|
1
|
Ji PX, Zhang P, Zhou HL, Yu H, Fu Y. MEX3A promotes cell proliferation by regulating the RORA/β-catenin pathway in hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:102084. [DOI: 10.4251/wjgo.v17.i4.102084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 01/27/2025] [Accepted: 02/14/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND MEX3A is a member of the human homologous gene MEX-3 family. It has been shown to promote cell proliferation and migration in various cancers, indicating its potential clinical significance. However, the role of MEX3A in hepatocellular carcinoma (HCC) remains largely unexplored, with limited reports available in the literature.
AIM To investigate expression and clinical significance of MEX3A in HCC and explore its potential role in tumor progression.
METHODS We analyzed MEX3A mRNA expression in HCC and adjacent tissues using data from The Cancer Genome Atlas (TCGA). The correlation between MEX3A expression and overall survival (OS) was evaluated. Immunohistochemistry was performed on HCC surgical specimens to validate MEX3A expression and its association with clinical parameters, including hepatitis B virus (HBV) positivity, tumor differentiation and tumor size. Additionally, MEX3A knockdown HCC cell lines were constructed to explore the biological functions of MEX3A. Cell proliferation was assessed using cell counting kit-8 and clone formation assays, while cell cycle progression was analyzed by flow cytometry. The effects of MEX3A on the Wnt/β-catenin signaling pathway were examined by western blotting and immunofluorescence. Cell migration was evaluated using scratch and Transwell assays. Finally, the role of the transcription factor RORA in mediating MEX3A effects was explored by silencing RORA and analyzing its impact on cell proliferation and protein expression.
RESULTS TCGA data analysis revealed that MEX3A mRNA expression was significantly higher in HCC tissues compared to adjacent tissues. Higher MEX3A expression was associated with poorer OS. These findings were validated in HCC surgical specimens. Immunohistochemistry confirmed elevated MEX3A expression in HCC tissues and showed positive correlations with Ki-67 and vimentin levels. MEX3A expression was closely related to HBV positivity, tumor differentiation and tumor size. Mechanistic studies demonstrated that MEX3A knockdown inhibited cell proliferation and cell cycle progression, as shown by reduced expression of β-catenin, c-Myc and cyclin D1. Additionally, MEX3A knockdown inhibited the nuclear entry of β-catenin, thereby suppressing the activation of downstream oncogenic pathways. MEX3A depletion significantly reduced the migratory ability of HCC cells, likely through downregulation of the epithelial-mesenchymal transition pathway. Transcription factor analysis identified RORA as a potential mediator of MEX3A effects. Silencing RORA antagonized the effects of MEX3A on cell proliferation and the expression of β-catenin, c-Myc and cyclin D1.
CONCLUSION MEX3A promotes cell proliferation in HCC by regulating the RORA/β-catenin pathway. Our findings suggest that MEX3A could serve as a prognostic marker and therapeutic target for HCC.
Collapse
Affiliation(s)
- Peng-Xiang Ji
- Hand Surgery Laboratory, Suzhou Ruihua Orthopedic Hospital, Suzhou Medical College of Soochow University, Suzhou 215104, Jiangsu Province, China
| | - Ping Zhang
- Hand Surgery Laboratory, Suzhou Ruihua Orthopedic Hospital, Suzhou Medical College of Soochow University, Suzhou 215104, Jiangsu Province, China
| | - Hui-Ling Zhou
- Department of Pathology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou 225300, Jiangsu Province, China
| | - Hong Yu
- Department of Pathology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou 225300, Jiangsu Province, China
| | - Yi Fu
- Department of Human Anatomy, Histology and Embryology, Suzhou Medical College of Soochow University, Suzhou 215123, Jiangsu Province, China
| |
Collapse
|
|
2
|
Li B, Ming H, Qin S, Nice EC, Dong J, Du Z, Huang C. Redox regulation: mechanisms, biology and therapeutic targets in diseases. Signal Transduct Target Ther 2025; 10:72. [PMID: 40050273 PMCID: PMC11885647 DOI: 10.1038/s41392-024-02095-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 10/09/2024] [Accepted: 11/21/2024] [Indexed: 03/09/2025] Open
Abstract
Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both the onset and progression of various diseases. Under physiological conditions, oxidative free radicals generated by the mitochondrial oxidative respiratory chain, endoplasmic reticulum, and NADPH oxidases can be effectively neutralized by NRF2-mediated antioxidant responses. These responses elevate the synthesis of superoxide dismutase (SOD), catalase, as well as key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption of this finely tuned equilibrium is closely linked to the pathogenesis of a wide range of diseases. Recent advances have broadened our understanding of the molecular mechanisms underpinning this dysregulation, highlighting the pivotal roles of genomic instability, epigenetic modifications, protein degradation, and metabolic reprogramming. These findings provide a foundation for exploring redox regulation as a mechanistic basis for improving therapeutic strategies. While antioxidant-based therapies have shown early promise in conditions where oxidative stress plays a primary pathological role, their efficacy in diseases characterized by complex, multifactorial etiologies remains controversial. A deeper, context-specific understanding of redox signaling, particularly the roles of redox-sensitive proteins, is critical for designing targeted therapies aimed at re-establishing redox balance. Emerging small molecule inhibitors that target specific cysteine residues in redox-sensitive proteins have demonstrated promising preclinical outcomes, setting the stage for forthcoming clinical trials. In this review, we summarize our current understanding of the intricate relationship between oxidative stress and disease pathogenesis and also discuss how these insights can be leveraged to optimize therapeutic strategies in clinical practice.
Collapse
Affiliation(s)
- Bowen Li
- Department of Biotherapy, Institute of Oxidative Stress Medicine, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, PR China
| | - Hui Ming
- Department of Biotherapy, Institute of Oxidative Stress Medicine, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, PR China
| | - Siyuan Qin
- Department of Biotherapy, Institute of Oxidative Stress Medicine, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, PR China
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, PR China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Jingsi Dong
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Zhongyan Du
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
- Key Laboratory of Blood-stasis-toxin Syndrome of Zhejiang Province, Hangzhou, China.
| | - Canhua Huang
- Department of Biotherapy, Institute of Oxidative Stress Medicine, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, PR China.
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, PR China.
| |
Collapse
|
|
3
|
Alfaro-García JP, Orozco-Castaño CA, Sánchez-Rendón JA, Casanova-Yépes HF, Vicente-Manzanares M, Gallego-Gómez JC. Characterization of the Temporal Dynamics of the Endothelial-Mesenchymal-like Transition Induced by Soluble Factors from Dengue Virus Infection in Microvascular Endothelial Cells. Int J Mol Sci 2025; 26:2139. [PMID: 40076764 PMCID: PMC11900998 DOI: 10.3390/ijms26052139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 02/22/2025] [Accepted: 02/25/2025] [Indexed: 03/14/2025] Open
Abstract
Dengue virus (DV) infection poses a severe life-threatening risk in certain cases. This is mainly due to endothelial dysregulation, which causes plasma leakage and hemorrhage. However, the etiology of DV-induced endothelial dysregulation remains incompletely understood. To identify the potential mechanisms of endothelial dysregulation caused by DV, the effects of conditioned media from Dengue virus (CMDV) on the mechanics and transcriptional profile of the endothelial cells were examined using permeability assays, atomic force microscopy, In-Cell Western blot and in silico transcriptomics. Exposure of HMEC-1 cells to the CMDV increased endothelial permeability and cellular stiffness. It also induced the expression of the key proteins associated with endothelial-to-mesenchymal transition (EndMT). These data support the notion that the DV promotes endothelial dysfunction by triggering transcriptional programs that compromise the endothelial barrier function. Understanding the molecular mechanisms underlying DV-induced endothelial dysregulation is crucial for developing targeted therapeutic strategies to mitigate the severe outcomes associated with dengue infection.
Collapse
Affiliation(s)
- Jenny Paola Alfaro-García
- Grupo Medicina de Translación—Facultad de Medicina, Universidad de Antioquia, Medellín 050010, Colombia;
| | | | - Julián Andrés Sánchez-Rendón
- Grupo de Coloides—Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia, Medellín 050010, Colombia; (J.A.S.-R.); (H.F.C.-Y.)
| | - Herley Fernando Casanova-Yépes
- Grupo de Coloides—Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia, Medellín 050010, Colombia; (J.A.S.-R.); (H.F.C.-Y.)
| | - Miguel Vicente-Manzanares
- Molecular Mechanisms Program, Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)—University of Salamanca, 37007 Salamanca, Spain
| | - Juan Carlos Gallego-Gómez
- Grupo Medicina de Translación—Facultad de Medicina, Universidad de Antioquia, Medellín 050010, Colombia;
| |
Collapse
|
|
4
|
Kong D, Zhang Y, Jiang L, Long N, Wang C, Qiu M. Comprehensive analysis reveals the tumor suppressor role of macrophage signature gene FCER1G in hepatocellular carcinoma. Sci Rep 2025; 15:3995. [PMID: 39893200 PMCID: PMC11787346 DOI: 10.1038/s41598-025-88071-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 01/23/2025] [Indexed: 02/04/2025] Open
Abstract
Hepatocellular carcinoma (HCC) progression is closely linked to the role of macrophages. This study utilized single-cell RNA sequencing and genomic analysis to explore the characteristic genes of macrophages in HCC and their impact on patient prognosis. We obtained single-cell se-quencing data from seven HCC samples in the GEO database. Through principal component analysis and t-SNE dimensionality reduction, we identified 2,000 highly variable genes and per-formed clustering and annotation of 17 cell clusters, revealing 482 macrophage-related feature genes. A LASSO regression model based on these genes was developed to predict the prognosis of HCC patients, with validation in the TCGA-LIHC cohort demonstrating model accuracy (AUC = 0.78, 0.72, 0.71 for 1-, 3-, and 5-year survival rates, respectively). Additionally, patients in the high-risk group exhibited elevated tumor stemness scores, although no significant differences were observed in microsatellite instability (MSI) and tumor mutational burden (TMB) scores. Immune-related analyses revealed that FCER1G expression was downregulated in HCC and was associated with key pathways such as apoptosis and ferroptosis. Reduced FCER1G expression significantly affected HCC cell proliferation and migration. Our prognostic model provides new insights into precision and immunotherapy for HCC and holds significant implications for future clinical applications.
