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Aguayo F, Tapia JC, Calaf GM, Muñoz JP, Osorio JC, Guzmán-Venegas M, Moreno-León C, Levican J, Andrade-Madrigal C. The Role of Xenobiotics and Anelloviruses in Colorectal Cancer: Mechanisms and Perspectives. Int J Mol Sci 2025; 26:4354. [PMID: 40362591 PMCID: PMC12072659 DOI: 10.3390/ijms26094354] [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: 02/24/2025] [Revised: 04/29/2025] [Accepted: 05/01/2025] [Indexed: 05/15/2025] Open
Abstract
Xenobiotics are non-natural chemical compounds to which the human population is exposed. Chronic exposure to certain xenobiotics is associated with various diseases, including cancer development. Anelloviruses (AVs), including Torque Teno Virus (TTV), Torque Teno Mini Virus (TTMV), and Torque Teno Midi Virus (TTMDV), are ubiquitous viruses found in the general population. As no disease has been definitively associated with AVs, they are sometimes referred to as "viruses awaiting a disease". This review explores the potential roles of xenobiotics and AVs in colorectal cancer (CRC) development and suggests a potential interplay between them. Evidence suggests an association between certain xenobiotics (like pesticides, cigarette smoke components, and dietary factors) and CRC, while such an association is less clear for AVs. The high prevalence of AVs suggests these infections alone may be insufficient to disrupt homeostasis; thus, additional factors might be required to promote disease, potentially including cancer.
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Affiliation(s)
- Francisco Aguayo
- Laboratorio de Oncovirología, Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad de Tarapacá, Arica 1000000, Chile; (J.C.O.); (M.G.-V.); (C.M.-L.); (C.A.-M.)
| | - Julio C. Tapia
- Laboratorio de Transformación Celular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Av. Independencia 1027, Santiago 8380453, Chile
| | - Gloria M. Calaf
- Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000000, Chile;
| | - Juan P. Muñoz
- Laboratorio de Bioquímica, Departamento de Química, Facultad de Ciencias, Universidad de Tarapacá, Arica 1000007, Chile;
| | - Julio C. Osorio
- Laboratorio de Oncovirología, Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad de Tarapacá, Arica 1000000, Chile; (J.C.O.); (M.G.-V.); (C.M.-L.); (C.A.-M.)
| | - Matías Guzmán-Venegas
- Laboratorio de Oncovirología, Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad de Tarapacá, Arica 1000000, Chile; (J.C.O.); (M.G.-V.); (C.M.-L.); (C.A.-M.)
| | - Carolina Moreno-León
- Laboratorio de Oncovirología, Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad de Tarapacá, Arica 1000000, Chile; (J.C.O.); (M.G.-V.); (C.M.-L.); (C.A.-M.)
| | - Jorge Levican
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
| | - Cristian Andrade-Madrigal
- Laboratorio de Oncovirología, Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad de Tarapacá, Arica 1000000, Chile; (J.C.O.); (M.G.-V.); (C.M.-L.); (C.A.-M.)
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Le Y, Zhou L, He Y, Zhou J, Zhan J, Zhang H, Chen X, Xiong J, Fang Z, Xiang X. SNX5 facilitates the progression of gastric cancer by increasing the membrane localization of LRP5. Oncogene 2025; 44:1182-1196. [PMID: 39922976 DOI: 10.1038/s41388-025-03298-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 01/05/2025] [Accepted: 02/03/2025] [Indexed: 02/10/2025]
Abstract
Endocytosis is essential for cancer cell motility, which is predominantly mediated by the sorting nexin (SNX) family. Previous studies have demonstrated that SNX5 is elevated in several tumors, while its clinical significance and underlying mechanism in gastric cancer (GC) remain uninvestigated. In this study, we reported that SNX5 is highly expressed in GC and promotes the malignant biological behavior of GC cells. Its upregulation is closely related to poor prognosis in GC patients. Mechanistically, we observed an interaction between SNX5 and low-density lipoprotein receptor-related protein5 (LRP5) in GC cells. SNX5 inhibits LRP5 internalization and promotes its recycling to the cell membrane, which prevents LRP5 from being degraded in the lysosome. The increased membrane localization of LRP5 facilitates β-catenin stabilization, thus activating the Wnt signaling pathway, leading to tumorigenesis and progression.
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Affiliation(s)
- Yi Le
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Avenue, Nanchang, 330006, Jiangxi, China
- Department of Jiangxi Key Laboratory for Individualized Cancer Therapy, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China
| | - Ling Zhou
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Avenue, Nanchang, 330006, Jiangxi, China
- Department of Jiangxi Key Laboratory for Individualized Cancer Therapy, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China
| | - Yan He
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Avenue, Nanchang, 330006, Jiangxi, China
- Department of Jiangxi Key Laboratory for Individualized Cancer Therapy, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China
| | - Juanjuan Zhou
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Avenue, Nanchang, 330006, Jiangxi, China
- Department of Jiangxi Key Laboratory for Individualized Cancer Therapy, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China
| | - Jinbo Zhan
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Avenue, Nanchang, 330006, Jiangxi, China
- Department of Jiangxi Key Laboratory for Individualized Cancer Therapy, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China
| | - Hongjiao Zhang
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Avenue, Nanchang, 330006, Jiangxi, China
- Department of Jiangxi Key Laboratory for Individualized Cancer Therapy, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China
| | - Xiao Chen
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Avenue, Nanchang, 330006, Jiangxi, China
- Department of Jiangxi Key Laboratory for Individualized Cancer Therapy, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Avenue, Nanchang, 330006, Jiangxi, China.
- Department of Jiangxi Key Laboratory for Individualized Cancer Therapy, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China.
| | - Ziling Fang
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Avenue, Nanchang, 330006, Jiangxi, China.
- Department of Jiangxi Key Laboratory for Individualized Cancer Therapy, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China.
| | - Xiaojun Xiang
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Avenue, Nanchang, 330006, Jiangxi, China.
- Department of Jiangxi Key Laboratory for Individualized Cancer Therapy, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China.
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Huang Z, Cong Z, Luo J, Qiu B, Wang K, Gao C, Xu Y, Yang N, Zou Z, Hu L, Shen Y. Association between cancer-associated fibroblasts and prognosis of neoadjuvant chemoradiotherapy in esophageal squamous cell carcinoma: a bioinformatics analysis based on single-cell RNA sequencing. Cancer Cell Int 2025; 25:74. [PMID: 40025479 PMCID: PMC11871762 DOI: 10.1186/s12935-025-03709-x] [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: 11/30/2024] [Accepted: 02/20/2025] [Indexed: 03/04/2025] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is a prevalent and aggressive subtype of esophageal cancer, posing a significant mortality and economic burden, especially in East and Southeast Asia. Current therapeutic strategies have limitations in improving patient survival, particularly regarding disease progression and resistance. This study aimed to investigate the impact of neoadjuvant chemoradiotherapy (NCRT) on the ESCC microenvironment. METHODS We utilized single-cell RNA sequencing to systematically characterize the tumor and cancer-associated fibroblasts (CAFs) subtypes. Marker genes of myofibroblastic CAFs (myCAFs) were employed to establish a prognostic model and verify its application in other datasets. Other experiments were conducted on clinical samples to explore potential ESCC risk-related genes. RESULTS Our bioinformatics and statistical analyses revealed an increased proportion of fibroblasts and epithelial cells in NCRT and identified the Ep_c1 subtype associated with a better prognosis. Further results indicated a complex communication network between Ep_c1 and myCAFs. The top 30 marker genes of myCAFs were used to construct a prognostic signature with a significant response to immunotherapy. Finally, experiments identified Complement C1s subcomponent (C1S), Decorin (DCN), and Neuroblastoma suppression of tumorigenicity 1 (NBL1) as potential ESCC risk-related genes. CONCLUSION Our findings highlight the dynamic alterations in the post-NCRT ESCC microenvironment and provide a foundation for the development of personalized treatment and immunotherapeutic approaches. Future studies are warranted to further validate these findings and explore their clinical implications.
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Affiliation(s)
- Zhao Huang
- Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210000, China
- Department of Cardiothoracic Surgery, The 960th Hospital of PLA, Jinan, Shandong Province, 250000, China
| | - Zhuangzhuang Cong
- Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210000, China
| | - Jing Luo
- Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210000, China
| | - Bingmei Qiu
- Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210000, China
| | - Kang Wang
- Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210000, China
| | - Chuan Gao
- Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210000, China
| | - Yang Xu
- Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210000, China
| | - Nan Yang
- Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210000, China
| | - Zhiqiang Zou
- Department of Cardiothoracic Surgery, The 960th Hospital of PLA, Jinan, Shandong Province, 250000, China.
| | - Liwen Hu
- Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210000, China.
| | - Yi Shen
- Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210000, China.
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van Wier SP, Beekman AM. Peptide design to control protein-protein interactions. Chem Soc Rev 2025; 54:1684-1698. [PMID: 39817557 PMCID: PMC11736853 DOI: 10.1039/d4cs00243a] [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: 05/20/2024] [Indexed: 01/18/2025]
Abstract
Targeting of protein-protein interactions has become of huge interest in every aspect of medicinal and biological sciences. The control of protein interactions selectively offers the opportunity to control biological processes while limiting off target effects. This interest has massively increased with the development of cryo-EM and protein structure prediction with tools such as RosettaFold and AlphaFold. When designing molecules to control protein interactions, either inhibition or stabilisation, a starting point is commonly peptide design. This tutorial review describes that process, highlighting the selection of an initial sequence with and without structural information. Subsequently, methods for how the sequence can be analysed for key residues and how this information can be used to optimise the ligand efficiency are highlighted. Finally a discussion on how peptides can be further modified to increase their affinity and cell permeability, improving their drug-like properties, is presented.
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Affiliation(s)
- Suzanne P van Wier
- School of Chemistry, Pharmacy & Pharmacology, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
| | - Andrew M Beekman
- School of Chemistry, Pharmacy & Pharmacology, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
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Li C, Dong L, Zhu L, Guan W. Diagnostic utility of LEF1 and β-catenin in WNT pathway tumors with CTNNB1 mutation. World J Surg Oncol 2025; 23:30. [PMID: 39881334 PMCID: PMC11776337 DOI: 10.1186/s12957-025-03675-8] [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: 11/18/2024] [Accepted: 01/19/2025] [Indexed: 01/31/2025] Open
Abstract
OBJECTIVE This study aimed to compare the expression of lymphoid enhancer factor 1 (LEF1) and β-catenin in basal cell adenoma (BA), desmoid-type fibromatosis (DF), and pancreatic solid pseudopapillary neoplasm (SPN) to evaluate their diagnostic utility in tumors associated with the WNT/β-catenin signaling pathway harboring the mutation of CTNNB1 gene 3 exon. METHODS Eighty tumor patients, including 26 BAs, 30 DFs, and 24 SPNs, were analyzed. Immunohistochemical staining was identified positive (nuclear staining of LEF1 and β-catenin in > 50% of tumor cells). The diagnostic rate of LEF1 alone, β-catenin alone, and their combination were compared for each tumor type and all patients. RESULTS Compared to β-catenin, when LEF1 alone was used for diagnosis, the diagnostic rate increased by 46.16% for BA, 16.67% for SPN, and 11.25% for all patients, but decreased by 23.34% for DF. The combined use of β-catenin and LEF1 significantly increased the diagnostic ratio in BA (46.16%), SPN (16.67%), and all patients (21.25%), but only marginally in DF (3.33%). In terms of all WNT pathway tumors with CTNNB1 gene mutation encompassed by our study, statistical analysis revealed no significant difference between LEF1 alone and β-catenin alone. However, their combined application was highly significant (P = 0.001) . CONCLUSION While β-catenin is commonly used as a marker for WNT pathway tumors, its variable expression and localization can be challenging for diagnosis. Our study emphasizes the importance of LEF1 as a complementary marker to β-catenin in diagnosing BA, DF, SPN, and other WNT pathway tumors activated by exon 3 CTNNB1 gene mutation. The combined use of LEF1 and β-catenin enhances diagnostic accuracy and may help the identification of these tumor types.
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Affiliation(s)
- Can Li
- Department of Pathology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Lingdan Dong
- Department of Pathology, Maternal and Child health Hospital of Hubei Province, Wuhan, China
| | - Li Zhu
- Department of Pathology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Wenbin Guan
- Department of Pathology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai, 200092, China.
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Iluta S, Nistor M, Buruiana S, Dima D. Wnt Signaling Pathway in Tumor Biology. Genes (Basel) 2024; 15:1597. [PMID: 39766864 PMCID: PMC11675244 DOI: 10.3390/genes15121597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 12/02/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
Relapse and metastasis are the major challenges that stand in the way of cancer healing and survival, mainly attributed to cancer stem cells (CSCs). Their capabilities of self-renewal and tumorigenic potential leads to treatment resistance development. CSCs function through signaling pathways such as the Wnt/β-catenin cascade. While commonly involved in embryogenesis and adult tissues homeostasis, the dysregulation of the Wnt pathway has direct correlations with tumorigenesis, metastasis, and drug resistance. The development of therapies that target CSCs and bulk tumors is both crucial and urgent. However, the extensive crosstalk present between Wnt and other signaling networks (Hedgehog and Notch) complicates the development of efficient long-term therapies with minimal side-effects on normal tissues. Despite the obstacles, the emergence of Wnt inhibitors and subsequent modulation of the signaling pathways would provide dynamic therapeutic approaches to impairing CSCs and reversing resistance mechanisms.
