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da Silva IV, Lopes PA, Fonseca E, Vigia E, Paulino J, Soveral G. The Association of Aquaporins with MAPK Signaling Pathway Unveils Potential Prognostic Biomarkers for Pancreatic Cancer: A Transcriptomics Approach. Biomolecules 2025; 15:488. [PMID: 40305202 PMCID: PMC12024632 DOI: 10.3390/biom15040488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 03/17/2025] [Accepted: 03/25/2025] [Indexed: 05/02/2025] Open
Abstract
Pancreatic cancer is one of the most lethal and challenging malignancies. Its severity is primarily linked to the constitutively activated mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. Aquaporins (AQPs) are frequently overexpressed in pancreatic cancer, playing crucial roles in cell signaling, and consequently promoting cell migration, proliferation, and invasion. Here, we investigate the transcriptomics of key players in epithelial-mesenchymal transition (EMT) and the MAPK/ERK signaling pathway in pancreatic cancer tissues, correlating them with tumor AQP expression to highlight their potential as diagnostic or prognostic tools. The transcriptomics analysis was conducted in 24 paired pancreatic tumors and adjacent healthy tissues, and analyses were performed considering the patients' age and gender, as well as tumor invasiveness and aggressiveness. Our results revealed strong positive Pearson correlation coefficients between AQP3 and c-Jun, and between AQP5 and CDH1/EGFR in pancreatic tumors but not in healthy tissues, with posterior in vitro confirmation in pancreatic cancer BxPC3 cells, suggesting a shift in the regulatory mechanisms of gene expression that certainly affect the physiology of the tissue, influencing cancer initiation and progression. This study underscores the interplay between AQPs and cancer signaling pathways, opening new avenues for defining novel clinical biomarkers and improving the early detection of pancreatic cancer.
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Affiliation(s)
- Inês V. da Silva
- Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal
- Department of Pharmaceutical Sciences and Medicines, Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal
| | - Paula A. Lopes
- Centro de Investigação Interdisciplinar em Sanidade Animal (CIISA), Faculdade de Medicina Veterinária, Universidade de Lisboa, 1300-477 Lisbon, Portugal
- Laboratório Associado para Ciência Animal e Veterinária (AL4AnimalS), Faculdade de Medicina Veterinária, Universidade de Lisboa, 1300-477 Lisbon, Portugal
| | - Elisabete Fonseca
- Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal
- Department of Pharmaceutical Sciences and Medicines, Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal
| | - Emanuel Vigia
- Hepatobiliopancreatic and Transplantation Center, Hospital de Curry Cabral (CHULC), 1050-099 Lisbon, Portugal
- NOVA Medical School, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal
| | - Jorge Paulino
- NOVA Medical School, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal
- Hospital da Luz, 1500-650 Lisbon, Portugal
| | - Graça Soveral
- Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal
- Department of Pharmaceutical Sciences and Medicines, Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal
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Kwon TU, Kwon YJ, Park H, Lee H, Kwak JH, Kang KW, Chun YJ. Steroid sulfatase suppresses keratinization by inducing proteasomal degradation of E-cadherin via Hakai regulation. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2025; 1872:119898. [PMID: 39764917 DOI: 10.1016/j.bbamcr.2025.119898] [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: 09/10/2024] [Revised: 12/24/2024] [Accepted: 01/02/2025] [Indexed: 03/14/2025]
Abstract
X-linked ichthyosis (XLI) is a genetic disorder characterized by a steroid sulfatase (STS) deficiency inducing excessive cholesterol sulfate accumulation and keratinization. Our study utilizes STS knockout mice to reproduce the hyperkeratinization typical of XLI, providing a valuable model for investigating the underlying mechanisms. From the experiment of STS-deficient keratinocytes using the CRISPR/Cas9 system, we observed upregulation of E-cadherin, which is associated with keratinocyte differentiation and stratification. This was accompanied by elevated levels of keratinization markers, including involucrin and loricrin. We also found an increased expression of SULT2B1, which converts cholesterol to cholesterol sulfate, further accelerating cholesterol sulfate accumulation. As a result, STS deficiency and cholesterol sulfate accumulation lead to decreased expression of Hakai, the ubiquitin E3 ligase for E-cadherin. With reduced Hakai, endocytosis and ubiquitin-mediated degradation of E-cadherin are inhibited, resulting in its stabilization. This stabilization of E-cadherin is accompanied by increased expression of involucrin and loricrin, which is suppressed when the N-terminal extracellular domain of E-cadherin, responsible for cell-cell adhesion, is genetically modified. We propose that inhibition of E-cadherin, genetic modification of the N-terminal extracellular domain, and treatment with miR-6766 targeting E-cadherin significantly reduce the expression of keratinization markers, suggesting a potential therapeutic approach. We further suggest that the increased expression of E-cadherin observed in keratinocytes with STS deficiency is regulated by Hakai, underscoring the central role of E-cadherin in the pathogenesis of XLI.
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Affiliation(s)
- Tae-Uk Kwon
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Yeo-Jung Kwon
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Hyemin Park
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Hyein Lee
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Ji-Heung Kwak
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Keon Wook Kang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Young-Jin Chun
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974, Republic of Korea.
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Carlantoni C, Liekfeld LMH, Beerens M, Frye M. Same same but different? How blood and lymphatic vessels induce cell contact inhibition. Biochem Soc Trans 2025; 53:BST20240573. [PMID: 39912714 DOI: 10.1042/bst20240573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 01/07/2025] [Accepted: 01/14/2025] [Indexed: 02/07/2025]
Abstract
Endothelial cells (ECs) migrate, sprout, and proliferate in response to (lymph)angiogenic mitogens, such as vascular endothelial growth factors. When ECs reach high confluency and encounter spatial confinement, they establish mature cell-cell junctions, reduce proliferation, and enter a quiescent state through a process known as contact inhibition. However, EC quiescence is modulated not only by spatial confinement but also by other mechano-environmental factors, including blood or lymph flow and extracellular matrix properties. Changes in physical forces and intracellular signaling can disrupt contact inhibition, resulting in aberrant proliferation and vascular dysfunction. Therefore, it is critical to understand the mechanisms by which endothelial cells regulate contact inhibition. While contact inhibition has been well studied in blood endothelial cells (BECs), its regulation in lymphatic endothelial cells (LECs) remains largely unexplored. Here, we review the current knowledge on extrinsic stimuli and intrinsic molecular pathways that govern endothelial contact inhibition and highlight nuanced differences between BECs and LECs. Furthermore, we provide perspectives for future research on lymphatic contact inhibition. A deeper understanding of the BEC and LEC-specific pathways underlying contact inhibition may enable targeted modulation of this process in blood or lymphatic vessels with relevance to lymphatic or blood vascular-specific disorders.
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Affiliation(s)
- Claudia Carlantoni
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
- German Centre of Cardiovascular Research (DZHK), Partner Site Hamburg, Luebeck, Kiel, Hamburg, Germany
| | - Leon M H Liekfeld
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Manu Beerens
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
- German Centre of Cardiovascular Research (DZHK), Partner Site Hamburg, Luebeck, Kiel, Hamburg, Germany
| | - Maike Frye
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
- German Centre of Cardiovascular Research (DZHK), Partner Site Hamburg, Luebeck, Kiel, Hamburg, Germany
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Hirsch RM, Premsankar S, Kurnit KC, Chiou LF, Rabjohns EM, Lee HN, Broaddus RR, Vaziri C, Bowser JL. CD73 restrains mutant β-catenin oncogenic activity in endometrial carcinomas. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.18.624183. [PMID: 39605508 PMCID: PMC11601622 DOI: 10.1101/2024.11.18.624183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Missense mutations in exon 3 of CTNNB1, the gene encoding β-catenin, are associated with poor outcomes in endometrial carcinomas (EC). Clinically, CTNNB1 mutation status has been difficult to use as a predictive biomarker as β-catenin oncogenic activity is modified by other factors, and these determinants are unknown. Here we reveal that CD73 restrains the oncogenic activity of exon 3 β-catenin mutants, and its loss associates with recurrence. Using 7 patient-specific mutants, with genetic deletion or ectopic expression of CD73, we show that CD73 loss increases β-catenin-TCF/LEF transcriptional activity. In cells lacking CD73, membrane levels of mutant β-catenin decreased which corresponded with increased levels of nuclear and chromatin-bound mutant β-catenin. These results suggest CD73 sequesters mutant β-catenin to the membrane to limit its oncogenic activity. Adenosine A1 receptor deletion phenocopied increased β-catenin-TCF/LEF activity seen with NT5E deletion, suggesting that the effect of CD73 loss on mutant β-catenin is mediated via attenuation of adenosine receptor signaling. RNA-seq analyses revealed that NT5E deletion alone drives pro-tumor Wnt/β-catenin gene expression and, with CD73 loss, β-catenin mutants dysregulate zinc-finger and non-coding RNA gene expression. We identify CD73 as a novel regulator of oncogenic β-catenin and help explain variability in patient outcomes in CTNNB1 mutant EC.
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Affiliation(s)
- Rebecca M. Hirsch
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
- Curriculum in Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA
| | - Sunthoshini Premsankar
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
- Chancellor’s Science Scholars Program, University of North Carolina, Chapel Hill, NC, USA
| | - Katherine C. Kurnit
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA
| | - Lilly F. Chiou
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
- Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC, USA
| | - Emily M. Rabjohns
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
- Curriculum in Pathobiology and Translational Science, University of North Carolina, Chapel Hill, NC, USA
| | - Hannah N. Lee
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Russell R. Broaddus
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
- UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Cyrus Vaziri
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
- UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Jessica L. Bowser
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
- UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
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Hui San S, Ching Ngai S. E-cadherin re-expression: Its potential in combating TRAIL resistance and reversing epithelial-to-mesenchymal transition. Gene 2024; 909:148293. [PMID: 38373660 DOI: 10.1016/j.gene.2024.148293] [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: 10/13/2023] [Revised: 02/08/2024] [Accepted: 02/15/2024] [Indexed: 02/21/2024]
Abstract
The major limitation of conventional chemotherapy drugs is their lack of specificity for cancer cells. As a selective apoptosis-inducing agent, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has emerged as an attractive alternative. However, most of the cancer cells are found to be either intrinsically resistant to the TRAIL protein or may develop resistance after multiple treatments, and TRAIL resistance can induce epithelial-to-mesenchymal transition (EMT) at a later stage, promoting cancer invasion and migration. Interestingly, E-cadherin loss has been linked to TRAIL resistance and initiation of EMT, making E-cadherin re-expression a potential target to overcome these obstacles. Recent research suggests that re-expressing E-cadherin may reduce TRAIL resistance by enhancing TRAIL-induced apoptosis and preventing EMT by modulating EMT signalling factors. This reversal of EMT, can also aid in improving TRAIL-induced apoptosis. Therefore, this review provides remarkable insights into the mechanisms underlying E-cadherin re-expression, clinical implications, and potentiation, as well as the research gaps of E-cadherin re-expression in the current cancer treatment.
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Affiliation(s)
- Ser Hui San
- School of Biosciences, Faculty of Science and Engineering, University of Nottingham Malaysia, 43500 Semenyih, Selangor, Malaysia
| | - Siew Ching Ngai
- School of Biosciences, Faculty of Science and Engineering, University of Nottingham Malaysia, 43500 Semenyih, Selangor, Malaysia.
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Wu P, Wang X, Yin M, Zhu W, Chen Z, Zhang Y, Jiang Z, Shi L, Zhu Q. ULK1 Mediated Autophagy-Promoting Effects of Rutin-Loaded Chitosan Nanoparticles Contribute to the Activation of NF-κB Signaling Besides Inhibiting EMT in Hep3B Hepatoma Cells. Int J Nanomedicine 2024; 19:4465-4493. [PMID: 38779103 PMCID: PMC11110815 DOI: 10.2147/ijn.s443117] [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: 10/04/2023] [Accepted: 05/08/2024] [Indexed: 05/25/2024] Open
Abstract
Background Liver cancer remains to be one of the leading causes of cancer worldwide. The treatment options face several challenges and nanomaterials have proven to improve the bioavailability of several drug candidates and their applications in nanomedicine. Specifically, chitosan nanoparticles (CNPs) are extremely biodegradable, pose enhanced biocompatibility and are considered safe for use in medicine. Methods CNPs were synthesized by ionic gelation, loaded with rutin (rCNPs) and characterized by ultraviolet-visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FTIR), dynamic light scattering (DLS) and transmission electron microscopy (TEM). The rCNPs were tested for their cytotoxic effects on human hepatoma Hep3B cells, and experiments were conducted to determine the mechanism of such effects. Further, the biocompatibility of the rCNPs was tested on L929 fibroblasts, and their hemocompatibility was determined. Results Initially, UV-vis and FTIR analyses indicated the possible loading of rutin on rCNPs. Further, the rutin load was quantitatively measured using Ultra-Performance Liquid Chromatography (UPLC) and the concentration was 88 µg/mL for 0.22 micron filtered rCNPs. The drug loading capacity (LC%) of the rCNPs was observed to be 13.29 ± 0.68%, and encapsulation efficiency (EE%) was 19.55 ± 1.01%. The drug release was pH-responsive as 88.58% of the drug was released after 24 hrs at the lysosomal pH 5.5, whereas 91.44% of the drug was released at physiological pH 7.4 after 102 hrs. The cytotoxic effects were prominent in 0.22 micron filtered samples of 5 mg/mL rutin precursor. The particle size for the rCNPs at this concentration was 144.1 nm and the polydispersity index (PDI) was 0.244, which is deemed to be ideal for tumor targeting. A zeta potential (ζ-potential) value of 16.4 mV indicated rCNPs with good stability. The IC50 value for the cytotoxic effects of rCNPs on human hepatoma Hep3B cells was 9.7 ± 0.19 μg/mL of rutin load. In addition, the increased production of reactive oxygen species (ROS) and changes in mitochondrial membrane potential (MMP) were observed. Gene expression studies indicated that the mechanism for cytotoxic effects of rCNPs on Hep3B cells was due to the activation of Unc-51-like autophagy-activating kinase (ULK1) mediated autophagy and nuclear factor kappa B (NF-κB) signaling besides inhibiting the epithelial-mesenchymal Transition (EMT). In addition, the rCNPs were less toxic on NCTC clone 929 (L929) fibroblasts in comparison to the Hep3B cells and possessed excellent hemocompatibility (less than 2% of hemolysis). Conclusion The synthesized rCNPs were pH-responsive and possessed the physicochemical properties suitable for tumor targeting. The particles were effectively cytotoxic on Hep3B cells in comparison to normal cells and possessed excellent hemocompatibility. The very low hemolytic profile of rCNPs indicates that the drug could be administered intravenously for cancer therapy.