Collapse
Affiliation(s)
- Deyu Kong
- Department of Clinical Laboratory, The Second Affiliated Hospital of Chengdu Medical College, National Nuclear Corporation 416 Hospital, Chengdu, Sichuan, China
| | - Yiping Zhang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Chengdu Medical College, National Nuclear Corporation 416 Hospital, Chengdu, Sichuan, China
| | - Linxin Jiang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Chengdu Medical College, National Nuclear Corporation 416 Hospital, Chengdu, Sichuan, China
| | - Nana Long
- Sichuan Integrative Medicine Hospital, 610041, Chengdu, Sichuan, China
| | - Chengcheng Wang
- Sichuan Integrative Medicine Hospital, 610041, Chengdu, Sichuan, China
| | - Min Qiu
- School of Laboratory Medicine, Chengdu Medical College, Chengdu, China.
| |
Collapse
|
|
5
|
Narain R, Muncie-Vasic JM, Weaver VM. Forcing the code: tension modulates signaling to drive morphogenesis and malignancy. Genes Dev 2025; 39:163-181. [PMID: 39638568 PMCID: PMC11789492 DOI: 10.1101/gad.352110.124] [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] [Indexed: 12/07/2024]
Abstract
Development and disease are regulated by the interplay between genetics and the signaling pathways stimulated by morphogens, growth factors, and cytokines. Experimental data highlight the importance of mechanical force in regulating embryonic development, tissue morphogenesis, and malignancy. Force not only sculpts tissue movements to drive embryogenesis and morphogenesis but also modifies the context of biochemical signaling and gene expression to regulate cell and tissue fate. Not surprisingly, experiments have demonstrated that perturbations in cell tension drive malignancy and metastasis by altering biochemical signaling and gene expression through modifications in cytoskeletal tension, transmembrane receptor structure and function, and organelle phenotype that enhance cell growth and survival, alter metabolism, and foster cell migration and invasion. At the tissue level, tumor-associated forces disrupt cell-cell adhesions to perturb tissue organization, compromise vascular integrity to induce hypoxia, and interfere with antitumor immunity to foster metastasis and treatment resistance. Exciting new approaches now exist with which to clarify the relationship between mechanotransduction, biochemical signaling, and gene expression in development and disease. Indeed, gaining insight into these interactions is essential to unravel molecular mechanisms that regulate development and clarify the molecular basis of cancer.
Collapse
Affiliation(s)
- Radhika Narain
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California 94143, USA
- Graduate Program in Bioengineering, University of California, San Francisco and University of California, Berkeley, Berkeley, California 94720, USA
| | | | - Valerie M Weaver
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California 94143, USA;
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California 94143, USA
- Department of Radiation Oncology, University of California, San Francisco, San Francisco, California 94143, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, California 94143
- UCSF Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94143, USA
| |
Collapse
|
|
6
|
赵 文, 阮 何, 汪 思, 程 羽, 雷 淼, 赵 久, 刘 传. [Inhibiting Yes-associated protein alleviates CCl 4 liver fibrosis in mice by reducing epithelial mesenchymal transition]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2024; 44:1839-1849. [PMID: 39523083 PMCID: PMC11526463 DOI: 10.12122/j.issn.1673-4254.2024.10.01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Indexed: 11/16/2024]
Abstract
OBJECTIVE To explore whether Yes-associated protein (YAP) affects occurrence and progression of liver fibrosis by regulating epithelial-mesenchymal transition (EMT). METHODS In a 8-week-old C57BL/6 mouse model of CCl4-induced liver fibrosis, the effect of verteporfin (a YAP inhibitor) intervention was assessed with HE staining and by detecting liver biochemistry and expressions of YAP and EMT-related genes using immunohistochemistry and Western blotting. Transcriptome and proteomic sequencing and informatics analysis were used to investigate the main downstream pathways of YAP in liver fibrosis. Serum levels of YAP, N-cadherin, vimentin and Twist were examined in 60 healthy individuals, 60 patients with chronic hepatitis B (CHB), and 60 patients with HBV-related liver cirrhosis. In another 24 C57BL/6 mice, the effects of Twist inhibitor alone or in combination with harmine (a YAP activator) on CCl4-induced liver fibrosis were evaluated by histopathological examination and Western blotting. RESULTS The mouse models of liver fibrosis showed obvious structural damages of the liver lobes with formation of pseudolobules, and verteporfin treatment significantly improved these pathologies and lowered plasma ALT and AST levels of the mice. Transcriptome and proteomic sequencing and informatics analysis suggested that N-cadherin and Twist were differentially expressed in liver fibrosis in close correlation with YAP. Inhibition of YAP obviously downregulated hepatic N-cadherin and Twist protein expressions in the mice with liver fibrosis. In patients with CHB and liver cirrhosis, serum levels of YAP elevated obviously with the severity of liver fibrosis and were significantly correlated with N-cadherin, vimentin and Twist levels. In mice with liver fibrosis, inhibiting Twist effectively improved liver inflammation and fibrosis, while the combined treatment with YAP activator worsened hepatic collagen fiber deposition and increased hepatic YAP and α-SMA expressions. CONCLUSION EMT is an important pathogenic mechanism of liver fibrosis, and inhibiting YAP can alleviate liver fibrosis by reducing EMT.
Collapse
|
|
7
|
Liu X, Zhang W, Gu J, Wang J, Wang Y, Xu Z. Single-cell SERS imaging of dual cell membrane receptors expression influenced by extracellular matrix stiffness. J Colloid Interface Sci 2024; 668:335-342. [PMID: 38678888 DOI: 10.1016/j.jcis.2024.04.170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 04/21/2024] [Accepted: 04/23/2024] [Indexed: 05/01/2024]
Abstract
Membrane receptors perform a diverse range of cellular functions, accounting for more than half of all drug targets. The mechanical microenvironment regulates cell behaviors and phenotype. However, conventional analysis methods of membrane receptors often ignore the effects of the extracellular matrix stiffness, failing to reveal the heterogeneity of cell membrane receptors expression. Herein, we developed an in-situ surface-enhanced Raman scattering (SERS) imaging method to visualize single-cell membrane receptors on substrates with different stiffness. Two SERS substrates, Au@4-mercaptobenzonitrile@Ag@Sgc8c and Au@4-pethynylaniline@Ag@SYL3c, were employed to specifically target protein tyrosine kinase-7 (PTK7) and epithelial cell adhesion molecule (EpCAM), respectively. The polyacrylamide (PA) gels with tunable stiffness (2.5-25 kPa) were constructed to mimic extracellular matrix. The simultaneous SERS imaging of dual membrane receptors on single cancer cells on substrates with different stiffness was achieved. Our findings reveal decreased expression of PTK7 and EpCAM on cells cultured on stiffer substrates and higher migration ability of the cells. The results elucidate the heterogeneity of membrane receptors expression of cells cultured on the substrates with different stiffness. This single-cell analysis method offers an in-situ platform for investigating the impacts of extracellular matrix stiffness on the expression of membrane receptors, providing insights into the role of cell membrane receptors in cancer metastasis.
Collapse
Affiliation(s)
- Xiaopeng Liu
- Research Center for Analytical Sciences, Northeastern University, Shenyang 110819, PR China
| | - Wenshu Zhang
- Research Center for Analytical Sciences, Northeastern University, Shenyang 110819, PR China
| | - Jiahui Gu
- Research Center for Analytical Sciences, Northeastern University, Shenyang 110819, PR China
| | - Jie Wang
- Research Center for Analytical Sciences, Northeastern University, Shenyang 110819, PR China
| | - Yue Wang
- Research Center for Analytical Sciences, Northeastern University, Shenyang 110819, PR China
| | - Zhangrun Xu
- Research Center for Analytical Sciences, Northeastern University, Shenyang 110819, PR China.
| |
Collapse
|
|
8
|
Aydin H, Ozcelikkale A, Acar A. Exploiting Matrix Stiffness to Overcome Drug Resistance. ACS Biomater Sci Eng 2024; 10:4682-4700. [PMID: 38967485 PMCID: PMC11322920 DOI: 10.1021/acsbiomaterials.4c00445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 06/12/2024] [Accepted: 06/17/2024] [Indexed: 07/06/2024]
Abstract
Drug resistance is arguably one of the biggest challenges facing cancer research today. Understanding the underlying mechanisms of drug resistance in tumor progression and metastasis are essential in developing better treatment modalities. Given the matrix stiffness affecting the mechanotransduction capabilities of cancer cells, characterization of the related signal transduction pathways can provide a better understanding for developing novel therapeutic strategies. In this review, we aimed to summarize the recent advancements in tumor matrix biology in parallel to therapeutic approaches targeting matrix stiffness and its consequences in cellular processes in tumor progression and metastasis. The cellular processes governed by signal transduction pathways and their aberrant activation may result in activating the epithelial-to-mesenchymal transition, cancer stemness, and autophagy, which can be attributed to drug resistance. Developing therapeutic strategies to target these cellular processes in cancer biology will offer novel therapeutic approaches to tailor better personalized treatment modalities for clinical studies.
Collapse
Affiliation(s)
- Hakan
Berk Aydin
- Department
of Biological Sciences, Middle East Technical
University, 06800, Ankara, Turkey
| | - Altug Ozcelikkale
- Department
of Mechanical Engineering, Middle East Technical
University, 06800, Ankara, Turkey
- Graduate
Program of Biomedical Engineering, Middle
East Technical University, 06800, Ankara, Turkey
| | - Ahmet Acar
- Department
of Biological Sciences, Middle East Technical
University, 06800, Ankara, Turkey
| |
Collapse
|
|
9
|
Ji A, Li H, Fu X, Zhang Y, Liu Y. Long non-coding RNA NEAT1 induced by BHLHE40 activates Wnt/β-catenin signaling and potentiates colorectal cancer progression. Cell Div 2024; 19:25. [PMID: 39098910 PMCID: PMC11299305 DOI: 10.1186/s13008-024-00129-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 07/22/2024] [Indexed: 08/06/2024] Open
Abstract
BACKGROUND Nuclear-enriched abundant transcript 1 (NEAT1), a long noncoding RNA (lncRNA), has been implicated in the colorectal cancer (CRC) progression. However, its upstream mechanism has not been well studied. In the present study, the functions and mechanisms of NEAT1 in CRC were investigated. METHODS The NEAT1 expression in CRC tissues and CRC cells was analyzed by RT-qPCR. The genes co-expressed with NEAT1 in CRC were obtained from UALCAN, which were intersected with the transcription factors targeting NEAT1 from hTFtarget. Dual-luciferase assay, RT-qPCR, and ChIP were conducted to analyze the transcriptional regulatory relationship between BHLHE40 and NEAT1. LoVo and HCT-15 cells knocking down BHLHE40 and overexpressing NEAT1 were subjected to MTT, Transwell, Western blot, and flow cytometry to examine the malignant aggressiveness of CRC cells. The effects of knocking down BHLHE40 and overexpressing NEAT1 on tumor and lung metastasis were investigated in mice using HE and immunohistochemical analyses. RESULTS NEAT1 and BHLHE40 were significantly overexpressed in CRC tissues and cells. BHLHE40 has a binding relationship with the NEAT1 promoter. Knockdown of BHLHE40 resulted in a reverted malignant phenotype in vitro and slowed tumor growth and metastasis dissemination in vivo, which were reversed by NEAT1 overexpression. Overexpression of BHLHE40 increased Wnt/β-catenin pathway activity, but knockdown of NEAT1 decreased Wnt/β-catenin pathway activity. CONCLUSIONS BHLHE40 mediates the transcriptional activation of NEAT1, which activates the Wnt/β-catenin pathway and promotes the CRC progression.