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Affiliation(s)
- Sabina Iluta
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 400347 Cluj Napoca, Romania;
| | - Madalina Nistor
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400347 Cluj Napoca, Romania
| | - Sanda Buruiana
- Department of Hematology, Nicolae Testemitanu University of Medicine and Pharmacy, 2004 Chisinau, Moldova;
| | - Delia Dima
- Department of Hematology, Ion Chiricuta Oncology Institute, 400015 Cluj Napoca, Romania
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Lan YL, Zou S, Chen R. Update on the intriguing roles of AQP4 expression and redistribution in the progression and treatment of glioma. Ann Med 2024; 56:2401111. [PMID: 39247976 PMCID: PMC11385637 DOI: 10.1080/07853890.2024.2401111] [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: 07/22/2023] [Revised: 04/26/2024] [Accepted: 05/02/2024] [Indexed: 09/10/2024] Open
Abstract
Aquaporin 4 (AQP4) is abundant in the human brain and has an important role in brain homeostasis and diseases. AQP4 expression has been found to be associated with glioma malignancies. However, the complete understanding of the biological processes and curative importance of AQP4 in glioma remains unclear. The impact of AQP4 subcellular mislocalization on glioma progression and the precise mechanisms regarding AQP4 translocation in glioma need further investigation. In this review, we update recent findings about disturbed AQP4 expression in glioma and explore targeting AQP4 to modulate the glioma progression. Thereafter we discuss some possible mechanisms of action of AQP4 translocations in glioma. The present article offers an appropriate introduction to the potential involvement of AQP4 in the emergence and progression of glioma. Both comprehensive research into the mechanisms and systematically intervention studies focusing on AQP4 are essential. By embracing this strategy, we can obtain a new and insightful outlook on managing cancerous glioma. Although the observations summarized in this review should be confirmed with more studies, we believe that they could provide critical information for the design of more focused research that will allow for systematic and definitive evaluation of the role of AQP4 in glioma treatments.
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Affiliation(s)
- Yu-Long Lan
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, Zhejiang, China
- Clinical Research Center for Neurological Diseases, Hangzhou, Zhejiang, China
| | - Shuang Zou
- Key Laboratory of Neuropharmacology and Translational Medicine, School of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Ruoli Chen
- School of Pharmacy and Bioengineering, Keele University, Staffordshire, UK
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Waldrup B, Carranza F, Jin Y, Amzaleg Y, Postel M, Craig DW, Carpten JD, Salhia B, Ricker CN, Culver JO, Chavez CE, Stern MC, Baezconde-Garbanati L, Lenz HJ, Velazquez-Villarreal EI. Integrative multi-omics profiling of colorectal cancer from a Hispanic/Latino cohort of patients. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.11.03.24316599. [PMID: 39606335 PMCID: PMC11601710 DOI: 10.1101/2024.11.03.24316599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Colorectal cancer contributes to cancer-related deaths and health disparities in the Hispanic and Latino community. To probe both the biological and genetic bases of the disparities, we characterized features of colorectal cancer in terms of somatic alterations and genetic similarity. Specifically, we conducted a comprehensive genome-scale analysis of 67 Hispanic and Latino samples. We performed DNA exome sequencing for somatic mutations, somatic copy number alterations, and genetic similarity. We also performed RNA sequencing for differential gene expression, cellular pathways, and gene fusions. We analyzed all samples for 22 important CRC gene mutations, 8 gene amplifications, and 25 CRC gene fusions. Then, we compared our data from the Hispanic and Latino samples to publicly available, Non-Hispanic White (NHW) cohorts. According to our analyses, twenty-four percent of colorectal carcinomas were hypermutated when patients were of Peruvians-from-Lima-like (1KG-PEL-like) genetic similarity population from the 1000 genome project. Moreover, most of these cases occurred in patients who were less than fiay years old age at diagnosis. Excluding hypermutated tumors, approximately 55% of colon cancers and 58% of rectum cancers exhibited two similar features: 1) the paderns of genomic alterations; 2) percentage of 1KG-PEL-like. We analyzed all samples -- which had a median 1KG-PEL-like proportion of 55% -- for 22 important CRC gene mutations, 8 gene amplifications, and 25 CRC gene fusions. One notable example of a frequently observed gene mutation was SMAD4. Samples with SMAD4 alterations, which are known to support tumor growth and progression, had the highest 1KG-PEL-like proportion (63%). According to our results from risk association analyses and differential gene expression, SMAD4 alterations were significant when we compared Hispanic and Latino samples to NHW cohorts. Of the 8 drug-targetable amplifications, PIK3CA and PI3K exhibited an average 1KG-PEL-like of over 55%. Of the 25 relevant CRC gene fusions, targetable genes included ALK, FGFR1, RAF1, and PTPRK; PTPRK was observed in a sample with the highest 1KG-PEL-like proportion (95%). Using Integrative analysis, we also detected recurrent alterations in the WNT, TGFB, TP53, IGF2/PI3K, and RTK/RAS pathways. Importantly, these alterations mostly occurred in young patients with high 1KG-PEL-like. These findings highlight the potential for tailoring precision medicine therapeutics to an underrepresented population. Our study advances the molecular profiling of CRC in Hispanics and Latinos. In toto, genetic similarity appears to be an important component in understanding colorectal carcinogenesis and has the potential to advance cancer health disparities research.
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Affiliation(s)
- B Waldrup
- City of Hope, Beckman Research Institute, Department of Integrative Translational Sciences, Duarte, CA
| | - F Carranza
- City of Hope, Beckman Research Institute, Department of Integrative Translational Sciences, Duarte, CA
| | - Y Jin
- City of Hope, Beckman Research Institute, Department of Integrative Translational Sciences, Duarte, CA
| | - Y Amzaleg
- City of Hope, Beckman Research Institute, Department of Integrative Translational Sciences, Duarte, CA
| | - M Postel
- University of Southern California, Keck School of Medicine of USC, Department of Translational Genomics, Los Angeles, CA
| | - D W Craig
- City of Hope, Beckman Research Institute, Department of Integrative Translational Sciences, Duarte, CA
- City of Hope Comprehensive Cancer Center, Duarte, CA
| | - J D Carpten
- City of Hope, Beckman Research Institute, Department of Integrative Translational Sciences, Duarte, CA
- City of Hope Comprehensive Cancer Center, Duarte, CA
| | - B Salhia
- University of Southern California, Keck School of Medicine of USC, Department of Translational Genomics, Los Angeles, CA
- University of Southern California, USC Norris Comprehensive Cancer Center, Los Angeles, CA
| | - C N Ricker
- University of Southern California, USC Norris Comprehensive Cancer Center, Los Angeles, CA
- University of Southern California, Keck School of Medicine of USC, Division of Medical Oncology, Los Angeles, CA
| | - J O Culver
- University of Southern California, USC Norris Comprehensive Cancer Center, Los Angeles, CA
- University of Southern California, Keck School of Medicine of USC, Division of Medical Oncology, Los Angeles, CA
| | - C E Chavez
- University of Southern California, USC Norris Comprehensive Cancer Center, Los Angeles, CA
| | - M C Stern
- University of Southern California, USC Norris Comprehensive Cancer Center, Los Angeles, CA
- University of Southern California, Keck School of Medicine of USC, Department of Population and Public Health Sciences, Los Angeles, CA
| | - L Baezconde-Garbanati
- University of Southern California, USC Norris Comprehensive Cancer Center, Los Angeles, CA
- University of Southern California, Keck School of Medicine of USC, Department of Population and Public Health Sciences, Los Angeles, CA
| | - H J Lenz
- University of Southern California, USC Norris Comprehensive Cancer Center, Los Angeles, CA
- University of Southern California, Keck School of Medicine of USC, Division of Medical Oncology, Los Angeles, CA
| | - E I Velazquez-Villarreal
- City of Hope, Beckman Research Institute, Department of Integrative Translational Sciences, Duarte, CA
- City of Hope Comprehensive Cancer Center, Duarte, CA
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Maurya VK, Ying Y, Lydon JP. A Mouse Model for Conditional Expression of Activated β-Catenin in Epidermal Keratinocytes. Transgenic Res 2024; 33:513-525. [PMID: 39110314 PMCID: PMC11588969 DOI: 10.1007/s11248-024-00402-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Accepted: 07/30/2024] [Indexed: 11/26/2024]
Abstract
We report the generation and characterization of the K5: CAT bigenic mouse in which the constitutively activated form of β-catenin (ΔN89 β-catenin) is conditionally expressed in cytokeratin-5 (K5) positive epidermal keratinocytes. Following short-term doxycycline intake during the telogen resting phase, the adult K5: CAT bigenic develops enlarged pilosebaceous units that expand deep into the dermis, an expansion usually observed during the anagen growth phase. Prolonged doxycycline treatment results in significant thickening and folding of the K5: CAT epidermis. During this persistent induction period, there is clear evidence of increased keratinocyte proliferation, particularly in the epidermal basal cell layer and the outer root sheath of the hair follicle. This unscheduled increase in cellular proliferation likely explains the decrease in hair density observed in the K5: CAT mouse following persistent doxycycline intake. Numerous hyperplastic endometrioid cysts, which display cornification toward their lumens, are also observed during this treatment period. Remarkably, de-induction of ΔN89 β-catenin expression through doxycycline withdrawal results in a marked reversal of the skin phenotype, suggesting that these morphological changes are dependent on continued signaling by β-catenin and/or its downstream molecular mediators. Joining a small group of mouse models for conditional β-catenin signaling, our K5: CAT mouse model will be particularly useful in identifying those molecular mediators of β-catenin that are responsible for initiating and maintaining these phenotypic responses in the K5: CAT skin. Such studies are predicted to shed more light on β-catenin signaling in epidermal epithelial morphogenesis, hair follicle cycling, and hair growth pathologies.
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Affiliation(s)
- Vineet K Maurya
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Yan Ying
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - John P Lydon
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
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10
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Li X, Liu Y, Tang Y, Xia Z. Transformation of macrophages into myofibroblasts in fibrosis-related diseases: emerging biological concepts and potential mechanism. Front Immunol 2024; 15:1474688. [PMID: 39386212 PMCID: PMC11461261 DOI: 10.3389/fimmu.2024.1474688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 09/06/2024] [Indexed: 10/12/2024] Open
Abstract
Macrophage-myofibroblast transformation (MMT) transforms macrophages into myofibroblasts in a specific inflammation or injury microenvironment. MMT is an essential biological process in fibrosis-related diseases involving the lung, heart, kidney, liver, skeletal muscle, and other organs and tissues. This process consists of interacting with various cells and molecules and activating different signal transduction pathways. This review deeply discussed the molecular mechanism of MMT, clarified crucial signal pathways, multiple cytokines, and growth factors, and formed a complex regulatory network. Significantly, the critical role of transforming growth factor-β (TGF-β) and its downstream signaling pathways in this process were clarified. Furthermore, we discussed the significance of MMT in physiological and pathological conditions, such as pulmonary fibrosis and cardiac fibrosis. This review provides a new perspective for understanding the interaction between macrophages and myofibroblasts and new strategies and targets for the prevention and treatment of MMT in fibrotic diseases.
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Affiliation(s)
- Xiujun Li
- Health Science Center, Chifeng University, Chifeng, China
| | - Yuyan Liu
- Rehabilitation Medicine College, Shandong Second Medical University, Jinan, China
| | - Yongjun Tang
- Department of Emergency, Affiliated Hospital of Chifeng University, Chifeng, China
| | - Zhaoyi Xia
- Department of Library, Children’s Hospital Affiliated to Shandong University, Jinan, China
- Department of Library, Jinan Children’s Hospital, Jinan, China
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11
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Niu S, Lu H, Li W, Hou Y. Immunohistochemical Expression of Lymphoid Enhancer-binding Factor 1 in Low-grade Endometrial Stromal Tumors. Int J Gynecol Pathol 2024; 43:487-493. [PMID: 38085960 DOI: 10.1097/pgp.0000000000001001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/22/2024]
Abstract
Endometrial stromal tumors (ESTs) are uncommon uterine mesenchymal lesions. Nuclear expression of β-catenin, an indication of activated Wnt/β-catenin signaling pathway, was described in 50% to 92% of low-grade ESTs, including endometrial stromal nodule and low-grade endometrial stromal sarcoma. Activation of the Wnt/β-catenin signaling pathway leads to the translocation of β-catenin into the nucleus and interaction with the T-cell factor/lymphoid enhancer-binding factor-1 (LEF1) family of transcription factors to regulate cell proliferation, differentiation, migration, and survival. Immunohistochemical analysis of β-catenin and LEF1 was performed in 2 endometrial stromal nodules and 20 low-grade endometrial stromal sarcomas and demonstrated 90.9% and 81.8% positive rates for β-catenin and LEF1, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of β-catenin and LEF1 were 90.9% versus 81.8%, 81.0% versus 85.7%, 83.3% versus 85.7%, 89.5% versus 81.8%, respectively, in the diagnosis of low-grade ESTs. There is no statistical significance of the performance of β-catenin and LEF1 in all ESTs ( P = 0.664) or in primary or metastatic/recurrent settings ( P = 0.515 and 0.999, respectively). Only 3 smooth muscle tumors showed focal and weak positivity for LEF1. Our results indicate LEF1 can be a useful marker in aiding a diagnosis of low-grade EST and differentiating from smooth muscle tumors alone or in combination with β-catenin.
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Affiliation(s)
- Shuo Niu
- Department of Pathology and Laboratory Medicine, Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, North Carolina (S.N., H.L., W.L., Y.H.)
