Journal of Cell Communication and Signaling最新文献

The 11th International Workshop on the CCN Family of Genes organized in Nice from October 20th to October 24th, 2022, was the occasion to celebrate the 20th anniversary of the ICCNS meetings.

Calcified aortic valve disease (CAVD) is a major non-rheumatic heart valve disease in the world, with a high mortality rate and without suitable pharmaceutical therapy due to its complex mechanisms. Src-associated in mitosis 68-KD (Sam68), an RNA binding protein, has been reported as a signaling adaptor in numerous signaling pathways (Huot in Mol Cell Biol, 29(7), 1933-1943, 2009), particularly in inflammatory signaling pathways. The effects of Sam68 on the osteogenic differentiation process of hVICs and its regulation on signal transducer and activator of transcription 3 (STAT3) signaling pathway have been investigated in this study. Human aortic valve samples detection found that Sam68 expression was up-regulated in human calcific aortic valves. We used tumor necrosis factor α (TNF-α) as an activator for osteogenic differentiation in vitro and the result indicated that Sam68 was highly expressed after TNF-α stimulation. Overexpression of Sam68 promoted osteogenic differentiation of hVICs while Sam68 knockdown reversed this effect. Sam68 interaction with STAT3 was predicted by using String database and was verified in this study. Sam68 knockdown reduced phosphorylation of STAT3 activated by TNF-α and the downstream gene expression, which further influenced autophagy flux in hVICs. STAT3 knockdown alleviated the osteogenic differentiation and calcium deposition promoted by Sam68 overexpression. In conclusion, Sam68 interacts with STAT3 and participates in its phosphorylation to promote osteogenic differentiation of hVICs to induce valve calcification. Thus, Sam68 may be a new therapeutic target for CAVD.

CCN1 and CCN2 are matricellular proteins that are transcriptionally induced by various stimuli, including growth factors. CCN proteins act to facilitate signaling events involving extracellular matrix proteins. Lysophosphatidic acid (LPA) is a lipid that activates G protein-coupled receptors (GPCRs), enhancing proliferation, adhesion, and migration in many types of cancer cells. Our group previously reported that LPA induces production of CCN1 protein in human prostate cancer cell lines within 2–4 h. In these cells, the mitogenic activity of LPA is mediated by LPA Receptor 1 (LPAR1), a GPCR. There are multiple examples of the induction of CCN proteins by LPA, and by the related lipid mediator sphingosine-1-phosphate (S1P), in various cellular models. The signaling pathways responsible for LPA/S1P-induced CCN1/2 typically involve activation of the small GTP-binding protein Rho and the transcription factor YAP. Inducible CCNs can potentially play roles in downstream signal transduction events required for LPA and S1P-induced responses. Specifically, CCNs secreted into the extracellular space can facilitate the activation of additional receptors and signal transduction pathways, contributing to the biphasic delayed responses typically seen in response to growth factors acting via GPCRs. In some model systems, CCN1 and CCN2 play key roles in LPA/S1P-induced cell migration and proliferation. In this way, an extracellular signal (LPA or S1P) can activate GPCR-mediated intracellular signaling to induce the production of extracellular modulators (CCN1 and CCN2) that in turn initiate another round of intracellular signaling.

In celebration of the twentieth anniversary of the inception of the CCN society, and of the first post-Covid-19 live meeting, the executive board of the ICCNS had chosen Nice as the venue for the 11th International workshop on the CCN family of genes. On this occasion participation in the meeting was extended to colleagues from other cell signaling fields who were invited to present both an overview of their work and the future directions of their laboratory. Also, for the first time, the members of the JCCS Editorial Board were invited to participate in a JCCS special session during which all aspects of the journal « life » were addressed and opened to free critical discussion. The scientific presentations and the discussions that followed showed once more that an expansion of the session topics was beneficial to the quality of the meeting and confirmed that the ARBIOCOM project discussed last April in Nice was now on track to be launched in 2023. The participants unanimously welcomed Professor Attramadal’s proposition to organize the 2024, 12th International CCN workshop in Oslo, Norway.