Collapse
Affiliation(s)
- Anlong Ji
- Department of General Surgery, The Second Affiliated Hospital of Hainan Medical University, No. 368, Yehai Avenue, Haikou, 570216, Hainan, People's Republic of China
| | - Hui Li
- Department of Geriatrics, The Second Affiliated Hospital of Hainan Medical University, No. 368, Yehai Avenue, Haikou, 570216, Hainan, People's Republic of China
| | - Xiangwei Fu
- Department of General Surgery, The Second Affiliated Hospital of Hainan Medical University, No. 368, Yehai Avenue, Haikou, 570216, Hainan, People's Republic of China
| | - Yourong Zhang
- Department of General Surgery, The Second Affiliated Hospital of Hainan Medical University, No. 368, Yehai Avenue, Haikou, 570216, Hainan, People's Republic of China
| | - Yanhe Liu
- Department of General Surgery, The Second Affiliated Hospital of Hainan Medical University, No. 368, Yehai Avenue, Haikou, 570216, Hainan, People's Republic of China.
| |
Collapse
|
|
10
|
Ye Z, Zhu S, Li G, Lu J, Huang S, Du J, Shao Y, Ji Z, Li P. Early matrix softening contributes to vascular smooth muscle cell phenotype switching and aortic dissection through down-regulation of microRNA-143/145. J Mol Cell Cardiol 2024; 192:1-12. [PMID: 38718921 DOI: 10.1016/j.yjmcc.2024.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 05/04/2024] [Accepted: 05/04/2024] [Indexed: 05/14/2024]
Abstract
Thoracic aortic dissection (TAD) is characterized by extracellular matrix (ECM) dysregulation. Aberrations in the ECM stiffness can lead to changes in cellular functions. However, the mechanism by which ECM softening regulates vascular smooth muscle cell (VSMCs) phenotype switching remains unclear. To understand this mechanism, we cultured VSMCs in a soft extracellular matrix and discovered that the expression of microRNA (miR)-143/145, mediated by activation of the AKT signalling pathway, decreased significantly. Furthermore, overexpression of miR-143/145 reduced BAPN-induced aortic softening, switching the VSMC synthetic phenotype and the incidence of TAD in mice. Additionally, high-throughput sequencing of immunoprecipitated RNA indicated that the TEA domain transcription factor 1 (TEAD1) is a common target gene of miR-143/145, which was subsequently verified using a luciferase reporter assay. TEAD1 is upregulated in soft ECM hydrogels in vitro, whereas the switch to a synthetic phenotype in VSMCs decreases after TEAD1 knockdown. Finally, we verified that miR-143/145 levels are associated with disease severity and prognosis in patients with thoracic aortic dissection. ECM softening, as a result of promoting the VSMCs switch to a synthetic phenotype by downregulating miR-143/145, is an early trigger of TAD and provides a therapeutic target for this fatal disease. miR-143/145 plays a role in the early detection of aortic dissection and its severity and prognosis, which can offer information for future risk stratification of patients with dissection.
Collapse
Affiliation(s)
- Zhaofei Ye
- Beijing Anzhen Hospital of Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, China
| | - Shuolin Zhu
- Beijing Anzhen Hospital of Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, China
| | - Guoqi Li
- Beijing Anzhen Hospital of Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, China
| | - Jie Lu
- Beijing Anzhen Hospital of Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, China
| | - Shan Huang
- Beijing Anzhen Hospital of Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, China
| | - Jie Du
- Beijing Anzhen Hospital of Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, China
| | - Yihui Shao
- Beijing Anzhen Hospital of Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, China.
| | - Zhili Ji
- Beijing Chaoyang Hospital of Capital Medical University, China.
| | - Ping Li
- Beijing Anzhen Hospital of Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, China.
| |
Collapse
|
|
11
|
Lund LM, Marchi AN, Alderfer L, Hall E, Hammer J, Trull KJ, Hanjaya-Putra D, White KA. Intracellular pH dynamics respond to microenvironment stiffening and mediate vasculogenic mimicry through β-catenin. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.04.597454. [PMID: 38895391 PMCID: PMC11185592 DOI: 10.1101/2024.06.04.597454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Dysregulated intracellular pH (pHi) dynamics and an altered tumor microenvironment have emerged as drivers of cancer cell phenotypes. However, the molecular integration between the physical properties of the microenvironment and dynamic intracellular signaling responses remains unclear. Here, we use two metastatic cell models, one breast and one lung, to assess pHi response to varying extracellular matrix (ECM) stiffness. To experimentally model ECM stiffening, we use two tunable-stiffness hydrogel systems: Matrigel and hyaluronic acid (HA) gels, which mimic the increased protein secretion and crosslinking associated with ECM stiffening. We find that single-cell pHi decreases with increased ECM stiffness in both hydrogel systems and both metastatic cell types. We also observed that stiff ECM promotes vasculogenic mimicry (VM), a phenotype associated with metastasis and resistance. Importantly, we show that decreased pHi is both a necessary and sufficient mediator of VM, as raising pHi on stiff ECM reduces VM phenotypes and lowering pHi on soft ECM drives VM. We characterize β-catenin as a pH-dependent molecular mediator of pH-dependent VM, where stiffness-driven changes in β-catenin abundance can be overridden by increased pHi. We uncover a dynamic relationship between matrix stiffness and pHi, thus suggesting pHi dynamics can override mechanosensitive cell responses to the extracellular microenvironment.
Collapse
Affiliation(s)
- Leah M Lund
- Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556 USA
- Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617 USA
| | - Angelina N Marchi
- Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556 USA
- Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617 USA
| | - Laura Alderfer
- Bioengineering Graduate Program, Aerospace and Mechanical Engineering, University of Notre Dame, 153 Multidisciplinary Engineering Research Building, Notre Dame, IN 46556 USA
- Current: Vivodyne, Suite 775 601 Walnut Street, Philadelphia PA 19106 USA
| | - Eva Hall
- Bioengineering Graduate Program, Aerospace and Mechanical Engineering, University of Notre Dame, 153 Multidisciplinary Engineering Research Building, Notre Dame, IN 46556 USA
| | - Jacob Hammer
- Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556 USA
- Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617 USA
| | - Keelan J Trull
- Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556 USA
- Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617 USA
| | - Donny Hanjaya-Putra
- Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617 USA
- Bioengineering Graduate Program, Aerospace and Mechanical Engineering, University of Notre Dame, 153 Multidisciplinary Engineering Research Building, Notre Dame, IN 46556 USA
- Chemical and Biomolecular Engineering, University of Notre Dame, 250 Nieuwland Hall, Notre Dame, IN 46556 USA
| | - Katharine A White
- Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556 USA
- Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN 46617 USA
| |
Collapse
|
|
12
|
Qiu H, Fu Y, Guo Z, Zhang X, Wang X, Wu H. Dysregulated microRNAs and long non-coding RNAs associated with extracellular matrix stiffness. Exp Cell Res 2024; 437:114014. [PMID: 38547959 DOI: 10.1016/j.yexcr.2024.114014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 03/20/2024] [Accepted: 03/22/2024] [Indexed: 04/02/2024]
Abstract
Extracellular matrix (ECM) stiffness regulates development and homeostasis in vivo and affects both physiological and pathological processes. A variety of studies have demonstrated that mRNAs, such as Piezo1, integrin β1, and Yes-associated protein (YAP)/tafazzin (TAZ), can sense the mechanical signals induced by ECM stiffness and transmit them from the extracellular space into the cytoplasm. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have been reported to play important roles in various cellular processes. Therefore, the interactions between ncRNAs and ECM stiffness, as well as the underlying molecular mechanisms, have become intriguing. In this review, we summarize recent findings on miRNAs and lncRNAs that interact with ECM stiffness. Several miRNAs and lncRNAs are involved in the progression of liver cancer, breast cancer, osteosarcoma, and cardiovascular diseases under the regulation of ECM stiffness. Through these ncRNAs, cellular behaviors including cell differentiation, proliferation, adhesion, migration, invasion, and epithelial-mesenchymal transition (EMT) are affected by ECM stiffness. We also integrate the ncRNA signaling pathways associated with ECM stiffness, in which typical signaling pathways like integrin β1/TGFβ1, phosphatidylinositol-3 kinase (PI3K)/AKT, and EMT are involved. Although our understanding of the relationships between ncRNAs and ECM stiffness is still limited, further investigations may provide new insights for disease treatment. ECM-associated ncRNAs may serve as disease biomarkers or be targeted by drugs.
Collapse
Affiliation(s)
- Huimin Qiu
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Yangpu, 200093, Shanghai, China; Collaborative Innovation Center for Biomedicine, Shanghai University of Medicine & Health Sciences, Pudong, 201318, Shanghai, China.
| | - Yi Fu
- Collaborative Innovation Center for Biomedicine, Shanghai University of Medicine & Health Sciences, Pudong, 201318, Shanghai, China.
| | - Zhinan Guo
- Collaborative Innovation Center for Biomedicine, Shanghai University of Medicine & Health Sciences, Pudong, 201318, Shanghai, China; School of Sports and Health, Shanghai University of Sport, Yangpu, 200438, Shanghai, China.
| | - Xinjia Zhang
- School of Medical Instruments, Shanghai University of Medicine & Health Sciences, Pudong, 201318, Shanghai, China.
| | - Xinyue Wang
- School of Medical Instruments, Shanghai University of Medicine & Health Sciences, Pudong, 201318, Shanghai, China.
| | - Hailong Wu
- Collaborative Innovation Center for Biomedicine, Shanghai University of Medicine & Health Sciences, Pudong, 201318, Shanghai, China.
| |
Collapse
|
|
13
|
Mai Y, Liao C, Wang S, Zhou X, Meng L, Chen C, Qin Y, Deng G. High glucose-induced NCAPD2 upregulation promotes malignant phenotypes and regulates EMT via the Wnt/β-catenin signaling pathway in HCC. Am J Cancer Res 2024; 14:1685-1711. [PMID: 38726276 PMCID: PMC11076239 DOI: 10.62347/hynz9211] [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: 10/18/2023] [Accepted: 03/29/2024] [Indexed: 05/12/2024] Open
Abstract
Diabetes mellitus (DM) is recognized as a risk factor for hepatocellular carcinoma (HCC). High glucose levels have been implicated in inducing epithelial-mesenchymal transition (EMT), contributing to the progression of various cancers. However, the molecular crosstalk remains unclear. This study aimed to elucidate the molecular mechanisms linking DM to HCC. Initially, the expression of NCAPD2 in HCC cells and patients was measured. A series of functional in vitro assays to examine the effects of NCAPD2 on the malignant behaviors and EMT of HCC under high glucose conditions were then conducted. Furthermore, the impacts of NCAPD2 knockdown on HCC proliferation and the β-catenin pathway were investigated in vivo. In addition, bioinformatics methods were performed to analyze the mechanisms and pathways involving NCAPD2, as well as its association with immune infiltration and drug sensitivity. The findings indicated that NCAPD2 was overexpressed in HCC, particularly in patients with DM, and its aberrant upregulation was linked to poor prognosis. In vitro experiments demonstrated that high glucose upregulated NCAPD2 expression, enhancing proliferation, invasion, and EMT, while knockdown of NCAPD2 reversed these effects. In vivo studies suggested that NCAPD2 knockdown might suppress HCC growth via the β-catenin pathway. Functional enrichment analysis revealed that NCAPD2 was involved in cell cycle regulation and primarily interacted with NCAPG, SMC4, and NCAPH. Additionally, NCAPD2 was positively correlated with EMT and the Wnt/β-catenin pathway, whereas knockdown of NCAPD2 inhibited the Wnt/β-catenin pathway. Moreover, NCAPD2 expression was significantly associated with immune cell infiltration, immune checkpoints, and drugs sensitivity. In conclusion, our study identified NCAPD2 as a novel oncogene in HCC and as a potential therapeutic target for HCC patients with DM.