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12
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Ren H, Ou Q, Pu Q, Lou Y, Yang X, Han Y, Liu S. Comprehensive Review on Bimolecular Fluorescence Complementation and Its Application in Deciphering Protein-Protein Interactions in Cell Signaling Pathways. Biomolecules 2024; 14:859. [PMID: 39062573 PMCID: PMC11274695 DOI: 10.3390/biom14070859] [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: 06/24/2024] [Revised: 07/14/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024] Open
Abstract
Signaling pathways are responsible for transmitting information between cells and regulating cell growth, differentiation, and death. Proteins in cells form complexes by interacting with each other through specific structural domains, playing a crucial role in various biological functions and cell signaling pathways. Protein-protein interactions (PPIs) within cell signaling pathways are essential for signal transmission and regulation. The spatiotemporal features of PPIs in signaling pathways are crucial for comprehending the regulatory mechanisms of signal transduction. Bimolecular fluorescence complementation (BiFC) is one kind of imaging tool for the direct visualization of PPIs in living cells and has been widely utilized to uncover novel PPIs in various organisms. BiFC demonstrates significant potential for application in various areas of biological research, drug development, disease diagnosis and treatment, and other related fields. This review systematically summarizes and analyzes the technical advancement of BiFC and its utilization in elucidating PPIs within established cell signaling pathways, including TOR, PI3K/Akt, Wnt/β-catenin, NF-κB, and MAPK. Additionally, it explores the application of this technology in revealing PPIs within the plant hormone signaling pathways of ethylene, auxin, Gibberellin, and abscisic acid. Using BiFC in conjunction with CRISPR-Cas9, live-cell imaging, and ultra-high-resolution microscopy will enhance our comprehension of PPIs in cell signaling pathways.
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Affiliation(s)
| | | | | | | | | | | | - Shiping Liu
- State Key Laboratory of Resource Insects, Southwest University, Chongqing 400716, China; (H.R.); (Q.O.); (Q.P.); (Y.L.); (X.Y.); (Y.H.)
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13
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ISHIKAWA K, CHAMBERS JK, UCHIDA K. Activation of the Wnt/β-catenin signaling pathway and CTNNB1 mutations in canine intestinal epithelial proliferative lesions. J Vet Med Sci 2024; 86:748-755. [PMID: 38811188 PMCID: PMC11251820 DOI: 10.1292/jvms.24-0125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 05/16/2024] [Indexed: 05/31/2024] Open
Abstract
Nuclear expression of β-catenin has been reported in canine intestinal epithelial tumors (IETs) and colorectal inflammatory polyps (CIPs) with dysplastic epithelia. However, the role of the Wnt/β-catenin signaling pathway in these lesions remains unclear. To investigate the association between the nuclear β-catenin expression and the activation of the Wnt/β-catenin signaling pathway, immunohistochemistry and mutation analyses were conducted on 64 IETs and 20 CIPs. IETs and CIPs with β-catenin nuclear and/or cytoplasm immunolabeling were classified as β-catenin (+). The immunostaining scores of c-Myc and Cyclin D1 and Ki-67 index were significantly higher in β-catenin (+) cases than in β-catenin (-) cases. Identical APC mutations (p.E154D and p.K155X) were detected in 6/41 β-catenin (+) IETs; all 6 of IETs with APC mutations were Jack Russell Terriers. CTNNB1 mutations were detected in 29/42 β-catenin (+) IETs, 3/11 β-catenin (+) CIPs, and 2/22 β-catenin (-) IETs, most of which were hotspots associated with human colorectal carcinoma. In one Miniature Dachshund diagnosed with a CIP that subsequently developed into an IET, the same CTNNB1 mutation was detected in both lesions. The immunohistochemical results suggest that cell proliferative activity in β-catenin (+) cases may be associated with activation of the Wnt/β-catenin signaling pathway. The mutation analysis results suggest that CTNNB1 mutations may be associated with cytoplasmic β-catenin accumulation in IET and CIP. Furthermore, the dysplastic epithelium in CIP may progress to IET through the activation of the Wnt/β-catenin signaling pathway by the CTNNB1 mutation.
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Affiliation(s)
- Kento ISHIKAWA
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - James K CHAMBERS
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Kazuyuki UCHIDA
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
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14
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Zhang Y, Xie JZ, Jiang YL, Yang SJ, Wei H, Yang Y, Wang JZ. Homocysteine-potentiated Kelch-like ECH-associated protein 1 promotes senescence of neuroblastoma 2a cells via inhibiting ubiquitination of β-catenin. Eur J Neurosci 2024; 59:2732-2747. [PMID: 38501537 DOI: 10.1111/ejn.16318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 12/24/2023] [Accepted: 02/25/2024] [Indexed: 03/20/2024]
Abstract
Elevated serum homocysteine (Hcy) level is a risk factor for Alzheimer's disease (AD) and accelerates cell aging. However, the mechanism by which Hcy induces neuronal senescence remains largely unknown. In this study, we observed that Hcy significantly promoted senescence in neuroblastoma 2a (N2a) cells with elevated β-catenin and Kelch-like ECH-associated protein 1 (KEAP1) levels. Intriguingly, Hcy promoted the interaction between KEAP1 and the Wilms tumor gene on the X chromosome (WTX) while hampering the β-catenin-WTX interaction. Mechanistically, Hcy attenuated the methylation level of the KEAP1 promoter CpG island and activated KEAP1 transcription. However, a slow degradation rate rather than transcriptional activation contributed to the high level of β-catenin. Hcy-upregulated KEAP1 competed with β-catenin to bind to WTX. Knockdown of both β-catenin and KEAP1 attenuated Hcy-induced senescence in N2a cells. Our data highlight a crucial role of the KEAP1-β-catenin pathway in Hcy-induced neuronal-like senescence and uncover a promising target for AD treatment.
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Affiliation(s)
- Yao Zhang
- Endocrine Department of Liyuan Hospital; Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia-Zhao Xie
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Precision Medical Center, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Yan-Li Jiang
- Endocrine Department of Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shao-Juan Yang
- Endocrine Department of Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui Wei
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ying Yang
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian-Zhi Wang
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
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15
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Dopeso H, Rodrigues P, Cartón-García F, Macaya I, Bilic J, Anguita E, Jing L, Brotons B, Vivancos N, Beà L, Sánchez-Martín M, Landolfi S, Hernandez-Losa J, Ramon y Cajal S, Nieto R, Vicario M, Farre R, Schwartz S, van Ijzendoorn SC, Kobayashi K, Martinez-Barriocanal Á, Arango D. RhoA downregulation in the murine intestinal epithelium results in chronic Wnt activation and increased tumorigenesis. iScience 2024; 27:109400. [PMID: 38523777 PMCID: PMC10959657 DOI: 10.1016/j.isci.2024.109400] [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: 04/26/2023] [Revised: 12/23/2023] [Accepted: 02/28/2024] [Indexed: 03/26/2024] Open
Abstract
Rho GTPases are molecular switches regulating multiple cellular processes. To investigate the role of RhoA in normal intestinal physiology, we used a conditional mouse model overexpressing a dominant negative RhoA mutant (RhoAT19N) in the intestinal epithelium. Although RhoA inhibition did not cause an overt phenotype, increased levels of nuclear β-catenin were observed in the small intestinal epithelium of RhoAT19N mice, and the overexpression of multiple Wnt target genes revealed a chronic activation of Wnt signaling. Elevated Wnt signaling in RhoAT19N mice and intestinal organoids did not affect the proliferation of intestinal epithelial cells but significantly interfered with their differentiation. Importantly, 17-month-old RhoAT19N mice showed a significant increase in the number of spontaneous intestinal tumors. Altogether, our results indicate that RhoA regulates the differentiation of intestinal epithelial cells and inhibits tumor initiation, likely through the control of Wnt signaling, a key regulator of proliferation and differentiation in the intestine.
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Affiliation(s)
- Higinio Dopeso
- Group of Biomedical Research in Digestive Tract Tumors, Vall d’Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Paulo Rodrigues
- Group of Biomedical Research in Digestive Tract Tumors, Vall d’Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Fernando Cartón-García
- Group of Biomedical Research in Digestive Tract Tumors, Vall d’Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Irati Macaya
- Group of Biomedical Research in Digestive Tract Tumors, Vall d’Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Josipa Bilic
- Group of Biomedical Research in Digestive Tract Tumors, Vall d’Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Estefanía Anguita
- Group of Biomedical Research in Digestive Tract Tumors, Vall d’Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Group of Molecular Oncology, Biomedical Research Institute of Lleida (IRBLleida), 25198 Lleida, Spain
| | - Li Jing
- Group of Biomedical Research in Digestive Tract Tumors, Vall d’Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Group of Molecular Oncology, Biomedical Research Institute of Lleida (IRBLleida), 25198 Lleida, Spain
| | - Bruno Brotons
- Group of Molecular Oncology, Biomedical Research Institute of Lleida (IRBLleida), 25198 Lleida, Spain
| | - Núria Vivancos
- Group of Molecular Oncology, Biomedical Research Institute of Lleida (IRBLleida), 25198 Lleida, Spain
| | - Laia Beà
- Group of Molecular Oncology, Biomedical Research Institute of Lleida (IRBLleida), 25198 Lleida, Spain
| | - Manuel Sánchez-Martín
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
- Servicio de Transgénesis, Nucleus, Universidad de Salamanca, 37007 Salamanca, Spain
- Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
| | - Stefania Landolfi
- Translational Molecular Pathology, Vall d'Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Javier Hernandez-Losa
- Translational Molecular Pathology, Vall d'Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Santiago Ramon y Cajal
- Translational Molecular Pathology, Vall d'Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Rocío Nieto
- Group of Biomedical Research in Digestive Tract Tumors, Vall d’Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - María Vicario
- Digestive System Research Unit, Vall d’Hebron University Hospital Research Institute (VHIR), 08035 Barcelona, Spain
| | - Ricard Farre
- Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven 3000, Belgium
| | - Simo Schwartz
- Group of Drug Delivery and Targeting, Vall d'Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Clinical Biochemistry Department, Vall d'Hebron University Hospital, 08035 Barcelona, Spain
| | - Sven C.D. van Ijzendoorn
- Department of Biomedical Sciences of Cells and Systems, Section Molecular Cell Biology, University of Groningen, University Medical Center Groningen, Groningen 9713 GZ, the Netherlands
| | - Kazuto Kobayashi
- Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Águeda Martinez-Barriocanal
- Group of Biomedical Research in Digestive Tract Tumors, Vall d’Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Group of Molecular Oncology, Biomedical Research Institute of Lleida (IRBLleida), 25198 Lleida, Spain
| | - Diego Arango
- Group of Biomedical Research in Digestive Tract Tumors, Vall d’Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Group of Molecular Oncology, Biomedical Research Institute of Lleida (IRBLleida), 25198 Lleida, Spain
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16
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Zhou Y, Zhang Q, Zhao Z, Hu X, You Q, Jiang Z. Targeting kelch-like (KLHL) proteins: achievements, challenges and perspectives. Eur J Med Chem 2024; 269:116270. [PMID: 38490062 DOI: 10.1016/j.ejmech.2024.116270] [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: 01/02/2024] [Revised: 02/07/2024] [Accepted: 02/19/2024] [Indexed: 03/17/2024]
Abstract
Kelch-like proteins (KLHLs) are a large family of BTB-containing proteins. KLHLs function as the substrate adaptor of Cullin 3-RING ligases (CRL3) to recognize substrates. KLHLs play pivotal roles in regulating various physiological and pathological processes by modulating the ubiquitination of their respective substrates. Mounting evidence indicates that mutations or abnormal expression of KLHLs are associated with various human diseases. Targeting KLHLs is a viable strategy for deciphering the KLHLs-related pathways and devising therapies for associated diseases. Here, we comprehensively review the known KLHLs inhibitors to date and the brilliant ideas underlying their development.
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Affiliation(s)
- Yangguo Zhou
- Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Qiong Zhang
- Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Ziquan Zhao
- Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Xiuqi Hu
- Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Qidong You
- Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| | - Zhengyu Jiang
- Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
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17
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Wolfram L, Gimpel C, Schwämmle M, Clark SJ, Böhringer D, Schlunck G. The impact of substrate stiffness on morphological, transcriptional and functional aspects in RPE. Sci Rep 2024; 14:7488. [PMID: 38553490 PMCID: PMC11344127 DOI: 10.1038/s41598-024-56661-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 03/08/2024] [Indexed: 04/02/2024] Open
Abstract
Alterations in the structure and composition of Bruch's membrane (BrM) and loss of retinal pigment epithelial (RPE) cells are associated with various ocular diseases, notably age-related macular degeneration (AMD) as well as several inherited retinal diseases (IRDs). We explored the influence of stiffness as a major BrM characteristic on the RPE transcriptome and morphology. ARPE-19 cells were plated on soft ( E = 30 kPa ) or stiff ( E = 80 kPa ) polyacrylamide gels (PA gels) or standard tissue culture plastic (TCP). Next-generation sequencing (NGS) data on differentially expressed small RNAs (sRNAs) and messenger RNAs (mRNAs) were validated by qPCR, immunofluorescence or western blotting. The microRNA (miRNA) fraction of sRNAs grew with substrate stiffness and distinct miRNAs such as miR-204 or miR-222 were differentially expressed. mRNA targets of differentially expressed miRNAs were stably expressed, suggesting a homeostatic effect of miRNAs. mRNA transcription patterns were substrate stiffness-dependent, including components of Wnt/beta-catenin signaling, Microphthalmia-Associated Transcription Factor (MITF) and Dicer. These findings highlight the relevance of mechanical properties of the extracellular matrix (ECM) in cell culture experiments, especially those focusing on ECM-related diseases, such as AMD.
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Affiliation(s)
- Lasse Wolfram
- Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
- Department for Ophthalmology, Institute for Ophthalmic Research, Eberhard Karls University of Tübingen, Tübingen, Germany.
