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Journal of Hematology & Oncology Feb 2020MicroRNA-612 (miR-612) has been proven to suppress EMT, stemness, and tumor metastasis of hepatocellular carcinoma (HCC) via PI3K/AKT2 and Sp1/Nanog signaling. However,...
BACKGROUND
MicroRNA-612 (miR-612) has been proven to suppress EMT, stemness, and tumor metastasis of hepatocellular carcinoma (HCC) via PI3K/AKT2 and Sp1/Nanog signaling. However, its biological roles on HCC progression are far from elucidated.
METHODS
We found direct downstream target of miR-612, hadha by RNA immunoprecipitation and sequencing. To explore its biological characteristic, potential molecular mechanism, and clinical relevance in HCC patients, we performed several in-vitro and in-vivo models, as well as human tissue chip.
RESULTS
Ectopic expression of miR-612 could partially reverse the level of HADHA, then suppress function of pseudopods, and diminish metastatic and invasive potential of HCC by lipid reprogramming. In detail, miR-612 might reduce invadopodia formation via HADHA-mediated cell membrane cholesterol alteration and accompanied with the inhibition of Wnt/β-catenin regulated EMT occurrence. Our results showed that the maximum oxygen consumption rates (OCR) of HCCLM3 and HCCLM3 cells were decreased nearly by 40% and 60% of their counterparts (p < 0.05). The levels of acetyl CoA were significantly decreased, about 1/3 (p > 0.05) or 1/2 (p < 0.05) of their controls, in exogenous miR-612 or hadha-shRNA transfected HCCLM3 cell lines. Besides, overexpression of hadha cell lines had a high expression level of total cholesterol, especially 27-hydroxycholesterol (p < 0.005). SREBP2 protein expression level as well as its downstream targets, HMGCS1, HMGCR, MVD, SQLE were all deregulated by HADHA. Meanwhile, the ATP levels were reduced to 1/2 and 1/4 in HCCLM3 (p < 0.05) and HCCLM3 (p < 0.01) respectively. Moreover, patients with low miR-612 levels and high HADHA levels had a poor prognosis with shorter overall survival.
CONCLUSION
miR-612 can suppress the formation of invadopodia, EMT, and HCC metastasis and by HADHA-mediated lipid programming, which may provide a new insight of miR-612 on tumor metastasis and progression.
Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Humans; Lipid Metabolism; Liver Neoplasms; Male; MicroRNAs; Middle Aged; Mitochondrial Trifunctional Protein, alpha Subunit; Neoplasm Invasiveness; Podosomes
PubMed: 32033570
DOI: 10.1186/s13045-019-0841-3 -
Faculty Reviews 2021One of the strategies used by cells to degrade and remodel the extracellular matrix (ECM) is based on invadosomes, actin-based force-producing cell-ECM contacts that... (Review)
Review
One of the strategies used by cells to degrade and remodel the extracellular matrix (ECM) is based on invadosomes, actin-based force-producing cell-ECM contacts that function in adhesion and migration and are characterized by their capacity to mediate pericellular proteolysis of ECM components. Invadosomes found in normal cells are called podosomes, whereas invadosomes of invading cancer cells are named invadopodia. Despite their broad involvement in cell migration and in protease-dependent ECM remodeling and their detection in living organisms and in fresh tumor tissue specimens, the specific composition and dynamic behavior of podosomes and invadopodia and their functional relevance remain poorly understood. Here, we discuss recent findings that underline commonalities and peculiarities of podosome and invadopodia in terms of organization and function and propose an updated definition of these cellular protrusions, which are increasingly relevant in patho-physiological tissue remodeling.
PubMed: 34046643
DOI: 10.12703/r/10-39 -
Small GTPases Jul 2020Actin remodeling plays an essential role in diverse cellular processes such as cell motility, vesicle trafficking or cytokinesis. The scaffold protein and actin... (Review)
Review
Actin remodeling plays an essential role in diverse cellular processes such as cell motility, vesicle trafficking or cytokinesis. The scaffold protein and actin nucleation promoting factor Cortactin is present in virtually all actin-based structures, participating in the formation of branched actin networks. It has been involved in the control of endocytosis, and vesicle trafficking, axon guidance and organization, as well as adhesion, migration and invasion. To migrate and invade through three-dimensional environments, cells have developed specialized actin-based structures called invadosomes, a generic term to designate invadopodia and podosomes. Cortactin has emerged as a critical regulator of invadosome formation, function and disassembly. Underscoring this role, Cortactin is frequently overexpressed in several types of invasive cancers. Herein we will review the roles played by Cortactin in these specific invasive structures.