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Affiliation(s)
- Peng Wu
- Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Xiaoyong Wang
- The People’s Hospital of Rugao, Nantong, People’s Republic of China
| | - Min Yin
- Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Wenjie Zhu
- Kangda College of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Zheng Chen
- Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Yang Zhang
- Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Ziyu Jiang
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People’s Republic of China
| | - Longqing Shi
- Department of Hepatobiliary and Pancreatic Surgery, Third Affiliated Hospital of Soochow University, Jiangsu, People’s Republic of China
| | - Qiang Zhu
- Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
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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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Yang L, Chen H, Yang C, Hu Z, Jiang Z, Meng S, Liu R, Huang L, Yang K. Research progress on the regulatory mechanism of integrin-mediated mechanical stress in cells involved in bone metabolism. J Cell Mol Med 2024; 28:e18183. [PMID: 38506078 PMCID: PMC10951882 DOI: 10.1111/jcmm.18183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 01/14/2024] [Accepted: 02/04/2024] [Indexed: 03/21/2024] Open
Abstract
Mechanical stress is an internal force between various parts of an object that resists external factors and effects that cause an object to deform, and mechanical stress is essential for various tissues that are constantly subjected to mechanical loads to function normally. Integrins are a class of transmembrane heterodimeric glycoprotein receptors that are important target proteins for the action of mechanical stress stimuli on cells and can convert extracellular physical and mechanical signals into intracellular bioelectrical signals, thereby regulating osteogenesis and osteolysis. Integrins play a bidirectional regulatory role in bone metabolism. In this paper, relevant literature published in recent years is reviewed and summarized. The characteristics of integrins and mechanical stress are introduced, as well as the mechanisms underlying responses of integrin to mechanical stress stimulation. The paper focuses on integrin-mediated mechanical stress in different cells involved in bone metabolism and its associated signalling mechanisms. The purpose of this review is to provide a theoretical basis for the application of integrin-mediated mechanical stress to the field of bone tissue repair and regeneration.
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Affiliation(s)
- Li Yang
- Department of Periodontology, Hospital of StomatologyZunyi Medical UniversityZunyiChina
| | - Hong Chen
- Department of Periodontology, Hospital of StomatologyZunyi Medical UniversityZunyiChina
| | - Chanchan Yang
- Department of Periodontology, Hospital of StomatologyZunyi Medical UniversityZunyiChina
| | - Zhengqi Hu
- Department of Periodontology, Hospital of StomatologyZunyi Medical UniversityZunyiChina
| | - Zhiliang Jiang
- Department of Periodontology, Hospital of StomatologyZunyi Medical UniversityZunyiChina
| | - Shengzi Meng
- Department of Periodontology, Hospital of StomatologyZunyi Medical UniversityZunyiChina
| | | | - Lan Huang
- Department of Periodontology, Hospital of StomatologyZunyi Medical UniversityZunyiChina
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Chen MC, Devi HS, Pien HF, Wen SFM, Sheu JL, Tsai BCK, Huang CY, Lin YJ. Novel chromium (III)-based compound for inhibition of oxaliplatin-resistant colorectal cancer progression. Am J Cancer Res 2024; 14:979-995. [PMID: 38590406 PMCID: PMC10998745 DOI: 10.62347/xtrt2780] [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: 10/15/2023] [Accepted: 02/26/2024] [Indexed: 04/10/2024] Open
Abstract
Colorectal cancer (CRC) ranks as the third leading cause of cancer-related mortality worldwide. The current standard of care includes systemic chemotherapy with cytotoxic agents, offering palliative relief for severe CRC cases and serving as the primary therapy for metastatic recurrence. However, the development of chemoresistance poses a substantial obstacle in the realm of chemotherapy. This study delved into the potential of a novel chromium (III)-based compound, hexaacetotetraaquadihydroxochromium (III) diiron (III) nitrate, for CRC treatment. The therapeutic promise of this innovative chromium (III)-based compound was explored by utilizing LoVo colon cancer cells and an in-vivo mouse model of CRC. Various dosages of the compound were administered to LoVo parental cells and LoVo oxaliplatin-resistant cells. Findings unveiled that a concentration of 2000 μg/mL of the chromium (III) compound significantly inhibited mesenchymal transition and the migratory and invasive properties of LoVo oxaliplatin-resistant cells. This novel chromium (III)-based compound also demonstrated similar efficacy in other different CRC cell lines. The tumor growth was in the in-vivo mouse model was reduced by this compound. Moreover, the chromium (III)-based compound induced apoptosis by triggering the endoplasmic reticulum (ER) stress pathway in LoVo oxaliplatin-resistant cells. This study illuminates the capacity of the novel chromium (III)-based compound to impede the progression and growth of chemotherapy-resistant CRC. This discovery instills confidence in the potential of this compound as a therapeutic agent for CRC, even in the face of drug resistance. It holds the promise of serving as a valuable asset in the future treatment of chemotherapy-resistant CRC.
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Affiliation(s)
- Ming-Cheng Chen
- Division of Colorectal Surgery, Department of Surgery, Taichung Veterans General HospitalTaichung, Taiwan
- Faculty of Medicine, National Yang Ming Chiao Tung UniversityTaipei, Taiwan
| | - Hema Sri Devi
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationHualien, Taiwan
| | | | | | | | - Bruce Chi-Kang Tsai
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationHualien, Taiwan
| | - Chih-Yang Huang
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationHualien, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical UniversityTaichung, Taiwan
- Department of Medical Research, China Medical University HospitalTaichung, Taiwan
- Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and TechnologyHualien, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Asia UniversityTaichung, Taiwan
| | - Yu-Jung Lin
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationHualien, Taiwan
- School of Post-Baccalaureate Chinese Medicine, College of Medicine, Tzu Chi UniversityHualien, Taiwan
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BharathwajChetty B, Sajeev A, Vishwa R, Aswani BS, Alqahtani MS, Abbas M, Kunnumakkara AB. Dynamic interplay of nuclear receptors in tumor cell plasticity and drug resistance: Shifting gears in malignant transformations and applications in cancer therapeutics. Cancer Metastasis Rev 2024; 43:321-362. [PMID: 38517618 DOI: 10.1007/s10555-024-10171-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 01/19/2024] [Indexed: 03/24/2024]
Abstract
Recent advances have brought forth the complex interplay between tumor cell plasticity and its consequential impact on drug resistance and tumor recurrence, both of which are critical determinants of neoplastic progression and therapeutic efficacy. Various forms of tumor cell plasticity, instrumental in facilitating neoplastic cells to develop drug resistance, include epithelial-mesenchymal transition (EMT) alternatively termed epithelial-mesenchymal plasticity, the acquisition of cancer stem cell (CSC) attributes, and transdifferentiation into diverse cell lineages. Nuclear receptors (NRs) are a superfamily of transcription factors (TFs) that play an essential role in regulating a multitude of cellular processes, including cell proliferation, differentiation, and apoptosis. NRs have been implicated to play a critical role in modulating gene expression associated with tumor cell plasticity and drug resistance. This review aims to provide a comprehensive overview of the current understanding of how NRs regulate these key aspects of cancer biology. We discuss the diverse mechanisms through which NRs influence tumor cell plasticity, including EMT, stemness, and metastasis. Further, we explore the intricate relationship between NRs and drug resistance, highlighting the impact of NR signaling on chemotherapy, radiotherapy and targeted therapies. We also discuss the emerging therapeutic strategies targeting NRs to overcome tumor cell plasticity and drug resistance. This review also provides valuable insights into the current clinical trials that involve agonists or antagonists of NRs modulating various aspects of tumor cell plasticity, thereby delineating the potential of NRs as therapeutic targets for improved cancer treatment outcomes.
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Affiliation(s)
- Bandari BharathwajChetty
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Anjana Sajeev
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Ravichandran Vishwa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Babu Santha Aswani
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, 61421, Saudi Arabia
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, 61421, Saudi Arabia
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India.
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11
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Frey N, Ouologuem L, Blenninger J, Siow WX, Thorn-Seshold J, Stöckl J, Abrahamian C, Fröhlich T, Vollmar AM, Grimm C, Bartel K. Endolysosomal TRPML1 channel regulates cancer cell migration by altering intracellular trafficking of E-cadherin and β 1-integrin. J Biol Chem 2024; 300:105581. [PMID: 38141765 PMCID: PMC10825694 DOI: 10.1016/j.jbc.2023.105581] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 11/23/2023] [Accepted: 12/04/2023] [Indexed: 12/25/2023] Open
Abstract
Metastasis still accounts for 90% of all cancer-related death cases. An increase of cellular mobility and invasive traits of cancer cells mark two crucial prerequisites of metastasis. Recent studies highlight the involvement of the endolysosomal cation channel TRPML1 in cell migration. Our results identified a widely antimigratory effect upon loss of TRPML1 function in a panel of cell lines in vitro and reduced dissemination in vivo. As mode-of-action, we established TRPML1 as a crucial regulator of cytosolic calcium levels, actin polymerization, and intracellular trafficking of two promigratory proteins: E-cadherin and β1-integrin. Interestingly, KO of TRPML1 differentially interferes with the recycling process of E-cadherin and β1-integrin in a cell line-dependant manner, while resulting in the same phenotype of decreased migratory and adhesive capacities in vitro. Additionally, we observed a coherence between reduction of E-cadherin levels at membrane site and phosphorylation of NF-κB in a β-catenin/p38-mediated manner. As a result, an E-cadherin/NF-κB feedback loop is generated, regulating E-cadherin expression on a transcriptional level. Consequently, our findings highlight the role of TRPML1 as a regulator in migratory processes and suggest the ion channel as a suitable target for the inhibition of migration and invasion.
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Affiliation(s)
- Nadine Frey
- Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Lina Ouologuem
- Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Julia Blenninger
- Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Wei-Xiong Siow
- Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Julia Thorn-Seshold
- Department of Pharmacy, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Jan Stöckl
- Gene Center, Laboratory for Functional Genome Analysis, Ludwig Maximilians-University Munich, Munich, Germany
| | - Carla Abrahamian
- Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Thomas Fröhlich
- Gene Center, Laboratory for Functional Genome Analysis, Ludwig Maximilians-University Munich, Munich, Germany
| | - Angelika M Vollmar
- Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Christian Grimm
- Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Karin Bartel
- Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, Munich, Germany.
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12
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Sosnovski KE, Braun T, Amir A, BenShoshan M, Abbas-Egbariya H, Ben-Yishay R, Anafi L, Avivi C, Barshack I, Denson LA, Haberman Y. Reduced LHFPL3-AS2 lncRNA expression is linked to altered epithelial polarity and proliferation, and to ileal ulceration in Crohn disease. Sci Rep 2023; 13:20513. [PMID: 37993670 PMCID: PMC10665440 DOI: 10.1038/s41598-023-47997-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 11/21/2023] [Indexed: 11/24/2023] Open
Abstract
Disruption of intestinal epithelial functions is linked to Crohn disease (CD) pathogenesis. We identified a widespread reduction in the expression of long non-coding RNAs (lncRNAs) including LHFPL3-AS2 in the treatment-naïve CD ileum of the RISK pediatric cohort. We validated the reduction of LHFPL3-AS2 in adult CD and noted a further reduction in patients with more severe CD from the RISK cohort. LHFPL3-AS2 knockdown in Caco-2 cells robustly affected epithelial monolayer morphogenesis with markedly reduced confluency and spreading, showing atypical rounding, and clumping. mRNA-seq analysis of LHFPL3-AS2 knockdown cells highlighted the reduction of genes and pathways linked with apical polarity, actin bundles, morphogenesis, and the b-catenin-TCF4 complex. LHFPL3-AS2 knockdown significantly reduced the ability of cells to form an internal lumen within the 3-dimensional (3D) cyst model, with mislocalization of actin and adherent and tight junction proteins, affecting epithelial polarity. LHFPL3-AS2 knockdown also resulted in defective mitotic spindle formation and consequent reduction in epithelial proliferation. Altogether, we show that LHFPL3-AS2 reduction affects epithelial morphogenesis, polarity, mitotic spindle formation, and proliferation, which are key processes in maintaining epithelial homeostasis in CD. Reduced expression of LHFPL3-AS2 in CD patients and its further reduction with ileal ulceration outcome, emphasizes its significance in this context.