- Department for Ophthalmology, University Eye Clinic, Eberhard Karls University of Tübingen, Tübingen, Germany.
| | - Clara Gimpel
- Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Neurology, Schlosspark-Klinik Charlottenburg, Berlin, Germany
| | - Melanie Schwämmle
- Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Simon J Clark
- Department for Ophthalmology, Institute for Ophthalmic Research, Eberhard Karls University of Tübingen, Tübingen, Germany
- Department for Ophthalmology, University Eye Clinic, Eberhard Karls University of Tübingen, Tübingen, Germany
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK
| | - Daniel Böhringer
- Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Günther Schlunck
- Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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18
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Fang KT, Su CS, Layos JJ, Lau NYS, Cheng KH. Haploinsufficiency of Adenomatous Polyposis Coli Coupled with Kirsten Rat Sarcoma Viral Oncogene Homologue Activation and P53 Loss Provokes High-Grade Glioblastoma Formation in Mice. Cancers (Basel) 2024; 16:1046. [PMID: 38473403 DOI: 10.3390/cancers16051046] [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: 11/04/2023] [Revised: 01/19/2024] [Accepted: 02/06/2024] [Indexed: 03/14/2024] Open
Abstract
Glioblastoma multiforme (GBM) is the most common and deadly type of brain tumor originating from glial cells. Despite decades of clinical trials and research, there has been limited success in improving survival rates. However, molecular pathology studies have provided a detailed understanding of the genetic alterations associated with the formation and progression of glioblastoma-such as Kirsten rat sarcoma viral oncogene homolog (KRAS) signaling activation (5%), P53 mutations (25%), and adenomatous polyposis coli (APC) alterations (2%)-laying the groundwork for further investigation into the biological and biochemical basis of this malignancy. These analyses have been crucial in revealing the sequential appearance of specific genetic lesions at distinct histopathological stages during the development of GBM. To further explore the pathogenesis and progression of glioblastoma, here, we developed the glial-fibrillary-acidic-protein (GFAP)-Cre-driven mouse model and demonstrated that activated KRAS and p53 deficiencies play distinct and cooperative roles in initiating glioma tumorigenesis. Additionally, the combination of APC haploinsufficiency with mutant Kras activation and p53 deletion resulted in the rapid progression of GBM, characterized by perivascular inflammation, large necrotic areas, and multinucleated giant cells. Consequently, our GBM models have proven to be invaluable resources for identifying early disease biomarkers in glioblastoma, as they closely mimic the human disease. The insights gained from these models may pave the way for potential advancements in the diagnosis and treatment of this challenging brain tumor.
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Affiliation(s)
- Kuan-Te Fang
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
| | - Chuan-Shiang Su
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
| | - Jhoanna Jane Layos
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
| | - Nga Yin Sadonna Lau
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
| | - Kuang-Hung Cheng
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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19
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Zhang F, Bischof H, Burgstaller S, Bourgeois BMR, Malli R, Madl T. Genetically encoded fluorescent sensor to monitor intracellular arginine methylation. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY. B, BIOLOGY 2024; 252:112867. [PMID: 38368636 DOI: 10.1016/j.jphotobiol.2024.112867] [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: 12/26/2023] [Revised: 02/03/2024] [Accepted: 02/12/2024] [Indexed: 02/20/2024]
Abstract
Arginine methylation (ArgMet), as a post-translational modification, plays crucial roles in RNA processing, transcriptional regulation, signal transduction, DNA repair, apoptosis and liquid-liquid phase separation (LLPS). Since arginine methylation is associated with cancer pathogenesis and progression, protein arginine methyltransferases have gained interest as targets for anti-cancer therapy. Despite considerable process made to elucidate (patho)physiological mechanisms regulated by arginine methylation, there remains a lack of tools to visualize arginine methylation with high spatiotemporal resolution in live cells. To address this unmet need, we generated an ArgMet-sensitive genetically encoded, Förster resonance energy transfer-(FRET) based biosensor, called GEMS, capable of quantitative real-time monitoring of ArgMet dynamics. We optimized these biosensors by using different ArgMet-binding domains, arginine-glycine-rich regions and adjusting the linkers within the biosensors to improve their performance. Using a set of mammalian cell lines and modulators, we demonstrated the applicability of GEMS for monitoring changes in arginine methylation with single-cell and temporal resolution. The GEMS can facilitate the in vitro screening to find potential protein arginine methyltransferase inhibitors and will contribute to a better understanding of the regulation of ArgMet related to differentiation, development and disease.
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Affiliation(s)
- Fangrong Zhang
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou 350122, China; Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria
| | - Helmut Bischof
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria
| | - Sandra Burgstaller
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria
| | - Benjamin M R Bourgeois
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; Otto Loewi Research Center, Medicinal Chemistry, Medical University of Graz, 8010 Graz, Austria
| | - Roland Malli
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria
| | - Tobias Madl
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; Otto Loewi Research Center, Medicinal Chemistry, Medical University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria.
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Menezes RDS, Dornas MC, Campos CFF, Rodeiro DB, Carrerette FB, Oliveira RV, de Souza BA, Alves de Souza Carvalho G, Brito IADA, Silva DA, Damião R, Porto LC. Evaluation of HNF1B, KLK3, ELAC2, TMPRSS2-ERG, and CTNNB1 polymorphisms associated with prostate cancer in samples of patients from HUPE-UERJ. Prostate 2024; 84:166-176. [PMID: 37839045 DOI: 10.1002/pros.24635] [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: 04/28/2023] [Revised: 09/08/2023] [Accepted: 09/26/2023] [Indexed: 10/17/2023]
Abstract
PURPOSE Prostate cancer (PCa) is the leading cause of death among men in 48 countries. Genetic alterations play a significant role in PCa carcinogenesis. For the hypothesis of this research, five unique polymorphisms (SNP) were investigated in different genes that showed to be associated in different ways with PCa: rs4430796, rs2735839, rs4792311, rs12329760, and rs28931588, respectively for the genes HNF1B, KLK3, ELAC2, TMPRSS2-ERG, and CTNNB1. PATIENTS AND METHODS Blood samples from 426 subjects were evaluated: 290 controls (161 females and 129 males) and 136 PCa patients. SNP were determined by real-time polymerase chain reaction. TaqMan SNP genotyping assay. In the control samples, the SNPs were defined in association with the self-reported ethnicity, and in 218 control samples with markers with ancestry indicators. The genes were in Hardy-Weinberg equilibrium. One hundred and seventy control samples were matched by ethnicity for comparison with the PCa samples. RESULTS The G allele at rs28931588 was monomorphic in both patients and controls studied. Significant differences were observed in allelic and genotypic frequencies between the control and Pca samples in rs2735839 (KLK3; p = 0.002 and χ2 = 8.73 and p = 0.01, respectively), by the global frequency and in the dominant model rs2735839_GG (odds ratio [OR] = 0.51, p = 0.02). AA and GA genotypes at rs4792311 (ELAC2) were more frequent in patients with Gleason 7(4 + 3), 8, and 9 (n = 37%-59.7%) compared to patients with Gleason 6 and 7(3 + 4) (n = 26%-40.0%) conferring a protective effect on the GG genotype (OR = 0.45, p = 0.02). The same genotype showed an OR = 2.71 (p = 0.01) for patients with low severity. The HNF1B-KLK3-ELAC2-TMPRSS2-ERG haplotypes: GAAT, AAAT, GAGT, and AAGT were more frequent in patients with Pca with OR ranging from 4.65 to 2.48. CONCLUSIONS Higher frequencies of risk alleles were confirmed in the SNPs, KLK3 rs2735839_A, ELAC2 rs4792311_A, and TMPRSS2 rs12329760_T in patients with Pca. Rs2735839_A was associated with risk of Pca and rs4792311_A with severity and Gleason score of 7(4 + 3) or greater. There is a need for careful observation of rs2735839 and rs4792311 in association with the prostatic biopsy due to the increased risk of Pca.
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Affiliation(s)
- Raphaela Dos Santos Menezes
- Human and Experimental Biology Graduate Program, IBRAG, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Maria Cristina Dornas
- Urology Teaching Assistance Unit (UDA), FCM, Pedro Ernesto University Hospital (HUPE) and the Piquet Carneiro University Polyclinic (PPC), Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Carlos Frederico Ferreira Campos
- Anatomopathological Service Pedro Ernesto University Hospital (HUPE), FCM, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Daniela Bouzas Rodeiro
- Urology Teaching Assistance Unit (UDA), FCM, Pedro Ernesto University Hospital (HUPE) and the Piquet Carneiro University Polyclinic (PPC), Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Fabricio Borges Carrerette
- Urology Teaching Assistance Unit (UDA), FCM, Pedro Ernesto University Hospital (HUPE) and the Piquet Carneiro University Polyclinic (PPC), Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Romulo Vianna Oliveira
- Tissue Repair and Histocompatibility Technological Core (Tixus), Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Brenda Amaral de Souza
- Tissue Repair and Histocompatibility Technological Core (Tixus), Rio de Janeiro State University, Rio de Janeiro, Brazil
| | | | | | - Dayse Aparecida Silva
- Laboratory of DNA Diagnostic, IBRAG, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Ronaldo Damião
- Urology Teaching Assistance Unit (UDA), FCM, Pedro Ernesto University Hospital (HUPE) and the Piquet Carneiro University Polyclinic (PPC), Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Luís Cristóvão Porto
- Tissue Repair and Histocompatibility Technological Core (Tixus), Rio de Janeiro State University, Rio de Janeiro, Brazil
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Xiao W, Hu C, Ni Y, Wang J, Jiao K, Zhou M, Li Z. 27-Hydroxycholesterol activates the GSK-3β/β-catenin signaling pathway resulting in intestinal fibrosis by inducing oxidative stress: effect of dietary interventions. Inflamm Res 2024; 73:289-304. [PMID: 38184500 DOI: 10.1007/s00011-023-01835-8] [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: 07/15/2023] [Revised: 11/30/2023] [Accepted: 12/09/2023] [Indexed: 01/08/2024] Open
Abstract
OBJECTIVE Intestinal fibrosis, a common and serious complication of inflammatory bowel disease (IBD), results from chronic inflammation. A high-cholesterol diet may be a risk factor for IBD and 27-hydroxylcholesterol (27HC) is the main human cholesterol metabolite. This study investigated whether 27HC can induce intestinal fibrosis. METHODS The effects of cholesterol and 27HC on intestinal fibrosis were assessed in zebrafish and human intestinal epithelial Caco-2 cells. RESULTS Cholesterol and 27HC induced intestinal inflammation and collagen deposition, inhibited E-cadherin (E-ca) expression in the intestinal epithelium, and promoted nuclear translocation of β-catenin in zebrafish. Cholesterol and 27HC up-regulated expression of COL-1, α-SMA, CTGF, TIMP1, N-cadherin, vimentin, glycogen synthesis kinase-3β (GSK-3β) and β-catenin, but inhibited E-ca, in Caco-2 cells. The expression of these proteins was inhibited by CYP27A1 knockdown and β-catenin knockdown. 27HC-induced nuclear translocation of β-catenin occurs in Caco-2 cells. p38, ERK, and AKT activate β-catenin and thereby participate in 27HC-induced epithelia-mesenchymal transition (EMT) and fibrosis. 27HC-increased oxidative stress and the fibrosis and EMT markers, the nuclear translocation of β-catenin, and the up-regulation of p-cell kinase proteins promoted by 27HC were inhibited by N-acetyl-L-cysteine (NAC). Folic acid (FA), resveratrol (RES), and NAC all ameliorated the 27HC-induced effects in Caco-2 cells and zebrafish. CONCLUSION A high-cholesterol diet caused intestinal fibrosis in zebrafish, mediated by a major cholesterol metabolite, 27HC. 27HC increased oxidative stress and activated p38, ERK, AKT, and β-catenin, leading to EMT of epithelial cells and intestinal fibrosis. FA and RES both ameliorated intestinal fibrosis by restraining 27HC-induced β-catenin activation.
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Affiliation(s)
- Wei Xiao
- The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Chunyan Hu
- The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yifan Ni
- The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jie Wang
- The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Kailin Jiao
- Department of Nutrition, The Second Affiliated Hospital, Air Force Medical University, Xi'an, China.
| | - Ming Zhou
- The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
| | - Zhong Li
- The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
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Das P, Majumder R, Sen N, Nandi SK, Ghosh A, Mandal M, Basak P. A computational analysis to evaluate deleterious SNPs of GSK3β, a multifunctional and regulatory protein, for metabolism, wound healing, and migratory processes. Int J Biol Macromol 2024; 256:128262. [PMID: 37989431 DOI: 10.1016/j.ijbiomac.2023.128262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 10/04/2023] [Accepted: 11/17/2023] [Indexed: 11/23/2023]
Abstract
This study focused on GSK-3β, a critical serine/threonine kinase with diverse cellular functions. However, there is limited understanding of the impact of non-synonymous single nucleotide polymorphisms (nsSNPs) on its structure and function. Through an exhaustive in-silico investigation 12 harmful nsSNPs were predicted from a pool of 172 acquired from the NCBI dbSNP database using 12 established tools that detects deleterious SNPs. Consistently, these nsSNPs were discovered in locations with high levels of conservation. Notably, the three harmful nsSNPs F67C, A83T, and T138I were situated in the active/binding site of GSK-3β, which may affect the protein's capacity to bind to substrates and other proteins. Molecular dynamics simulations revealed that the F67C and T138I mutants had stable structures, indicating rigidness, whereas the A83T mutant was unstable. Analysis of secondary structures revealed different modifications in all mutant forms, which may affect the stability, functioning, and interactions of the protein. These mutations appear to alter the structural dynamics of GSK-3β, which may have functional ramifications, such as the formation of novel secondary structures and variations in coil-to-helix transitions. In conclusion, this study illuminates the possible structural and functional ramifications of these GSK-3 nsSNPs, revealing how protein compactness, stiffness, and interactions may affect biological activities.