Collapse
Affiliation(s)
- Yuhua Mai
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, China
| | - Chuanjie Liao
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of EducationNanning 530021, Guangxi, China
| | - Shengyu Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, China
| | - Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, China
| | - Liheng Meng
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, China
| | - Cuihong Chen
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, China
| | - Yingfen Qin
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, China
| | - Ganlu Deng
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of EducationNanning 530021, Guangxi, China
| |
Collapse
|
|
14
|
Lin S, He X, Wang Y, Chen Y, Lin A. Emerging role of lncRNAs as mechanical signaling molecules in mechanotransduction and their association with Hippo-YAP signaling: a review. J Zhejiang Univ Sci B 2024; 25:280-292. [PMID: 38584091 PMCID: PMC11009445 DOI: 10.1631/jzus.b2300497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 12/11/2023] [Indexed: 04/09/2024]
Abstract
Cells within tissues are subject to various mechanical forces, including hydrostatic pressure, shear stress, compression, and tension. These mechanical stimuli can be converted into biochemical signals through mechanoreceptors or cytoskeleton-dependent response processes, shaping the microenvironment and maintaining cellular physiological balance. Several studies have demonstrated the roles of Yes-associated protein (YAP) and its homolog transcriptional coactivator with PDZ-binding motif (TAZ) as mechanotransducers, exerting dynamic influence on cellular phenotypes including differentiation and disease pathogenesis. This regulatory function entails the involvement of the cytoskeleton, nucleoskeleton, integrin, focal adhesions (FAs), and the integration of multiple signaling pathways, including extracellular signal-regulated kinase (ERK), wingless/integrated (WNT), and Hippo signaling. Furthermore, emerging evidence substantiates the implication of long non-coding RNAs (lncRNAs) as mechanosensitive molecules in cellular mechanotransduction. In this review, we discuss the mechanisms through which YAP/TAZ and lncRNAs serve as effectors in responding to mechanical stimuli. Additionally, we summarize and elaborate on the crucial signal molecules involved in mechanotransduction.
Collapse
Affiliation(s)
- Siyi Lin
- College of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Xinyu He
- College of Life Sciences, Zhejiang University, Hangzhou 310058, China
- Cancer Center, Zhejiang University, Hangzhou 310058, China
- Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, China
| | - Ying Wang
- College of Life Sciences, Zhejiang University, Hangzhou 310058, China
- Cancer Center, Zhejiang University, Hangzhou 310058, China
- Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, China
| | - Yu Chen
- College of Life Sciences, Zhejiang University, Hangzhou 310058, China
- Cancer Center, Zhejiang University, Hangzhou 310058, China
- Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, China
| | - Aifu Lin
- College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
- Cancer Center, Zhejiang University, Hangzhou 310058, China.
- Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, China.
- International School of Medicine, International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu 322000, China.
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Hangzhou 310058, China.
- Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing 314100, China.
| |
Collapse
|
|
15
|
Saleh RO, Alkhafaji AT, Mohammed JS, Bansal P, Kaur H, Ahmad I, Hjazi A, Mohammed IH, Jawad MA, Zwamel AH. LncRNA NEAT1 in the pathogenesis of liver-related diseases. Cell Biochem Funct 2024; 42:e4006. [PMID: 38622913 DOI: 10.1002/cbf.4006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 03/20/2024] [Accepted: 03/27/2024] [Indexed: 04/17/2024]
Abstract
Nuclear paraspeckle assembly transcript 1 (NEAT1) is a long noncoding RNA (lncRNA) that is widely expressed in a variety of mammalian cell types. Altered expression levels of the lncRNA NEAT1 have been reported in liver-related disorders including cancer, fatty liver disease, liver fibrosis, viral hepatitis, and hepatic ischemia. lncRNA NEAT1 mostly acts as a competing endogenous RNA (ceRNA) to sponge various miRNAs (miRs) to regulate different functions. In regard to hepatic cancers, the elevated expression of NEAT1 has been reported to have a relation with the proliferation, migration, angiogenesis, apoptosis, as well as epithelial-mesenchymal transition (EMT) of cancer cells. Furthermore, NEAT1 upregulation has contributed to the pathogenesis of other liver diseases such as fibrosis. In this review, we summarize and discuss the molecular mechanisms by which NEAT1 contributes to liver-related disorders including acute liver failure, nonalcoholic fatty liver disease (NAFLD), liver fibrosis, and liver carcinoma, providing novel insights and introducing NEAT1 as a potential therapeutic target in these diseases.
Collapse
Affiliation(s)
- Raed Obaid Saleh
- Department of Medical Laboratory Techniques, Al-Maarif University College, Al-Anbar, Iraq
| | | | | | - Pooja Bansal
- Department of Biotechnology and Genetics, Jain (Deemed-to-be) University, Bengaluru, Karnataka, India
- Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan, India
| | - Harpreet Kaur
- School of Basic & Applied Sciences, Shobhit University, Gangoh, Uttar Pradesh, India
- Department of Health & Allied Sciences, Arka Jain University, Jamshedpur, Jharkhand, India
| | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | | | - Mohammed Abed Jawad
- Department of Medical Laboratories Technology, Al-Nisour University College, Baghdad, Iraq
| | - Ahmed Hussein Zwamel
- Medical laboratory technique college, the Islamic University, Najaf, Iraq
- Medical laboratory technique college, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical laboratory technique college, the Islamic University of Babylon, Babylon, Iraq
| |
Collapse
|
|
16
|
Kim YJ, Lee DB, Jeong E, Jeon JY, Kim HD, Kang H, Kim YK. Magnetically Stimulated Integrin Binding Alters Cell Polarity and Affects Epithelial-Mesenchymal Plasticity in Metastatic Cancer Cells. ACS APPLIED MATERIALS & INTERFACES 2024; 16:8365-8377. [PMID: 38319067 DOI: 10.1021/acsami.3c16720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2024]
Abstract
Inorganic nanoparticles (NPs) have been widely recognized for their stability and biocompatibility, leading to their widespread use in biomedical applications. Our study introduces a novel approach that harnesses inorganic magnetic nanoparticles (MNPs) to stimulate apical-basal polarity and induce epithelial traits in cancer cells, targeting the hybrid epithelial/mesenchymal (E/M) state often linked to metastasis. We employed mesocrystalline iron oxide MNPs to apply an external magnetic field, disrupting normal cell polarity and simulating an artificial cellular environment. These led to noticeable changes in the cell shape and function, signaling a shift toward the hybrid E/M state. Our research suggests that apical-basal stimulation in cells through MNPs can effectively modulate key cellular markers associated with both epithelial and mesenchymal states without compromising the structural properties typical of mesenchymal cells. These insights advance our understanding of how cells respond to physical cues and pave the way for novel cancer treatment strategies. We anticipate that further research and validation will be instrumental in exploring the full potential of these findings in clinical applications, ensuring their safety and efficacy.
Collapse
Affiliation(s)
- Yu Jin Kim
- Institute for High Technology Materials and Devices, Korea University, Seoul 02841, Korea
| | - Dae Beom Lee
- Department of Materials Science and Engineering, Korea University, Seoul 02841, Korea
| | - Eunjin Jeong
- Department of Materials Science and Engineering, Korea University, Seoul 02841, Korea
| | - Joo Yeong Jeon
- Seoul Center, Korea Basic Science Institute, Seoul 03759, Korea
| | - Hee-Dae Kim
- Department of Basic Medical Sciences, University of Arizona College of Medicine─Phoenix, Phoenix, Arizona 85004, United States
| | - Heemin Kang
- Department of Materials Science and Engineering, Korea University, Seoul 02841, Korea
| | - Young Keun Kim
- Institute for High Technology Materials and Devices, Korea University, Seoul 02841, Korea
- Department of Materials Science and Engineering, Korea University, Seoul 02841, Korea
| |
Collapse
|
|
17
|
Wendong Y, Jiali J, Qiaomei F, Yayun W, Xianze X, Zheng S, Wei H. Biomechanical forces and force-triggered drug delivery in tumor neovascularization. Biomed Pharmacother 2024; 171:116117. [PMID: 38171243 DOI: 10.1016/j.biopha.2023.116117] [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: 11/02/2023] [Revised: 12/25/2023] [Accepted: 12/29/2023] [Indexed: 01/05/2024] Open
Abstract
Tumor angiogenesis is one of the typical hallmarks of tumor occurrence and development, and tumor neovascularization also exhibits distinct characteristics from normal blood vessels. As the number of cells and matrix inside the tumor increases, the biomechanical force is enhanced, specifically manifested as solid stress, fluid stress, stiffness, and topology. This mechanical microenvironment also provides shelter for tumors and intensifies angiogenesis, providing oxygen and nutritional support for tumor progression. During tumor development, the biomechanical microenvironment also emerges, which in turn feeds back to regulate the tumor progression, including tumor angiogenesis, and biochemical and biomechanical signals can regulate tumor angiogenesis. Blood vessels possess inherent sensitivity to mechanical stimuli, but compared to the extensive research on biochemical signal regulation, the study of the regulation of tumor neovascularization by biomechanical signals remains relatively scarce. Biomechanical forces can affect the phenotypic characteristics and mechanical signaling pathways of tumor blood vessels, directly regulating angiogenesis. Meanwhile, they can indirectly regulate tumor angiogenesis by causing an imbalance in angiogenesis signals and affecting stromal cell function. Understanding the regulatory mechanism of biomechanical forces in tumor angiogenesis is beneficial for better identifying and even taming the mechanical forces involved in angiogenesis, providing new therapeutic targets for tumor vascular normalization. Therefore, we summarized the composition of biomechanical forces and their direct or indirect regulation of tumor neovascularization. In addition, this review discussed the use of biomechanical forces in combination with anti-angiogenic therapies for the treatment of tumors, and biomechanical forces triggered delivery systems.
Collapse
Affiliation(s)
- Yao Wendong
- Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310005, China
| | - Jiang Jiali
- Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310005, China
| | - Fan Qiaomei
- Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310005, China
| | - Weng Yayun
- Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310005, China
| | - Xie Xianze
- Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310005, China
| | - Shi Zheng
- Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310005, China.
| | - Huang Wei
- Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310005, China.
| |
Collapse
|
|
18
|
Hussain MS, Afzal O, Gupta G, Goyal A, Almalki WH, Kazmi I, Alzarea SI, Alfawaz Altamimi AS, Kukreti N, Chakraborty A, Singh SK, Dua K. Unraveling NEAT1's complex role in lung cancer biology: a comprehensive review. EXCLI JOURNAL 2024; 23:34-52. [PMID: 38343745 PMCID: PMC10853633 DOI: 10.17179/excli2023-6553] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 11/30/2023] [Indexed: 09/05/2024]
Abstract
This review delves into the pivotal role of the long non-coding RNA NEAT1 in cancer biology, particularly in lung cancer (LC). It emphasizes NEAT1's unique subcellular localization and active involvement in gene regulation and chromatin remodeling. The review highlights NEAT1's impact on LC development and progression, including cell processes such as proliferation, migration, invasion, and resistance to therapy, positioning it as a potential diagnostic marker and therapeutic target. The complex web of NEAT1's regulatory interactions with proteins and microRNAs is explored, alongside challenges in targeting it therapeutically. The review concludes optimistically, suggesting future avenues for research and personalized LC therapies, shedding light on NEAT1's crucial role in LC. See also the Graphical abstract(Fig. 1).