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Affiliation(s)
- Katya E Sosnovski
- Sheba Medical Center, Tel-Hashomer, Affiliated with the Tel Aviv University, Tel Aviv, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Tzipi Braun
- Sheba Medical Center, Tel-Hashomer, Affiliated with the Tel Aviv University, Tel Aviv, Israel
| | - Amnon Amir
- Sheba Medical Center, Tel-Hashomer, Affiliated with the Tel Aviv University, Tel Aviv, Israel
| | - Marina BenShoshan
- Sheba Medical Center, Tel-Hashomer, Affiliated with the Tel Aviv University, Tel Aviv, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Haya Abbas-Egbariya
- Sheba Medical Center, Tel-Hashomer, Affiliated with the Tel Aviv University, Tel Aviv, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Rakefet Ben-Yishay
- Sheba Medical Center, Tel-Hashomer, Affiliated with the Tel Aviv University, Tel Aviv, Israel
| | - Liat Anafi
- Sheba Medical Center, Tel-Hashomer, Affiliated with the Tel Aviv University, Tel Aviv, Israel
| | - Camilla Avivi
- Sheba Medical Center, Tel-Hashomer, Affiliated with the Tel Aviv University, Tel Aviv, Israel
| | - Iris Barshack
- Sheba Medical Center, Tel-Hashomer, Affiliated with the Tel Aviv University, Tel Aviv, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Lee A Denson
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Yael Haberman
- Sheba Medical Center, Tel-Hashomer, Affiliated with the Tel Aviv University, Tel Aviv, Israel.
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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13
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Men X, Zhu W. Silencing of Perilipin 3 Inhibits Lung Adenocarcinoma Cell Immune Resistance by Regulating the Transcription of PD-L1 Through c-Myc. Immunol Invest 2023; 52:815-831. [PMID: 37578465 DOI: 10.1080/08820139.2023.2244976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/15/2023]
Abstract
BACKGROUND Perilipin 3 (PLIN3), a lipid droplet-associated protein, is found to be highly expressed in human cancers. This study aimed to investigate the biological functions and underlying mechanism of PLIN3 in lung adenocarcinoma (LUAD). METHODS To analyse PLIN3 expression in normal and cancerous tissues, relevance between PLIN3 expression and survival prognosis, and to predict the pathways related to PLIN3, bioinformatic analysis was performed. In A549 and H1299 cells, qRT-PCR or western blotting was used to determine mRNA/protein expression of PLIN3, PD-L1, and c-Myc. In A549 and H1299 cells, CCK-8 assay, EdU, and flow cytometry were used to assess cell viability, proliferation, and apoptosis. Chip and luciferase reporter assays were performed to verify the binding of PD-L1 with c-Myc. The functions of PLIN3 were examined in vivo in a xenograft tumor model. RESULTS In LUAD tissues and cells, PLIN3 expression was downregulated. A shorter survival time was observed in patients with high PLIN3 expression than in patients with low PLIN3 expression. Silencing of PLIN3 inhibited cell proliferation, PD-L1 expression, and Myc pathway, as well as induced apoptosis in LUAD cells. c-Myc acts as a transcription factor of PD-L1. Moreover, the inhibitory actions of PLIN3 silencing on c-Myc and PD-L1 expression as well as cell proliferation and stimulatory action of PLIN3 silencing on cell apoptosis were reversed by c-Myc overexpression. In vivo, PLIN3 silencing inhibited the growth of xenograft tumour and reduced PLIN3, PD-L1, and c-Myc protein expression. CONCLUSION Silencing of PLIN3 inhibited tumour growth by regulating the Myc/PD-L1 pathway.
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Affiliation(s)
- Xuelin Men
- Department of Respiratory and Critical Care II, The Fourth People's Hospital of Jinan, Jinan, Shandong, P.R. China
| | - Wei Zhu
- Department of Respiratory and Critical Care II, The Fourth People's Hospital of Jinan, Jinan, Shandong, P.R. China
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14
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Wang H, Mazzocca A, Gao P. Cadherin dysregulation in gastric cancer: insights into gene expression, pathways, and prognosis. J Gastrointest Oncol 2023; 14:2064-2082. [PMID: 37969819 PMCID: PMC10643585 DOI: 10.21037/jgo-23-700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 10/12/2023] [Indexed: 11/17/2023] Open
Abstract
Background The Cadherin gene family holds immense significance in maintaining the integrity and functionality of stomach tissues, playing crucial roles in cell-cell adhesion, cell migration and differentiation. Dysregulation of cadherin expression and function has been closely associated with various gastric diseases, particularly gastric cancer (GC). Understanding the regulation and clinical implications of cadherin genes in GC is essential to improve our knowledge and to identify new potential prognostic markers and therapeutic targets. Methods In this study, we provide an overview on the role of cadherin family genes in GC using bioinformatics analysis. We analyzed the expression, mutational status, and prognostic value of these genes based on available public datasets. Our methodology involved data mining, differential expression analysis, functional enrichment analysis, and survival analysis to explore the association between cadherin gene expression and clinical outcomes in GC patients. Additionally, we investigated the relationship between cadherin expression and immune cell infiltration to gain insights into the tumor microenvironment's role in GC progression. Results Our bioinformatics analysis revealed significant differential expression of 16 cadherin genes in GC samples compared to normal tissues. Approximately up to 52% of the analyzed cancer samples exhibited genomic alterations in these cadherins, indicating their potential relevance in GC development. Functional enrichment analysis demonstrated that these differentially expressed cadherins were closely associated with critical cellular processes, including cell adhesion and immune-modulation. Remarkably, lower expression levels of most cadherin genes were linked to improved prognosis in GC patients, suggesting their potential importance as valuable prognostic biomarkers. Conclusions The findings deriving from our comprehensive study provide important insights into the dysregulation of cadherin genes in GC and their impact on gene expression, molecular pathways, and prognosis. The associations with clinical outcomes and immune cell infiltration highlight the potential role of cadherin genes as prognostic biomarkers and therapeutic targets in GC.
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Affiliation(s)
- Huan Wang
- Department of Medical Oncology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China
| | | | - Puyue Gao
- Department of Digestive Medicine, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China
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15
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Ahn M, Cho WW, Lee H, Park W, Lee SH, Back JW, Gao Q, Gao G, Cho DW, Kim BS. Engineering of Uniform Epidermal Layers via Sacrificial Gelatin Bioink-Assisted 3D Extrusion Bioprinting of Skin. Adv Healthc Mater 2023; 12:e2301015. [PMID: 37537366 DOI: 10.1002/adhm.202301015] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/19/2023] [Indexed: 08/05/2023]
Abstract
To reconstruct an ideal full-thickness skin model, basal keratinocytes must be distributed as a confluent monolayer on the dermis. However, the currently available extrusion bioprinting method for the skin is limited when producing an air-exposed cellular monolayer because the cells are encapsulated within a bioink. This is the first study to use sacrificial gelatin-assisted extrusion bioprinting to reproduce a uniform and stratified epidermal layer. Experimental analyses of the rheological properties, printability, cell viability, and initial keratinocyte adhesion shows that the optimal gelatin bioink concentration is 4 wt.%. The appropriate thickness of the bioprinted gelatin structure for achieving a confluent keratinocyte layer is determined to be 400 µm. The suggested strategy generates a uniform keratinocyte monolayer with tight junctions throughout the central and peripheral regions, whereas manual seeding generates non-uniform cellular aggregates and vacancies. These results influence gene expression, exhibiting a propensity for epidermal differentiation. Finally, the gelatin-assisted keratinocytes are bioprinted onto a dermis composed of gelatin methacryloyl and dermis-derived decellularized extracellular matrix to establish a full-thickness skin model. Thus, this strategy leads to significant improvements in epidermal differentiation/stratification. The findings demonstrate that the gelatin-assisted approach is advantageous for recreating reliable full-thickness skin models with significant consistency for mass production.
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Affiliation(s)
- Minjun Ahn
- Medical Research Institute, Pusan National University, Yangsan, 626841, Republic of Korea
| | - Won-Woo Cho
- Department of Mechanical Engineering, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea
| | - Hanju Lee
- School of Biomedical Convergence Engineering, Pusan National University, Yangsan, 626841, Republic of Korea
| | - Wonbin Park
- Department of Mechanical Engineering, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea
| | - Seok-Hyeon Lee
- School of Biomedical Convergence Engineering, Pusan National University, Yangsan, 626841, Republic of Korea
| | - Jae Woo Back
- School of Biomedical Convergence Engineering, Pusan National University, Yangsan, 626841, Republic of Korea
| | - Qiqi Gao
- School of Medical Technology, Beijing Institute of Technology, Beijing, 100081, China
| | - Ge Gao
- School of Medical Technology, Beijing Institute of Technology, Beijing, 100081, China
| | - Dong-Woo Cho
- Department of Mechanical Engineering, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea
| | - Byoung Soo Kim
- Medical Research Institute, Pusan National University, Yangsan, 626841, Republic of Korea
- School of Biomedical Convergence Engineering, Pusan National University, Yangsan, 626841, Republic of Korea
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Khan NG, Tungekar B, Adiga D, Chakrabarty S, Rai PS, Kabekkodu SP. Alterations induced by Bisphenol A on cellular organelles and potential relevance on human health. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2023; 1870:119505. [PMID: 37286138 DOI: 10.1016/j.bbamcr.2023.119505] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 04/29/2023] [Accepted: 05/26/2023] [Indexed: 06/09/2023]
Abstract
Bisphenol A (BPA) is a chemical partially soluble in water and exists in a solid state. Its structural similarity with estrogen makes it an endocrine-disrupting chemical. BPA can disrupt signaling pathways at very low doses and may cause organellar stress. According to in vitro and in vivo studies, BPA interacts with various cell surface receptors to cause organellar stress, producing free radicals, cellular toxicity, structural changes, DNA damage, mitochondrial dysfunction, cytoskeleton remodeling, centriole duplication, and aberrant changes in several cell signaling pathways. The current review summarizes the impact of BPA exposure on the structural and functional aspects of subcellular components of cells such as the nucleus, mitochondria, endoplasmic reticulum, lysosome, ribosome, Golgi apparatus, and microtubules and its consequent impact on human health.
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Affiliation(s)
- Nadeem G Khan
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Bushra Tungekar
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Divya Adiga
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India; Center for DNA Repair and Genome Stability (CDRGS), Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Padmalatha S Rai
- Department of Biotechnology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India; Center for DNA Repair and Genome Stability (CDRGS), Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
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Wang J, Koch DT, Hofmann FO, Härtwig D, Beirith I, Janssen KP, Bazhin AV, Niess H, Werner J, Renz BW, Ilmer M. WNT enhancing signals in pancreatic cancer are transmitted by LGR6. Aging (Albany NY) 2023; 15:10897-10914. [PMID: 37770230 PMCID: PMC10637827 DOI: 10.18632/aging.205101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 07/17/2023] [Indexed: 10/03/2023]
Abstract
The G-protein-coupled receptor LGR6 associates with ligands of the R-Spondin (RSPO) family to potentiate preexisting signals of the canonical WNT pathway. However, its importance in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we show that LGR6 is differentially expressed in various PDAC cell lines of mesenchymal and epithelial phenotype, respectively, siding with the latter subsets. LGR6 expression is altered based upon the cells' WNT activation status. Furthermore, extrinsic enhancement of WNT pathway signaling increased LGR6 expression suggestive of a reinforcing self-regulatory loop in highly WNT susceptible cells. Downregulation of LGR6 on the other hand, seemed to tamper those effects. Last, downregulation of LGR6 reduced cancer stemness as determined by functional in vitro assays. These findings shed new insights into regulatory mechanisms for the canonical WNT pathway in pancreatic cancer cells. It may also have potential value for treatment stratification of PDAC.
