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Desiphering the Network of Cell Receptors and Matrix in Health and Disease

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Natural and Bio-inspired Molecules".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 33411

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Dr. Marco Franchi

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Guest Editor

Department for Life Quality Studies QUVI, Alma Mater Studiorum, University of Bologna, Bologna, Italy
Interests: cancer invasion; extracellular matrix (ECM); epithelial-to-mesenchymal (EMT); 3D cultures; collagen
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Dr. Zoi Piperigkou

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Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece
Interests: extracellular matrix; cell signaling; estrogen receptors; proteoglycans; breast cancer biomarkers; molecular targeting
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Extracellular matrices (ECMs) are specialized, dynamic scaffolds composed of a variety of functional macromolecules that interact with each other to mediate physiological functions of cells within tissues, such as cell proliferation, survival, migration, and differentiation, thus maintaining tissue functions and homeostasis. The basic ECM components involve proteoglycans (PGs), glycosaminoglycans, collagen, elastin, laminins, fibronectin, glycoproteins, and several matricellular proteins. Intriguingly, ECM molecules interact with resident cells through numerous cell surface receptors, including integrins, cell surface PGs, hyaluronan receptors, discoidin domain receptors (DDRs), and nonconventional receptors, such as growth factor receptors, toll-like receptors (TLRs), endothelial intracellular adhesion molecules (ICAMs) and transient receptor potential canonical (TRPCs) channels. Cell receptors transmit chemical and mechanical signals to ECMs that mediate cell responses, such as cell adhesion, differentiation and migration, cytoskeleton conformation, and cell signaling. Considering the critical roles of cell receptors in matrix assembly and cell functions, the benefit of understanding the complex mechanisms underlying their roles both in normal and in pathological conditions, such as fibrosis, osteoarthritis, genetic disorders, and cancer, arises. The scope of this Special Issue of Biomolecules, titled “Deciphering the Network of Cell Receptors and Matrix in Health and Disease”, is to welcome state-of-the-art reviews, original research articles, as well as short contributions that will address the significance of cell receptors in health and disease.

Prof. Marco Franchi
Dr. Zoi Piperigkou
Guest Editors

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Keywords

Cell receptors
Extracellular matrix
Cell signaling
Biomarkers
Pharmacological targeting

Published Papers (6 papers)

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Research

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31 pages, 5733 KiB

Open AccessArticle

Initial Identification of UDP-Glucose Dehydrogenase as a Prognostic Marker in Breast Cancer Patients, Which Facilitates Epirubicin Resistance and Regulates Hyaluronan Synthesis in MDA-MB-231 Cells

by Daiana L. Vitale, Ilaria Caon, Arianna Parnigoni, Ina Sevic, Fiorella M. Spinelli, Antonella Icardi, Alberto Passi, Davide Vigetti and Laura Alaniz

Biomolecules 2021, 11(2), 246; https://doi.org/10.3390/biom11020246 - 09 Feb 2021

Cited by 15 | Viewed by 2741

Abstract

UDP-glucose-dehydrogenase (UGDH) synthesizes UDP-glucuronic acid. It is involved in epirubicin detoxification and hyaluronan synthesis. This work aimed to evaluate the effect of UGDH knockdown on epirubicin response and hyaluronan metabolism in MDA-MB-231 breast cancer cells. Additionally, the aim was to determine UGDH as a possible prognosis marker in breast cancer. We studied UGDH expression in tumors and adjacent tissue from breast cancer patients. The prognostic value of UGDH was studied using a public Kaplan–Meier plotter. MDA-MB-231 cells were knocked-down for UGDH and treated with epirubicin. Epirubicin-accumulation and apoptosis were analyzed by flow cytometry. Hyaluronan-coated matrix and metabolism were determined. Autophagic-LC3-II was studied by Western blot and confocal microscopy. Epirubicin accumulation increased and apoptosis decreased during UGDH knockdown. Hyaluronan-coated matrix increased and a positive modulation of autophagy was detected. Higher levels of UGDH were correlated with worse prognosis in triple-negative breast cancer patients that received chemotherapy. High expression of UGDH was found in tumoral tissue from HER2^--patients. However, UGDH knockdown contributes to epirubicin resistance, which might be associated with increases in the expression, deposition and catabolism of hyaluronan. The results obtained allowed us to propose UGDH as a new prognostic marker in breast cancer, positively associated with development of epirubicin resistance and modulation of extracellular matrix. Full article