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Affiliation(s)
- Pratik Das
- School of Bioscience and Engineering, Jadavpur University, Kolkata, India
| | - Ranabir Majumder
- Cancer Biology Lab, School of Medical Science & Technology, Indian Institute of Technology Kharagpur, India
| | - Nandita Sen
- Molecular biology wing, Dept of Biotechnology, PES University, Bangalore, India
| | - Samit Kumar Nandi
- Department of Veterinary Surgery & Radiology, West Bengal University of Animal and Fishery Sciences, Kolkata, India
| | - Arabinda Ghosh
- Department of Computational Biology and Biotechnology, Mahapurusha Srimanta Sankaradeva Viswavidyalaya, Guwahati Unit, Guwahati, Assam, India
| | - Mahitosh Mandal
- Cancer Biology Lab, School of Medical Science & Technology, Indian Institute of Technology Kharagpur, India
| | - Piyali Basak
- School of Bioscience and Engineering, Jadavpur University, Kolkata, India.
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Rodriguez FD, Covenas R. Association of Neurokinin-1 Receptor Signaling Pathways with Cancer. Curr Med Chem 2024; 31:6460-6486. [PMID: 37594106 DOI: 10.2174/0929867331666230818110812] [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: 02/03/2023] [Revised: 06/14/2023] [Accepted: 07/01/2023] [Indexed: 08/19/2023]
Abstract
BACKGROUND Numerous biochemical reactions leading to altered cell proliferation cause tumorigenesis and cancer treatment resistance. The mechanisms implicated include genetic and epigenetic changes, modified intracellular signaling, and failure of control mechanisms caused by intrinsic and extrinsic factors alone or combined. No unique biochemical events are responsible; entangled molecular reactions conduct the resident cells in a tissue to display uncontrolled growth and abnormal migration. Copious experimental research supports the etiological responsibility of NK-1R (neurokinin-1 receptor) activation, alone or cooperating with other mechanisms, in cancer appearance in different tissues. Consequently, a profound study of this receptor system in the context of malignant processes is essential to design new treatments targeting NK-1R-deviated activity. METHODS This study reviews and discusses recent literature that analyzes the main signaling pathways influenced by the activation of neurokinin 1 full and truncated receptor variants. Also, the involvement of NK-1R in cancer development is discussed. CONCLUSION NK-1R can signal through numerous pathways and cross-talk with other receptor systems. The participation of override or malfunctioning NK-1R in malignant processes needs a more precise definition in different types of cancers to apply satisfactory and effective treatments. A long way has already been traveled: the current disposal of selective and effective NK-1R antagonists and the capacity to develop new drugs with biased agonistic properties based on the receptor's structural states with functional significance opens immediate research action and clinical application.
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Affiliation(s)
- Francisco David Rodriguez
- Department of Biochemistry and Molecular Biology, Faculty of Chemical Sciences, University of Salamanca, 37007 Salamanca, Spain
- Group GIR USAL: BMD (Bases Moleculares del Desarrollo), University of Salamanca, Salamanca, Spain
| | - Rafael Covenas
- Group GIR USAL: BMD (Bases Moleculares del Desarrollo), University of Salamanca, Salamanca, Spain
- Laboratory of Neuroanatomy of the Peptidergic Systems, Institute of Neurosciences of Castilla y León (INCYL), University of Salamanca, 37007 Salamanca, Spain
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24
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Hu X, Ju Y, Zhang YK. Ivermectin as a potential therapeutic strategy for glioma. J Neurosci Res 2024; 102:e25254. [PMID: 37814994 DOI: 10.1002/jnr.25254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 09/22/2023] [Accepted: 09/24/2023] [Indexed: 10/11/2023]
Abstract
Ivermectin (IVM), a semi-synthetic macrolide parasiticide, has demonstrated considerable effectiveness in combating internal and external parasites, particularly nematodes and arthropods. Its remarkable ability to control parasites has earned it significant recognition, culminating in Satoshi Omura and William C. Campbell's receipt of the 2015 Nobel Prize in Physiology or Medicine for their contributions to the development of IVM. In recent years, investigations have revealed that IVM possesses antitumor properties. It can suppress the growth of various cancer cells, including glioma, through a multitude of mechanisms such as selective targeting of tumor-specific proteins, inducing programmed cell death, and modulation of tumor-related signaling pathways. Hence, IVM holds tremendous potential as a novel anticancer drug. This review seeks to provide an overview of the underlying mechanisms that enable IVM's capacity to suppress glioma. Furthermore, it aims to elucidate the challenges and prospects associated with utilizing IVM as a new anticancer agent.
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Affiliation(s)
- Xing Hu
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, PR China
| | - Yan Ju
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, PR China
| | - Yue-Kang Zhang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, PR China
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Chen CH, Chen CJ, Huang YC, Huang PS, Chi HC, Chuang HC, Lin MH, Huang TH, Hsu JT, Chen CY. Secreted Frizzled-Related Protein 4 Induces Gastric Cancer Progression and Resistance to Cisplatin and Oxaliplatin via β-Catenin Dysregulation. Chemotherapy 2023; 69:150-164. [PMID: 38071975 DOI: 10.1159/000533767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 08/18/2023] [Indexed: 09/05/2024]
Abstract
INTRODUCTION Gastric cancer is the fifth most common cancer and third leading cause of cancer-related death worldwide. There are three main ways to treat gastric cancer: surgical resection, radiation therapy, and drug therapy. Furthermore, combinations of two to three regimens can improve survival. However, the survival outcomes of chemotherapy in advanced gastric cancer patients are still unsatisfactory. Unfortunately, no widely useful biomarkers have been verified to predict the efficacy of chemotherapy for locally advanced gastric cancer. METHODS An MTT assay was used to determine the cell viability after cisplatin or oxaliplatin treatment. Western blotting and immunohistochemistry were utilized to examine the secreted frizzled-related protein 4 (sFRP4) level and associated signaling pathways. Immunofluorescence staining was utilized to analyze the location of β-catenin. Colony formation and Transwell assays were used to analyze the functions related with cisplatin, oxaliplatin, and sFRP4. RESULTS We have found that gastric cancer patients treated with combinations of 5-fluorouracil (5-FU) and cisplatin regimens have better survival rates than those treated with 5-FU-based chemotherapy alone. sFRP4 was selected as a potential target from stringent analysis and intersection of 5-FU and cisplatin resistance-related gene sets. sFRP4 was shown to be overexpressed in clinical gastric tumor tissues and positively correlated with a worse survival rate. In addition, sFRP4 and β-catenin were upregulated in cisplatin- and oxaliplatin-resistant gastric cancer cells compared to parental cells. Immunofluorescence staining and nuclear fractionation showed that β-catenin was translocated from the cytosol into the nucleus. Moreover, sFRP4 was detected in the conditioned medium of these resistant cells, which indicates that sFRP4 might have an extracellular role in chemotherapy resistance. Increased migration capacity and dysregulation of epithelial-mesenchymal transition-related markers, which might result from the dysregulation of sFRP4, were observed in cisplatin- and oxaliplatin-resistant gastric cancer cells. DISCUSSION/CONCLUSION In summary, sFRP4 might play a critical role in resistance to cisplatin and oxaliplatin, cell metastasis, and poor prognosis in gastric cancer via the Wnt-β-catenin pathway. Investigations of the molecular mechanism underlying sFRP4-modulated cancer progression and chemotherapeutic outcomes can provide additional therapeutic strategies for gastric cancer.
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Affiliation(s)
- Chun-Han Chen
- Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Chih-Jung Chen
- Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Yi-Ching Huang
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Po-Shuan Huang
- Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biochemical and Biomedical Engineering, Chang Gung University, Taoyuan, Taiwan
| | - Hsiang-Cheng Chi
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
| | - Huei-Chieh Chuang
- Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chiayi, Taiwan
- Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Meng-Hung Lin
- Health Information and Epidemiology Laboratory, Chang Gung Memorial Hospital, Chiayi Branch, Taiwan
| | - Tzu-Hao Huang
- Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Jun-Te Hsu
- Chang Gung University College of Medicine, Taoyuan, Taiwan
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Cheng-Yi Chen
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Dev A, Vachher M, Prasad CP. β-catenin inhibitors in cancer therapeutics: intricacies and way forward. Bioengineered 2023; 14:2251696. [PMID: 37655825 PMCID: PMC10478749 DOI: 10.1080/21655979.2023.2251696] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 08/19/2023] [Accepted: 08/21/2023] [Indexed: 09/02/2023] Open
Abstract
β-catenin is an evolutionary conserved, quintessential, multifaceted protein that plays vital roles in cellular homeostasis, embryonic development, organogenesis, stem cell maintenance, cell proliferation, migration, differentiation, apoptosis, and pathogenesis of various human diseases including cancer. β-catenin manifests both signaling and adhesive features. It acts as a pivotal player in intracellular signaling as a component of versatile WNT signaling cascade involved in embryonic development, homeostasis as well as in carcinogenesis. It is also involved in Ca2+ dependent cell adhesion via interaction with E-cadherin at the adherens junctions. Aberrant β-catenin expression and its nuclear accumulation promote the transcription of various oncogenes including c-Myc and cyclinD1, thereby contributing to tumor initiation, development, and progression. β-catenin's expression is closely regulated at various levels including its stability, sub-cellular localization, as well as transcriptional activity. Understanding the molecular mechanisms of regulation of β-catenin and its atypical expression will provide researchers not only the novel insights into the pathogenesis and progression of cancer but also will help in deciphering new therapeutic avenues. In the present review, we have summarized the dual functions of β-catenin, its role in signaling, associated mutations as well as its role in carcinogenesis and tumor progression of various cancers. Additionally, we have discussed the challenges associated with targeting β-catenin molecule with the presently available drugs and suggested the possible way forward in designing new therapeutic alternatives against this oncogene.
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Affiliation(s)
- Arundhathi Dev
- Department of Medical Oncology (Laboratory), DR BRAIRCH, All India Institute of Medical Sciences, New Delhi, India
| | - Meenakshi Vachher
- Department of Biochemistry, Institute of Home Economics, University of Delhi, New Delhi, India
| | - Chandra Prakash Prasad
- Department of Medical Oncology (Laboratory), DR BRAIRCH, All India Institute of Medical Sciences, New Delhi, India
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Li W, Kawaguchi K, Tanaka S, He C, Maeshima Y, Suzuki E, Toi M. Cellular senescence triggers intracellular acidification and lysosomal pH alkalinized via ATP6AP2 attenuation in breast cancer cells. Commun Biol 2023; 6:1147. [PMID: 37993606 PMCID: PMC10665353 DOI: 10.1038/s42003-023-05433-6] [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: 03/22/2023] [Accepted: 10/09/2023] [Indexed: 11/24/2023] Open
Abstract
Several chemotherapeutic drugs induce senescence in cancer cells; however, the mechanisms underlying intracellular pH dysregulation in senescent cells remain unclear. Adenosine triphosphatase H+ transporting accessory protein 2 (ATP6AP2) plays a critical role in maintaining pH homeostasis in cellular compartments. Herein, we report the regulatory role of ATP6AP2 in senescent breast cancer cells treated with doxorubicin (Doxo) and abemaciclib (Abe). A decline in ATP6AP2 triggers aberrant pH levels that impair lysosomal function and cause immune profile changes in senescent breast cancer cells. Doxo and Abe elicited a stable senescent phenotype and altered the expression of senescence-related genes. Additionally, senescent cells show altered inflammatory and immune transcriptional profiles due to reprogramming of the senescence-associated secretory phenotype. These findings elucidate ATP6AP2-mediated cellular pH regulation and suggest a potential link in immune profile alteration during therapy-induced senescence in breast cancer cells, providing insights into the mechanisms involved in the senescence response to anticancer therapy.
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Affiliation(s)
- Wei Li
- Department of Breast Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Kosuke Kawaguchi
- Department of Breast Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.
| | - Sunao Tanaka
- Department of Breast Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Chenfeng He
- Department of Breast Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Yurina Maeshima
- Department of Breast Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Eiji Suzuki
- Kobe City Medical Center General Hospital, 2-1-1 Minatojimaminami-cho, Chuo-ku, Kobe, 650-0047, Japan
| | - Masakazu Toi
- Department of Breast Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan
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Ghorani E, Swanton C, Quezada SA. Cancer cell-intrinsic mechanisms driving acquired immune tolerance. Immunity 2023; 56:2270-2295. [PMID: 37820584 DOI: 10.1016/j.immuni.2023.09.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 09/11/2023] [Accepted: 09/11/2023] [Indexed: 10/13/2023]
Abstract
Immune evasion is a hallmark of cancer, enabling tumors to survive contact with the host immune system and evade the cycle of immune recognition and destruction. Here, we review the current understanding of the cancer cell-intrinsic factors driving immune evasion. We focus on T cells as key effectors of anti-cancer immunity and argue that cancer cells evade immune destruction by gaining control over pathways that usually serve to maintain physiological tolerance to self. Using this framework, we place recent mechanistic advances in the understanding of cancer immune evasion into broad categories of control over T cell localization, antigen recognition, and acquisition of optimal effector function. We discuss the redundancy in the pathways involved and identify knowledge gaps that must be overcome to better target immune evasion, including the need for better, routinely available tools that incorporate the growing understanding of evasion mechanisms to stratify patients for therapy and trials.
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Affiliation(s)
- Ehsan Ghorani
- Cancer Immunology and Immunotherapy Unit, Department of Surgery and Cancer, Imperial College London, London, UK; Department of Medical Oncology, Imperial College London Hospitals, London, UK.
| | - Charles Swanton
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Department of Oncology, University College London Hospitals, London, UK
| | - Sergio A Quezada
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London, UK.