Topics: Animals; Cortactin; Humans; Podosomes
PubMed: 29172953
DOI: 10.1080/21541248.2017.1405773 -
Biomolecules Feb 2023The interface between the cellular actin network and diverse forms of integrin-mediated cell adhesions displays a unique capacity to serve as accurate chemical and... (Review)
Review
The interface between the cellular actin network and diverse forms of integrin-mediated cell adhesions displays a unique capacity to serve as accurate chemical and mechanical sensors of the cell's microenvironment. Focal adhesion-like structures of diverse cell types, podosomes in osteoclasts, and invadopodia of invading cancer cells display distinct morphologies and apparent functions. Yet, all three share a similar composition and mode of coupling between a protrusive structure (the lamellipodium, the core actin bundle of the podosome, and the invadopodia protrusion, respectively), and a nearby adhesion site. Cytoskeletal or external forces, applied to the adhesion sites, trigger a cascade of unfolding and activation of key adhesome components (e.g., talin, vinculin, integrin), which in turn, trigger the assembly of adhesion sites and generation of adhesion-mediated signals that affect cell behavior and fate. The structural and molecular mechanisms underlying the dynamic crosstalk between the actin cytoskeleton and the adhesome network are discussed.
Topics: Actins; Integrins; Cytoskeleton; Cell Adhesion; Actin Cytoskeleton
PubMed: 36830665
DOI: 10.3390/biom13020294 -
Nature Communications Sep 2023The activation and accumulation of lung fibroblasts resulting in aberrant deposition of extracellular matrix components, is a pathogenic hallmark of Idiopathic Pulmonary...
The activation and accumulation of lung fibroblasts resulting in aberrant deposition of extracellular matrix components, is a pathogenic hallmark of Idiopathic Pulmonary Fibrosis, a lethal and incurable disease. In this report, increased expression of TKS5, a scaffold protein essential for the formation of podosomes, was detected in the lung tissue of Idiopathic Pulmonary Fibrosis patients and bleomycin-treated mice. Τhe profibrotic milieu is found to induce TKS5 expression and the formation of prominent podosome rosettes in lung fibroblasts, that are retained ex vivo, culminating in increased extracellular matrix invasion. Tks5 mice are found resistant to bleomycin-induced pulmonary fibrosis, largely attributed to diminished podosome formation in fibroblasts and decreased extracellular matrix invasion. As computationally predicted, inhibition of src kinase is shown to potently attenuate podosome formation in lung fibroblasts and extracellular matrix invasion, and bleomycin-induced pulmonary fibrosis, suggesting pharmacological targeting of podosomes as a very promising therapeutic option in pulmonary fibrosis.
Topics: Animals; Humans; Mice; Adaptor Proteins, Vesicular Transport; Bleomycin; Extracellular Matrix; Fibroblasts; Idiopathic Pulmonary Fibrosis; Podosomes; Proto-Oncogene Proteins pp60(c-src)
PubMed: 37735172
DOI: 10.1038/s41467-023-41614-x -
Nature Communications Jul 2022Podosomes are actin-enriched adhesion structures important for multiple cellular processes, including migration, bone remodeling, and phagocytosis. Here, we characterize...
Podosomes are actin-enriched adhesion structures important for multiple cellular processes, including migration, bone remodeling, and phagocytosis. Here, we characterize the structure and organization of phagocytic podosomes using interferometric photoactivated localization microscopy, a super-resolution microscopy technique capable of 15-20 nm resolution, together with structured illumination microscopy and localization-based super-resolution microscopy. Phagocytic podosomes are observed during frustrated phagocytosis, a model in which cells attempt to engulf micropatterned IgG antibodies. For circular patterns, this results in regular arrays of podosomes with well-defined geometry. Using persistent homology, we develop a pipeline for semi-automatic identification and measurement of podosome features. These studies reveal an hourglass shape of the podosome actin core, a protruding knob at the bottom of the core, and two actin networks extending from the core. Additionally, the distributions of paxillin, talin, myosin II, α-actinin, cortactin, and microtubules relative to actin are characterized.
Topics: Actins; Microscopy; Myosin Type II; Podosomes; Talin
PubMed: 35896550
DOI: 10.1038/s41467-022-32038-0 -
European Journal of Cell Biology Apr 2022Podosomes are highly dynamic actin-rich structures in a variety of cell types, especially monocytic cells. They fulfill multiple functions such as adhesion,... (Review)
Review
Podosomes are highly dynamic actin-rich structures in a variety of cell types, especially monocytic cells. They fulfill multiple functions such as adhesion, mechanosensing, or extracellular matrix degradation, thus allowing cells to detect and respond to a changing environment. These abilities are based on an intricate architecture that enables podosomes to sense mechanical properties of their substratum and to transduce them intracellularly in order to generate an appropriate cellular response. These processes are enabled through the tightly orchestrated interplay of more than 300 different components that are dynamically recruited during podosome formation and turnover. In this review, we discuss the different phases of the podosome life cycle and the current knowledge on regulatory factors that impact on the genesis, activity, dissolution and reemergence of podosomes. We also highlight mechanoregulatory processes that become important during these different stages, on the level of individual podosomes, and also at podosome sub- and superstructures.