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Affiliation(s)
- Jing Wang
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
- Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, P.R. China
| | - Dominik T. Koch
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
| | - Felix O. Hofmann
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
| | - Daniel Härtwig
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
| | - Iris Beirith
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
| | - Klaus Peter Janssen
- Department of Surgery, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Bavaria, Germany
| | - Alexandr V. Bazhin
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Bavaria, Germany
- Bavarian Cancer Research Center (BZKF), LMU Munich, Munich, Bavaria, Germany
| | - Hanno Niess
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
| | - Jens Werner
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Bavaria, Germany
- Bavarian Cancer Research Center (BZKF), LMU Munich, Munich, Bavaria, Germany
| | - Bernhard W. Renz
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Bavaria, Germany
- Bavarian Cancer Research Center (BZKF), LMU Munich, Munich, Bavaria, Germany
| | - Matthias Ilmer
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Bavaria, Germany
- Bavarian Cancer Research Center (BZKF), LMU Munich, Munich, Bavaria, Germany
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18
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Wang D, Wu S, He J, Sun L, Zhu H, Zhang Y, Liu S, Duan X, Wang Y, Xu T. FAT4 overexpression promotes antitumor immunity by regulating the β-catenin/STT3/PD-L1 axis in cervical cancer. J Exp Clin Cancer Res 2023; 42:222. [PMID: 37658376 PMCID: PMC10472690 DOI: 10.1186/s13046-023-02758-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 07/10/2023] [Indexed: 09/03/2023] Open
Abstract
BACKGROUND FAT4 (FAT Atypical Cadherin 4) is a member of the cadherin-associated protein family, which has been shown to function as a tumor suppressor by inhibiting proliferation and metastasis. The Wnt/β-catenin pathway activation is highly associated with PD-L1-associated tumor immune escape. Here, we report the mechanism by which FAT4 overexpression regulates anti-tumor immunity in cervical cancer by inhibiting PD-L1 N-glycosylation and cell membrane localization in a β-catenin-dependent manner. METHODS FAT4 expression was first detected in cervical cancer tissues and cell lines. Cell proliferation, clone formation, and immunofluorescence were used to determine the tumor suppressive impact of FAT4 overexpression in vitro, and the findings were confirmed in immunodeficient and immunocomplete mice xenografts. Through functional and mechanistic experiments in vivo and in vitro, we investigated how FAT4 overexpression affects the antitumor immunity via the β-catenin/STT3/PD-L1 axis. RESULTS FAT4 is downregulated in cervical cancer tissues and cell lines. We determined that FAT4 binds to β-catenin and antagonizes its nuclear localization, promotes phosphorylation and degradation of β-catenin by the degradation complexes (AXIN1, APC, GSK3β, CK1). FAT4 overexpression decreases programmed death-ligand 1 (PD-L1) mRNA expression at the transcriptional level, and causes aberrant glycosylation of PD-L1 via STT3A at the post-translational modifications (PTMs) level, leading to its endoplasmic reticulum (ER) accumulation and polyubiquitination-dependent degradation. We found that FAT4 overexpression promotes aberrant PD-L1 glycosylation and degradation in a β-catenin-dependent manner, thereby increasing cytotoxic T lymphocyte (CTL) activity in immunoreactive mouse models. CONCLUSIONS These findings address the basis of Wnt/β-catenin pathway activation in cervical cancer and provide combination immunotherapy options for targeting the FAT4/β-catenin/STT3/PD-L1 axis. Schematic cartoons showing the antitumor immunity mechanism of FAT4. (left) when Wnts bind to their receptors, which are made up of Frizzled proteins and LRP5/6, the cytoplasmic protein DVL is activated, inducing the aggregation of degradation complexes (AXIN, GSK3β, CK1, APC) to the receptor. Subsequently, stable β-catenin translocates into the nucleus and binds to TCF/LEF and TCF7L2 transcription factors, leading to target genes transcription. The catalytically active subunit of oligosaccharyltransferase, STT3A, enhances PD-L1 glycosylation, and N-glycosylated PD-L1 translocates to the cell membrane via the ER-to-Golgi pathway, resulting in immune evasion. (Right) FAT4 exerts antitumor immunity mainly through following mechanisms: (i) FAT4 binds to β-catenin and antagonizes its nuclear localization, promotes phosphorylation and degradation of β-catenin by the degradation complexes (AXIN1, APC, GSK3β, CK1); (ii) FAT4 inhibits PD-L1 and STT3A transcription in a β-catenin-dependent manner and induces aberrant PD-L1 glycosylation and ubiquitination-dependent degradation; (iii) Promotes activation of cytotoxic T lymphocytes (CTL) and infiltration into the tumor microenvironment.
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Affiliation(s)
- Dongying Wang
- Obstetrics and Gynecology Department, The Second Hospital of Jilin University, 218 Zi Qiang Street, Changchun, Jilin 130041 China
| | - Shuying Wu
- Obstetrics and Gynecology Department, The Second Hospital of Jilin University, 218 Zi Qiang Street, Changchun, Jilin 130041 China
| | - Jiaxing He
- Obstetrics and Gynecology Department, The Second Hospital of Jilin University, 218 Zi Qiang Street, Changchun, Jilin 130041 China
| | - Luguo Sun
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, Jilin 130024 China
| | - Hongming Zhu
- Obstetrics and Gynecology Department, The Second Hospital of Jilin University, 218 Zi Qiang Street, Changchun, Jilin 130041 China
| | - Yuxuan Zhang
- Obstetrics and Gynecology Department, The Second Hospital of Jilin University, 218 Zi Qiang Street, Changchun, Jilin 130041 China
| | - Shanshan Liu
- Obstetrics and Gynecology Department, The Second Hospital of Jilin University, 218 Zi Qiang Street, Changchun, Jilin 130041 China
| | - Xuefeng Duan
- Obstetrics and Gynecology Department, The Second Hospital of Jilin University, 218 Zi Qiang Street, Changchun, Jilin 130041 China
| | - Yanhong Wang
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, Jilin 130024 China
- Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266071 China
| | - Tianmin Xu
- Obstetrics and Gynecology Department, The Second Hospital of Jilin University, 218 Zi Qiang Street, Changchun, Jilin 130041 China
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19
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Lin WH, Cooper LM, Anastasiadis PZ. Cadherins and catenins in cancer: connecting cancer pathways and tumor microenvironment. Front Cell Dev Biol 2023; 11:1137013. [PMID: 37255594 PMCID: PMC10225604 DOI: 10.3389/fcell.2023.1137013] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 05/03/2023] [Indexed: 06/01/2023] Open
Abstract
Cadherin-catenin complexes are integral components of the adherens junctions crucial for cell-cell adhesion and tissue homeostasis. Dysregulation of these complexes is linked to cancer development via alteration of cell-autonomous oncogenic signaling pathways and extrinsic tumor microenvironment. Advances in multiomics have uncovered key signaling events in multiple cancer types, creating a need for a better understanding of the crosstalk between cadherin-catenin complexes and oncogenic pathways. In this review, we focus on the biological functions of classical cadherins and associated catenins, describe how their dysregulation influences major cancer pathways, and discuss feedback regulation mechanisms between cadherin complexes and cellular signaling. We discuss evidence of cross regulation in the following contexts: Hippo-Yap/Taz and receptor tyrosine kinase signaling, key pathways involved in cell proliferation and growth; Wnt, Notch, and hedgehog signaling, key developmental pathways involved in human cancer; as well as TGFβ and the epithelial-to-mesenchymal transition program, an important process for cancer cell plasticity. Moreover, we briefly explore the role of cadherins and catenins in mechanotransduction and the immune tumor microenvironment.
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20
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Liu DX, Hao SL, Yang WX. Crosstalk Between β-CATENIN-Mediated Cell Adhesion and the WNT Signaling Pathway. DNA Cell Biol 2023; 42:1-13. [PMID: 36399409 DOI: 10.1089/dna.2022.0424] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Cell adhesion and stable signaling regulation are fundamental ways of maintaining homeostasis. Among them, the Wnt/β-CATENIN signaling plays a key role in embryonic development and maintenance of body dynamic homeostasis. At the same time, the key signaling molecule β-CATENIN in the Wnt signaling can also function as a cytoskeletal linker protein to regulate tissue barriers, cell migration, and morphogenesis. Dysregulation of the balance between Wnt signaling and adherens junctions can lead to disease. How β-CATENIN maintains the independence of these two functions, or mediates the interaction and balance of these two functions, has been explored and debated for a long time. In this study, we will focus on five aspects of β-CATENIN chaperone molecules, phosphorylation of β-CATENIN and related proteins, epithelial mesenchymal transition, β-CATENIN homolog protein γ-CATENIN and disease, thus deepening the understanding of the Wnt/β-CATENIN signaling and the homeostasis between cell adhesion and further addressing related disease problems.
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Affiliation(s)
- Ding-Xi Liu
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou, China
| | - Shuang-Li Hao
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou, China
| | - Wan-Xi Yang
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou, China
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21
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Tran F, Lee E, Cuddapah S, Choi BH, Dai W. MicroRNA-Gene Interactions Impacted by Toxic Metal(oid)s during EMT and Carcinogenesis. Cancers (Basel) 2022; 14:5818. [PMID: 36497298 PMCID: PMC9741118 DOI: 10.3390/cancers14235818] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/21/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022] Open
Abstract
Chronic environmental exposure to toxic metal(loid)s significantly contributes to human cancer development and progression. It is estimated that approximately 90% of cancer deaths are a result of metastasis of malignant cells, which is initiated by epithelial-mesenchymal transition (EMT) during early carcinogenesis. EMT is regulated by many families of genes and microRNAs (miRNAs) that control signaling pathways for cell survival, death, and/or differentiation. Recent mechanistic studies have shown that toxic metal(loid)s alter the expression of miRNAs responsible for regulating the expression of genes involved in EMT. Altered miRNA expressions have the potential to be biomarkers for predicting survival and responses to treatment in cancers. Significantly, miRNAs can be developed as therapeutic targets for cancer patients in the clinic. In this mini review, we summarize key findings from recent studies that highlight chemical-miRNA-gene interactions leading to the perturbation of EMT after exposure to toxic metal(loid)s including arsenic, cadmium, nickel, and chromium.
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Affiliation(s)
| | | | | | - Byeong Hyeok Choi
- Division of Environmental Medicine, Department of Medicine, Grossman School of Medicine, New York University, New York, NY 10010, USA
| | - Wei Dai
- Division of Environmental Medicine, Department of Medicine, Grossman School of Medicine, New York University, New York, NY 10010, USA
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22
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Zhou S, Li P, Qin L, Huang S, Dang N. Transcription factor YY1 contributes to human melanoma cell growth through modulating the p53 signaling pathway. Exp Dermatol 2022; 31:1563-1578. [PMID: 35730240 DOI: 10.1111/exd.14628] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 06/07/2022] [Accepted: 06/19/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND Melanoma has a higher mortality rate than any other skin cancer, and its cases are increasing. The transcription factor YY1 has been proven to be involved in tumor progression; however, the role of YY1 in melanoma is not well understood. METHODS This study investigates how YY1 functions in melanoma progression, and it also elucidates the underlying mechanisms involved. RESULTS We have found that in clinical human melanoma tissues, YY1 is overexpressed compared to YY1 expression in normal melanocytes and skin tissues. Cellular immunofluorescence shows that YY1 is mainly located in the nucleus. YY1 knockdown reduces proliferation, migration, and invasion of melanoma cell lines. Moreover, the apoptosis rate of cells is significantly increased in low-YY1 environments. The overexpression of YY1 resulted in decreased apoptotic rates in melanoma cells. YY1 also affects the expression of EMT-related proteins. Additional experiments reveal that YY1 knockdown disrupts the interaction of MDM2-p53, and that it both stabilizes and increases p53 activity. The upregulation of p53 expression in turn stimulates p21 expression just as it suppresses CDK4 expression, which then induces cells that were arrested in the G1 phase. The effect then is to constrain cell proliferation in melanoma cells. Upon activation of the p53 pathway, Bax, a pro-apoptotic protein, is upregulated, and Bcl-2, an anti-apoptotic protein, was downregulated in A375 cells. CONCLUSIONS The findings of this study provide novel insights into the pathology of melanoma as well as the role that YY1 plays in tumor progression. The findings also suggest that targeting YY1 has the potential to improve the diagnosis and treatment of melanoma.
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Affiliation(s)
- Shumin Zhou
- School of Clinical Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China.,Linyi people's Hospital, Linyi, Shandong, China
| | - Pin Li
- Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong, China
| | - Li Qin
- School of Clinical Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Shuhong Huang
- Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong, China.,Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Ningning Dang
- Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
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23
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Aibara D, Takahashi S, Yagai T, Kim D, Brocker CN, Levi M, Matsusue K, Gonzalez FJ. Gene repression through epigenetic modulation by PPARA enhances hepatocellular proliferation. iScience 2022; 25:104196. [PMID: 35479397 PMCID: PMC9036120 DOI: 10.1016/j.isci.2022.104196] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 02/22/2022] [Accepted: 03/31/2022] [Indexed: 11/25/2022] Open
Abstract
Peroxisome proliferator-activated receptor α (PPARA) is a key mediator of lipid metabolism and inflammation. Activation of PPARA in rodents causes hepatocyte proliferation, but the underlying mechanism is poorly understood. This study focused on genes repressed by PPARA and analyzed the mechanism by which PPARA promotes hepatocyte proliferation in mice. Activation of PPARA by agonist treatment was autoregulated, and induced expression of the epigenetic regulator UHRF1 via activation of the newly described PPARA target gene E2f8, which, in turn, regulates Uhrf1. UHRF1 strongly repressed the expression of CDH1 via methylation of the Cdh1 promoter marked with H3K9me3. Repression of CDH1 by PPARA activation was reversed by PPARA deficiency or knockdown of E2F8 or UHRF1. Furthermore, a forced expression of CDH1 inhibited expression of the Wnt signaling target genes such as Myc after PPARA activation, and suppressed hepatocyte hyperproliferation. These results demonstrate that the PPARA-E2F8-UHRF1-CDH1 axis causes epigenetic regulation of hepatocyte proliferation.
PPARA activation induces the UHRF1 expression via novel PPARA target gene E2f8 Induction of UHRF1 by PPARA activation represses Cdh1 gene marked with H3K9me3 CDH1 suppresses hepatocyte proliferation after PPARA activation Autoinduction of PPARA by agonist enhances cell proliferation via E2F8-UHRF1-CDH1
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Affiliation(s)
- Daisuke Aibara
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Faculty of Pharmaceutical Science, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
| | - Shogo Takahashi
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC 20057, USA
- Corresponding author
| | - Tomoki Yagai
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Donghwan Kim
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Chad N. Brocker
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Moshe Levi
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC 20057, USA
| | - Kimihiko Matsusue
- Faculty of Pharmaceutical Science, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
| | - Frank J. Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Corresponding author
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24
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Rogers MP, Mi Z, Li NY, Wai PY, Kuo PC. Tumor: Stroma Interaction and Cancer. EXPERIENTIA SUPPLEMENTUM (2012) 2022; 113:59-87. [PMID: 35165860 DOI: 10.1007/978-3-030-91311-3_2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The understanding of how normal cells transform into tumor cells and progress to invasive cancer and metastases continues to evolve. The tumor mass is comprised of a heterogeneous population of cells that include recruited host immune cells, stromal cells, matrix components, and endothelial cells. This tumor microenvironment plays a fundamental role in the acquisition of hallmark traits, and has been the intense focus of current research. A key regulatory mechanism triggered by these tumor-stroma interactions includes processes that resemble epithelial-mesenchymal transition, a physiologic program that allows a polarized epithelial cell to undergo biochemical and cellular changes and adopt mesenchymal cell characteristics. These cellular adaptations facilitate enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, and greatly increased production of ECM components. Indeed, it has been postulated that cancer cells undergo epithelial-mesenchymal transition to invade and metastasize.In the following discussion, the physiology of chronic inflammation, wound healing, fibrosis, and tumor invasion will be explored. The key regulatory cytokines, transforming growth factor β and osteopontin, and their roles in cancer metastasis will be highlighted.