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Soltanfar A, Meimandi Parizi A, Foad-Noorbakhsh M, Sayyari M, Iraji A. The healing effects of thymoquinone on experimentally induced traumatic tendinopathy in rabbits. J Orthop Surg Res 2023; 18:233. [PMID: 36949516 PMCID: PMC10035262 DOI: 10.1186/s13018-023-03706-8] [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: 07/28/2022] [Accepted: 03/13/2023] [Indexed: 03/24/2023] Open
Abstract
OBJECTIVES Thymoquinone is a major bioactive compound present in the black seeds of the Nigella sativa. Tendon injuries are almost 50% of all musculoskeletal injuries. The recovery of tendon after surgery has become a significant challenge in orthopedics. DESIGN The purpose of this study was to investigate the healing effect of thymoquinone injections in 40 New Zealand rabbits tendon traumatic models. MATERIALS AND METHODS Tendinopathy was induced by trauma using surgical forceps on the Achilles tendon. Animals were randomly divided into 4 groups: (1) normal saline injection (control), (2) DMSO injection, (3) thymoquinone 5% w/w injection, and (4) thymoquinone 10% w/w injection. Forty-two days after surgery, biochemical and histopathological evaluations were done, and biomechanical evaluation was conducted 70 days after surgery. RESULTS Breakpoint and yield points in treatment groups were significantly higher compared to control and DMSO groups. Hydroxyproline content in the 10% thymoquinone receiving group was higher than all groups. Edema and hemorrhage in the histopathological evaluation were significantly lower in the thymoquinone 10% and thymoquinone 5% receiving groups compared to control and DMSO groups. Collagen fibers, collagen fibers with fibrocytes, and collagen fibers with fibroblasts were significantly higher in the thymoquinone 10% and thymoquinone 5% receiving groups compared to control groups. CONCLUSIONS Thymoquinone injection in the tendon in the concentration of 10% w/w is a simple and low-cost healing agent that could enhance mechanical and collagen synthesis in traumatic tendinopathy models in rabbit.
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Affiliation(s)
- Alireza Soltanfar
- Division of Surgery, Department of Clinical Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Abdolhamid Meimandi Parizi
- Division of Surgery, Department of Clinical Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran.
| | - Mohammad Foad-Noorbakhsh
- Division of Pharmacology and Toxicology, Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Mansour Sayyari
- Department of Pathobiology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Aida Iraji
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
- Central Research Laboratory, Shiraz University of Medical Sciences, Shiraz, Iran.
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Royer-Bertrand B, Lebon S, Craig A, Maeder J, Mittaz-Crettol L, Fodstad H, Superti-Furga A, Good JM. Developmental disorder and spastic paraparesis in two sisters with a TCF7L2 truncating variant inherited from a mosaic mother. Am J Med Genet A 2023; 191:1658-1663. [PMID: 36905089 DOI: 10.1002/ajmg.a.63173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 02/01/2023] [Accepted: 02/21/2023] [Indexed: 03/12/2023]
Affiliation(s)
- Beryl Royer-Bertrand
- Division of Genetic Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Sébastien Lebon
- Unit of Pediatric Neurology and Neurorehabilitation, Department of Pediatrics, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Ailsa Craig
- Division of Genetic Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Johanna Maeder
- Unit of Pediatric Neurology and Neurorehabilitation, Department of Pediatrics, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Laureane Mittaz-Crettol
- Division of Genetic Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Heidi Fodstad
- Division of Genetic Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Andrea Superti-Furga
- Division of Genetic Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Jean-Marc Good
- Division of Genetic Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
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Reprogramming of palmitic acid induced by dephosphorylation of ACOX1 promotes β-catenin palmitoylation to drive colorectal cancer progression. Cell Discov 2023; 9:26. [PMID: 36878899 PMCID: PMC9988979 DOI: 10.1038/s41421-022-00515-x] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 12/30/2022] [Indexed: 03/08/2023] Open
Abstract
Metabolic reprogramming is a hallmark of cancer. However, it is not well known how metabolism affects cancer progression. We identified that metabolic enzyme acyl-CoA oxidase 1 (ACOX1) suppresses colorectal cancer (CRC) progression by regulating palmitic acid (PA) reprogramming. ACOX1 is highly downregulated in CRC, which predicts poor clinical outcome in CRC patients. Functionally, ACOX1 depletion promotes CRC cell proliferation in vitro and colorectal tumorigenesis in mouse models, whereas ACOX1 overexpression inhibits patient-derived xenograft growth. Mechanistically, DUSP14 dephosphorylates ACOX1 at serine 26, promoting its polyubiquitination and proteasomal degradation, thereby leading to an increase of the ACOX1 substrate PA. Accumulated PA promotes β-catenin cysteine 466 palmitoylation, which inhibits CK1- and GSK3-directed phosphorylation of β-catenin and subsequent β-Trcp-mediated proteasomal degradation. In return, stabilized β-catenin directly represses ACOX1 transcription and indirectly activates DUSP14 transcription by upregulating c-Myc, a typical target of β-catenin. Finally, we confirmed that the DUSP14-ACOX1-PA-β-catenin axis is dysregulated in clinical CRC samples. Together, these results identify ACOX1 as a tumor suppressor, the downregulation of which increases PA-mediated β-catenin palmitoylation and stabilization and hyperactivates β-catenin signaling thus promoting CRC progression. Particularly, targeting β-catenin palmitoylation by 2-bromopalmitate (2-BP) can efficiently inhibit β-catenin-dependent tumor growth in vivo, and pharmacological inhibition of DUSP14-ACOX1-β-catenin axis by Nu-7441 reduced the viability of CRC cells. Our results reveal an unexpected role of PA reprogramming induced by dephosphorylation of ACOX1 in activating β-catenin signaling and promoting cancer progression, and propose the inhibition of the dephosphorylation of ACOX1 by DUSP14 or β-catenin palmitoylation as a viable option for CRC treatment.
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Chen J, Wang D, Chen H, Gu J, Jiang X, Han F, Cao J, Liu W, Liu J. TMEM196 inhibits lung cancer metastasis by regulating the Wnt/β-catenin signaling pathway. J Cancer Res Clin Oncol 2023; 149:653-667. [PMID: 36355209 DOI: 10.1007/s00432-022-04363-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 09/14/2022] [Indexed: 11/11/2022]
Abstract
PURPOSE The TMEM196 protein, which comprises four membrane-spanning domains, belongs to the TMEM protein family. TMEM196 was identified as a candidate tumor suppressor gene in lung cancer. However, its role and mechanism in lung cancer metastasis remain unclear. Here, we study the role of TMEM196 in tumor metastasis to further verify the function in lung cancer. METHODS In this study, we used qRT-PCR, western blot analysis and immunohistochemistry to examine the expression levels of TMEM196 and related proteins in lung cancer tissues and tumor cells. We utilized Transwell assays, xenograft nude mouse models, and TMEM196-/- mouse models to evaluate the effects of TMEM196 on tumor invasion and metastasis. Finally, we used bioinformatics analysis and dual-luciferase reporter gene assays to explore the molecular mechanism of TMEM196 as a tumor suppressor. RESULTS We found that TMEM196 mRNA and protein expression levels were significantly decreased in lung cancer tissues and cells. Low expression of TMEM196 in clinical patients was associated with poor prognosis. TMEM196 strongly inhibited tumor metastasis and progression in vitro and in vivo. The primary lung tumors induced by tail vein-inoculated B16 cells in TMEM196-/- mice were significantly larger than those in TMEM196+/+ mice. Mechanistically, TMEM196 inhibited the Wnt signaling pathway and repressed β-catenin promoter transcription. TMEM196 silencing in lung cancer cells and mice resulted in significant upregulation of the expression of β-catenin and Wnt signaling pathway downstream target genes (MMP2 and MMP7). Decreasing β-catenin expression in TMEM196-silenced cancer cells attenuated the antimetastatic effect of TMEM196. CONCLUSIONS Our results revealed that TMEM196 acts as a novel lung cancer metastasis suppressor via the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Jianping Chen
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China
| | - Dandan Wang
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China.,Laboratory of Cell Signal Transduction, Henan Provincial Engineering Centre for Tumor Molecular Medicine, Medical School of Henan University, Kaifeng, People's Republic of China
| | - Hongqiang Chen
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China
| | - Jin Gu
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China
| | - Xiao Jiang
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China
| | - Fei Han
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China
| | - Jia Cao
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China
| | - Wenbin Liu
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China. .,Department of Environmental Health, College of Preventive Medicine, Third Military Medical University (Army Medical University), 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China.
| | - Jinyi Liu
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China.
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Abstract
Deregulation of transcription factors is critical to hallmarks of cancer. Genetic mutations, gene fusions, amplifications or deletions, epigenetic alternations, and aberrant post-transcriptional modification of transcription factors are involved in the regulation of various stages of carcinogenesis, including cancer initiation, progression, and metastasis. Thus, targeting the dysfunctional transcription factors may lead to new cancer therapeutic strategies. However, transcription factors are conventionally considered as "undruggable." Here, we summarize the recent progresses in understanding the regulation of transcription factors in cancers and strategies to target transcription factors and co-factors for preclinical and clinical drug development, particularly focusing on c-Myc, YAP/TAZ, and β-catenin due to their significance and interplays in cancer.
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Affiliation(s)
- Zhipeng Tao
- Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
| | - Xu Wu
- Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
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Wang G, Li L, Li Y, Zhang LH. Toosendanin reduces cisplatin resistance in ovarian cancer through modulating the miR-195/ERK/β-catenin pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 109:154571. [PMID: 36610147 DOI: 10.1016/j.phymed.2022.154571] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/27/2022] [Accepted: 11/19/2022] [Indexed: 06/17/2023]
Abstract
BACKGROUND Cisplatin (DDP) resistance is prevalent in ovarian cancer (OC) patients and contributes to the poor prognosis. Therefore, it is of great significance to develop new agent to intervene and even reverse DDP resistance in OC. Toosendanin (TSN), a triterpenoid extracted from the bark or fruits of Melia toosendan Sieb et Zucc, has been proved to possess significant antitumor activities. However, the efficacy of TSN on DDP resistance in OC has not been reported yet. PURPOSE The aim of this study is to investigate the effects of TSN on DDP resistance in OC and explore the molecular mechanism in vitro and in vivo. METHODS Human OC cell line (SKOV3) and DDP-resistant cell line (SKOV3/DDP) were used. Cell proliferation was measured by CCK-8 and colony formation assay. Annexin V/PI double staining and hoechst 33342 nuclear staining were employed to detect cell apoptosis. Transwell and wound-healing assay were used to determine the invasion and migration potential of cells respectively. Quantitative real-time PCR (qPCR) and western blotting were performed to detect the expression of molecules related to miR-195/ERK/β-catenin pathway. The effects and mechanism of TSN on DDP resistance of OC in vivo was investigated using xenograft model, TUNEL staining assay and immunohistochemistry. RESULTS TSN improved the DDP sensitivity of SKOV3/DDP cells in vitro and in vivo, reflected in promoting inhibition of proliferation, invasion, migration and epithelial mesenchymal transformation (EMT) as well as induction of apoptosis by DDP. TSN could modulate the miR-195/ERK/β-catenin axis by upregulating the miR-195-5p expression and then suppressing ERK/GSK3β/β-catenin pathway which were activated in SKOV3/DDP cells. Moreover, co-treatment of β-catenin pathway activator LiCl or miR-195-5p silencing partially recovered the DDP resistance which was previously repressed by TSN. CONCLUSION Both in vitro and in vivo data demonstrated that TSN could reduce DDP resistance in OC through regulating the miR-195/ERK/β-catenin pathway, highlighting the potential of TSN as an effective agent for favoring overcoming clinical DDP resistance in OC.
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Affiliation(s)
- Ge Wang
- Department of Traditional Chinese and Western medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.
| | - Lu Li
- Department of Traditional Chinese and Western medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Yan Li
- Department of Traditional Chinese and Western medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Li-Hong Zhang
- Department of Traditional Chinese and Western medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
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Kang JI, Choi YK, Han SC, Kim HG, Hong SW, Kim J, Kim JH, Hyun JW, Yoo ES, Kang HK. Limonin, a Component of Immature Citrus Fruits, Activates Anagen Signaling in Dermal Papilla Cells. Nutrients 2022; 14:nu14245358. [PMID: 36558517 PMCID: PMC9787355 DOI: 10.3390/nu14245358] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/14/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Hair loss remains a significant problem that is difficult to treat; therefore, there is a need to identify safe natural materials that can help patients with hair loss. We evaluated the hair anagen activation effects of limonin, which is abundant in immature citrus fruits. Limonin increased the proliferation of rat dermal papilla cells (rDPC) by changing the levels of cyclin D1 and p27, and increasing the number of BrdU-positive cells. Limonin increased autophagy by decreasing phosphorylated mammalian target of rapamycin levels and increasing the phospho-Raptor, ATG7 and LC3B. Limonin also activated the Wnt/β-catenin pathway by increasing phospho-β-catenin levels. XAV939, a Wnt/β-catenin inhibitor, inhibited these limonin-induced changes, including induced autophagy, BrdU-positive cells, and cell proliferation. Limonin increased the phosphorylated AKT levels in both two-dimensional cultured rDPC and three-dimensional spheroids. Treatment with the PI3K inhibitor wortmannin inhibited limonin-induced proliferation, and disrupted other limonin-mediated changes, including decreased p27, increased BrdU-positive cells, induced autophagy, and increased ATG7 and LC3B levels. Wortmannin also inhibited limonin-induced cyclin D1 and LC3 expression in spheroids. Collectively, these results indicate that limonin can enhance anagen signaling by activating autophagy via targeting the Wnt/β-catenin and/or PI3K/AKT pathways in rDPC, highlighting a candidate nutrient for hair loss treatment.