It is a renewed pleasure to wish our authors, editorial board members, and readership an excellent new year, full of professional and personal satisfactions. According to the Chinese Horoscope, 2023, the Year of Water Rabbit, is predicted to be quiet; a year to step back, assess the situation and make plans. It will be the time to carefully appraise, with the patience of the Water Rabbit, the future and scientific wealth of our Journal. Based on a few aspects of the CCN3 biology status that remain open questions, I am presenting below a short summary of a few CCN research directions that in my eyes, become necessary to undertake through wide-angle collaborative approaches.

Hepatic ischemia–reperfusion (I/R) injury is a severe clinical syndrome, causing a profound medical and socioeconomic burden worldwide. This study aimed to explore underlying biomarkers and treatment targets in the progression of hepatic I/R injury. We screened gene expression profiles of the hepatic I/R injury from the Gene Expression Omnibus (GEO) database, downloaded expression profiles data (GSE117066). Differentially expressed genes (DEGs) were identified through cluster of the PPI network, and enrichment pathways were conducted based on gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The bioinformatics analysis was used to identify biomarkers that alleviate hepatic I/R injury. Finally, the effects of hub gene were investigated by in vitro and in vivo experiments. A total of 162 DEGs (76 up-regulated and 86 down-regulated genes) were extracted between sham and I/R, and 248 DEGs (118 up-regulated and 130 down-regulated genes) were extracted between I/R and ischemic postconditioning (IPO). The cluster of the PPI network and maximal clique centrality (MCC) method of the common DEGs were performed to identify the phosphoserine aminotransferase 1 (PSAT1) as the potential gene for hepatic I/R injury. Then, the H-E, TUNEL and PCNA staining were indicated that the hepatic injury score was highest in I/R 6 h. The expression level of apoptosis-related proteins was consistent with the pathological results. Both gain- and loss-of-function assays demonstrated that hepatic I/R injury was alleviated by PSAT1. PSAT1 may play crucial roles in hepatic I/R injury and thus serves as a hub biomarker for hepatic I/R injury prognosis and individual-based treatment.

Cellular communication network factor (CCN) 3, which is one of the founding members of the CCN family, displays diverse functions. However, this protein generally represses the proliferation of a variety of cells. Along with skeletal development, CCN3 is produced in cartilaginous anlagen, growth plate cartilage and epiphysial cartilage. Interestingly, CCN3 is drastically induced in the growth plates of mice lacking CCN2, which promotes endochondral ossification. Notably, chondrocytes in these mutant mice with elevated CCN3 production also suffer from impaired glycolysis and energy metabolism, suggesting a critical role of CCN3 in cartilage metabolism. Recently, CCN3 was found to be strongly induced by impaired glycolysis, and in our study, we located an enhancer that mediated CCN3 regulation via starvation. Subsequent investigations specified regulatory factor binding to the X-box 1 (RFX1) as a transcription factor mediating this CCN3 regulation. Impaired glycolysis is a serious problem, resulting in an energy shortage in cartilage without vasculature. CCN3 produced under such starved conditions restricts energy consumption by repressing cell proliferation, leading chondrocytes to quiescence and survival. This CCN3 regulatory system is indicated to play an important role in articular cartilage maintenance, as well as in skeletal development. Furthermore, CCN3 continues to regulate cartilage metabolism even during the aging process, probably utilizing this regulatory system. Altogether, CCN3 seems to prevent “overwork” by chondrocytes to ensure their sustainable life in cartilage by sensing energy metabolism. Similar roles are suspected to exist in relation to systemic metabolism, since CCN3 is found in the bloodstream.

