: 02/21/2025] Open
Abstract
The advancement in the understanding of cancer immune evasion has manifested the development of cancer immunotherapeutic approaches such as checkpoint inhibitors and interleukin agonists. Although cancer immunotherapy breakthroughs have demonstrated improved potency for cancer treatment, only a fraction of patients effectively respond to these treatments. Moreover, there is compelling evidence indicating that cancer cells develop a unique microenvironment through adaptive metabolic reprogramming, which aberrantly modulates host immunity to evade immunosurveillance. As part of the tumor cell adaptive metabolic switch, lactate is produced and released into the tumor environment. Recent studies have shown that lactate significantly modulates immune functions, especially in innate immune cells. Dendritic cells (DCs) and macrophages (MΦs) are specialized antigen-presenting cells serving as key players in innate immunity and anticancer-associated immune responses. Although most studies have shown that lactate affects immune phenotypes (e.g., surface protein expression and cytokine production), the cell signaling network mediated by lactate is not fully understood. In the present study, we identified the key signaling pathways in bone marrow-derived DCs and MΦs that were changed by cancer-relevant concentrations of lactate. First, transcriptome analysis was used to guide notable signaling pathways mediated by lactate. Subsequently, biomolecular techniques, including immunoblotting, flow cytometry, and immunofluorescence imaging were performed to corroborate the changes in these key signaling pathways at the protein level. The results indicated that lactate differentially impacted the biochemical networks of DCs and MΦs. While lactate mainly altered STAT3, ERK, and p38 MAPK signaling cascades in DCs, the STAT1 and GSK-3β signaling in MΦs were the major pathways significantly impacted by lactate. This study identifies key biochemical pathways in innate immune cells that are impacted by lactate, which advances our understanding of the interplay between the tumor microenvironment and innate immunity.
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Affiliation(s)
- Rapeepat Sangsuwan
- Department of Biomedical Engineering, University of California, Davis, CA, 95616, USA
- Laboratory of Natural Products, Chulabhorn Research Institute, Bangkok, 10210, Thailand
| | - Bhasirie Thuamsang
- Department of Biomedical Engineering, University of California, Davis, CA, 95616, USA
| | - Noah Pacifici
- Department of Biomedical Engineering, University of California, Davis, CA, 95616, USA
| | - Phum Tachachartvanich
- Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok, 10210, Thailand
| | - Devan Murphy
- Department of Molecular and Cell Biology, University of California, Davis, CA, 95616, USA
| | - Abhineet Ram
- Department of Molecular and Cell Biology, University of California, Davis, CA, 95616, USA
| | - John Albeck
- Department of Molecular and Cell Biology, University of California, Davis, CA, 95616, USA
| | - Jamal S. Lewis
- Department of Biomedical Engineering, University of California, Davis, CA, 95616, USA
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, FL, 32611, USA
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43
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Ding Y, Chen Q. Wnt/β-catenin signaling pathway: an attractive potential therapeutic target in osteosarcoma. Front Oncol 2025; 14:1456959. [PMID: 40028002 PMCID: PMC11867957 DOI: 10.3389/fonc.2024.1456959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Accepted: 12/24/2024] [Indexed: 03/05/2025] Open
Abstract
Osteosarcoma (OS) is the most common bone malignancy in children and adolescents, and although current neoadjuvant chemotherapy has shown efficacy against OS, the long-term survival rate for patients with OS remains low, highlighting the need to find more effective treatments. In cancer cells, abnormal activation of signaling pathways can widely affect cell activity from growth and proliferation to apoptosis, invasion and metastasis. Wnt/β-catenin is a complex and unique signaling pathway that is considered to be one of the most important carcinogenic pathways in human cancer. Research have confirmed that the Wnt/β-catenin signaling pathway is an important driving factor for the occurrence and development of osteosarcoma, and abnormal activation of this pathway can promote the pathological processes of cell proliferation, invasion, migration, tumor angiogenesis and chemical resistance of osteosarcoma. However, inhibition of Wnt/β-catenin signaling pathway can effectively inhibit or reverse the above pathological processes. Therefore, manipulating the expression or function of the Wnt/β-catenin pathway may be a potential targeted pathway for the treatment of OS. In this review, we describe the characteristics of the Wnt/β-catenin signaling pathway and summarize the role and mechanism of this pathway in OS. This paper discusses the therapeutic significance of inhibiting or targeting Wnt/β-catenin pathway in OS and the shortcomings of current studies on this pathway in OS and the problems to be solved. This review helps us to understand the role of Wnt/β-catenin on OS, and provides a theoretical basis and new ideas for targeting Wnt/β-catenin pathway as a therapeutic target for OS.