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Affiliation(s)
- Jung-Il Kang
- Jeju Research Center for Natural Medicine, Jeju National University, Jeju 63243, Republic of Korea
| | - Youn Kyoung Choi
- Jeju Research Center for Natural Medicine, Jeju National University, Jeju 63243, Republic of Korea
| | - Sang-Chul Han
- Department of Medicine, School of Medicine, Jeju National University, Jeju 63243, Republic of Korea
| | - Hyeon Gyu Kim
- Department of Medicine, School of Medicine, Jeju National University, Jeju 63243, Republic of Korea
| | - Seok Won Hong
- Department of Medicine, School of Medicine, Jeju National University, Jeju 63243, Republic of Korea
| | - Jungeun Kim
- Department of Chemistry & Cosmetics, Jeju National University, Jeju 63243, Republic of Korea
| | - Jae Hoon Kim
- Department of Biotechnology, College of Applied Life Science, SARI, Jeju National University, Jeju 63243, Republic of Korea
- Subtropical/Tropical Organism Gene Bank, Jeju National University, Jeju 63243, Republic of Korea
| | - Jin Won Hyun
- Jeju Research Center for Natural Medicine, Jeju National University, Jeju 63243, Republic of Korea
- Department of Medicine, School of Medicine, Jeju National University, Jeju 63243, Republic of Korea
| | - Eun-Sook Yoo
- Jeju Research Center for Natural Medicine, Jeju National University, Jeju 63243, Republic of Korea
- Department of Medicine, School of Medicine, Jeju National University, Jeju 63243, Republic of Korea
| | - Hee-Kyoung Kang
- Jeju Research Center for Natural Medicine, Jeju National University, Jeju 63243, Republic of Korea
- Department of Medicine, School of Medicine, Jeju National University, Jeju 63243, Republic of Korea
- Correspondence: ; Tel.: +82-64-754-3846; Fax: +82-64-702-2687
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Ali SR, Humphreys KJ, Simpson K, McKinnon RA, Meech R, Michael MZ. Functional high-throughput screen identifies microRNAs that promote butyrate-induced death in colorectal cancer cells. MOLECULAR THERAPY - NUCLEIC ACIDS 2022; 30:30-47. [PMID: 36189423 PMCID: PMC9485215 DOI: 10.1016/j.omtn.2022.08.037] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 08/24/2022] [Indexed: 12/24/2022]
Abstract
The gut fermentation product butyrate displays anti-cancer properties in the human proximal colon, including the ability to inhibit proliferation and induce apoptosis in colorectal cancer (CRC) cells. A natural histone deacetylase inhibitor (HDACi), butyrate can alter histone acetylation patterns in CRC cells, and thereby regulate global gene expression, including the non-coding transcriptome and microRNAs (miRNAs). Dysregulated miRNA expression affects CRC development and progression; however, the interplay between miRNA activity and butyrate response remains to be elucidated. A high-throughput functional screen was employed to identify miRNAs that can act as enhancers of the anti-cancer properties of butyrate. Validation studies confirmed that several miRNAs, including miR-125b, miR-181a, miR-593, and miR-1227, enhanced apoptosis, decreased proliferation, and promoted cell-cycle arrest in the presence of butyrate. Pathway analyses of predicted miRNA target genes highlighted their likely involvement in critical cancer-related growth pathways, including WNT and PI3K signaling. Several cancer-associated miRNA targets, including TRIM29, COX2, PIK3R3, CCND1, MET, EEF2K, DVL3, and NUP62 were synergistically regulated by the combination of cognate miRNAs and butyrate. Overall, this study has exposed the potential of miRNAs to act as enhancers of the anti-cancer effects of HDAC inhibition and identifies specific miRNAs that might be exploited for therapeutic benefit.
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Anifowose SO, Alqahtani WSN, Al-Dahmash BA, Sasse F, Jalouli M, Aboul-Soud MAM, Badjah-Hadj-Ahmed AY, Elnakady YA. Efforts in Bioprospecting Research: A Survey of Novel Anticancer Phytochemicals Reported in the Last Decade. Molecules 2022; 27:molecules27238307. [PMID: 36500400 PMCID: PMC9738008 DOI: 10.3390/molecules27238307] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 11/10/2022] [Accepted: 11/22/2022] [Indexed: 11/30/2022] Open
Abstract
Bioprospecting natural products to find prominent agents for medical application is an area of scientific endeavor that has produced many clinically used bioactive compounds, including anticancer agents. These compounds come from plants, microorganisms, and marine life. They are so-called secondary metabolites that are important for a species to survive in the hostile environment of its respective ecosystem. The kingdom of Plantae has been an important source of traditional medicine in the past and is also enormously used today as an exquisite reservoir for detecting novel bioactive compounds that are potent against hard-to-treat maladies such as cancer. Cancer therapies, especially chemotherapies, are fraught with many factors that are difficult to manage, such as drug resistance, adverse side effects, less selectivity, complexity, etc. Here, we report the results of an exploration of the databases of PubMed, Science Direct, and Google Scholar for bioactive anticancer phytochemicals published between 2010 and 2020. Our report is restricted to new compounds with strong-to-moderate bioactivity potential for which mass spectroscopic structural data are available. Each of the phytochemicals reported in this review was assigned to chemical classes with peculiar anticancer properties. In our survey, we found anticancer phytochemicals that are reported to have selective toxicity against cancer cells, to sensitize MDR cancer cells, and to have multitarget effects in several signaling pathways. Surprisingly, many of these compounds have limited follow-up studies. Detailed investigations into the synthesis of more functional derivatives, chemical genetics, and the clinical relevance of these compounds are required to achieve safer chemotherapy.
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Affiliation(s)
- Saheed O. Anifowose
- Department of Zoology, College of Science, King Saud University, Riyadh 11415, Saudi Arabia
| | - Wejdan S. N. Alqahtani
- Department of Zoology, College of Science, King Saud University, Riyadh 11415, Saudi Arabia
| | - Badr A. Al-Dahmash
- Department of Zoology, College of Science, King Saud University, Riyadh 11415, Saudi Arabia
| | - Florenz Sasse
- Institute for Pharmaceutical Biology, Technical University of Braunschweig, 38124 Braunschweig, Germany
| | - Maroua Jalouli
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia
| | - Mourad A. M. Aboul-Soud
- Chair of Medical and Molecular Genetics Research, Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 11433, Saudi Arabia
| | | | - Yasser A. Elnakady
- Department of Zoology, College of Science, King Saud University, Riyadh 11415, Saudi Arabia
- Correspondence:
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Wang L, Zhou S, Liu G, Lyu T, Shi L, Dong Y, He S, Zhang H. The Mechanisms of Fur Development and Color Formation in American Mink Revealed Using Comparative Transcriptomics. Animals (Basel) 2022; 12:ani12223088. [PMID: 36428316 PMCID: PMC9686883 DOI: 10.3390/ani12223088] [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: 10/10/2022] [Revised: 10/31/2022] [Accepted: 11/07/2022] [Indexed: 11/11/2022] Open
Abstract
American mink fur is an important economic product, but the molecular mechanisms underlying its color formation and fur development remain unclear. We used RNA-seq to analyze the skin transcriptomes of young and adult mink with two different hair colors. The mink comprised black adults (AB), white adults (AW), black juveniles (TB), and white juveniles (TW) (three each). Through pair comparison and cross-screening among different subgroups, we found that 13 KRTAP genes and five signaling pathways (the JAK-STAT signaling pathway (cfa04630), signaling pathways regulating pluripotency of stem cells (cfa04550), ECM-receptor interaction (cfa04512), focal adhesion (cfa04510), and the Ras signaling pathway (cfa04014)) were related to mink fur development. We also found that members of a tyrosinase family (TYR, TYRP1, and TYRP2) are involved in mink hair color formation. The expression levels of TYR were higher in young black mink than in young white mink, but this phenomenon was not observed in adult mink. Our study found significant differences in adult and juvenile mink skin transcriptomes, which may shed light on the mechanisms of mink fur development. At the same time, the skin transcriptomes of black and white mink also showed differences, with the results varying by age, suggesting that the genes regulating hair color are active in early development rather than in adulthood. The results of this study provide molecular support in breeding for mink coat color and improving fur quality.
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Affiliation(s)
- Lidong Wang
- College of Life Sciences, Qufu Normal University, Qufu 273165, China
| | - Shengyang Zhou
- College of Life Sciences, Qufu Normal University, Qufu 273165, China
| | - Guangshuai Liu
- College of Life Sciences, Qufu Normal University, Qufu 273165, China
| | - Tianshu Lyu
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin 150040, China
| | - Lupeng Shi
- College of Life Sciences, Qufu Normal University, Qufu 273165, China
| | - Yuehuan Dong
- College of Life Sciences, Qufu Normal University, Qufu 273165, China
| | - Shangbin He
- College of Life Sciences, Qufu Normal University, Qufu 273165, China
| | - Honghai Zhang
- College of Life Sciences, Qufu Normal University, Qufu 273165, China
- Correspondence:
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Saranya I, Akshaya R, Selvamurugan N. Regulation of Wnt signaling by non-coding RNAs during osteoblast differentiation. Differentiation 2022; 128:57-66. [DOI: 10.1016/j.diff.2022.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/10/2022] [Accepted: 10/11/2022] [Indexed: 11/03/2022]
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Bhattacharya A, Wei J, Song W, Gao B, Tian C, Wu SA, Wang J, Chen L, Fang D, Qi L. SEL1L-HRD1 ER-associated degradation suppresses hepatocyte hyperproliferation and liver cancer. iScience 2022; 25:105183. [PMID: 36238898 PMCID: PMC9550610 DOI: 10.1016/j.isci.2022.105183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/15/2022] [Accepted: 09/20/2022] [Indexed: 11/02/2022] Open
Abstract
Endoplasmic reticulum (ER) homeostasis has been implicated in the pathogenesis of various forms of cancer; however, our understanding of the role of ER quality control mechanisms in tumorigenesis remains incomplete. Here, we show that the SEL1L-HRD1 complex of ER-associated degradation (ERAD) suppresses hepatocyte proliferation and tumorigenesis in mice. Hepatocyte-specific deletion of Sel1L or Hrd1 predisposed mice to diet/chemical-induced tumors. Proteomics screen from SEL1L-deficient livers revealed WNT5A, a tumor suppressor, as an ERAD substrate. Indeed, nascent WNT5A was misfolding prone and degraded by SEL1L-HRD1 ERAD in a quality control capacity. In the absence of ERAD, WNT5A misfolds is largely retained in the ER and forms high-molecular weight aggregates, thereby depicting a loss-of-function effect and attenuating WNT5A-mediated suppression of hepatocyte proliferation. In humans, SEL1L-HRD1 ERAD expression correlated positively with survival time for patients with liver cancer. Overall, our data reveal a key role of SEL1L-HRD1 ERAD in suppressing hepatocyte proliferation and liver cancer.
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Affiliation(s)
- Asmita Bhattacharya
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA
- Graduate Program of Genetics, Genomics and Development, Cornell University, Ithaca, NY 14853, USA
| | - Juncheng Wei
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Wenxin Song
- School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China
| | - Beixue Gao
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Chunyan Tian
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 102206, China
| | - Shuangcheng Alivia Wu
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA
| | - Jian Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 102206, China
| | - Ligong Chen
- School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China
| | - Deyu Fang
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Ling Qi
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA
- Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48105, USA
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41
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Asgharian P, Tazekand AP, Hosseini K, Forouhandeh H, Ghasemnejad T, Ranjbar M, Hasan M, Kumar M, Beirami SM, Tarhriz V, Soofiyani SR, Kozhamzharova L, Sharifi-Rad J, Calina D, Cho WC. Potential mechanisms of quercetin in cancer prevention: focus on cellular and molecular targets. Cancer Cell Int 2022; 22:257. [PMID: 35971151 PMCID: PMC9380290 DOI: 10.1186/s12935-022-02677-w] [Citation(s) in RCA: 108] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 08/08/2022] [Indexed: 02/07/2023] Open
Abstract
Over the past few years, the cancer-related disease has had a high mortality rate and incidence worldwide, despite clinical advances in cancer treatment. The drugs used for cancer therapy, have high side effects in addition to the high cost. Subsequently, to reduce these side effects, many studies have suggested the use of natural bioactive compounds. Among these, which have recently attracted the attention of many researchers, quercetin has such properties. Quercetin, a plant flavonoid found in fresh fruits, vegetables and citrus fruits, has anti-cancer properties by inhibiting tumor proliferation, invasion, and tumor metastasis. Several studies have demonstrated the anti-cancer mechanism of quercetin, and these mechanisms are controlled through several signalling pathways within the cancer cell. Pathways involved in this process include apoptotic, p53, NF-κB, MAPK, JAK/STAT, PI3K/AKT, and Wnt/β-catenin pathways. In addition to regulating these pathways, quercetin controls the activity of oncogenic and tumor suppressor ncRNAs. Therefore, in this comprehensive review, we summarized the regulation of these signalling pathways by quercetin. The modulatory role of quercetin in the expression of various miRNAs has also been discussed. Understanding the basic anti-cancer mechanisms of these herbal compounds can help prevent and manage many types of cancer.
