The CCN axis in cancer development and progression

Yeger, Herman; Perbal, Bernard

doi:10.1007/s12079-021-00618-2

Cited by 18 publications

(22 citation statements)

References 104 publications

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“…Although DR is the leading cause of blindness in developed and developing countries (39), the underlying pathogenic mechanisms have not been fully elucidated. The CCN family proteins are composed of four domains (IGFBP, VWC, TSP1, and CT) and functions at the cell matrix boundary or within the nucleus to modulatory gene transcription (40). The first identified member of the CCN family was CCN1, which was described as an angiogenic factor (41).…”

Section: Discussionmentioning

confidence: 99%

Diabetes Promotes Retinal Vascular Endothelial Cell Injury by Inducing CCN1 Expression

Wang

et al. 2021

Front. Cardiovasc. Med.

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Purpose: Diabetic retinopathy (DR) is one of the most common diabetic microvascular complications. However, the pathogenesis of DR has not yet been fully elucidated. This study aimed to discover novel and key molecules involved in the pathogenesis of DR, which could potentially be targets for therapeutic DR intervention.Methods: To identify potential genes involved in the pathogenesis of DR, we analyzed the public database of neovascular membranes (NVMs) from patients with proliferative diabetic retinopathy (PDR) and healthy controls (HCs) (GSE102485, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE102485). Further, we compared these findings by performing RNA-sequencing analysis of peripheral blood mononuclear cells (PBMC) from patients with DR, control patients with non-complicated diabetes mellitus (DMC), and HCs. To determine the critical role of candidate genes in DR, knockdown or knockout was performed in human retinal vascular endothelial cells (HRVECs). The oxidative stress pathway, as well as tight junction integrity, was analyzed.Results: Transcriptional profiles showed distinct patterns between the NVMs of patients with DR and those of the HCs. Those genes enriched in either extracellular matrix (ECM)-receptor interaction or focal adhesion pathways were considerably upregulated. Both pathways were important for maintaining the integrity of retinal vascular structure and function. Importantly, the gene encoding the matricellular protein CCN1, a key gene in cell physiology, was differentially expressed in both pathways. Knockdown of CCN1 by small interfering RNA (siRNA) or knockout of CCN1 by the CRISPR-Cas9 technique in HRVECs significantly increased the levels of VE-cadherin, reduced the level of NADPH oxidase 4 (NOX4), and inhibited the generation of reactive oxygen species (ROS).Conclusion: The present study identifies CCN1 as an important regulator in the pathogenesis of DR. Increased expression of CCN1 stimulates oxidative stress and disrupts tight junction integrity in endothelial cells by inducing NOX4. Thus, targeting the CCN1/NOX4 axis provides a therapeutic strategy for treating DR by alleviating endothelial cell injury.

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Section: Discussionmentioning

confidence: 99%

Diabetes Promotes Retinal Vascular Endothelial Cell Injury by Inducing CCN1 Expression

Wang

et al. 2021

Front. Cardiovasc. Med.

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“…In addition to fibrosis, a number of studies have indicated the profound involvement of CCN2 and CCN3 in human malignancies [ 138 ]. In some cases, the yin–yang emergence of CCN2 and CCN3 is retained, whereas the CCN2/CCN3 bidirectional regulation system appears to be collapsed in the others [ 87 , 139 , 140 , 141 , 142 ].…”

Section: Ccn2-ccn3 Interplay In Malignanciesmentioning

confidence: 99%

Molecular and Genetic Interactions between CCN2 and CCN3 behind Their Yin–Yang Collaboration