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Affiliation(s)
- Michael P Rogers
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Zhiyong Mi
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Neill Y Li
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Philip Y Wai
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Paul C Kuo
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA.
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25
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Sohn SH, Sul HJ, Kim BJ, Kim HS, Zang DY. Entrectinib Induces Apoptosis and Inhibits the Epithelial-Mesenchymal Transition in Gastric Cancer with NTRK Overexpression. Int J Mol Sci 2021; 23:ijms23010395. [PMID: 35008821 PMCID: PMC8745632 DOI: 10.3390/ijms23010395] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/24/2021] [Accepted: 12/29/2021] [Indexed: 01/16/2023] Open
Abstract
Tropomyosin receptor kinase (TRK) and receptor tyrosine kinase (RTK class VII) expression are important in many human diseases, especially cancers, including colorectal, lung, and gastric cancer. Using RNA sequencing analysis, we evaluated the mRNA expression and mutation profiles of gastric cancer patients with neurotropic tropomyosin receptor kinase (NTRK) 1-3 overexpression (defined as a ≥2.0-fold change). Furthermore, we screened eight TRK inhibitors in NCI-N87, SNU16, MKN28, MKN7, and AGS cells. Among these inhibitors, entrectinib showed the highest inhibitory activity; therefore, this drug was selected for analysis of its therapeutic mechanisms in gastric cancer. Entrectinib treatment induced apoptosis in NTRK1-3-expressing and VEGFR2-expressing NCI-N87 and AGS cells, but it had no effect on NTRK1-3-, VEGFR2-, TGFBR1-, and CD274-expressing MKN7 cells. SNU16 and MKN28 cells with low NTRK1-3 expression were not affected by entrectinib. Therefore, a mechanistic study was conducted in NCI-N87 (high expression of NTRK1-3 but mutation of NTRK3), AGS (high expression of NTRK1-3) and MKN28 (low expression of NTRK1-3) gastric cancer cell lines. Entrectinib treatment significantly reduced expression levels of phosphorylated NFκB, AKT, ERK, and β-catenin in NCI-N87 and AGS cells, whereas it upregulated the expression levels of ECAD in NCI-N87 cells. Together, these results suggest that entrectinib has anti-cancer activity not only in GC cells overexpressing pan NTRK but also in VEGFR2 GC cells via the inhibition of the pan NTRK and VEGFR signaling pathways.
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Affiliation(s)
- Sung-Hwa Sohn
- Hallym Translational Research Institute, Hallym University Sacred Heart Hospital, Anyang 14066, Korea; (S.-H.S.); (H.J.S.)
| | - Hee Jung Sul
- Hallym Translational Research Institute, Hallym University Sacred Heart Hospital, Anyang 14066, Korea; (S.-H.S.); (H.J.S.)
| | - Bum Jun Kim
- Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang 14068, Korea; (B.J.K.); (H.S.K.)
| | - Hyeong Su Kim
- Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang 14068, Korea; (B.J.K.); (H.S.K.)
| | - Dae Young Zang
- Hallym Translational Research Institute, Hallym University Sacred Heart Hospital, Anyang 14066, Korea; (S.-H.S.); (H.J.S.)
- Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang 14068, Korea; (B.J.K.); (H.S.K.)
- Correspondence: ; Tel.: +82-31-380-4167
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26
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Lohani S, Funato Y, Akieda Y, Mizutani K, Takai Y, Ishitani T, Miki H. A novel role of PRL in regulating epithelial cell density by inducing apoptosis at confluence. J Cell Sci 2021; 135:273809. [PMID: 34931244 DOI: 10.1242/jcs.258550] [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: 02/12/2021] [Accepted: 12/02/2021] [Indexed: 11/20/2022] Open
Abstract
Maintaining proper epithelial cell density is essential for the survival of multicellular organisms. While regulation of cell density through apoptosis is well known, its mechanistic details remain elusive. Here, we report the involvement of membrane-anchored phosphatase of regenerating liver (PRL), originally known for its role in cancer malignancy, in this process. In epithelial MDCK cells, upon confluence, doxycycline-induced expression of PRL upregulated apoptosis, reducing the cell density. This could be circumvented by artificially reducing the cell density via stretching the cell-seeded silicon chamber. Moreover, siRNA-mediated knockdown of endogenous PRL blocked apoptosis, leading to greater cell density. Mechanistically, PRL promoted apoptosis by upregulating the translation of E-cadherin and activating TGF-β pathway. Morpholino-mediated inhibition of PRL expression in zebrafish embryos caused developmental defect with reduced apoptosis and increased epithelial cell density during convergent extension. This study revealed a novel role of PRL in regulating density-dependent apoptosis in vertebrate epithelium.
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Affiliation(s)
- Sweksha Lohani
- Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
| | - Yosuke Funato
- Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
| | - Yuki Akieda
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
| | - Kiyohito Mizutani
- Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0047, Japan
| | - Yoshimi Takai
- Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0047, Japan
| | - Tohru Ishitani
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.,Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka 565-0871, Japan
| | - Hiroaki Miki
- Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.,Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka 565-0871, Japan
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27
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Plant-Derived Chinese Medicine Monomers on Ovarian Cancer via the Wnt/ β-Catenin Signaling Pathway: Review of Mechanisms and Prospects. JOURNAL OF ONCOLOGY 2021; 2021:6852867. [PMID: 34912456 PMCID: PMC8668291 DOI: 10.1155/2021/6852867] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 10/03/2021] [Accepted: 11/22/2021] [Indexed: 02/07/2023]
Abstract
Ovarian cancer (OC) is a common malignant tumor of the female reproductive system and has a high morbidity and mortality rate. The progression and metastasis of OC are complex and involve multiple signaling pathways. The Wnt/β-catenin signaling pathway is closely related to OC, and therefore blocking the activation of the Wnt/β-catenin signaling directly or inhibiting related genes, and molecular targets is of great value in treating OC. Toxicities such as myelotoxicity, cardiotoxicity, genotoxicity, and vasospasm are the major side effects for common anticancer drugs and are well documented. There is, therefore, a need to develop new, effective, safer, and more affordable anticancer drugs from alternative sources. In recent years, plant-derived Chinese medicine monomers have drawn increasing attention due to their high safety, low toxicity, minimal side effects, and antitumor effects. Plant-derived Chinese medicine monomers are effective against multiple targets and can regulate the growth, proliferation, apoptosis, invasion, and migration of OC as well as reverse drug resistance by regulating the Wnt/β-catenin signaling pathway. In this review, we summarize and provide mechanisms and prospects for the use of plant-derived Chinese medicines for the prevention and treatment of OC.
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28
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Ghuwalewala S, Ghatak D, Das S, Roy S, Das P, Butti R, Gorain M, Nath S, Kundu GC, Roychoudhury S. MiRNA-146a/AKT/β-Catenin Activation Regulates Cancer Stem Cell Phenotype in Oral Squamous Cell Carcinoma by Targeting CD24. Front Oncol 2021; 11:651692. [PMID: 34712602 PMCID: PMC8546321 DOI: 10.3389/fonc.2021.651692] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 09/16/2021] [Indexed: 01/06/2023] Open
Abstract
CD44highCD24low population has been previously reported as cancer stem cells (CSCs) in Oral Squamous Cell Carcinoma (OSCC). Increasing evidence suggests potential involvement of microRNA (miRNA) network in modulation of CSC properties. MiRNAs have thus emerged as crucial players in tumor development and maintenance. However, their role in maintenance of OSCC stem cells remains unclear. Here we report an elevated expression of miR-146a in the CD44highCD24low population within OSCC cells and primary HNSCC tumors. Moreover, over-expression of miR-146a results in enhanced stemness phenotype by augmenting the CD44highCD24low population. We demonstrate that miR-146a stabilizes β-catenin with concomitant loss of E-cadherin and CD24. Interestingly, CD24 is identified as a novel functional target of miR-146a and ectopic expression of CD24 abrogates miR-146a driven potential CSC phenotype. Mechanistic analysis reveals that higher CD24 levels inhibit AKT phosphorylation leading to β-catenin degradation. Using stably expressing miR-146a/CD24 OSCC cell lines, we also validate that the miR-146a/CD24/AKT loop significantly alters tumorigenic ability in vivo. Furthermore, we confirmed that β-catenin trans-activates miR-146a, thereby forming a positive feedback loop contributing to stem cell maintenance. Collectively, our study demonstrates that miR-146a regulates CSCs in OSCC through CD24-AKT-β-catenin axis.
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Affiliation(s)
- Sangeeta Ghuwalewala
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology, Kolkata, India
| | - Dishari Ghatak
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology, Kolkata, India
| | - Sumit Das
- Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science (NCCS), Pune, India
| | - Stuti Roy
- Division of Research, Saroj Gupta Cancer Centre and Research Institute, Kolkata, India
| | - Pijush Das
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology, Kolkata, India
| | - Ramesh Butti
- Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science (NCCS), Pune, India
| | - Mahadeo Gorain
- Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science (NCCS), Pune, India
| | - Somsubhra Nath
- Division of Research, Saroj Gupta Cancer Centre and Research Institute, Kolkata, India
| | - Gopal C Kundu
- Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science (NCCS), Pune, India
| | - Susanta Roychoudhury
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology, Kolkata, India.,Division of Research, Saroj Gupta Cancer Centre and Research Institute, Kolkata, India
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29
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Integrin αEβ7 + T cells direct intestinal stem cell fate decisions via adhesion signaling. Cell Res 2021; 31:1291-1307. [PMID: 34518654 DOI: 10.1038/s41422-021-00561-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 08/18/2021] [Indexed: 12/11/2022] Open
Abstract
Intestinal stem cell (ISC) differentiation is regulated precisely by a niche in the crypt, where lymphocytes may interact with stem and transient amplifying (TA) cells. However, whether and how lymphocyte-stem/TA cell contact affects ISC differentiation is largely unknown. Here, we uncover a novel role of T cell-stem/TA cell contact in ISC fate decisions. We show that intestinal lymphocyte depletion results in skewed ISC differentiation in mice, which can be rescued by T cell transfer. Mechanistically, integrin αEβ7 expressed on T cells binds to E-cadherin on ISCs and TA cells, triggering E-cadherin endocytosis and the consequent Wnt and Notch signaling alterations. Blocking αEβ7-E-cadherin adhesion suppresses Wnt signaling and promotes Notch signaling in ISCs and TA cells, leading to defective ISC differentiation. Thus, αEβ7+ T cells regulate ISC differentiation at single-cell level through cell-cell contact-mediated αEβ7-E-cadherin adhesion signaling, highlighting a critical role of the T cell-stem/TA cell contact in maintaining intestinal homeostasis.
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30
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Wang J, Yan HB, Zhang Q, Liu WY, Jiang YH, Peng G, Wu FZ, Liu X, Yang PY, Liu F. Enhancement of E-cadherin expression and processing and driving of cancer cell metastasis by ARID1A deficiency. Oncogene 2021; 40:5468-5481. [PMID: 34290402 DOI: 10.1038/s41388-021-01930-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/04/2021] [Accepted: 06/28/2021] [Indexed: 02/07/2023]
Abstract
The ARID1A gene, which encodes a subunit of the SWI/SNF chromatin remodeling complex, has been found to be frequently mutated in many human cancer types. However, the function and mechanism of ARID1A in cancer metastasis are still unclear. Here, we show that knockdown of ARID1A increases the ability of breast cancer cells to proliferate, migrate, invade, and metastasize in vivo. The ARID1A-related SWI/SNF complex binds to the second exon of CDH1 and negatively modulates the expression of E-cadherin/CDH1 by recruiting the transcriptional repressor ZEB2 to the CDH1 promoter and excluding the presence of RNA polymerase II. The silencing of CDH1 attenuated the migration, invasion, and metastasis of breast cancer cells in which ARID1A was silenced. ARID1A depletion increased the intracellular enzymatic processing of E-cadherin and the production of C-terminal fragment 2 (CTF2) of E-cadherin, which stabilized β-catenin by competing for binding to the phosphorylation and degradation complex of β-catenin. The matrix metalloproteinase inhibitor GM6001 inhibited the production of CTF2. In zebrafish and nude mice, ARID1A silencing or CTF2 overexpression activated β-catenin signaling and promoted migration/invasion and metastasis of cancer cells in vivo. The inhibitors GM6001, BB94, and ICG-001 suppressed the migration and invasion of cancer cells with ARID1A-deficiency. Our findings provide novel insights into the mechanism of ARID1A metastasis and offer a scientific basis for targeted therapy of ARID1A-deficient cancer cells.