Topics: Actins; Podosomes
PubMed: 35334303
DOI: 10.1016/j.ejcb.2022.151218 -
Philosophical Transactions of the Royal... Aug 2019Podosomes are a singular category of integrin-mediated adhesions important in the processes of cell migration, matrix degradation and cancer cell invasion. Despite a...
Podosomes are a singular category of integrin-mediated adhesions important in the processes of cell migration, matrix degradation and cancer cell invasion. Despite a wealth of biochemical studies, the effects of mechanical forces on podosome integrity and dynamics are poorly understood. Here, we show that podosomes are highly sensitive to two groups of physical factors. First, we describe the process of podosome disassembly induced by activation of myosin-IIA filament assembly. Next, we find that podosome integrity and dynamics depends upon membrane tension and can be experimentally perturbed by osmotic swelling and deoxycholate treatment. We have also found that podosomes can be disrupted in a reversible manner by single or cyclic radial stretching of the substratum. We show that disruption of podosomes induced by osmotic swelling is independent of myosin-II filaments. The inhibition of the membrane sculpting protein, dynamin-II, but not clathrin, resulted in activation of myosin-IIA filament formation and disruption of podosomes. The effect of dynamin-II inhibition on podosomes was, however, independent of myosin-II filaments. Moreover, formation of organized arrays of podosomes in response to microtopographic cues (the ridges with triangular profile) was not accompanied by reorganization of myosin-II filaments. Thus, mechanical elements such as myosin-II filaments and factors affecting membrane tension/sculpting independently modulate podosome formation and dynamics, underlying a versatile response of these adhesion structures to intracellular and extracellular cues. This article is part of a discussion meeting issue 'Forces in cancer: interdisciplinary approaches in tumour mechanobiology'.
Topics: Cell Movement; Humans; Nonmuscle Myosin Type IIA; Podosomes; Tumor Cells, Cultured
PubMed: 31431172
DOI: 10.1098/rstb.2018.0228 -
Cellular Signalling Aug 2011Podosomes are ventral adhesion structures prominent in cells of the myeloid lineage. A common aspect of these cells is that they are highly motile and must to traverse... (Review)
Review
Podosomes are ventral adhesion structures prominent in cells of the myeloid lineage. A common aspect of these cells is that they are highly motile and must to traverse multiple tissue barriers in order to perform their functions. Recently podosomes have gathered attention from researchers as important cellular structures that can influence cell adhesion, motility and matrix remodeling. Adhesive and soluble ligands act via transmembrane receptors and propagate signals to the leukocyte cytoskeleton via small G proteins of the Rho family, tyrosine kinases and scaffold proteins and are able to induce podosome formation and rearrangements. Manipulation of the signals that regulate podosome formation and dynamics can therefore be a strategy to interfere with leukocyte functions in a multitude of pathological settings, such as infections, atherosclerosis and arthritis. Here, we review the major signaling molecules that act in the formation and regulation of podosomes.
Topics: Actins; Cell Adhesion; Cell Surface Extensions; Leukocytes; Membrane Glycoproteins; Protein-Tyrosine Kinases; Signal Transduction; rho GTP-Binding Proteins
PubMed: 21342664
DOI: 10.1016/j.cellsig.2011.02.004 -
The FEBS Journal Oct 2022Invadosomes are protrusive and mechanosensitive actin devices critical for cell migration, invasion, and extracellular matrix remodeling. The dynamic, proteolytic, and... (Review)
Review
Invadosomes are protrusive and mechanosensitive actin devices critical for cell migration, invasion, and extracellular matrix remodeling. The dynamic, proteolytic, and protrusive natures of invadosomes have made these structures fascinating and attracted many scientists to develop new technologies for their analysis. With these exciting methodologies, many biochemical and biophysical properties of invadosomes have been well characterized and appreciated, and those discoveries elegantly explained the biological and pathological effects of invadosomes in human health and diseases. In this review, we focus on these commonly used or newly developed methods for invadosome analysis and effort to reason some discrepancies among those assays. Finally, we explore the opposite regulatory mechanisms among invadosomes and focal adhesions, another actin-rich adhesive structures, and speculate a potential rule for their switch.
Topics: Actins; Cell Movement; Extracellular Matrix; Humans; Podosomes; Proteolysis
PubMed: 34196119
DOI: 10.1111/febs.16098