The therapeutic potential of purinergic signaling has been explored for a wide variety of diseases, including those related to the skin. In this study, we used the self-assembled skin substitutes (SASS), a highly functional reconstructed human skin model, which shares many properties with normal human skin, to study the impact of purinergic receptors agonists, such as ATP, UTP and a P2Y receptor antagonist, Reactive Blue 2 during wound healing. After treating the wounded skins, we evaluated the wound area, reepithelialization, length of migrating tongues toward the wound, quality of the skins through the cytokeratin 10 and laminin-5 expression, epidermal and dermal cell proliferation. In addition, the expression of the main ectoenzymes capable of hydrolyzing nucleotides were investigated through the wounded SASS regions: unwounded region, wound margin, intermediate region and migrating epidermal tongue. After 3 days, under the UTP treatment, the wounded SASS showed an increase in the reepithelialization and in the proliferation of keratinocytes and fibroblasts, without altering the quality of the skin. We also identified the presence of the ectoenzymes NTPDase1 and NPP1 in the reconstructed human skin model, suggesting their involvement in wound healing. Considering the need for new therapies capable of promoting healing in complex wounds, although these results are still preliminary, they suggest the involvement of extracellular nucleotides in human skin healing and the importance to understand their role in this mechanism. New experiments it will be necessary to determine the mechanisms by which the purinergic signaling is involved in the skin wound healing.

Glial cell line-derived neurotrophic factor (GDNF) signals through a multi-component receptor system predominantly consisting of glycosyl-phosphatidylinositol-anchored GDNF family receptor alpha-1 (GFRα1) and the Rearranged during transfection (RET) receptor tyrosine kinase. GDNF/RET signaling is vital to the central and peripheral nervous system, kidney morphogenesis, and spermatogenesis. In addition, the dysregulation of the GDNF/RET signaling has been implicated in the pathogenesis of cancers. Despite the extensive research on GDNF/RET signaling, a molecular network of reactions induced by GDNF reported across the published literature. However, a comprehensive GDNF/RET pathway resource is currently unavailable. We describe an integrated signaling pathway reaction map of GDNF/RET consisting of 1151 molecular reactions. These include information pertaining to 52 molecular association events, 70 enzyme catalysis events, 36 activation/inhibition events, 22 translocation events, 856 gene regulation events, and 115 protein-level expression events induced by GDNF in diverse cell types. We developed a comprehensive GDNF/RET signaling network map based on these molecular reactions. The pathway map was made accessible through WikiPathways database (https://www.wikipathways.org/index.php/Pathway:WP5143).

The tumorigenic properties of prostate cancer are regulated by advanced hormonal regulation-mediated complex molecular signals. Therefore, characterizing the regulation of these signal transduction systems is crucial for understanding prostate cancer biology. Recent studies have shown that endoplasmic reticulum (ER)-localized protein quality control mechanisms, including ER-associated degradation (ERAD) and unfolded protein response (UPR) signaling contribute to prostate carcinogenesis and to the development of drug resistance. It has also been determined that these systems are tightly regulated by androgens. However, the role of estrogenic signaling in prostate cancer and its effects on protein quality control mechanisms is not fully understood. Herein, we investigated the regulatory effects of estrogens on ERAD and UPR and their impacts on prostate carcinogenesis. We found that estrogens strongly regulated the ERAD components and IRE1⍺ branch of UPR by Er⍺/β/AR axis. Besides, estrogenic signaling rigorously regulated the tumorigenicity of prostate cancer cells by promoting c-Myc expression and epithelial-mesenchymal transition (EMT). Moreover, estrogenic signal blockage significantly decreased the tumorigenic features of prostate cancer cells. Additionally, simultaneous inhibition of androgenic/estrogenic signals more efficiently inhibited tumorigenicity of prostate cancer cells, including proliferation, migration, invasion and colonial growth. Furthermore, computational-based molecular docking, molecular dynamics simulations and MMPBSA calculations supported the estrogenic stimulation of AR. Present findings suggested that ERAD components and IRE1⍺ signaling are tightly regulated by estrogen-stimulated AR and Er⍺/β. Our data suggest that treatment approaches targeting the co-inhibition of androgenic/estrogenic signals may pave the way for new treatment approaches to be developed for prostate cancer.