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Affiliation(s)
- Jie Wang
- Minhang Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical of Sciences, Fudan University, Shanghai, China
| | - Hai-Bo Yan
- Minhang Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical of Sciences, Fudan University, Shanghai, China
| | - Qian Zhang
- Minhang Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical of Sciences, Fudan University, Shanghai, China
| | - Wei-Yan Liu
- Minhang Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical of Sciences, Fudan University, Shanghai, China
| | - Ying-Hua Jiang
- Minhang Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical of Sciences, Fudan University, Shanghai, China
| | - Gang Peng
- Institutes of Brain Science, Fudan University, Shanghai, China
| | - Fei-Zhen Wu
- Department of Systems Biology for Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xin Liu
- Department of Central Laboratory Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Peng-Yuan Yang
- Minhang Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical of Sciences, Fudan University, Shanghai, China.
- Department of Systems Biology for Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
- Department of Chemistry, Fudan University, Shanghai, China.
| | - Feng Liu
- Minhang Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical of Sciences, Fudan University, Shanghai, China.
- Department of Systems Biology for Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
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31
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Hiremath IS, Goel A, Warrier S, Kumar AP, Sethi G, Garg M. The multidimensional role of the Wnt/β-catenin signaling pathway in human malignancies. J Cell Physiol 2021; 237:199-238. [PMID: 34431086 DOI: 10.1002/jcp.30561] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/28/2021] [Accepted: 08/09/2021] [Indexed: 02/06/2023]
Abstract
Several signaling pathways have been identified as important for developmental processes. One of such important cascades is the Wnt/β-catenin signaling pathway, which can regulate various physiological processes such as embryonic development, tissue homeostasis, and tissue regeneration; while its dysregulation is implicated in several pathological conditions especially cancers. Interestingly, deregulation of the Wnt/β-catenin pathway has been reported to be closely associated with initiation, progression, metastasis, maintenance of cancer stem cells, and drug resistance in human malignancies. Moreover, several genetic and experimental models support the inhibition of the Wnt/β-catenin pathway to answer the key issues related to cancer development. The present review focuses on different regulators of Wnt pathway and how distinct mutations, deletion, and amplification in these regulators could possibly play an essential role in the development of several cancers such as colorectal, melanoma, breast, lung, and leukemia. Additionally, we also provide insights on diverse classes of inhibitors of the Wnt/β-catenin pathway, which are currently in preclinical and clinical trial against different cancers.
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Affiliation(s)
- Ishita S Hiremath
- Department of Bioengineering, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
| | - Arul Goel
- La Canada High School, La Canada Flintridge, California, USA
| | - Sudha Warrier
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, Karnataka, India.,Cuor Stem Cellutions Pvt Ltd, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, Karnataka, India
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Cancer Science Institute of Singapore and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Manoj Garg
- Amity Institute of Biotechnology, Amity University, Manesar, Haryana, India
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32
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An Y, Zhou J, Lin G, Wu H, Cong L, Li Y, Qiu X, Shi W. Clinicopathological and Molecular Characteristics of Colorectal Signet Ring Cell Carcinoma: A Review. Pathol Oncol Res 2021; 27:1609859. [PMID: 34381313 PMCID: PMC8351516 DOI: 10.3389/pore.2021.1609859] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 07/14/2021] [Indexed: 12/24/2022]
Abstract
Colorectal signet ring cell carcinoma (SRCC) is a rare subtype of colorectal cancer (CRC) with unique characteristics. Due to the limited researches on it, a comprehensive and in-depth understanding of this subtype is still lacking. In this article, we summarize the clinicopathological features and molecular characteristics of colorectal SRCC based on a literature review. Clinically, SRCC has been associated with young age, proximal site preference, advanced tumor stage, high histological grade, high rate of lymph node involvement, frequent peritoneal metastasis, and a significantly poor prognosis. Regarding molecular characteristics, in SRCC, the mutation burden of the classic signaling pathways that include WNT/β-catenin, RAS/RAF/MAPK, and PI3K/AKT/mTOR signaling pathways are generally reduced. In contrast, some genes related to the “epithelial-mesenchymal transition (EMT) process” and the “stem cell properties”, including RNF43, CDH1, and SMAD4, as well as the related TGF-β signaling pathway have been observed more frequently altered in SRCC than in conventional adenocarcinoma (AC). In many studies but not in others, SRCC showed a higher frequency of BRAF mutation, microsatellite instability-high (MSI-H) and CpG island methylator phenotype (CIMP) positive status compared to AC. It has been proposed that colorectal SRCC consists of two subtypes, in which the MSI+/CIMP+/BRAF+/CD3+/PD-L1+ hypermethylated genotype is more common in the proximal colon, and may represent the potential candidate for immunotherapy. Understanding the special molecular mechanisms related to the aggressive biology of SRCC is of great importance, which may provide a theoretical basis for the development of more targeted and effective treatments for this refractory disease.
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Affiliation(s)
- Yang An
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jiaolin Zhou
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guole Lin
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huanwen Wu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lin Cong
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yunhao Li
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoyuan Qiu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weikun Shi
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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33
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Li JN, Sun HL, Wang MY, Chen PS. E-cadherin Interacts With Posttranslationally-Modified AGO2 to Enhance miRISC Activity. Front Cell Dev Biol 2021; 9:671244. [PMID: 34291046 PMCID: PMC8287304 DOI: 10.3389/fcell.2021.671244] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 05/31/2021] [Indexed: 12/21/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs which post-transcriptionally suppress target mRNAs expression and/or translation to modulate pathophyological processes. Expression and function of miRNAs are fine-tuned by a conserved biogenesis machinery involves two RNase-dependent processing steps of miRNA maturation and the final step of miRNA-induced silencing complex (miRISC)-mediated target silencing. A functional miRISC requires Argonaute 2 (AGO2) as an essential catalytic component which plays central roles in miRISC function. We uncovered a post-translational regulatory mechanism of AGO2 by E-cadherin. Mechanistically, E-cadherin activates ERK to phosphorylate AGO2, along with enhanced protein glycosylation. Consequently, the phosphorylated AGO2 was stabilized and ultimately resulted in induced miRISC activity on gene silencing. This study revealed a novel pathway for miRNA regulation through an E-cadherin-mediated miRISC activation.
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Affiliation(s)
- Jie-Ning Li
- College of Medicine, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hui-Lung Sun
- Department of Chemistry, Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, United States
| | - Ming-Yang Wang
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- Department of Surgical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Pai-Sheng Chen
- College of Medicine, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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34
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Cheng KJ, Mejia Mohammed EH, Khong TL, Mohd Zain S, Thavagnanam S, Ibrahim ZA. IL-1α and colorectal cancer pathogenesis: Enthralling candidate for anti-cancer therapy. Crit Rev Oncol Hematol 2021; 163:103398. [PMID: 34147647 DOI: 10.1016/j.critrevonc.2021.103398] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 01/04/2023] Open
Abstract
Inflammation has been well-established as a hallmark of colorectal cancer (CRC). Interleukin-1 alpha (IL-1α) is one of the primary inflammatory mediators driving the pathogenesis of inflammation-associated CRC. This systematic review presents the roles of IL-1α in the pathogenesis of the disease. Bibliographic databases PubMed, Science Direct, Scopus and Web of Science were systematically searched for articles that addresses the relationship between IL-1α and colorectal cancer. We highlighted various mechanisms by which IL-1α promotes the pathogenesis of CRC including enhancement of angiogenesis, metastasis, resistance to therapy, and inhibition of tumour suppressive genes. We also discussed the potential mechanisms by which IL-1α expression is induced or secreted in various studies. Beyond these, the systematic review also highlights several potential therapeutic strategies which should be further explored in the future; to target IL-1α and/or its associated pathways; paving our way in finding effective treatments for CRC patients.
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Affiliation(s)
- Kim Jun Cheng
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | | | - Tak Loon Khong
- Department of Surgery, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Shamsul Mohd Zain
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Surendran Thavagnanam
- Department of Paediatrics, Royal London Hospital, Whitechapel Rd, Whitechapel, E1 1FR London, United Kingdom
| | - Zaridatul Aini Ibrahim
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia.
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35
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Herrera A, Menendez A, Torroba B, Ochoa A, Pons S. Dbnl and β-catenin promote pro-N-cadherin processing to maintain apico-basal polarity. J Cell Biol 2021; 220:212044. [PMID: 33939796 PMCID: PMC8097490 DOI: 10.1083/jcb.202007055] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 02/15/2021] [Accepted: 03/15/2021] [Indexed: 12/30/2022] Open
Abstract
The neural tube forms when neural stem cells arrange into a pseudostratified, single-cell–layered epithelium, with a marked apico-basal polarity, and in which adherens junctions (AJs) concentrate in the subapical domain. We previously reported that sustained β-catenin expression promotes the formation of enlarged apical complexes (ACs), enhancing apico-basal polarity, although the mechanism through which this occurs remained unclear. Here, we show that β-catenin interacts with phosphorylated pro-N-cadherin early in its transit through the Golgi apparatus, promoting propeptide excision and the final maturation of N-cadherin. We describe a new β-catenin–dependent interaction of N-cadherin with Drebrin-like (Dbnl), an actin-binding protein that is involved in anterograde Golgi trafficking of proteins. Notably, Dbnl knockdown led to pro-N-cadherin accumulation and limited AJ formation. In brief, we demonstrate that Dbnl and β-catenin assist in the maturation of pro-N-cadherin, which is critical for AJ formation and for the recruitment AC components like aPKC and, consequently, for the maintenance of apico-basal polarity.
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Affiliation(s)
- Antonio Herrera
- Instituto de Biología Molecular de Barcelona, Parc Científic de Barcelona, Barcelona, Spain
| | - Anghara Menendez
- Instituto de Biología Molecular de Barcelona, Parc Científic de Barcelona, Barcelona, Spain
| | - Blanca Torroba
- Instituto de Biología Molecular de Barcelona, Parc Científic de Barcelona, Barcelona, Spain
| | - Andrea Ochoa
- Instituto de Biología Molecular de Barcelona, Parc Científic de Barcelona, Barcelona, Spain
| | - Sebastián Pons
- Instituto de Biología Molecular de Barcelona, Parc Científic de Barcelona, Barcelona, Spain
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36
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Lou Z, Lin W, Zhao H, Jiao X, Wang C, Zhao H, Liu L, Liu Y, Xie Q, Huang X, Huang H, Zhao L. Alkaline phosphatase downregulation promotes lung adenocarcinoma metastasis via the c-Myc/RhoA axis. Cancer Cell Int 2021; 21:217. [PMID: 33858415 PMCID: PMC8050923 DOI: 10.1186/s12935-021-01919-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 04/07/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Lung adenocarcinoma (LUAD) metastasis significantly reduces patient survival; hence inhibiting the metastatic ability of lung cancer cells will greatly prolong patient survival. Alkaline phosphatase (ALPL), a homodimeric cell surface phosphohydrolase, is reported to play a controversial role in prostate cancer and ovarian cancer cell migration; however, the function of ALPL in LUAD and the related mechanisms remain unclear. METHODS TCGA database was used to analysis the expression of ALPL, and further verification was performed in a cohort of 36 LUAD samples by qPCR and western blot. Soft-agar assay, transwell assay and lung metastasis assay were employed to detect the function of ALPL in LUAD progression. The qPCR, luciferase promoter reporter assay and western blot were used to clarify the molecular mechanisms of ALPL in promoting metastasis in LUAD. RESULTS ALPL was downregulated in LUAD, and the disease-free survival rate of patients with low ALPL was significantly reduced. Further studies showed that overexpression of ALPL in LUAD cell lines did not significantly affect cell proliferation, but it did significantly attenuate lung metastasis in a mouse model. ALPL downregulation in LUAD led to a decrease in the amount of phosphorylated (p)-ERK. Because p-ERK promotes the classical c-Myc degradation pathway, the decrease in p-ERK led to the accumulation of c-Myc and therefore to an increase in RhoA transcription, which enhanced LUAD cell metastasis. CONCLUSION ALPL specially inhibits the metastasis of LUAD cells by affecting the p-ERK/c-Myc/RhoA axis, providing a theoretical basis for the targeted therapy of clinical LUAD.
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Affiliation(s)
- Zhefeng Lou
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Weiwei Lin
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Huirong Zhao
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Xueli Jiao
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Cong Wang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - He Zhao
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Lu Liu
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Yu Liu
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Qipeng Xie
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Xing Huang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, School of Medicine, the First Affiliated Hospital, Zhejiang University, Hangzhou, 310003, Zhejiang, China.
| | - Haishan Huang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
| | - Lingling Zhao
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
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37
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Godwin I, Anto NP, Bava SV, Babu MS, Jinesh GG. Targeting K-Ras and apoptosis-driven cellular transformation in cancer. Cell Death Discov 2021; 7:80. [PMID: 33854056 PMCID: PMC8047025 DOI: 10.1038/s41420-021-00457-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/23/2021] [Accepted: 03/21/2021] [Indexed: 02/07/2023] Open
Abstract
Cellular transformation is a major event that helps cells to evade apoptosis, genomic instability checkpoints, and immune surveillance to initiate tumorigenesis and to promote progression by cancer stem cell expansion. However, the key molecular players that govern cellular transformation and ways to target cellular transformation for therapy are poorly understood to date. Here we draw key evidences from the literature on K-Ras-driven cellular transformation in the context of apoptosis to shed light on the key players that are required for cellular transformation and explain how aiming p53 could be useful to target cellular transformation. The defects in key apoptosis regulators such as p53, Bax, and Bak lead to apoptosis evasion, cellular transformation, and genomic instability to further lead to stemness, tumorigenesis, and metastasis via c-Myc-dependent transcription. Therefore enabling key apoptotic checkpoints in combination with K-Ras inhibitors will be a promising therapeutic target in cancer therapy.