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Affiliation(s)
- Yi Ding
- Department of Spine Surgery, Ganzhou People's Hospital, Ganzhou, China
- Department of Spine Surgery, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, Ganzhou, China
| | - Qin Chen
- Department of Spine Surgery, Ganzhou People's Hospital, Ganzhou, China
- Department of Spine Surgery, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, Ganzhou, China
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44
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Deng L, He XC, Chen S, Zhang N, Deng F, Scott A, He Y, Tsuchiya D, Smith SE, Epp M, Malloy S, Liu F, Hembree M, Mu Q, Haug JS, Malagola E, Hassan H, Petentler K, Egidy R, Maddera L, Russell J, Wang Y, Li H, Zhao C, Perera A, Wang TC, Kuo CJ, Li L. Frizzled5 controls murine intestinal epithelial cell plasticity through organization of chromatin accessibility. Dev Cell 2025; 60:352-363.e6. [PMID: 39579769 PMCID: PMC11794035 DOI: 10.1016/j.devcel.2024.10.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 04/15/2024] [Accepted: 10/29/2024] [Indexed: 11/25/2024]
Abstract
The homeostasis of the intestinal epithelium relies on intricate yet insufficiently understood mechanisms of intestinal epithelial plasticity. Here, we elucidate the pivotal role of Frizzled5 (Fzd5), a Wnt pathway receptor, as a determinant of murine intestinal epithelial cell fate. Deletion of Fzd5 in Lgr5+ intestinal stem cells (ISCs) impairs their self-renewal, whereas its deletion in Krt19+ cells disrupts lineage generation, without affecting crypt integrity in either case. However, a broader deletion of Fzd5 across the epithelium leads to substantial crypt deterioration. Integrated analysis of single-cell RNA sequencing (scRNA-seq) and single-cell ATAC-seq (scATAC-seq) identifies that Fzd5 governs chromatin accessibility, orchestrating the regulation of stem- and lineage-related gene expression mainly in ISCs and progenitor cells. In summary, our findings provide insights into the regulatory role of Fzd5 in governing intestinal epithelial plasticity.
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Affiliation(s)
- Lu Deng
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Xi C He
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Shiyuan Chen
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Ning Zhang
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Fengyan Deng
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Allison Scott
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Yanfeng He
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Dai Tsuchiya
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Sarah E Smith
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Michael Epp
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Seth Malloy
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Fang Liu
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Mark Hembree
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Qinghui Mu
- Department of Medicine, Stanford University, Stanford, CA 94305, USA
| | - Jeffrey S Haug
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Ermanno Malagola
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA
| | - Huzaifa Hassan
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | | | - Rhonda Egidy
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Lucinda Maddera
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Jonathon Russell
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Yan Wang
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Hua Li
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Chongbei Zhao
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Anoja Perera
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Timothy C Wang
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA
| | - Calvin J Kuo
- Department of Medicine, Stanford University, Stanford, CA 94305, USA
| | - Linheng Li
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA; Department of Pathology and Laboratory Medicine and Division of Medical Oncology, Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
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45
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Yu XH, Guo XN, Li K, Li JW, Wang K, Wang D, Liu BC. The Role of Wnt5a in Inflammatory Diseases. Immunology 2025; 174:203-212. [PMID: 39668514 DOI: 10.1111/imm.13882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Revised: 10/08/2024] [Accepted: 11/22/2024] [Indexed: 12/14/2024] Open
Abstract
Wnt5a plays an important role in cell development and maturation and is closely associated with various diseases, such as malignant tumours, metabolic disorders, fibrosis, growth and development. Recent studies have shown that Wnt5a expression and signal transduction are strongly involved in the inflammatory response. This study comprehensively reviewed the latest research progress on the association between Wnt5a and several inflammatory diseases, such as sepsis, asthma, chronic obstructive pulmonary disease, tuberculosis, rheumatoid arthritis, atherosclerosis and psoriasis vulgare. We elucidated the mechanism by which the Wnt5a protein is involved in the pathogenesis of these diseases, providing a basis for the prevention and treatment of inflammatory diseases.
