Piezo1 impairs hepatocellular tumor growth via deregulation of the MAPK-mediated YAP signaling pathway

Cancer metastasis is one of the leading causes of death worldwide, motivating research into identifying new methods of preventing cancer metastasis. Recently there has been increasing interest in understanding how cancer cells transduce mechanical forces into biochemical signals, as metastasis is a process that consists of a wide range of physical forces. For instance, the circulatory system through which disseminating cancer cells must transit is an environment characterized by variable fluid shear stress due to blood flow. Cancer cells and other cells can transduce physical stimuli into biochemical responses using the mechanosensitive ion channel Piezo1, which is activated by membrane deformations that occur when cells are exposed to physical forces. When active, Piezo1 opens, allowing for calcium flux into the cell. Calcium, as a ubiquitous second-messenger cation, is associated with many signaling pathways involved in cancer metastasis, such as angiogenesis, cell migration, intravasation, and proliferation. In this review, we discuss the roles of Piezo1 in each stage of cancer metastasis in addition to its roles in immune cell activation and cancer cell death.

Channeling the Force: Piezo1 Mechanotransduction in Cancer Metastasis.

Purpose: We used bibliometric methods to evaluate the global scientific output of research on Piezo channels and explore the current status and trends in this field over the past decade. Methods: Piezo channel-related studies published in 2010-2020 were retrieved from Web of Science. The R bibliometrix package was used for quantitative and qualitative analyses of publication outputs and author contributions. VOSviewer was used to construct networks based on co-authorship of countries/institutions/authors, co-citation analysis of journals/references, citation analysis of documents, and co-occurrence of keywords. Results: In total, 556 related articles and reviews were included in the final analysis. The number of publications has increased substantially with time. The country and institution contributing the most to this field was the United States and Scripps Research Institute, respectively. Ardem Patapoutian was the most productive author and ranked first among the cited authors, h-index, and m-index. The top cited reference was the article published by Coste B et al. in Science (2010) that identified Piezo1/2 in mammalian cells. The top journals in terms of the number of selected articles and citations were Nature Communications and Nature, respectively. The co-occurrence analysis revealed that Piezo channels are involved a variety of cell types (Merkel cells, neurons, endothelial cells, red blood cells), physiological processes (touch sensation, blood pressure, proprioception, vascular development), related ion channels (transient receptor potential, Gardos), and diseases (pain, distal arthrogryposis, dehydrated hereditary stomatocytosis, cancer), and pharmacology (Yoda1, GsMTx-4). Conclusion: Our bibliometric analysis shows that Piezo channel research continues to be a hotspot. The focus has evolved from Piezo identification to architecture, activation mechanism, roles in diseases, and pharmacology.

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Trends in Piezo Channel Research Over the Past Decade: A Bibliometric Analysis.

Application of artificial intelligence for improving early detection and prediction of therapeutic outcomes for gastric cancer in the era of precision oncology.

This article reviews the dynamic interactions of the tumour microenvironment, highlighting the roles of acetyl-CoA and melatonergic pathway regulation in determining the interactions between oxidative phosphorylation (OXPHOS) and glycolysis across the array of cells forming the tumour microenvironment. Many of the factors associated with tumour progression and immune resistance, such as yin yang (YY)1 and glycogen synthase kinase (GSK)3β, regulate acetyl-CoA and the melatonergic pathway, thereby having significant impacts on the dynamic interactions of the different types of cells present in the tumour microenvironment. The association of the aryl hydrocarbon receptor (AhR) with immune suppression in the tumour microenvironment may be mediated by the AhR-induced cytochrome P450 (CYP)1b1-driven 'backward' conversion of melatonin to its immediate precursor N-acetylserotonin (NAS). NAS within tumours and released from tumour microenvironment cells activates the brain-derived neurotrophic factor (BDNF) receptor, TrkB, thereby increasing the survival and proliferation of cancer stem-like cells. Acetyl-CoA is a crucial co-substrate for initiation of the melatonergic pathway, as well as co-ordinating the interactions of OXPHOS and glycolysis in all cells of the tumour microenvironment. This provides a model of the tumour microenvironment that emphasises the roles of acetyl-CoA and the melatonergic pathway in shaping the dynamic intercellular metabolic interactions of the various cells within the tumour microenvironment. The potentiation of YY1 and GSK3β by O-GlcNAcylation will drive changes in metabolism in tumours and tumour microenvironment cells in association with their regulation of the melatonergic pathway. The emphasis on metabolic interactions across cell types in the tumour microenvironment provides novel future research and treatment directions.

Tumour Microenvironment: Roles of the Aryl Hydrocarbon Receptor, O-GlcNAcylation, Acetyl-CoA and Melatonergic Pathway in Regulating Dynamic Metabolic Interactions across Cell Types-Tumour Microenvironment and Metabolism.