Collapse
Affiliation(s)
- Md Sadique Hussain
- School of Pharmaceutical Sciences, Jaipur National University, Jagatpura 302017, Jaipur, India
| | - Obaid Afzal
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj, 11942, Saudi Arabia
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura 302017, Mahal Road, Jaipur, India
- Centre for Transdisciplinary Research, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, India
| | - Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University, Mathura, U. P., India
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sami I. Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia
| | | | - Neelam Kukreti
- School of Pharmacy, Graphic Era Hill University, Dehradun 248007, India
| | - Amlan Chakraborty
- Faculty of Biology, Medicine and Health, The University of Manchester, Oxford Road, Manchester M13 9PL, U.K
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, VIC 3800, Australia
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, 144411, India
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, Australia
| | - Kamal Dua
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, Australia
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia
| |
Collapse
|
|
19
|
Horta CA, Doan K, Yang J. Mechanotransduction pathways in regulating epithelial-mesenchymal plasticity. Curr Opin Cell Biol 2023; 85:102245. [PMID: 37804773 PMCID: PMC10796216 DOI: 10.1016/j.ceb.2023.102245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/16/2023] [Accepted: 09/03/2023] [Indexed: 10/09/2023]
Abstract
The extracellular matrix (ECM) provides structural support for cells and mediates cell-stromal communications. In addition to ECM proteins, mechanical force exerted from the ECM serves as a critical regulator of many biological processes. Epithelial-mesenchymal transition (EMT) is a cellular process by which epithelial cells loosen their cellular junctions and migrate and invade in a more mesenchymal fashion. Recent studies show that increasing ECM stiffness can impinge on cellular signaling pathways through mechanotransduction to promote carcinoma cells to undergo EMT, suggesting that mechanical force exerted by the ECM plays a critical role in tumor invasion and metastasis. Here, we highlight recent work utilizing innovative approaches to study mechanotransduction and summarize newly discovered mechanisms by which mechanosensors and responders regulate EMT during tumor progression and metastasis.
Collapse
Affiliation(s)
- Calista A Horta
- Department of Pharmacology, Moores Cancer Center, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Khoa Doan
- Department of Pharmacology, Moores Cancer Center, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Jing Yang
- Department of Pharmacology, Moores Cancer Center, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA, 92093, USA.
| |
Collapse
|
|
20
|
Zhang YZ, Li MZ, Wang GX, Wang DW. Bibliometric analysis of the global research status and trends of mechanotransduction in cancer. World J Clin Oncol 2023; 14:518-534. [PMID: 38059188 PMCID: PMC10696219 DOI: 10.5306/wjco.v14.i11.518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 09/14/2023] [Accepted: 10/16/2023] [Indexed: 11/22/2023] Open
Abstract
BACKGROUND The development of cancer is thought to involve the dynamic crosstalk between the tumor cells and the microenvironment they inhabit. Such crosstalk is thought to involve mechanotransduction, a process whereby the cells sense mechanical cues such as stiffness, and translate these into biochemical signals, which have an impact on the subsequent cellular activities. Bibliometric analysis is a statistical method that involves investigating different aspects (including authors' names and affiliations, article keywords, journals and citations) of large volumes of literature. Despite an increase in mechanotransduction-related research in recent years, there are currently no bibliometric studies that describe the global status and trends of mechanotransduction-related research in the cancer field. AIM To investigate the global research status and trends of mechanotransduction in cancer from a bibliometric viewpoint. METHODS Literature on mechanotransduction in cancer published from January 1, 1900 to December 31, 2022 was retrieved from the Web of Science Core Collection. Excel and GraphPad software carried out the statistical analysis of the relevant author, journal, organization, and country information. The co-authorship, keyword co-occurrence, and keyword burst analysis were visualized with VOSviewer and CiteSpace. RESULTS Of 597 publications from 745 institutions in 45 countries were published in 268 journals with 35510 citation times. With 270 articles, the United States is a well-established global leader in this field, and the University of California system, the most productive (n = 36) and influential institution (n = 4705 citations), is the most highly active in collaborating with other organizations. Cancers was the most frequent publisher with the highest H-index. The most productive researcher was Valerie M. Weaver, with 10 publications. The combined analysis of concurrent and burst keywords revealed that the future research hotspots of mechanotransduction in cancer were related to the plasma membrane, autophagy, piezo1/2, heterogeneity, cancer diagnosis, and post-transcriptional modifications. CONCLUSION Mechanotransduction-related cancer research remains a hot topic. The United States is in the leading position of global research on mechano-oncology after almost 30 years of investigations. Research group cooperations exist but remain largely domestic, lacking cross-national communications. The next big topic in this field is to explore how the plasma membrane and its localized mechanosensor can transduce mechanical force through post-transcriptional modifications and thereby participate in cellular activity regulations and cancer development.
Collapse
Affiliation(s)
- Yi-Zhan Zhang
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan 250021, Shandong Province, China
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Jinan 250021, Shandong Province, China
| | - Meng-Zhu Li
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan 250021, Shandong Province, China
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Jinan 250021, Shandong Province, China
| | - Guang-Xin Wang
- Shandong Innovation Center of Intelligent Diagnosis, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong Province, China
| | - Da-Wei Wang
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan 250021, Shandong Province, China
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Jinan 250021, Shandong Province, China
| |
Collapse
|
|
21
|
Zhang L, Zhang Q, Teng D, Guo M, Tang K, Wang Z, Wei X, Lin L, Zhang X, Wang X, Huang D, Ren C, Yang Q, Zhang W, Gao Y, Chen W, Chang Y, Zhang H. FGF9 Recruits β-Catenin to Increase Hepatic ECM Synthesis and Promote NASH-Driven HCC. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2301166. [PMID: 37566761 PMCID: PMC10558677 DOI: 10.1002/advs.202301166] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 07/20/2023] [Indexed: 08/13/2023]
Abstract
Most nonalcoholic steatohepatitis (NASH) patients develop severe fibrosis through extracellular matrix (ECM) accumulation, which can lead to hepatocellular carcinoma (HCC). Fibroblast growth factor 9 (FGF9) is involved in serial types of cancer; however, the specific role of FGF9 in NASH-driven HCC is not fully understood. This study finds that FGF9 is increased in patients with NASH-associated HCC. Furthermore, NASH-driven HCC mice models by feeding wildtype mice with high-fat/high-cholesterol (HFHC) diet and low dose carbon tetrachloride (CCl4 ) treatment is established; and identified that hepatic FGF9 is increased; with severe fibrosis. Additionally, AAV-mediated knockdown of FGF9 reduced the hepatic tumor burden of NASH-driven HCC mice models. Hepatocyte-specific FGF9 transgenic mice (FGF9Alb ) fed with a HFHC diet without CCl4 treatment exhibited an increased hepatic ECM and tumor burden. However, XAV-939 treatment blocked ECM accumulation and NASH-driven HCC in FGF9Alb mice fed with HFHC diet. Molecular mechanism studies show that FGF9 stimulated the expression of ECM related genes in a β-catenin dependent manner; and FGF9 exerts its effect on β-catenin stability via the ERK1/2-GSK-3β signaling pathway. In summary, the data provides evidence for the critical role of FGF9 in NASH-driven HCC pathogenesis; wherein it promotes the tumors formation through the ECM pathway.
Collapse
Affiliation(s)
- Lei Zhang
- Department of Biochemistry and Molecular BiologyMetabolic Disease Research CenterSchool of Basic MedicineAnhui Medical University230032HefeiChina
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education)Tianjin Key of Cellular Homeostasis and DiseaseDepartment of Physiology and PathophysiologyTianjin Medical University300070TianjinChina
| | - Qing Zhang
- Department of Biochemistry and Molecular BiologyMetabolic Disease Research CenterSchool of Basic MedicineAnhui Medical University230032HefeiChina
| | - Da Teng
- Department of Hepatopancreatobiliary SurgeryAffifiliated Chuzhou Hospital of Anhui Medical University (The First People's Hospital of Chuzhou)Chuzhou239001China
| | - Manyu Guo
- Department of Biochemistry and Molecular BiologyMetabolic Disease Research CenterSchool of Basic MedicineAnhui Medical University230032HefeiChina
| | - Kechao Tang
- Department of Biochemistry and Molecular BiologyMetabolic Disease Research CenterSchool of Basic MedicineAnhui Medical University230032HefeiChina
| | - Zhenglin Wang
- Department of General SurgeryThe First Affiliated Hospital of Anhui Medical University230022HefeiChina
| | - Xiang Wei
- Department of Biochemistry and Molecular BiologyMetabolic Disease Research CenterSchool of Basic MedicineAnhui Medical University230032HefeiChina
| | - Li Lin
- Department of Biochemistry and Molecular BiologyMetabolic Disease Research CenterSchool of Basic MedicineAnhui Medical University230032HefeiChina
| | - Xiaomin Zhang
- Department of Biochemistry and Molecular BiologyMetabolic Disease Research CenterSchool of Basic MedicineAnhui Medical University230032HefeiChina
| | - Xiuyun Wang
- Department of Biochemistry and Molecular BiologyMetabolic Disease Research CenterSchool of Basic MedicineAnhui Medical University230032HefeiChina
| | - Dake Huang
- Synthetic Laboratory of School of Basic Medicine SciencesAnhui Medical University230032HefeiChina
| | - Cuiping Ren
- Department of Microbiology and ParasitologySchool of Basic MedicineAnhui Medical University230032HefeiChina
| | - Qingsong Yang
- Department of Hepatopancreatobiliary SurgeryAffifiliated Chuzhou Hospital of Anhui Medical University (The First People's Hospital of Chuzhou)Chuzhou239001China
| | - Wenjun Zhang
- Department of Hepatopancreatobiliary SurgeryAffifiliated Chuzhou Hospital of Anhui Medical University (The First People's Hospital of Chuzhou)Chuzhou239001China
| | - Yong Gao
- Science and Technology Innovation CenterGuangzhou University of Chinese Medicine510006GuangzhouChina
| | - Wei Chen
- Department of General SurgeryThe First Affiliated Hospital of Anhui Medical University230022HefeiChina
| | - Yongsheng Chang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education)Tianjin Key of Cellular Homeostasis and DiseaseDepartment of Physiology and PathophysiologyTianjin Medical University300070TianjinChina
| | - Huabing Zhang
- Department of Biochemistry and Molecular BiologyMetabolic Disease Research CenterSchool of Basic MedicineAnhui Medical University230032HefeiChina
- The Affiliated Chuzhou Hospital of Anhui Medical University (The First People's Hospital of Chuzhou)Chuzhou239001China
| |
Collapse
|
|
22
|
Chen D, Wang J, Li Y, Xu C, Fanzheng M, Zhang P, Liu L. LncRNA NEAT1 suppresses cellular senescence in hepatocellular carcinoma via KIF11-dependent repression of CDKN2A. Clin Transl Med 2023; 13:e1418. [PMID: 37752791 PMCID: PMC10522973 DOI: 10.1002/ctm2.1418] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 09/02/2023] [Accepted: 09/07/2023] [Indexed: 09/28/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Therapeutic options for advanced HCC are limited, which is due to a lack of full understanding of pathogenesis. Cellular senescence is a state of cell cycle arrest, which plays important roles in the pathogenesis of HCC. Mechanisms underlying hepatocellular senescence are not fully understood. LncRNA NEAT1 acts as an oncogene and contributes to the development of HCC. Whether NEAT1 modulates hepatocellular senescence in HCC is unknown. METHODS The role of NEAT1 and KIF11 in cellular senescence and tumor growth in HCC was assessed both in vitro and in vivo. RNA pulldown, mass spectrometry, Chromatin immunoprecipitation (ChIP), luciferase reporter assays, RNA FISH and immunofluorescence (IF) staining were used to explore the detailed molecular mechanism of NEAT1 and KIF11 in cellular senescence of HCC. RESULTS We found that NEAT1 was upregulated in tumor tissues and hepatoma cells, which negatively correlated with a senescence biomarker CDKN2A encoding p16INK4a and p14ARF proteins. NEAT1 was reduced in senescent hepatoma cells induced by doxorubicin (DOXO) or serum starvation. Furthermore, NEAT1 deficiency caused senescence in cultured hepatoma cells, and protected against the progression of HCC in a mouse model. During senescence, NEAT1 translocated into cytosol and interacted with a motor protein KIF11, resulting in KIF11 protein degradation and subsequent increased expression of CDKN2A in cultured hepatoma cells. Furthermore, KIF11 knockdown caused senescence in cultured hepatoma cells. Genetic deletion of Kif11 in hepatocytes inhibited the development of HCC in a mouse model. CONCLUSIONS Conclusively, NEAT1 overexpression reduces senescence and promotes tumor progression in HCC tissues and hepatoma cells, whereas NEAT1 deficiency causes senescence and inhibits tumor progression in HCC. This is associated with KIF11-dependent repression of CDKN2A. These findings lay the foundation to develop potential therapies for HCC by inhibiting NEAT1 and KIF11 or inducing senescence.