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Affiliation(s)
- Xin-Hua Yu
- Department of Pediatrics, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Xin-Ning Guo
- Department of Cardiology, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Kui Li
- Department of Respiratory and Critical Care Medicine, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Jia-Wei Li
- Department of Respiratory and Critical Care Medicine, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Kaijin Wang
- Department of Respiratory and Critical Care Medicine, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Dan Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bi-Cui Liu
- Department of Respiratory and Critical Care Medicine, Bishan Hospital of Chongqing Medical University, Chongqing, China
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46
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Guo X, Yang L, Wang Y, Yuan M, Zhang W, He X, Wang Q. Wnt2bb signaling promotes pharyngeal chondrogenic precursor proliferation and chondrocyte maturation by activating Yap expression in zebrafish. J Genet Genomics 2025; 52:220-230. [PMID: 39566725 DOI: 10.1016/j.jgg.2024.11.006] [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: 07/21/2024] [Revised: 11/11/2024] [Accepted: 11/12/2024] [Indexed: 11/22/2024]
Abstract
Pharyngeal cartilage morphogenesis is crucial for the formation of craniofacial structures. Cranial neural crest cells are specified at the neural plate border, migrate to pharyngeal arches, and differentiate into pharyngeal chondrocytes, which subsequently flatten, elongate, and stack like coins during maturation. Although the developmental processes prior to chondrocyte maturation have been extensively studied, their subsequent changes in morphology and organization remain largely elusive. Here, we show that wnt2bb is expressed in the pharyngeal ectoderm adjacent to the chondrogenic precursor cells in zebrafish. Inactivation of Wnt2bb leads to a reduction in nuclear β-catenin, which impairs chondrogenic precursor proliferation and disrupts chondrocyte morphogenesis and organization, eventually causing a severe shrinkage of pharyngeal cartilages. Moreover, the decrease of β-catenin in wnt2bb-/- mutants is accompanied by the reduction of Yap expression. Reactivation of Yap can restore the proliferation of chondrocyte progenitors as well as the proper size, shape, and stacking of pharyngeal chondrocytes. Our findings suggest that Wnt/β-catenin signaling promotes Yap expression to regulate pharyngeal cartilage formation in zebrafish.
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Affiliation(s)
- Xiaojuan Guo
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100101, China
| | - Liping Yang
- Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China
| | - Yujie Wang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100101, China
| | - Mengna Yuan
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100101, China
| | - Wenqing Zhang
- Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China
| | - Xinyu He
- Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China.
| | - Qiang Wang
- Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China; Innovation Centre of Ministry of Education for Development and Diseases, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China.