Kubota

Kawata

Hattori

et al. 2022

IJMS

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Cellular communication network factor (CCN) 2 and 3 are the members of the CCN family that conduct the harmonized development of a variety of tissues and organs under interaction with multiple biomolecules in the microenvironment. Despite their striking structural similarities, these two members show contrastive molecular functions as well as temporospatial emergence in living tissues. Typically, CCN2 promotes cell growth, whereas CCN3 restrains it. Where CCN2 is produced, CCN3 disappears. Nevertheless, these two proteins collaborate together to execute their mission in a yin–yang fashion. The apparent functional counteractions of CCN2 and CCN3 can be ascribed to their direct molecular interaction and interference over the cofactors that are shared by the two. Recent studies have revealed the mutual negative regulation systems between CCN2 and CCN3. Moreover, the simultaneous and bidirectional regulatory system of CCN2 and CCN3 is also being clarified. It is of particular note that these regulations were found to be closely associated with glycolysis, a fundamental procedure of energy metabolism. Here, the molecular interplay and metabolic gene regulation that enable the yin–yang collaboration of CCN2 and CCN3 typically found in cartilage development/regeneration and fibrosis are described.

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“…CCN proteins actively participate in carcinogenesis, as their role has been clarified in every hallmark of cancer except inflammation (for a review see (Yeger and Perbal 2021 )). Nevertheless, the role of at least CCN1 and CCN2 in rheumatoid arthritis underscores their association with the regulation of proinflammatory cytokines in the microenvironment.…”

Section: Ccn Proteins In Sarcomas Of the Musculoskeletal Systemmentioning

confidence: 99%

“…Skeletal metastasis is associated with reduced patient quality of life, elevated medical costs and ultimately reduced overall survival (Coleman et al 2020 ). Matricellular proteins, as CCN family members, have been demonstrated to be involved in every hallmark of cancer (Chong et al 2012 ; Yeger and Perbal 2021 ). The present review aims to provide a comprehensive view of CCN proteins in the development, physiology, pathology, and malignancy of the musculoskeletal system.…”

Section: Introductionmentioning

confidence: 99%

CCN proteins in the musculoskeletal system: current understanding and challenges in physiology and pathology

Giusti

Scotlandi

2021

J. Cell Commun. Signal.

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The acronym for the CCN family was recently revised to represent “cellular communication network”. These six, small, cysteine-enriched and evolutionarily conserved proteins are secreted matricellular proteins, that convey and modulate intercellular communication by interacting with structural proteins, signalling factors and cell surface receptors. Their role in the development and physiology of musculoskeletal system, constituted by connective tissues where cells are interspersed in the cellular matrix, has been broadly studied. Previous research has highlighted a crucial balance of CCN proteins in mesenchymal stem cell commitment and a pivotal role for CCN1, CCN2 and their alter ego CCN3 in chondrogenesis and osteogenesis; CCN4 plays a minor role and the role of CCN5 and CCN6 is still unclear. CCN proteins also participate in osteoclastogenesis and myogenesis. In adult life, CCN proteins serve as mechanosensory proteins in the musculoskeletal system providing a steady response to environmental stimuli and participating in fracture healing. Substantial evidence also supports the involvement of CCN proteins in inflammatory pathologies, such as osteoarthritis and rheumatoid arthritis, as well as in cancers affecting the musculoskeletal system and bone metastasis. These matricellular proteins indeed show involvement in inflammation and cancer, thus representing intriguing therapeutic targets. This review discusses the current understanding of CCN proteins in the musculoskeletal system as well as the controversies and challenges associated with their multiple and complex roles, and it aims to link the dispersed knowledge in an effort to stimulate and guide readers to an area that the writers consider to have significant impact and relevant potentialities.

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The CCN axis in cancer development and progression

Cited by 18 publications

References 104 publications

Diabetes Promotes Retinal Vascular Endothelial Cell Injury by Inducing CCN1 Expression

Diabetes Promotes Retinal Vascular Endothelial Cell Injury by Inducing CCN1 Expression

Molecular and Genetic Interactions between CCN2 and CCN3 behind Their Yin–Yang Collaboration

CCN proteins in the musculoskeletal system: current understanding and challenges in physiology and pathology

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