Collapse
Affiliation(s)
- Danlei Chen
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
- Anhui Province Key Laboratory of Hepatopancreatobiliary SurgeryHefeiAnhuiChina
- Anhui Provincial Clinical Research Center for Hepatobiliary DiseasesHefeiAnhuiChina
| | - Jinghao Wang
- Zhejiang Cancer HospitalHangzhou Institute of MedicineChinese Academy of SciencesHangzhouZhejiangChina
| | - Yang Li
- Zhejiang Cancer HospitalHangzhou Institute of MedicineChinese Academy of SciencesHangzhouZhejiangChina
| | - Chenglin Xu
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Meng Fanzheng
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
- Anhui Province Key Laboratory of Hepatopancreatobiliary SurgeryHefeiAnhuiChina
- Anhui Provincial Clinical Research Center for Hepatobiliary DiseasesHefeiAnhuiChina
| | - Pengfei Zhang
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
- Zhejiang Cancer HospitalHangzhou Institute of MedicineChinese Academy of SciencesHangzhouZhejiangChina
| | - Lianxin Liu
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
- Anhui Province Key Laboratory of Hepatopancreatobiliary SurgeryHefeiAnhuiChina
- Anhui Provincial Clinical Research Center for Hepatobiliary DiseasesHefeiAnhuiChina
| |
Collapse
|
|
23
|
Verma BK, Chatterjee A, Kondaiah P, Gundiah N. Substrate Stiffness Modulates TGF-β Activation and ECM-Associated Gene Expression in Fibroblasts. Bioengineering (Basel) 2023; 10:998. [PMID: 37760100 PMCID: PMC10525202 DOI: 10.3390/bioengineering10090998] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 06/19/2023] [Accepted: 07/06/2023] [Indexed: 09/29/2023] Open
Abstract
Transforming growth factor-β (TGF-β) is a multifunctional cytokine that regulates the expression of ECM-associated genes during early injury. Tissue fibrosis development is driven by synergistic cues between the evolving biochemical and mechanical milieu. Few studies have addressed the role of substrate stiffness on TGF-β activity and extracellular matrix (ECM)-associated genes. We used a commercial formulation of polydimethylsiloxane (PDMS) to fabricate substrates of 40 kPa, 300 kPa, and 1.5 MPa stiffness, and cultured the HMF3S fibroblasts on substrates. We quantified TGF-β protein secreted by HMF3S cells on different substrates using a TGF-β responsive promoter reporter assay. We also tested for variations in gene expression levels on the substrates using RT-PCR and Western blotting and determined the MMP-2 and MMP-9 activities with gelatin zymography. The results showed that TGF-β protein activation was significantly compromised at lower stiffnesses. The expression of integrin α5 decreased on lower stiffness substrates and correlated with inefficient TGF-β protein activation. Collagen I, collagen III, and MMP-2 expression levels were lower on softer substrates; there was little MMP-9 activity on all substrates. Cell and nuclear morphologies were more rounded on compliant substrates, correlating with increased tubulin expression. Proliferations were higher on stiffer substrates, whereas cells on softer substrates showed cell cycle arrest. These results demonstrated critical feedback mechanisms between substrate stiffness and ECM regulation by fibroblasts, relevant in fibrosis.
Collapse
Affiliation(s)
- Brijesh Kumar Verma
- Centre for Biosystems Science and Engineering, Indian Institute of Science, Bengaluru 560012, India
| | - Aritra Chatterjee
- Centre for Biosystems Science and Engineering, Indian Institute of Science, Bengaluru 560012, India
| | - Paturu Kondaiah
- Department of Developmental Biology and Genetics, Indian Institute of Science, Bengaluru 560012, India
| | - Namrata Gundiah
- Department of Mechanical Engineering, Indian Institute of Science, Bengaluru 560012, India
| |
Collapse
|
|
24
|
Mereness JA, Piraino L, Chen CY, Moyston T, Song Y, Shubin A, DeLouise LA, Ovitt CE, Benoit DSW. Slow hydrogel matrix degradation enhances salivary gland mimetic phenotype. Acta Biomater 2023; 166:187-200. [PMID: 37150277 PMCID: PMC10330445 DOI: 10.1016/j.actbio.2023.05.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 04/17/2023] [Accepted: 05/02/2023] [Indexed: 05/09/2023]
Abstract
We recently developed a salivary gland tissue mimetic (SGm), comprised of salivary gland cells encapsulated in matrix metalloproteinase (MMP)-degradable poly(ethylene glycol) hydrogels within arrays of ∼320 µm diameter spherical cavities molded in PDMS. The SGm provides a functional and physiologically relevant platform well-suited to high-throughput drug screening for radioprotective compounds. However, the utility of the SGm would benefit from improved retention of acinar cell phenotype and function. We hypothesized that tuning biochemical cues presented within the PEG hydrogel matrix would improve maintenance of acinar cell phenotype and function by mimicking the natural extracellular matrix microenvironment of the intact gland. Hydrogels formed using slower-degrading MMP-sensitive peptide crosslinkers showed >2-fold increase in sphere number formed at 48 h, increased expression of acinar cell markers, and more robust response to calcium stimulation by the secretory agonist, carbachol, with reduced SGm tissue cluster disruption and outgrowth during prolonged culture. The incorporation of adhesive peptides containing RGD or IKVAV improved calcium flux response to secretory agonists at 14 days of culture. Tuning the hydrogel matrix improved cell aggregation, and promoted acinar cell phenotype, and stability of the SGm over 14 days of culture. Furthermore, combining this matrix with optimized media conditions synergistically prolonged the retention of the acinar cell phenotype in SGm. STATEMENT OF SIGNIFICANCE: Salivary gland (SG) dysfunction occurs due to off-target radiation due to head and neck cancer treatments. Progress in understanding gland dysfunction and developing therapeutic strategies for the SG are hampered by the lack of in vitro models, as salivary gland cells rapidly lose critical secretory function within 24 hours in vitro. Herein, we identify properties of poly(ethylene glycol) hydrogel matrices that enhance the secretory phenotype of SG tissue mimetics within the previously-described SG-microbubble tissue chip environment. Combining slow-degrading hydrogels with media conditions optimized for secretory marker expression further enhanced functional secretory response and secretory marker expression.
Collapse
Affiliation(s)
- Jared A Mereness
- Department of Biomedical Engineering, University of Rochester, United States
| | - Lindsay Piraino
- Department of Biomedical Engineering, University of Rochester, United States; Department of Dermatology, University of Rochester, United States; Materials Science Program, University of Rochester, Rochester, NY, United States
| | - Chiao Yun Chen
- Department of Biomedical Engineering, University of Rochester, United States
| | - Tracey Moyston
- Department of Biomedical Engineering, University of Rochester, United States
| | - Yuanhui Song
- Department of Biomedical Engineering, University of Rochester, United States; Knight Campus Department of Bioengineering, Syracuse University, Syracuse, NY, United States
| | - Andrew Shubin
- Department of Biomedical Engineering, University of Rochester, United States; Department of General Surgery, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Lisa A DeLouise
- Department of Biomedical Engineering, University of Rochester, United States; Department of Dermatology, University of Rochester, United States; Materials Science Program, University of Rochester, Rochester, NY, United States
| | - Catherine E Ovitt
- Department of Biomedical Genetics, University of Rochester, United States
| | - Danielle S W Benoit
- Department of Biomedical Engineering, University of Rochester, United States; Department of Dermatology, University of Rochester, United States; Materials Science Program, University of Rochester, Rochester, NY, United States; Department of Chemical Engineering, University of Rochester, United States; Center for Musculoskeletal Research, University of Rochester, Rochester, NY, United States; Knight Campus Bioengineering Department, University of Oregon, Eugene, OR, United States.
| |
Collapse
|
|
25
|
Chen Y, Liu Y, Chen S, Zhang L, Rao J, Lu X, Ma Y. Liver organoids: a promising three-dimensional model for insights and innovations in tumor progression and precision medicine of liver cancer. Front Immunol 2023; 14:1180184. [PMID: 37334366 PMCID: PMC10272526 DOI: 10.3389/fimmu.2023.1180184] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 05/23/2023] [Indexed: 06/20/2023] Open
Abstract
Primary liver cancer (PLC) is one type of cancer with high incidence rate and high mortality rate in the worldwide. Systemic therapy is the major treatment for PLC, including surgical resection, immunotherapy and targeted therapy. However, mainly due to the heterogeneity of tumors, responses to the above drug therapy differ from person to person, indicating the urgent needs for personalized treatment for PLC. Organoids are 3D models derived from adult liver tissues or pluripotent stem cells. Based on the ability to recapitulate the genetic and functional features of in vivo tissues, organoids have assisted biomedical research to make tremendous progress in understanding disease origin, progression and treatment strategies since their invention and application. In liver cancer research, liver organoids contribute greatly to reflecting the heterogeneity of liver cancer and restoring tumor microenvironment (TME) by co-organizing tumor vasculature and stromal components in vitro. Therefore, they provide a promising platform for further investigation into the biology of liver cancer, drug screening and precision medicine for PLC. In this review, we discuss the recent advances of liver organoids in liver cancer, in terms of generation methods, application in precision medicine and TME modeling.