(This article belongs to the Special Issue Desiphering the Network of Cell Receptors and Matrix in Health and Disease)

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25 pages, 23827 KiB

Open AccessArticle

Syndecan-1 Promotes Hepatocyte-Like Differentiation of Hepatoma Cells Targeting Ets-1 and AP-1

by Péter Hollósi, Lóránd Váncza, Katalin Karászi, Katalin Dobos, Bálint Péterfia, Enikő Tátrai, Péter Tátrai, Tibor Szarvas, Sándor Paku, László Szilák and Ilona Kovalszky

Biomolecules 2020, 10(10), 1356; https://doi.org/10.3390/biom10101356 - 23 Sep 2020

Cited by 5 | Viewed by 3362

Abstract

Syndecan-1 is a transmembrane heparan sulfate proteoglycan which is indispensable in the structural and functional integrity of epithelia. Normal hepatocytes display strong cell surface expression of syndecan-1; however, upon malignant transformation, they may lose it from their cell surfaces. In this study, we demonstrate that re-expression of full-length or ectodomain-deleted syndecan-1 in hepatocellular carcinoma cells downregulates phosphorylation of ERK1/2 and p38, with the truncated form exerting an even stronger effect than the full-length protein. Furthermore, overexpression of syndecan-1 in hepatoma cells is associated with a shift of heparan sulfate structure toward a highly sulfated type specific for normal liver. As a result, cell proliferation and proteolytic shedding of syndecan-1 from the cell surface are restrained, which facilitates redifferentiation of hepatoma cells to a more hepatocyte-like phenotype. Our results highlight the importance of syndecan-1 in the formation and maintenance of differentiated epithelial characteristics in hepatocytes partly via the HGF/ERK/Ets-1 signal transduction pathway. Downregulation of Ets-1 expression alone, however, was not sufficient to replicate the phenotype of syndecan-1 overexpressing cells, indicating the need for additional molecular mechanisms. Accordingly, a reporter gene assay revealed the inhibition of Ets-1 as well as AP-1 transcription factor-induced promoter activation, presumably an effect of the heparan sulfate switch. Full article

(This article belongs to the Special Issue Desiphering the Network of Cell Receptors and Matrix in Health and Disease)

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17 pages, 3061 KiB

Open AccessArticle

The Protective Role of Decorin in Hepatic Metastasis of Colorectal Carcinoma

by Andrea Reszegi, Zsolt Horváth, Katalin Karászi, Eszter Regős, Victoria Postniková, Péter Tátrai, András Kiss, Zsuzsa Schaff, Ilona Kovalszky and Kornélia Baghy

Biomolecules 2020, 10(8), 1199; https://doi.org/10.3390/biom10081199 - 18 Aug 2020

Cited by 11 | Viewed by 3798

Abstract

Decorin, the prototype member of the small leucine-rich proteoglycan gene family of extracellular matrix (ECM) proteins, acts as a powerful tumor suppressor by inducing the p21^Waf1/Cip1 cyclin-dependent kinase inhibitor, as well as through its ability to directly bind and block the action of several tyrosine kinase receptors. Our previous studies suggested that the lack of decorin promotes hepatic carcinogenesis in mice. Based on this, we set out to investigate whether excess decorin may protect against the liver metastases of colon carcinoma. We also analyzed the effect of decorin in tissue microarrays of human colon carcinoma liver metastasis and examined whether the tumor cells can directly influence the decorin production of myofibroblasts. In humans, low levels of decorin in the liver facilitated the development of colon carcinoma metastases in proportion with more aggressive phenotypes, indicating a possible antitumor action of the proteoglycan. In vitro, colon carcinoma cells inhibited decorin expression in LX2 hepatic stellate cells. Moreover, liver-targeted decorin delivery in mice effectively attenuated metastasis formation of colon cancer. Overexpressed decorin reduced the activity of multiple receptor tyrosine kinases (RTKs) including the epidermal growth factor receptor (EGFR), an important player in colorectal cancer (CRC) pathogenesis. Downstream of that, we observed weakened signaling of ERK1/2, PLCγ, Akt/mTOR, STAT and c-Jun pathways, while p38 MAPK/MSK/CREB and AMPK were upregulated culminating in enhanced p53 function. In conclusion, decorin may effectively inhibit metastatic tumor formation in the liver. Full article