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Whangbo M, Ko E, Kim D, Jeon C, Jo HR, Lee SH, Youn J, Jo S, Kim TH. Wnt5a exacerbates pathological bone features and trabecular bone loss in curdlan-injected SKG mice via osteoclast activation. BMB Rep 2025; 58:75-81. [PMID: 39681409 PMCID: PMC11875747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/20/2024] [Accepted: 12/10/2024] [Indexed: 12/18/2024] Open
Abstract
Many studies on osteoblasts have suggested that Wnt5a plays a crucial role in excessive osteoblast activity, which is responsible for ectopic new bone formation, but research on osteoclasts in ankylosing spondylitis (AS) remains relatively limited. This study aimed to explore whether Wnt5a influences osteoclastmediated bone resorption in curdlan-injected SKG mice, a model that mimics AS. Compared to the Vehicle group, the Wnt5a treatment group exhibited statistically higher clinical arthritis scores and increased hindpaw thickness values. Micro- computed tomography (microCT) analysis of hindpaws revealed a significant increase in inflamed and ectopic bone density in the Wnt5a-treated group compared to the Vehicle group. Histological examination also showed pronounced inflammation and structural bone damage in the bone marrow of ankles in the Wnt5a-treated group. Intriguingly, microCT analysis of the femur revealed that trabecular bone loss was markedly observed in the Wnt5a-treated group. Both the number of TRAP-positive osteoclasts and their activity were statistically greater in the Wnt5a-treated group compared to the Vehicle group. Serum markers of bone resorption, but not bone formation, were also significantly elevated in the Wnt5a-treated group. Notably, promotion of osteoclast differentiation by Wnt5a was inhibited following treatment with anti-Wnt5a. These findings suggest that targeting Wnt5a could be a promising strategy for mitigating pathological bone features in AS by modulating osteoclast activity. [BMB Reports 2025; 58(2): 75-81].
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Affiliation(s)
- Min Whangbo
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul 04763, Korea
- Department of Translational Medicine Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Eunae Ko
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul 04763, Korea
- Department of Translational Medicine Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Dongju Kim
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul 04763, Korea
- Department of Translational Medicine Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Chanhyeok Jeon
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul 04763, Korea
- Department of Translational Medicine Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Hye-Ryeong Jo
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul 04763, Korea
| | - Seung Hoon Lee
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul 04763, Korea
| | - Jeehee Youn
- Department of Anatomy & Cell Biology, College of Medicine, Hanyang University, Seoul 04763, Korea
| | - Sungsin Jo
- Department of Biology, College of Natural Sciences, Soonchunhyang University, Asan 31538, Korea
| | - Tae-Hwan Kim
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul 04763, Korea
- Department of Translational Medicine Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 04763, Korea
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48
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Schumacher MA, Thai MH, Hsieh JJ, Gramajo A, Liu CY, Frey MR. Wnt/β-catenin maintains epithelial IL-33 in the colonic stem and progenitor cell niche and drives its induction in colitis. Mucosal Immunol 2025; 18:248-256. [PMID: 39592069 PMCID: PMC11895084 DOI: 10.1016/j.mucimm.2024.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 11/13/2024] [Accepted: 11/20/2024] [Indexed: 11/28/2024]
Abstract
Interleukin (IL)-33 is a key responder to intestinal injury and inflammation. In the colon, it is expressed by several cell populations, with the specific cellular source likely determining its role. The colonic epithelium expresses IL-33; however, the factors controlling its production and the specific epithelial lineage(s) expressing IL-33 are poorly understood. We recently reported that colonic epithelial IL-33 is induced by inhibition of glycogen synthase kinase-3β (GSK3β), but the signaling pathway mediating this induction is unknown. Here we tested the role of Wnt/β-catenin signaling in regulating colonic epithelial IL-33 at homeostasis and in injury-induced colitis. Transcriptomic analysis shows that epithelial IL-33 localizes to stem and progenitor cells. Ligand activation of Wnt/β-catenin signaling induced IL-33 in colonic organoid and cell cultures. Furthermore, small-molecule disruption of β-catenin interaction with cyclic AMP response element binding protein (CBP) prevented epithelial IL-33 induction. Antagonism of CBP/β-catenin signaling also prevented rapid epithelial IL-33 induction in dextran sodium sulfate (DSS)-mediated colitis, and was associated with maintenance of crypt-expressed host defense peptides. Together, these findings show β-catenin-driven production of epithelial IL-33 is an early response to colonic injury that shapes the crypt base defense response and suggest an immunoregulatory role for the stem cell niche in tissue injury.