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Affiliation(s)
- Isha Godwin
- Saveetha Medical College, Thandalam, Chennai, Tamil Nadu, 602105, India.
| | - Nikhil Ponnoor Anto
- Shraga Segal Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beersheba, Israel
| | - Smitha V Bava
- Department of Biotechnology, University of Calicut, Malappuram, Kerala, 673635, India
| | - Mani Shankar Babu
- Department of Botany, University College, Thiruvananthapuram, Kerala, 695 034, India
| | - Goodwin G Jinesh
- Departments of Molecular Oncology, and Sarcoma, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA.
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38
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Nanodiamonds inhibit scratch-wound repair in lung epithelial cell monolayers by blocking cell migration and inhibiting cell proliferation. Toxicol Lett 2021; 341:83-93. [PMID: 33508333 DOI: 10.1016/j.toxlet.2021.01.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 01/11/2021] [Accepted: 01/20/2021] [Indexed: 12/29/2022]
Abstract
Proliferation and migration of lung epithelial cells following the injury to the epithelial lining of alveoli and airways in the lung are pivotal for remodeling and repair of the wound to restore normal lung function. In the present study, we examined the modulatory effect of carboxylated nanodiamonds (cNDs) on the cell division, migration, and adhesion of epithelial cells in the well-established in vitro model of wound repair and cell migration. Flow cytometry and confocal microscopy results indicated that both LA4 and A549 cells effectively internalized fluorescent carboxylated nanodiamonds (cFNDs) and the internalized nanodiamonds were essentially localized in the cytoplasmic region. Treatment with cNDs blocked the division and migration of cells to fill the scratch wound. Live cell imaging and time-lapse videography of the wound healing process indicated a significant inhibition of cell proliferation activity in cND-treated cells and blocked the wound repair process. Trans-well cell-migration assay results further support the inhibitory effect of cNDs on the cell migration process. Western blotting and immunofluorescence staining indicated that the crucial proteins involved in epithelial-mesenchymal transition (EMT) and cell migration i.e. β-catenin, Vimentin, NM-myosin, and Focal Adhesion Kinase (FAK) were downregulated after treatment with cNDs, while the expression of E-cadherin and Claudin-1, major cell adhesion markers remained unaltered. Taken together, our results indicate that the decline in cell proliferation activity, downregulation in the expression of various crucial protein like β-Catenin, NM-myosin, FAK, and Vimentin involved in the cell migration and unaltered expression of cell adhesion molecules E-cadherin and Claudin-1, may be the factors that contribute to the cND-mediated inhibition of EMT during the wound repair process in the monolayers of lung epithelial cells.
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39
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Kim HN, Ruan Y, Ogana H, Kim YM. Cadherins, Selectins, and Integrins in CAM-DR in Leukemia. Front Oncol 2020; 10:592733. [PMID: 33425742 PMCID: PMC7793796 DOI: 10.3389/fonc.2020.592733] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 10/22/2020] [Indexed: 12/12/2022] Open
Abstract
The interaction between leukemia cells and the bone microenvironment is known to provide drug resistance in leukemia cells. This phenomenon, called cell adhesion-mediated drug resistance (CAM-DR), has been demonstrated in many subsets of leukemia including B- and T-acute lymphoblastic leukemia (B- and T-ALL) and acute myeloid leukemia (AML). Cell adhesion molecules (CAMs) are surface molecules that allow cell-cell or cell-extracellular matrix (ECM) adhesion. CAMs not only recognize ligands for binding but also initiate the intracellular signaling pathways that are associated with cell proliferation, survival, and drug resistance upon binding to their ligands. Cadherins, selectins, and integrins are well-known cell adhesion molecules that allow binding to neighboring cells, ECM proteins, and soluble factors. The expression of cadherin, selectin, and integrin correlates with the increased drug resistance of leukemia cells. This paper will review the role of cadherins, selectins, and integrins in CAM-DR and the results of clinical trials targeting these molecules.
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Affiliation(s)
- Hye Na Kim
- Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Cancer and Blood Disease Institute, Los Angeles, CA, United States
| | - Yongsheng Ruan
- Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Cancer and Blood Disease Institute, Los Angeles, CA, United States.,Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Heather Ogana
- Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Cancer and Blood Disease Institute, Los Angeles, CA, United States
| | - Yong-Mi Kim
- Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Cancer and Blood Disease Institute, Los Angeles, CA, United States
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40
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Beck M, Baranger M, Moufok-Sadoun A, Bersuder E, Hinkel I, Mellitzer G, Martin E, Marisa L, Duluc I, de Reynies A, Gaiddon C, Freund JN, Gross I. The atypical cadherin MUCDHL antagonizes colon cancer formation and inhibits oncogenic signaling through multiple mechanisms. Oncogene 2020; 40:522-535. [PMID: 33188295 DOI: 10.1038/s41388-020-01546-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 10/12/2020] [Accepted: 10/28/2020] [Indexed: 01/24/2023]
Abstract
Cadherins form a large and pleiotropic superfamily of membranous proteins sharing Ca2+-binding repeats. While the importance of classic cadherins such as E- or N-cadherin for tumorigenesis is acknowledged, there is much less information about other cadherins that are merely considered as tissue-specific adhesion molecules. Here, we focused on the atypical cadherin MUCDHL that stood out for its unusual features and unique function in the gut. Analyses of transcriptomic data sets (n > 250) established that MUCDHL mRNA levels are down-regulated in colorectal tumors. Importantly, the decrease of MUCDHL expression is more pronounced in the worst-prognosis subset of tumors and is associated with decreased survival. Molecular characterization of the tumors indicated a negative correlation with proliferation-related processes (e.g., nucleic acid metabolism, DNA replication). Functional genomic studies showed that the loss of MUCDHL enhanced tumor incidence and burden in intestinal tumor-prone mice. Extensive structure/function analyses revealed that the mode of action of MUCDHL goes beyond membrane sequestration of ß-catenin and targets through its extracellular domain key oncogenic signaling pathways (e.g., EGFR, AKT). Beyond MUCDHL, this study illustrates how the loss of a gene critical for the morphological and functional features of mature cells contributes to tumorigenesis by dysregulating oncogenic pathways.
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Affiliation(s)
- Marine Beck
- Université de Strasbourg, Inserm, IRFAC UMR-S1113, 67200, Strasbourg, France
| | - Mathilde Baranger
- Université de Strasbourg, Inserm, IRFAC UMR-S1113, 67200, Strasbourg, France
| | - Ahlam Moufok-Sadoun
- Université de Strasbourg, Inserm, IRFAC UMR-S1113, 67200, Strasbourg, France
| | - Emilie Bersuder
- Université de Strasbourg, Inserm, IRFAC UMR-S1113, 67200, Strasbourg, France
| | - Isabelle Hinkel
- Université de Strasbourg, Inserm, IRFAC UMR-S1113, 67200, Strasbourg, France
| | - Georg Mellitzer
- Université de Strasbourg, Inserm, IRFAC UMR-S1113, 67200, Strasbourg, France
| | - Elisabeth Martin
- Université de Strasbourg, Inserm, IRFAC UMR-S1113, 67200, Strasbourg, France
| | | | - Isabelle Duluc
- Université de Strasbourg, Inserm, IRFAC UMR-S1113, 67200, Strasbourg, France
| | | | - Christian Gaiddon
- Université de Strasbourg, Inserm, IRFAC UMR-S1113, 67200, Strasbourg, France
| | - Jean-Noel Freund
- Université de Strasbourg, Inserm, IRFAC UMR-S1113, 67200, Strasbourg, France
| | - Isabelle Gross
- Université de Strasbourg, Inserm, IRFAC UMR-S1113, 67200, Strasbourg, France.
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Mishra R, Nathani S, Varshney R, Sircar D, Roy P. Berberine reverses epithelial-mesenchymal transition and modulates histone methylation in osteosarcoma cells. Mol Biol Rep 2020; 47:8499-8511. [PMID: 33074411 DOI: 10.1007/s11033-020-05892-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 10/03/2020] [Indexed: 02/07/2023]
Abstract
Osteosarcoma is the most frequently occurring cancer in children as well as young adolescents and the metastatic forms worsen this condition to a further great extent. The metastatic dissemination of cancer cells is often acquired through a process of epithelial-mesenchymal transition (EMT). Since, phytochemicals have attracted intense interest in recent years due to their diverse pharmacological effects, in the present study, we investigated if berberine, a naturally occurring isoquinoline quaternary alkaloid, could modulate the EMT in osteosarcoma cells. Our experimental studies showed that berberine reduced cell viability, colony formation, wound healing ability and migration of osteosarcoma cells. Also, berberine significantly reduced the expression of matrix metalloproteinase (MMP)-2, suggesting its inhibitory action on the matrix metalloproteinases that are required for cancer cell invasion. The significant reduction in the expression of vimentin, N-cadherin, fibronectin and increased expression of E-cadherin further suggested its role in the inhibition of EMT in osteosarcoma cells. The downregulation of H3K27me3, as well as the decreased expression of the histone methyl transferase enzyme EZH2, further substantiated the fact that the plant alkaloid can be used as an epigenetic modulator in the treatment of osteosarcoma. In conclusion, our findings suggest that berberine inhibits proliferation and migration of osteosarcoma cells and most importantly reverses EMT along with modulation of key epigenetic regulators.
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Affiliation(s)
- Rutusmita Mishra
- Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, 247 667, India
| | - Sandip Nathani
- Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, 247 667, India
| | - Ritu Varshney
- Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, 247 667, India
| | - Debabrata Sircar
- Plant Molecular Biology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, 247 667, India
| | - Partha Roy
- Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, 247 667, India.
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Kaszak I, Witkowska-Piłaszewicz O, Niewiadomska Z, Dworecka-Kaszak B, Ngosa Toka F, Jurka P. Role of Cadherins in Cancer-A Review. Int J Mol Sci 2020; 21:E7624. [PMID: 33076339 PMCID: PMC7589192 DOI: 10.3390/ijms21207624] [Citation(s) in RCA: 208] [Impact Index Per Article: 41.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 10/10/2020] [Accepted: 10/12/2020] [Indexed: 02/06/2023] Open
Abstract
Cadherins play an important role in tissue homeostasis, as they are responsible for cell-cell adhesion during embryogenesis, tissue morphogenesis, differentiation and carcinogenesis. Cadherins are inseparably connected with catenins, forming cadherin-catenin complexes, which are crucial for cell-to-cell adherence. Any dysfunction or destabilization of cadherin-catenin complex may result in tumor progression. Epithelial mesenchymal transition (EMT) is a mechanism in which epithelial cadherin (E-cadherin) expression is lost during tumor progression. However, during tumorigenesis, many processes take place, and downregulation of E-cadherin, nuclear β-catenin and p120 catenin (p120) signaling are among the most critical. Additional signaling pathways, such as Receptor tyrosine kinase (RTK), Rho GTPases, phosphoinositide 3-kinase (PI3K) and Hippo affect cadherin cell-cell adhesion and also contribute to tumor progression and metastasis. Many signaling pathways may be activated during tumorigenesis; thus, cadherin-targeting drugs seem to limit the progression of malignant tumor. This review discusses the role of cadherins in selected signaling mechanisms involved in tumor growth. The clinical importance of cadherin will be discussed in cases of human and animal cancers.
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Affiliation(s)
- Ilona Kaszak
- Department of Small Animal Diseases, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 02-787 Warsaw, Poland;
| | - Olga Witkowska-Piłaszewicz
- Department of Pathology and Veterinary Diagnostics, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 02-787 Warsaw, Poland
| | - Zuzanna Niewiadomska
- Carnivore Reproduction Study Center, Ecole Nationale Veterinaire d’Alfort, 94700 Maison Alfort, France;
| | - Bożena Dworecka-Kaszak
- Department of Preclinical Sciences, Institute of Veterinary Medicine; Warsaw University of Life Sciences, 02-787 Warsaw, Poland;
| | - Felix Ngosa Toka
- Center for Integrative Mammalian Research, Ross University School of Veterinary Medicine, BOX 334 Basseterre, Saint Kitts and Nevis, West Indies;
| | - Piotr Jurka
- Department of Small Animal Diseases, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 02-787 Warsaw, Poland;
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Ichikawa T, Stuckenholz C, Davidson LA. Non-junctional role of Cadherin3 in cell migration and contact inhibition of locomotion via domain-dependent, opposing regulation of Rac1. Sci Rep 2020; 10:17326. [PMID: 33060598 PMCID: PMC7567069 DOI: 10.1038/s41598-020-73862-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 09/07/2020] [Indexed: 11/08/2022] Open
Abstract
Classical cadherins are well-known adhesion molecules responsible for physically connecting neighboring cells and signaling this cell-cell contact. Recent studies have suggested novel signaling roles for "non-junctional" cadherins (NJCads); however, the function of cadherin signaling independent of cell-cell contacts remains unknown. In this study, mesendodermal cells and tissues from gastrula stage Xenopus laevis embryos demonstrate that deletion of extracellular domains of Cadherin3 (Cdh3; formerly C-cadherin in Xenopus) disrupts contact inhibition of locomotion. In both bulk Rac1 activity assays and spatio-temporal FRET image analysis, the extracellular and cytoplasmic Cdh3 domains disrupt NJCad signaling and regulate Rac1 activity in opposing directions. Stabilization of the cytoskeleton counteracted this regulation in single cell migration assays. Our study provides novel insights into adhesion-independent signaling by Cadherin3 and its role in regulating single and collective cell migration.