Collapse
Affiliation(s)
- Yukun Chen
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yujun Liu
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Shimin Chen
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Long Zhang
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Jiawei Rao
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xinjun Lu
- Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yi Ma
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
|
26
|
Du R, Li L, Ji J, Fan Y. Receptor-Ligand Binding: Effect of Mechanical Factors. Int J Mol Sci 2023; 24:ijms24109062. [PMID: 37240408 DOI: 10.3390/ijms24109062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/20/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023] Open
Abstract
Gaining insight into the in situ receptor-ligand binding is pivotal for revealing the molecular mechanisms underlying the physiological and pathological processes and will contribute to drug discovery and biomedical application. An important issue involved is how the receptor-ligand binding responds to mechanical stimuli. This review aims to provide an overview of the current understanding of the effect of several representative mechanical factors, such as tension, shear stress, stretch, compression, and substrate stiffness on receptor-ligand binding, wherein the biomedical implications are focused. In addition, we highlight the importance of synergistic development of experimental and computational methods for fully understanding the in situ receptor-ligand binding, and further studies should focus on the coupling effects of these mechanical factors.
Collapse
Affiliation(s)
- Ruotian Du
- Key Laboratory of Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China
| | - Long Li
- State Key Laboratory of Nonlinear Mechanics, Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China
| | - Jing Ji
- Key Laboratory of Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China
| | - Yubo Fan
- Key Laboratory of Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China
| |
Collapse
|
|
27
|
Hazra S, Dey S, Mandal BB, Ramachandran C. In Vitro Profiling of the Extracellular Matrix and Integrins Expressed by Human Corneal Endothelial Cells Cultured on Silk Fibroin-Based Matrices. ACS Biomater Sci Eng 2023; 9:2438-2451. [PMID: 37023465 DOI: 10.1021/acsbiomaterials.2c01566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
Developing a scaffold for culturing human corneal endothelial (HCE) cells is crucial as an alternative cell therapeutic approach to bridge the growing gap between the demand and availability of healthy donor corneas for transplantation. Silk films are promising substrates for the culture of these cells; however, their tensile strength is several-fold greater than the native basement membrane which can possibly influence the dynamics of cell-matrix interaction and the extracellular matrix (ECM) secreted by the cells in long-term culture. In our current study, we assessed the secretion of ECM and the expression of integrins by the HCE cells on Philosamia ricini (PR) and Antheraea assamensis (AA) silk films and fibronectin-collagen (FNC)-coated plastic dishes to understand the cell-ECM interaction in long-term culture. The expression of ECM proteins (collagens 1, 4, 8, and 12, laminin, and fibronectin) on silk was comparable to that on the native tissue. The thicknesses of collagen 8 and laminin at 30 days on both PR (4.78 ± 0.55 and 5.53 ± 0.51 μm, respectively) and AA (4.66 ± 0.72 and 5.71 ± 0.61 μm, respectively) were comparable with those of the native tissue (4.4 ± 0.63 and 5.28 ± 0.72 μm, respectively). The integrin expression by the cells on the silk films was also comparable to that on the native tissue, except for α3 whose fluorescence intensity was significantly higher on PR (p ≤ 0.01) and AA (p ≤ 0.001), compared to that on the native tissue. This study shows that the higher tensile strength of the silk films does not alter the ECM secretion or cell phenotype in long-term culture, confirming the suitability of using this material for engineering the HCE cells for transplantation.
Collapse
Affiliation(s)
- Swatilekha Hazra
- Hyderabad Eye Research Foundation, LV Prasad Eye Institute, Hyderabad 500034, India
- Manipal Academy of Higher Education, Manipal 576104, India
| | - Souradeep Dey
- Centre for Nanotechnology, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
| | - Biman B Mandal
- Biomaterials and Tissue Engineering Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
- Centre for Nanotechnology, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
- Jyoti and Bhupat Mehta School of Health Sciences & Technology, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
| | | |
Collapse
|
|
28
|
Yan CY, Zhao ML, Wei YN, Zhao XH. Mechanisms of drug resistance in breast cancer liver metastases: Dilemmas and opportunities. Mol Ther Oncolytics 2023; 28:212-229. [PMID: 36860815 PMCID: PMC9969274 DOI: 10.1016/j.omto.2023.02.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Breast cancer is the leading cause of cancer-related deaths in females worldwide, and the liver is one of the most common sites of distant metastases in breast cancer patients. Patients with breast cancer liver metastases face limited treatment options, and drug resistance is highly prevalent, leading to a poor prognosis and a short survival. Liver metastases respond extremely poorly to immunotherapy and have shown resistance to treatments such as chemotherapy and targeted therapies. Therefore, to develop and to optimize treatment strategies as well as to explore potential therapeutic approaches, it is crucial to understand the mechanisms of drug resistance in breast cancer liver metastases patients. In this review, we summarize recent advances in the research of drug resistance mechanisms in breast cancer liver metastases and discuss their therapeutic potential for improving patient prognoses and outcomes.
Collapse
Affiliation(s)
- Chun-Yan Yan
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, People’s Republic of China
| | - Meng-Lu Zhao
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, People’s Republic of China
| | - Ya-Nan Wei
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, People’s Republic of China
| | - Xi-He Zhao
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, People’s Republic of China
| |
Collapse
|
|
29
|
Calitz C, Rosenquist J, Degerstedt O, Khaled J, Kopsida M, Fryknäs M, Lennernäs H, Samanta A, Heindryckx F. Influence of extracellular matrix composition on tumour cell behaviour in a biomimetic in vitro model for hepatocellular carcinoma. Sci Rep 2023; 13:748. [PMID: 36639512 PMCID: PMC9839216 DOI: 10.1038/s41598-023-27997-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 01/11/2023] [Indexed: 01/15/2023] Open
Abstract
The tumor micro-environment (TME) of hepatocellular carcinoma (HCC) consists out of cirrhotic liver tissue and is characterized by an extensive deposition of extracellular matrix proteins (ECM). The evolution from a reversible fibrotic state to end-stage of liver disease, namely cirrhosis, is characterized by an increased deposition of ECM, as well as changes in the exact ECM composition, which both contribute to an increased liver stiffness and can alter tumor phenotype. The goal of this study was to assess how changes in matrix composition and stiffness influence tumor behavior. HCC-cell lines were grown in a biomimetic hydrogel model resembling the stiffness and composition of a fibrotic or cirrhotic liver. When HCC-cells were grown in a matrix resembling a cirrhotic liver, they increased proliferation and protein content, compared to those grown in a fibrotic environment. Tumour nodules spontaneously formed outside the gels, which appeared earlier in cirrhotic conditions and were significantly larger compared to those found outside fibrotic gels. These tumor nodules had an increased expression of markers related to epithelial-to-mesenchymal transition (EMT), when comparing cirrhotic to fibrotic gels. HCC-cells grown in cirrhotic gels were also more resistant to doxorubicin compared with those grown in fibrotic gels or in 2D. Therefore, altering ECM composition affects tumor behavior, for instance by increasing pro-metastatic potential, inducing EMT and reducing response to chemotherapy.
Collapse
Affiliation(s)
- Carlemi Calitz
- Department of Medical Cell Biology, Uppsala University, Husargatan 3, Box 571, 75431, Uppsala, Sweden
| | - Jenny Rosenquist
- Polymer Chemistry, Department of Chemistry-Ångström Laboratory, Uppsala University, Box 538, 75121, Uppsala, Sweden
| | - Oliver Degerstedt
- Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
| | - Jaafar Khaled
- Department of Medical Cell Biology, Uppsala University, Husargatan 3, Box 571, 75431, Uppsala, Sweden
| | - Maria Kopsida
- Department of Medical Cell Biology, Uppsala University, Husargatan 3, Box 571, 75431, Uppsala, Sweden
| | - Mårten Fryknäs
- Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala, Sweden
| | - Hans Lennernäs
- Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
| | - Ayan Samanta
- Polymer Chemistry, Department of Chemistry-Ångström Laboratory, Uppsala University, Box 538, 75121, Uppsala, Sweden
| | - Femke Heindryckx
- Department of Medical Cell Biology, Uppsala University, Husargatan 3, Box 571, 75431, Uppsala, Sweden.
| |
Collapse
|
|
30
|
Nintedanib-αVβ6 Integrin Ligand Conjugates Reduce TGF β-Induced EMT in Human Non-Small Cell Lung Cancer. Int J Mol Sci 2023; 24:ijms24021475. [PMID: 36674990 PMCID: PMC9861180 DOI: 10.3390/ijms24021475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 01/09/2023] [Accepted: 01/10/2023] [Indexed: 01/14/2023] Open
Abstract
Growth factors and cytokines released in the lung cancer microenvironment promote an epithelial-to-mesenchymal transition (EMT) that sustains the progression of neoplastic diseases. TGFβ is one of the most powerful inducers of this transition, as it induces overexpression of the fibronectin receptor, αvβ6 integrin, in cancer cells which, in turn, is strongly associated with EMT. Thus, αvβ6 integrin receptors may be exploited as a target for the selective delivery of anti-tumor agents. We introduce three novel synthesized conjugates, in which a selective αvβ6 receptor ligand is linked to nintedanib, a potent kinase inhibitor used to treat advanced adenocarcinoma lung cancer in clinics. The αvβ6 integrin ligand directs nintedanib activity to the target cells of the tumor microenvironment, avoiding the onset of negative side effects in normal cells. We found that the three conjugates inhibit the adhesion of cancer cells to fibronectin in a concentration-dependent manner and that αvβ6-expressing cells internalized the conjugated compounds, thus permitting nintedanib to inhibit 2D and 3D cancer cell growth and suppress the clonogenic ability of the EMT phenotype as well as intervening in other aspects associated with the EMT transition. These results highlight αvβ6 receptors as privileged access points for dual-targeting molecular conjugates engaged in an efficient and precise strategy against non-small cell lung cancer.
Collapse
|
|
31
|
Yamazaki K, Miyauchi E, Kato T, Sato K, Suda W, Tsuzuno T, Yamada-Hara M, Sasaki N, Ohno H, Yamazaki K. Dysbiotic human oral microbiota alters systemic metabolism via modulation of gut microbiota in germ-free mice. J Oral Microbiol 2022; 14:2110194. [PMID: 35966937 PMCID: PMC9373767 DOI: 10.1080/20002297.2022.2110194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Background The effect of oral microbiota on the intestinal microbiota has garnered growing attention as a mechanism linking periodontal diseases to systemic diseases. However, the salivary microbiota is diverse and comprises numerous bacteria with a largely similar composition in healthy individuals and periodontitis patients. Aim We explored how health-associated and periodontitis-associated salivary microbiota differently colonized the intestine and their subsequent systemic effects. Methods The salivary microbiota was collected from a healthy individual and a periodontitis patient and gavaged into C57BL/6NJcl[GF] mice. Gut microbial communities, hepatic gene expression profiles, and serum metabolites were analyzed. Results The gut microbial composition was significantly different between periodontitis-associated microbiota-administered (PAO) and health-associated oral microbiota-administered (HAO) mice. The hepatic gene expression profile demonstrated a distinct pattern between the two groups, with higher expression of lipid and glucose metabolism-related genes. Disease-associated metabolites such as 2-hydroxyisobutyric acid and hydroxybenzoic acid were elevated in PAO mice. These metabolites were significantly correlated with characteristic gut microbial taxa in PAO mice. Conversely, health-associated oral microbiota were associated with higher levels of beneficial serum metabolites in HAO mice. Conclusion The multi-omics approach used in this study revealed that periodontitis-associated oral microbiota is associated with the induction of disease phenotype when they colonized the gut of germ-free mice.