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Affiliation(s)
- Michael A Schumacher
- Department of Pediatrics, University of Southern California Keck School of Medicine. Los Angeles, CA, 90089; The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, 90027.
| | - Megan H Thai
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, 90027
| | - Jonathan J Hsieh
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, 90027
| | - Alexa Gramajo
- Department of Pediatrics, University of Southern California Keck School of Medicine. Los Angeles, CA, 90089; The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, 90027
| | - Cambrian Y Liu
- Department of Medicine, The University of Chicago, Chicago, IL, 60637
| | - Mark R Frey
- Department of Pediatrics, University of Southern California Keck School of Medicine. Los Angeles, CA, 90089; The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, 90027; Department of Biochemistry and Molecular Medicine, University of Southern California Keck School of Medicine. Los Angeles, CA, 90089
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49
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Whangbo M, Ko E, Kim D, Jeon C, Jo HR, Lee SH, Youn J, Jo S, Kim TH. Wnt5a exacerbates pathological bone features and trabecular bone loss in curdlan-injected SKG mice via osteoclast activation. BMB Rep 2025; 58:75-81. [PMID: 39681409 PMCID: PMC11875747 DOI: 10.5483/bmbrep.2024-0155] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/20/2024] [Accepted: 12/10/2024] [Indexed: 05/26/2025] Open
Abstract
Many studies on osteoblasts have suggested that Wnt5a plays a crucial role in excessive osteoblast activity, which is responsible for ectopic new bone formation, but research on osteoclasts in ankylosing spondylitis (AS) remains relatively limited. This study aimed to explore whether Wnt5a influences osteoclastmediated bone resorption in curdlan-injected SKG mice, a model that mimics AS. Compared to the Vehicle group, the Wnt5a treatment group exhibited statistically higher clinical arthritis scores and increased hindpaw thickness values. Micro- computed tomography (microCT) analysis of hindpaws revealed a significant increase in inflamed and ectopic bone density in the Wnt5a-treated group compared to the Vehicle group. Histological examination also showed pronounced inflammation and structural bone damage in the bone marrow of ankles in the Wnt5a-treated group. Intriguingly, microCT analysis of the femur revealed that trabecular bone loss was markedly observed in the Wnt5a-treated group. Both the number of TRAP-positive osteoclasts and their activity were statistically greater in the Wnt5a-treated group compared to the Vehicle group. Serum markers of bone resorption, but not bone formation, were also significantly elevated in the Wnt5a-treated group. Notably, promotion of osteoclast differentiation by Wnt5a was inhibited following treatment with anti-Wnt5a. These findings suggest that targeting Wnt5a could be a promising strategy for mitigating pathological bone features in AS by modulating osteoclast activity. [BMB Reports 2025; 58(2): 75-81].
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Affiliation(s)
- Min Whangbo
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul 04763, Korea
- Department of Translational Medicine Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Eunae Ko
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul 04763, Korea
- Department of Translational Medicine Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Dongju Kim
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul 04763, Korea
- Department of Translational Medicine Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Chanhyeok Jeon
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul 04763, Korea
- Department of Translational Medicine Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Hye-Ryeong Jo
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul 04763, Korea
| | - Seung Hoon Lee
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul 04763, Korea
| | - Jeehee Youn
- Department of Anatomy & Cell Biology, College of Medicine, Hanyang University, Seoul 04763, Korea
| | - Sungsin Jo
- Department of Biology, College of Natural Sciences, Soonchunhyang University, Asan 31538, Korea
| | - Tae-Hwan Kim
- Hanyang University Institute for Rheumatology Research (HYIRR), Seoul 04763, Korea
- Department of Translational Medicine Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 04763, Korea
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50
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Oskomić M, Tomić A, Barbarić L, Matić A, Kindl DC, Matovina M. KEAP1-NRF2 Interaction in Cancer: Competitive Interactors and Their Role in Carcinogenesis. Cancers (Basel) 2025; 17:447. [PMID: 39941813 PMCID: PMC11816071 DOI: 10.3390/cancers17030447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/21/2025] [Accepted: 01/24/2025] [Indexed: 02/16/2025] Open
Abstract
An American Cancer Society report estimates the emergence of around 2 million new cancer cases in the US in 2024 [...].
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Affiliation(s)
| | | | | | | | | | - Mihaela Matovina
- Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (M.O.); (A.T.); (L.B.); (A.M.); (D.C.K.)
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