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Affiliation(s)
- Takehiko Ichikawa
- Department of Bioengineering, University of Pittsburgh, 3501 Fifth Avenue, 5059-BST3, Pittsburgh, PA, 15260, USA
- Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa, 920-1192, Japan
| | - Carsten Stuckenholz
- Department of Bioengineering, University of Pittsburgh, 3501 Fifth Avenue, 5059-BST3, Pittsburgh, PA, 15260, USA
| | - Lance A Davidson
- Department of Bioengineering, University of Pittsburgh, 3501 Fifth Avenue, 5059-BST3, Pittsburgh, PA, 15260, USA.
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
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Bisphenol A impaired cell adhesion by altering the expression of adhesion and cytoskeleton proteins on human podocytes. Sci Rep 2020; 10:16638. [PMID: 33024228 PMCID: PMC7538920 DOI: 10.1038/s41598-020-73636-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 09/11/2020] [Indexed: 12/12/2022] Open
Abstract
Bisphenol A (BPA), a chemical -xenoestrogen- used in food containers is present in the urine of almost the entire population. Recently, several extensive population studies have proven a significant association between urinary excretion of BPA and albuminuria. The alteration of glomerular podocytes or "podocytopathy" is a common event in chronic albuminuric conditions. Since many podocytes recovered from patients' urine are viable, we hypothesized that BPA could impair podocyte adhesion capabilities. Using an in vitro adhesion assay, we observed that BPA impaired podocyte adhesion, an effect that was abrogated by Tamoxifen (an estrogen receptor blocker). Genomic and proteomic analyses revealed that BPA affected the expression of several podocyte cytoskeleton and adhesion proteins. Western blot and immunocytochemistry confirmed the alteration in the protein expression of tubulin, vimentin, podocin, cofilin-1, vinculin, E-cadherin, nephrin, VCAM-1, tenascin-C, and β-catenin. Moreover, we also found that BPA, while decreased podocyte nitric oxide production, it lead to overproduction of ion superoxide. In conclusion, our data show that BPA induced a novel type of podocytopathy characterizes by an impairment of podocyte adhesion, by altering the expression of adhesion and cytoskeleton proteins. Moreover, BPA diminished production of podocyte nitric oxide and induced the overproduction of oxygen-free metabolites. These data provide a mechanism by which BPA could participate in the pathogenesis and progression of renal diseases.
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Kim TW, Hong DW, Park JW, Hong SH. CB11, a novel purine-based PPARɣ ligand, overcomes radio-resistance by regulating ATM signalling and EMT in human non-small-cell lung cancer cells. Br J Cancer 2020; 123:1737-1748. [PMID: 32958825 PMCID: PMC7723055 DOI: 10.1038/s41416-020-01088-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 07/27/2020] [Accepted: 09/02/2020] [Indexed: 01/03/2023] Open
Abstract
Background Peroxisome proliferator-activated receptor γ (PPARγ) agonists frequently induce cell death in human non-small-cell lung cancer (NSCLC) cells. However, majority of NSCLC patients acquire resistance after cancer therapy, and it is still unclear. Methods In this study we investigated the apoptotic mechanism and the anti-cancer effects of a novel purine-based PPARγ agonist, CB11 (8-(2-aminophenyl)-3-butyl-1,6,7-trimethyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione), on human NSCLC cells. CB11 mediates PPARγ-dependent cell death, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) collapse, cell cycle arrest, lactate dehydrogenase (LDH) cytotoxicity, and caspase-3 activity in human NSCLC cells. Results CB11 causes cell death via ROS-mediated ATM-p53-GADD45α signalling in human NSCLC cells, and diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, decreases cell death by inhibiting CB11-mediated ATM signalling. In a xenograft experiment, CB11 dramatically reduced tumour volume when compared to a control group. Furthermore, CB11 induced cell death by inhibiting epithelial-to-mesenchymal transition (EMT) under radiation exposure in radiation-resistant human NSCLC cells. However, PPARγ deficiency inhibited cell death by blocking the ATM-p53 axis in radiation/CB11-induced radiation-resistant human NSCLC cells. Conclusions Taken together, our results suggest that CB11, a novel PPARγ agonist, may be a novel anti-cancer agent, and it could be useful in a therapeutic strategy to overcome radio-resistance in radiation-exposed NSCLC.
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Affiliation(s)
- Tae Woo Kim
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, 139-706, Republic of Korea
| | - Da-Won Hong
- Laboratory of RNA Cell Biology, Graduate Department of Bioconvergence Science and Technology, Dankook University, Jukjeon-ro 152, Suji-gu, Yongin-si, Gyeonggi-do, 16892, Republic of Korea
| | - Joung Whan Park
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, 139-706, Republic of Korea
| | - Sung Hee Hong
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, 139-706, Republic of Korea.
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Wang M, Chen X, Wu Y, Zheng Q, Chen W, Yan Y, Luan X, Shen C, Fang J, Zheng B, Yu J. RpS13 controls the homeostasis of germline stem cell niche through Rho1-mediated signals in the Drosophila testis. Cell Prolif 2020; 53:e12899. [PMID: 32896929 PMCID: PMC7574871 DOI: 10.1111/cpr.12899] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 08/15/2020] [Accepted: 08/18/2020] [Indexed: 12/20/2022] Open
Abstract
Objectives Stem cell niche regulated the renewal and differentiation of germline stem cells (GSCs) in Drosophila. Previously, we and others identified a series of genes encoding ribosomal proteins that may contribute to the self‐renewal and differentiation of GSCs. However, the mechanisms that maintain and differentiate GSCs in their niches were not well understood. Materials and Methods Flies were used to generate tissue‐specific gene knockdown. Small interfering RNAs were used to knockdown genes in S2 cells. qRT‐PCR was used to examine the relative mRNA expression level. TUNEL staining or flow cytometry assays were used to detect cell survival. Immunofluorescence was used to determine protein localization and expression pattern. Results Herein, using a genetic manipulation approach, we investigated the role of ribosomal protein S13 (RpS13) in testes and S2 cells. We reported that RpS13 was required for the self‐renewal and differentiation of GSCs. We also demonstrated that RpS13 regulated cell proliferation and apoptosis. Mechanistically, we showed that RpS13 regulated the expression of ribosome subunits and could moderate the expression of the Rho1, DE‐cad and Arm proteins. Notably, Rho1 imitated the phenotype of RpS13 in both Drosophila testes and S2 cells, and recruited cell adhesions, which was mediated by the DE‐cad and Arm proteins. Conclusion These findings uncover a novel mechanism of RpS13 that mediates Rho1 signals in the stem cell niche of the Drosophila testis.
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Affiliation(s)
- Min Wang
- Department of Gynecology, the Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
| | - Xia Chen
- Department of Gynecology, the Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
| | - Yibo Wu
- Human Reproductive and Genetic Center, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China
| | - Qianwen Zheng
- Department of Gynecology, the Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
| | - Wanyin Chen
- Department of Gynecology, the Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
| | - Yidan Yan
- Department of Gynecology, the Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
| | - Xiaojin Luan
- Department of Gynecology, the Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
| | - Cong Shen
- State Key Laboratory of Reproductive Medicine, Center for Reproduction and Genetics, Suzhou Municipal Hospital, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Jie Fang
- Department of Gynecology, the Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
| | - Bo Zheng
- State Key Laboratory of Reproductive Medicine, Center for Reproduction and Genetics, Suzhou Municipal Hospital, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Jun Yu
- Department of Gynecology, the Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
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Hu MN, Hu SH, Zhang XW, Xiong SM, Deng H. Overview on new progress of hereditary diffuse gastric cancer with CDH1 variants. TUMORI JOURNAL 2020; 106:346-355. [PMID: 32811340 DOI: 10.1177/0300891620949668] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Hereditary diffuse gastric cancer (HDGC), comprising 1%-3% of gastric malignances, has been associated with CDH1 variants. Accumulating evidence has demonstrated more than 100 germline CDH1 variant types. E-cadherin encoded by the CDH1 gene serves as a tumor suppressor protein. CDH1 promoter hypermethylation and other molecular mechanisms resulting in E-cadherin dysfunction are involved in the tumorigenesis of HDGC. Histopathology exhibits characteristic signet ring cells, and immunohistochemical staining may show negativity for E-cadherin and other signaling proteins. Early HDGC is difficult to detect by endoscopy due to the development of lesions beneath the mucosa. Prophylactic gastrectomy is the most recommended treatment for pathogenic CDH1 variant carriers. Recent studies have promoted the progression of promising molecular-targeted therapies and management strategies. This review summarizes recent advances in CDH1 variant types, tumorigenesis mechanisms, diagnosis, and therapy, as well as clinical implications for future gene therapies.
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Affiliation(s)
- Mu-Ni Hu
- Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Shu-Hui Hu
- Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Xing-Wei Zhang
- Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Shu-Min Xiong
- Department of Ophthalmology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Huan Deng
- Molecular Medicine and Genetics Center, the Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China.,Renmin Institute of Forensic Medicine in Jiangxi, Nanchang, Jiangxi Province, China
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Zhang J, He X, Chen X, Wu Y, Dong L, Cheng K, Lin J, Wang H, Weng W. Enhancing osteogenic differentiation of BMSCs on high magnetoelectric response films. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 113:110970. [DOI: 10.1016/j.msec.2020.110970] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 02/25/2020] [Accepted: 04/13/2020] [Indexed: 12/19/2022]
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Abedini A, Sayed C, Carter LE, Boerboom D, Vanderhyden BC. Non-canonical WNT5a regulates Epithelial-to-Mesenchymal Transition in the mouse ovarian surface epithelium. Sci Rep 2020; 10:9695. [PMID: 32546756 PMCID: PMC7298016 DOI: 10.1038/s41598-020-66559-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 05/22/2020] [Indexed: 01/06/2023] Open
Abstract
The ovarian surface epithelium (OSE) is a monolayer that covers the ovarian surface and is involved in ovulation by rupturing and enabling release of a mature oocyte and by repairing the wound after ovulation. Epithelial-to-mesenchymal transition (EMT) is a mechanism that may promote wound healing after ovulation. While this process is poorly understood in the OSE, in other tissues wound repair is known to be under the control of the local microenvironment and different growth factors such as the WNT signaling pathway. Among WNT family members, WNT4 and WNT5a are expressed in the OSE and are critical for the ovulatory process. The objective of this study was to determine the potential roles of WNT4 and WNT5a in regulating the OSE layer. Using primary cultures of mouse OSE cells, we found WNT5a, but not WNT4, promotes EMT through a non-canonical Ca2+-dependent pathway, up-regulating the expression of Vimentin and CD44, enhancing cell migration, and inhibiting the CTNNB1 pathway and proliferation. We conclude that WNT5a is a stimulator of the EMT in OSE cells, and acts by suppressing canonical WNT signaling activity and inducing the non-canonical Ca2+ pathway.
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Affiliation(s)
- Atefeh Abedini
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Céline Sayed
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Lauren E Carter
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Derek Boerboom
- Département de Biomédecine Vétérinaire, Faculté de médecine vétérinaire, Université de Montréal, St-Hyacinthe, Québec, Canada
| | - Barbara C Vanderhyden
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
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Jamal MH, Nunes ACF, Vaziri ND, Ramchandran R, Bacallao RL, Nauli AM, Nauli SM. Rapamycin treatment correlates changes in primary cilia expression with cell cycle regulation in epithelial cells. Biochem Pharmacol 2020; 178:114056. [PMID: 32470549 DOI: 10.1016/j.bcp.2020.114056] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Accepted: 05/22/2020] [Indexed: 02/07/2023]
Abstract
Primary cilia are sensory organelles that regulate cell cycle and signaling pathways. In addition to its association with cancer, dysfunction of primary cilia is responsible for the pathogenesis of polycystic kidney disease (PKD) and other ciliopathies. Because the association between cilia formation or length and cell cycle or division is poorly understood, we here evaluated their correlation in this study. Using Spectral Karyotyping (SKY) technique, we showed that PKD and the cancer/tumorigenic epithelial cells PC3, DU145, and NL20-TA were associated with abnormal ploidy. We also showed that PKD and the cancer epithelia were highly proliferative. Importantly, the cancer epithelial cells had a reduction in the presence and/or length of primary cilia relative to the normal kidney (NK) cells. We then used rapamycin to restore the expression and length of primary cilia in these cells. Our subsequent analyses indicated that both the presence and length of primary cilia were inversely correlated with cell proliferation. Collectively, our data suggest that restoring the presence and/or length of primary cilia may serve as a novel approach to inhibit cancer cell proliferation.
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Affiliation(s)
- Maha H Jamal
- Department of Biomedical and Pharmaceutical Sciences, Harry and Diane Rinker Health Science Campus, Chapman University, Irvine, CA, USA; Department of Pharmacology, School of Medicine, King Abdulaziz University, Jeddah, KSA, Saudi Arabia
| | - Ane C F Nunes
- Division of Nephrology and Hypertension, Department of Physiology and Biophysics Division of Nephrology and Hypertension, University of California, Irvine, USA
| | - Nosratola D Vaziri
- Division of Nephrology and Hypertension, Department of Physiology and Biophysics Division of Nephrology and Hypertension, University of California, Irvine, USA
| | - Ramani Ramchandran
- Department of Pediatrics, Developmental Vascular Biology Program, Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Robert L Bacallao
- Division of Nephrology, Department of Cellular and Integrative Physiology Indiana University School of Medicine, Indianapolis, IN, USA
| | - Andromeda M Nauli
- Department of Pharmaceutical Sciences, College of Pharmacy, Marshall B. Ketchum University, Fullerton, CA, USA
| | - Surya M Nauli
- Department of Biomedical and Pharmaceutical Sciences, Harry and Diane Rinker Health Science Campus, Chapman University, Irvine, CA, USA; Department of Medicine, University of California Irvine, Irvine, CA, USA.
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