The peritoneum, especially the omentum, is a common site for gastric cancer (GC) metastasis. Our aim was to expound the role and mechanisms of Piezo1 on GC omentum metastasis. A series of functional assays were performed to examine cell proliferation, clone formation, apoptosis, Ca2+ influx, mitochondrial membrane potential (MMP) and migration after overexpression or knockdown of Piezo1. A GC peritoneal implantation and metastasis model was conducted. After infection by si-Piezo1, the number and growth of tumours were observed in abdominal cavity. Fibre and angiogenesis were tested in metastatic tumour tissues. Piezo1 had higher expression in GC tissues with omentum metastasis and metastatic lymph node tissues than in GC tissues among 110 patients. High Piezo1 expression was associated with lymph metastasis, TNM and distant metastasis. Overexpressed Piezo1 facilitated cell proliferation and suppressed cell apoptosis in GC cells. Moreover, Ca2+ influx was elevated after up-regulation of Piezo1. Piezo1 promoted cell migration and Calpain1/2 expression via up-regulation of HIF-1α in GC cells. In vivo, Piezo1 knockdown significantly inhibited peritoneal metastasis of GC cells and blocked EMT process and angiogenesis. Our findings suggested that Piezo1 is a key component during GC omentum metastasis, which could be related to up-regulation of HIF-1α.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jcmm.16217

Piezo type mechanosensitive ion channel component 1 facilitates gastric cancer omentum metastasis.

ABSTRACT Ovarian cancer (OC) is a highly malignant cancer with great metastatic potential. Here we aimed to investigate the role of Piezo1, a gene related to the mechanical environment of the tumor, in promoting the metastasis of OC. We performed Piezo1 knockdown in A-1847 cells using small hairpin RNAs, and the cells were inoculated subcutaneously in nude mice. Piezo1 knockdown decreased the tumor growth rate of OC tumor xenografts in mice and reduced cell migration in vitro. Metastasis in the lung was also attenuated after Piezo1 knockdown as revealed by HE staining of the lung tissues, which was concomitant with downregulation of E-Cadherin and vimentin and upregulation of N-Cadherin analyzed using western blot analysis, suggesting suppressed epithelial-to-mesenchymal transition. Migration of Piezo1-knockdown cells was also analyzed for their migratory capabilities using the scratch assay. We also analyzed the key proteins in the Hippo/YAP signaling pathway using western blot after treating A-1847 and 3AO cells with a Piezo1 inducer, Yoda1. Piezo1 inducer Yoda1 activated Hippo/YAP signal in OC cells. In conclusion, Piezo1 is overexpressed in OC tissues and contributes to OC tumor growth and metastasis. Suppression of Piezo1 is a potential therapeutic strategy for OC.

https://www.tandfonline.com/doi/pdf/10.1080/19336950.2022.2099381?needAccess=true

Piezo1 activation facilitates ovarian cancer metastasis via Hippo/YAP signaling axis

Objective Increasing evidences suggest that mitochondrial calcium uniporter (MCU), a selective channel responsible for mitochondrial Ca2+ uptake, is involved in the progression of several cancers. In this study, we aimed to observe the clinical implications and biological functions of MCU in gastric cancer. Methods The expression of MCU in 90 pairs of gastric cancer tissues and adjacent normal tissues was examined using immunohistochemistry and correlation between MCU expression and clinical features was analyzed. After construction of stable MCU knockdown or overexpression gastric cancer cells, mitochondrial membrane potential (MMP), wound healing and transwell assays were performed to examine MMP levels, migration and invasion. Subcutaneous xenograft tumors induced by gastric cancer cells transfected with MCU siRNAs or controls were constructed. Immunofluorescence was used to detect CD34 expression. Western blot was used to detect the expression of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), epithelial-mesenchymal transition (EMT)-related proteins. Results MCU had a higher expression in gastric cancer tissues than normal tissues. Compared to gastric cancer tissues, its expression was significantly higher after omental metastasis. MCU expression was significantly correlated with depth of invasion (p=0.048), lymph metastasis (p=0.027), TNM stage (p=0.036) and distant metastasis (p=0.029). Patients with high MCU expression indicated a worse prognosis than those with its low expression (p=0.0098). MCU significantly increased the MMP levels of gastric cancer cells. Wound healing and transwell assay results showed that MCU promoted migration and invasion of gastric cancer cells. In vivo, MCU knockdown significantly inhibited tumor growth and angiogenesis. Both in vitro and in vivo, silencing MCU suppressed the expression of HIF-1α and VEGF as well as activity of EMT processes. Conclusion Our findings suggested that highly expressed MCU could promote migration, invasion, angiogenesis and growth of gastric cancer, which could become a potential therapeutic marker for gastric cancer.

The Regulatory Mechanism and Biological Significance of Mitochondrial Calcium Uniporter in the Migration, Invasion, Angiogenesis and Growth of Gastric Cancer

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Piezo type mechanosensitive ion channel component 1 facilitates gastric cancer omentum metastasis.

Piezo1 activation facilitates ovarian cancer metastasis via Hippo/YAP signaling axis

The Regulatory Mechanism and Biological Significance of Mitochondrial Calcium Uniporter in the Migration, Invasion, Angiogenesis and Growth of Gastric Cancer