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Affiliation(s)
- Parina Asgharian
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Pharmacognosy, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abbas Pirpour Tazekand
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Kamran Hosseini
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Haleh Forouhandeh
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tohid Ghasemnejad
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Ranjbar
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Muzaffar Hasan
- Agro Produce Processing Division, ICAR—Central Institute of Agricultural Engineering, Bhopal, 462038 India
| | - Manoj Kumar
- Chemical and Biochemical Processing Division, ICAR—Central Institute for Research on Cotton Technology, Mumbai, 400019 India
| | - Sohrab Minaei Beirami
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Vahideh Tarhriz
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saiedeh Razi Soofiyani
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Clinical Research Development Unit of Sina Educational, Research, and Treatment Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong, China
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42
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Kwang Sheng N, Wan Hitam WH. Acute Blindness in the Elderly With Craniopharyngioma. Cureus 2022; 14:e26880. [PMID: 35978761 PMCID: PMC9375858 DOI: 10.7759/cureus.26880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/06/2022] [Indexed: 11/16/2022] Open
Abstract
The afferent visual system is one of the most common structures involved in patients with craniopharyngioma, and the manifestations include deficits in visual acuity, color vision, and visual fields. Here, we report a case of craniopharyngioma that presented with acute blindness in an elderly man. A healthy 54-year-old man presented with an acute progressive blurring of vision and became blind in six weeks. He developed symptoms of increased intracranial pressure only a week after becoming blind. On examination, visual acuity in both eyes was no perception of light (NPL). He also had left esotropia with restriction of left eye abduction. Both pupils were not responsive to light. The anterior segment was normal in both eyes. Fundoscopy showed bilateral pale optic discs. Computed tomography scan and magnetic resonance imaging revealed a suprasellar mass consistent with craniopharyngioma that compressed the optic chiasma and adjacent brain structures with the presence of hydrocephalus. He underwent uneventful tumor debulking surgery. However, his vision remained NPL postoperatively. Ocular manifestations could be the only symptoms in craniopharyngioma. The delayed presentation may lead to a guarded prognosis.
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43
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Saroha HS, Kumar Guddeti R, Jacob JP, Kumar Pulukuri K, Karyala P, Pakala SB. MORC2/β-catenin signaling axis promotes proliferation and migration of breast cancer cells. Med Oncol 2022; 39:135. [PMID: 35727356 DOI: 10.1007/s12032-022-01728-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 04/05/2022] [Indexed: 02/06/2023]
Abstract
Although Microrchidia 2 (MORC2) is overexpressed in many types of human cancer, its role in breast cancer progression remains unknown. Here, we report that the chromatin remodeler MORC2 expression positively correlates with β-catenin expression in breast cancer cell lines and patients. Overexpression of MORC2 augmented the expression of β-catenin and its target genes, cyclin D1 and c-Myc. Consistent with these results, we found MORC2 knockdown resulted in decreased expression of β-catenin and its target genes. Surprisingly, we observed that c-Myc, the target gene of β-catenin, regulated the MORC2-β-catenin signaling axis through a feedback mechanism. We demonstrated that MORC2 regulates β-catenin expression and function by modulating the phosphorylation of AKT. In addition, we observed reduced proliferation and migration of MORC2 overexpressing breast cancer cells upon β-catenin inhibition. Overall, our results demonstrate that MORC2 promotes breast cancer cell proliferation and migration by regulating β-catenin signaling.
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Affiliation(s)
- Himanshu Singh Saroha
- Department of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, Karakambadi Road, Mangalam, Tirupati, Andhra Pradesh, 517507, India
| | - Rohith Kumar Guddeti
- Department of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, Karakambadi Road, Mangalam, Tirupati, Andhra Pradesh, 517507, India
| | - Jasmine P Jacob
- Department of Chemistry, Indian Institute of Science Education and Research (IISER) Tirupati, Karakambadi Road, Mangalam, Tirupati, Andhra Pradesh, 517507, India
| | - Kiran Kumar Pulukuri
- Department of Chemistry, Indian Institute of Science Education and Research (IISER) Tirupati, Karakambadi Road, Mangalam, Tirupati, Andhra Pradesh, 517507, India
| | - Prashanthi Karyala
- Department of Biotechnology, Faculty of Life and Allied Health Sciences, Ramaiah University of Applied Sciences, Bengaluru, 560054, India
| | - Suresh B Pakala
- Department of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, Karakambadi Road, Mangalam, Tirupati, Andhra Pradesh, 517507, India.
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44
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Yang J, Hu Y, Zhang B, Liang X, Li X. The JMJD Family Histone Demethylases in Crosstalk Between Inflammation and Cancer. Front Immunol 2022; 13:881396. [PMID: 35558079 PMCID: PMC9090529 DOI: 10.3389/fimmu.2022.881396] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 03/23/2022] [Indexed: 02/05/2023] Open
Abstract
Inflammation has emerged as a key player in regulating cancer initiation, progression, and therapeutics, acting as a double edged sword either facilitating cancer progression and therapeutic resistance or inducing anti-tumor immune responses. Accumulating evidence has linked the epigenetic modifications of histones to inflammation and cancer, and histone modifications-based strategies have shown promising therapeutic potentials against cancer. The jumonji C domain-containing (JMJD) family histone demethylases have exhibited multiple regulator functions in inflammatory processes and cancer development, and a number of therapeutic strategies targeting JMJD histone demethylases to modulate inflammatory cells and their products have been successfully evaluated in clinical or preclinical tumor models. This review summarizes current understanding of the functional roles and mechanisms of JMJD histone demethylases in crosstalk between inflammation and cancer, and highlights recent clinical and preclinical progress on harnessing the JMJD histone demethylases to regulate cancer-related inflammation for future cancer therapeutics.
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Affiliation(s)
- Jia Yang
- Department of Gynecology and Obstetrics and Pediatric Nephrology Nursing, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Yuan Hu
- Department of Gynecology and Obstetrics and Pediatric Nephrology Nursing, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Binjing Zhang
- State Key Laboratory of Oral Disease, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xiao Liang
- Department of Gynecology and Obstetrics and Pediatric Nephrology Nursing, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Xin Li
- State Key Laboratory of Oral Disease, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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45
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McCoy MA, Spicer D, Wells N, Hoogewijs K, Fiedler M, Baud MGJ. Biophysical Survey of Small-Molecule β-Catenin Inhibitors: A Cautionary Tale. J Med Chem 2022; 65:7246-7261. [PMID: 35581674 PMCID: PMC9150122 DOI: 10.1021/acs.jmedchem.2c00228] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
![]()
The canonical Wingless-related
integration site signaling pathway
plays a critical role in human physiology, and its dysregulation can
lead to an array of diseases. β-Catenin is a multifunctional
protein within this pathway and an attractive yet challenging therapeutic
target, most notably in oncology. This has stimulated the search for
potent small-molecule inhibitors binding directly to the β-catenin
surface to inhibit its protein–protein interactions and downstream
signaling. Here, we provide an account of the claimed (and some putative)
small-molecule ligands of β-catenin from the literature. Through
in silico analysis, we show that most of these molecules contain promiscuous
chemical substructures notorious for interfering with screening assays.
Finally, and in line with this analysis, we demonstrate using orthogonal
biophysical techniques that none of the examined small molecules bind
at the surface of β-catenin. While shedding doubts on their
reported mode of action, this study also reaffirms β-catenin
as a prominent target in drug discovery.
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Affiliation(s)
- Michael A McCoy
- School of Chemistry, University of Southampton, Southampton SO17 1BJ, U.K
| | - Dominique Spicer
- School of Chemistry, University of Southampton, Southampton SO17 1BJ, U.K
| | - Neil Wells
- School of Chemistry, University of Southampton, Southampton SO17 1BJ, U.K
| | - Kurt Hoogewijs
- National University of Ireland, University Road, Galway H91 TK33, Ireland
| | - Marc Fiedler
- Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, U.K
| | - Matthias G J Baud
- School of Chemistry, University of Southampton, Southampton SO17 1BJ, U.K
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46
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Chatterjee S, Sil PC. ROS-Influenced Regulatory Cross-Talk With Wnt Signaling Pathway During Perinatal Development. Front Mol Biosci 2022; 9:889719. [PMID: 35517861 PMCID: PMC9061994 DOI: 10.3389/fmolb.2022.889719] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 04/04/2022] [Indexed: 11/25/2022] Open
Abstract
Over a century ago, it was found that a rapid burst of oxygen is needed and produced by the sea urchin oocyte to activate fertilization and block polyspermy. Since then, scientific research has taken strides to establish that Reactive Oxygen Species (ROS), besides being toxic effectors of cellular damage and death, also act as molecular messengers in important developmental signaling cascades, thereby modulating them. Wnt signaling pathway is one such developmental pathway, which has significant effects on growth, proliferation, and differentiation of cells at the earliest embryonic stages of an organism, apart from being significant role-players in the instances of cellular transformation and cancer when this tightly-regulated system encounters aberrations. In this review, we discuss more about the Wnt and ROS signaling pathways, how they function, what roles they play overall in animals, and mostly about how these two major signaling systems cross paths and interplay in mediating major cellular signals and executing the predestined changes during the perinatal condition, in a systematic manner.
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Affiliation(s)
| | - Parames C. Sil
- Division of Molecular Medicine, Bose Institute, Kolkata, India
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47
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Deubiquitination of TNKS1 Regulates Wnt/β-Catenin to Affect the Expression of USP25 to Promote the Progression of Glioma. DISEASE MARKERS 2022; 2022:9087190. [PMID: 35450028 PMCID: PMC9017575 DOI: 10.1155/2022/9087190] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 03/11/2022] [Indexed: 12/15/2022]
Abstract
Objective To explore the regulatory effect of ubiquitin specific protease 25 (USP25) on glioma cell proliferation, migration, invasion, and its underlying mechanism. Methods The USP25-overexpressed and USP25-knockdown glioma cells were established on U251 and U87 cells, respectively. Glioma cell proliferation ability was evaluated by CCK-8 assay. Cell apoptosis and cell cycle were determined utilizing flow cytometry. The Transwell assay measured cell invasion with wound healing used for cell migration detection. Western blotting established key protein expression levels in the Wnt/β-catenin pathway. The coimmunoprecipitation was used to check Thankyrase 1 (TNKS1) ubiquitination levels. Results TNKS1 expression levels were found to be considerably repressed in USP25-knockdown glioma cells and elevated in USP25-overexpressed glioma cells, accompanied by Wnt/β-catenin pathway key protein downregulation and upregulation, respectively. Glioma cell invasion, migration, and proliferation activity were dramatically inhibited in USP25-knockdown glioma cells and promoted in USP25-overexpressed glioma cells. TNKS1 ubiquitination level was knowingly increased in USP25-knockdown glioma cells and reduced in USP25-overexpressed glioma cells, suggesting TNKS1 ubiquitination levels were negatively regulated by USP25. Conclusion USP25 facilitated glioma cell invasion, migration, and proliferation by regulating Wnt/β-catenin through the deubiquitination on TNKS1.
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48
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Chen B, Jiang W, Huang Y, Zhang J, Yu P, Wu L, Peng H. N 7-methylguanosine tRNA modification promotes tumorigenesis and chemoresistance through WNT/β-catenin pathway in nasopharyngeal carcinoma. Oncogene 2022; 41:2239-2253. [PMID: 35217794 DOI: 10.1038/s41388-022-02250-9] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 02/06/2022] [Accepted: 02/14/2022] [Indexed: 12/24/2022]
Abstract
Treatment selections are very limited for patients with advanced nasopharyngeal carcinoma (NPC) experiencing disease progression. Uncovering mechanisms underlying NPC progression is crucial for the development of novel treatments. Here we show that N7-methylguanosine (m7G) tRNA modification enzyme METTL1 and its partner WDR4 are significantly elevated in NPC and are associated with poor prognosis. Loss-of-function and gain-of-function assays demonstrated that METTL1/WDR4 promotes NPC growth and metastasis in vitro and in vivo. Mechanistically, ARNT was identified as an upstream transcription factor regulating METTL1 expression in NPC. METTL1 depletion resulted in decreased m7G tRNA modification and expression, which led to impaired codon recognition during mRNA translation, therefore reducing the translation efficiencies of mRNAs with higher m7G codons. METTL1 upregulated the WNT/β-catenin signaling pathway and promoted NPC cell epithelial-mesenchymal transition (EMT) and chemoresistance to cisplatin and docetaxel in vitro and in vivo. Overexpression of WNT3A bypassed the requirement of METTL1 for EMT and chemoresistance. This work uncovers novel insights into tRNA modification-mediated mRNA translation regulation and highlights the critical function of tRNA modification in cancer progression.
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Affiliation(s)
- Binbin Chen
- Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China
- Department of Clinical Nutrition, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, China
| | - Wei Jiang
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, Guilin, 541001, China
| | - Ying Huang
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, China
| | - Jian Zhang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou, 510095, P. R. China
| | - Peng Yu
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou, 510095, P. R. China
| | - Lirong Wu
- Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China.
| | - Hao Peng
- Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China.
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Maharati A, Zanguei AS, Khalili-Tanha G, Moghbeli M. MicroRNAs as the critical regulators of tyrosine kinase inhibitors resistance in lung tumor cells. Cell Commun Signal 2022; 20:27. [PMID: 35264191 PMCID: PMC8905758 DOI: 10.1186/s12964-022-00840-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/05/2022] [Indexed: 12/12/2022] Open
Abstract
Lung cancer is the second most common and the leading cause of cancer related deaths globally. Tyrosine Kinase Inhibitors (TKIs) are among the common therapeutic strategies in lung cancer patients, however the treatment process fails in a wide range of patients due to TKIs resistance. Given that the use of anti-cancer drugs can always have side effects on normal tissues, predicting the TKI responses can provide an efficient therapeutic strategy. Therefore, it is required to clarify the molecular mechanisms of TKIs resistance in lung cancer patients. MicroRNAs (miRNAs) are involved in regulation of various pathophysiological cellular processes. In the present review, we discussed the miRNAs that have been associated with TKIs responses in lung cancer. MiRNAs mainly exert their role on TKIs response through regulation of Tyrosine Kinase Receptors (TKRs) and down-stream signaling pathways. This review paves the way for introducing a panel of miRNAs for the prediction of TKIs responses in lung cancer patients.
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