Collapse
Affiliation(s)
- Kyoko Yamazaki
- Division of Periodontology, Niigata University Graduate School of Medical and Dental Sciences, Niigata Japan
| | - Eiji Miyauchi
- Laboratory for Intestinal Ecosystem, RIKEN Centre for Integrative Medical Sciences (IMS), Kanagawa Japan
- Laboratory of Mucosal Ecosystem Design, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma Japan
| | - Tamotsu Kato
- Laboratory for Intestinal Ecosystem, RIKEN Centre for Integrative Medical Sciences (IMS), Kanagawa Japan
- Immunobiology Laboratory, Graduate School of Medical Life Science, Yokohama City University, Kanagawa Japan
| | - Keisuke Sato
- Division of Periodontology, Niigata University Graduate School of Medical and Dental Sciences, Niigata Japan
| | - Wataru Suda
- Laboratory for Microbiome Sciences, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Takahiro Tsuzuno
- Division of Periodontology, Niigata University Graduate School of Medical and Dental Sciences, Niigata Japan
| | - Miki Yamada-Hara
- Division of Periodontology, Niigata University Graduate School of Medical and Dental Sciences, Niigata Japan
| | - Nobuo Sasaki
- Laboratory of Mucosal Ecosystem Design, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma Japan
| | - Hiroshi Ohno
- Laboratory for Intestinal Ecosystem, RIKEN Centre for Integrative Medical Sciences (IMS), Kanagawa Japan
- Immunobiology Laboratory, Graduate School of Medical Life Science, Yokohama City University, Kanagawa Japan
- Laboratory for Microbiome Sciences, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Kazuhisa Yamazaki
- Laboratory for Intestinal Ecosystem, RIKEN Centre for Integrative Medical Sciences (IMS), Kanagawa Japan
| |
Collapse
|
|
32
|
Zhang X, Wu X, Sun Y, Chu Y, Liu F, Chen C. TRIM44 regulates tumor immunity in gastric cancer through LOXL2-dependent extracellular matrix remodeling. Cell Oncol (Dordr) 2022; 46:423-435. [PMID: 36512309 DOI: 10.1007/s13402-022-00759-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 11/12/2022] [Accepted: 12/06/2022] [Indexed: 12/15/2022] Open
Abstract
PURPOSE Gastric cancer is a gastrointestinal malignancy with high mortality and poor prognosis, and the molecular mechanism of gastric tumorigenesis remains unclear. TRIM44 has been reported to be involved in tumor development. However, the role of TRIM44 in tumor immunity is largely unknown. METHODS We analyzed TRIM44 expression in clinical gastric cancer tissues and normal tissues by using western blot, quantitative real-time PCR and bioinformatics analyses. We further investigated the involvement of TRIM44 in tumor immunity in vivo and found that it was dependent on extracellular matrix remodeling. We detected the interaction between TRIM44 and LOXL2 by using immunofluorescence staining and coimmunoprecipitation assays. We observed that TRIM44 mediates the stability of LOXL2 by ubiquitination assays. RESULTS TRIM44 expression is high and is correlated with T-cell infiltration in gastric cancer. TRIM44 inhibits gastric tumorigenicity by regulating T-cell-mediated antitumor immunity and modulating the protein level of LOXL2. Mechanistically, TRIM44 directly binds to LOXL2 and affects the stability of LOXL2 to change extracellular matrix remodeling and influence tumor immunity. CONCLUSION These findings demonstrate that TRIM44 regulates the stability of LOXL2 to remodel the tumor extracellular matrix to modulate tumor immunity in gastric cancer and that the TRIM44/LOXL2 complex is a promising biomarker for gastric cancer prognosis and might be a novel immunotherapy target.
Collapse
Affiliation(s)
- Xin Zhang
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wenhua Road, 250012, JiNan, China
| | - Xiusheng Wu
- Department of General Surgery, Linyi People's Hospital, 105 Plaza Street, Linyi County, China
| | - Ying Sun
- Department of Blood quality Control, Yantai central blood station, 10 Haiyun Road, Yantai, China
| | - Yali Chu
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wenhua Road, 250012, JiNan, China
| | - Fengjun Liu
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wenhua Road, 250012, JiNan, China
| | - Cheng Chen
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wenhua Road, 250012, JiNan, China.
| |
Collapse
|
|
33
|
Li M, Zhao YY, Cui JF. Matrix stiffness in regulation of tumor angiogenesis. Shijie Huaren Xiaohua Zazhi 2022; 30:871-878. [DOI: 10.11569/wcjd.v30.i20.871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Angiogenesis is one of the most common malignant features of solid tumors such as liver cancer, pancreatic cancer, and gastrointestinal tumors, which is the basis of tumor growth, invasion, and metastasis. It is also an important target of anti-tumor therapy. Tumor angiogenesis is usually triggered by biochemical, hypoxic, and biomechanical factors in the microenvironment. The regulation of biochemical signals and hypoxic microenvironment in tumor angiogenesis have been widely documented, but the role of biomechanical signals in tumor angiogenesis has gradually begun to be uncovered in recent years. The vasculature system is naturally sensitive to mechanical stimuli. Recent studies have highlighted the important regulatory effects of biomechanical stimuli, such as matrix stiffness, fluid shear stress, and vascular lumen pressure, on the phenotype and functions of tumor blood vessels. In this paper, we summarize the new progress and internal mechanisms of matrix stiffness-mediated effects on tumor angiogenesis.
Collapse
Affiliation(s)
- Miao Li
- Department of Hepatic Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Ying-Ying Zhao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Jie-Feng Cui
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| |
Collapse
|
|
34
|
Building a tissue: mesenchymal and epithelial cell spheroids' mechanical properties at micro- and nanoscale. Acta Biomater 2022:S1742-7061(22)00621-3. [PMID: 36167239 DOI: 10.1016/j.actbio.2022.09.051] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 09/09/2022] [Accepted: 09/19/2022] [Indexed: 11/21/2022]
Abstract
Cell transitions between the epithelial and mesenchymal phenotypes provide the regulated morphogenesis and regeneration throughout the ontogenesis. The tissue mechanics and mechanotransduction play an essential role in these processes. Cell spheroids reproduce the cell density of native tissues and represent simple building blocks for the tissue engineering purposes. The mechanical properties of mesenchymal and epithelial cells have been extensively studied in 2D monolayer cultures, but have not been sufficiently compared in spheroids. Here, we have simultaneously applied several techniques to assess the mechanical parameters of such spheroids. The local surface mechanical properties were measured by AFM, and the bulk properties were analyzed with parallel-plate compression, as well as by observing cut opening after microdissection. The comparison of the collected data allowed us to apply the model of a solid body with surface tension, and estimate the parameters of this model. We found an expectedly higher surface tension in mesenchymal spheroids, as well as a higher bulk modulus and relaxation time. The two latter parameters agree with the bulk poroelastic behavior of spheroids, and with the higher cell density and extracellular matrix content in mesenchymal spheroids. The higher tension of the surface layer cells in mesenchymal cell spheroids was also confirmed by the viscoelastic AFM characterization. The cell phenotype affected the self-organization during the spheroid formation, as well as the structure, biomechanical properties, and spreading of spheroids. The obtained results will contribute to a more detailed description of spheroid and tissue biomechanics, and will help in controlling the tissue regeneration and morphogenesis. STATEMENT OF SIGNIFICANCE: Spheroids are widely used as building blocks for scaffold-based and scaffold-free strategies in tissue engineering. In the majority of the past studies, either the concept of a solid body or a liquid with surface tension was used to describe the biomechanical behavior of spheroids. Here, we have used a model which combines both aspects, a solid body with surface tension. The "solid" aspect was described as a visco-poroelastic material, affected by the liquid redistribution through the cells and ECM at the scale of the whole spheroid. A higher surface tension was found for mesenchymal spheroids than that for epithelial spheroids, observed as a higher stiffness of the spheroid surface, as well as a larger spontaneous opening of the cut edges after microdissection.
Collapse
|
|
35
|
Pressure Loading Induces DNA Damage in Human Hepatocyte Line L02 Cells via the ERK1/2-Dicer Signaling Pathway. Int J Mol Sci 2022; 23:ijms23105342. [PMID: 35628153 PMCID: PMC9140865 DOI: 10.3390/ijms23105342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/07/2022] [Accepted: 05/09/2022] [Indexed: 11/17/2022] Open
Abstract
Alteration of liver tissue mechanical microenvironment is proven to be a key factor for causing hepatocyte injury and even triggering the occurrence of hepatocellular carcinoma; however, the underlying mechanisms involved are not fully understood. In this study, using a customized, pressure-loading device, we assess the effect of pressure loading on DNA damage in human hepatocytes. We show that pressure loading leads to DNA damage and S-phase arresting in the cell cycle, and activates the DNA damage response in hepatocytes. Meanwhile, pressure loading upregulates Dicer expression, and its silencing exacerbates pressure-induced DNA damage. Moreover, pressure loading also activates ERK1/2 signaling molecules. Blockage of ERK1/2 signaling inhibits pressure-upregulated Dicer expression and exacerbates DNA damage by suppressing DNA damage response in hepatocytes. Our findings demonstrate that compressive stress loading induces hepatocyte DNA damage through the ERK1/2–Dicer signaling pathway, which provides evidence for a better understanding of the link between the altered mechanical environment and liver diseases.
Collapse
|
|
36
|
Yang X, Cao D, Ma W, Gao S, Wen G, Zhong J. Wnt signaling in triple-negative breast cancers: Its roles in molecular subtyping and cancer cell stemness and its crosstalk with non-coding RNAs. Life Sci 2022; 300:120565. [DOI: 10.1016/j.lfs.2022.120565] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 04/11/2022] [Accepted: 04/16/2022] [Indexed: 12/20/2022]
|
|
37
|
Quercetin Regulates Key Components of the Cellular Microenvironment during Early Hepatocarcinogenesis. Antioxidants (Basel) 2022; 11:antiox11020358. [PMID: 35204240 PMCID: PMC8868318 DOI: 10.3390/antiox11020358] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 02/03/2022] [Accepted: 02/08/2022] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a health problem worldwide due to its high mortality rate, and the tumor microenvironment (TME) plays a key role in the HCC progression. The current ineffective therapies to fight the disease still warrant the development of preventive strategies. Quercetin has been shown to have different antitumor activities; however, its effect on TME components in preneoplastic lesions has not been fully investigated yet. Here, we aimed to evaluate the effect of quercetin (10 mg/kg) on TME components during the early stages of HCC progression induced in the rat. Histopathological and immunohistochemical analyses showed that quercetin decreases the size of preneoplastic lesions, glycogen and collagen accumulation, the expression of cancer stem cells and myofibroblasts markers, and that of the transporter ATP binding cassette subfamily C member 3 (ABCC3), a marker of HCC progression and multi-drug resistance. Our results strongly suggest that quercetin has the capability to reduce key components of TME, as well as the expression of ABCC3. Thus, quercetin can be an alternative treatment for inhibiting the growth of early HCC tumors.
Collapse
|