(This article belongs to the Special Issue Desiphering the Network of Cell Receptors and Matrix in Health and Disease)

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13 pages, 2817 KiB

Open AccessArticle

Mapping the Interactome of the Nuclear Heparan Sulfate Proteoglycan Syndecan-1 in Mesothelioma Cells

by Ashish Kumar-Singh, Jatin Shrinet, Malgorzata Maria Parniewska, Jonas Fuxe, Katalin Dobra and Anders Hjerpe

Biomolecules 2020, 10(7), 1034; https://doi.org/10.3390/biom10071034 - 11 Jul 2020

Cited by 11 | Viewed by 2996

Abstract

Syndecan-1 (SDC1) is a cell surface heparan sulfate proteoglycan (HSPG), which regulates various signaling pathways controlling the proliferation and migration of malignant mesothelioma and other types of cancer. We have previously shown that SDC1 can translocate to the nucleus in mesothelioma cells through a tubulin-dependent transport mechanism. However, the role of nuclear SDC1 is largely unknown. Here, we performed co-immunoprecipitation (Co-IP) of SDC1 in a mesothelioma cell line to identify SDC1 interacting proteins. The precipitates contained a large number of proteins, indicating the recovery of protein networks. Proteomic analysis with a focus on nuclear proteins revealed an association with pathways related to cell proliferation and RNA synthesis, splicing and transport. In support of this, the top RNA splicing candidates were verified to interact with SDC1 by Co-IP and subsequent Western blot analysis. Further loss- and gain-of-function experiments showed that SDC1 influences RNA levels in mesothelioma cells. The results identify a proteomic map of SDC1 nuclear interactors in a mesothelioma cell line and suggest a previously unknown role for SDC1 in RNA biogenesis. The results should serve as a fundament for further studies to discover the role of nuclear SDC1 in normal and cancer cells of different origin. Full article

(This article belongs to the Special Issue Desiphering the Network of Cell Receptors and Matrix in Health and Disease)

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Review

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32 pages, 1883 KiB

Open AccessEditor’s ChoiceReview

The Human Epidermal Basement Membrane: A Shaped and Cell Instructive Platform That Aging Slowly Alters

by Eva Roig-Rosello and Patricia Rousselle

Biomolecules 2020, 10(12), 1607; https://doi.org/10.3390/biom10121607 - 27 Nov 2020

Cited by 49 | Viewed by 15005

Abstract

One of the most important functions of skin is to act as a protective barrier. To fulfill this role, the structural integrity of the skin depends on the dermal-epidermal junction—a complex network of extracellular matrix macromolecules that connect the outer epidermal layer to the underlying dermis. This junction provides both a structural support to keratinocytes and a specific niche that mediates signals influencing their behavior. It displays a distinctive microarchitecture characterized by an undulating pattern, strengthening dermal-epidermal connectivity and crosstalk. The optimal stiffness arising from the overall molecular organization, together with characteristic anchoring complexes, keeps the dermis and epidermis layers extremely well connected and capable of proper epidermal renewal and regeneration. Due to intrinsic and extrinsic factors, a large number of structural and biological changes accompany skin aging. These changes progressively weaken the dermal–epidermal junction substructure and affect its functions, contributing to the gradual decline in overall skin physiology. Most changes involve reduced turnover or altered enzymatic or non-enzymatic post-translational modifications, compromising the mechanical properties of matrix components and cells. This review combines recent and older data on organization of the dermal-epidermal junction, its mechanical properties and role in mechanotransduction, its involvement in regeneration, and its fate during the aging process. Full article

(This article belongs to the Special Issue Desiphering the Network of Cell Receptors and Matrix in Health and Disease)

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39 pages, 7906 KiB

Open AccessEditor’s ChoiceReview

Interplay between Cell-Surface Receptors and Extracellular Matrix in Skin

by Svenja Kleiser and Alexander Nyström

Biomolecules 2020, 10(8), 1170; https://doi.org/10.3390/biom10081170 - 11 Aug 2020

Cited by 18 | Viewed by 4777

Abstract

Skin consists of the epidermis and dermis, which are connected by a specialized basement membrane—the epidermal basement membrane. Both the epidermal basement membrane and the underlying interstitial extracellular matrix (ECM) created by dermal fibroblasts contain distinct network-forming macromolecules. These matrices play various roles in order to maintain skin homeostasis and integrity. Within this complex interplay of cells and matrices, cell surface receptors play essential roles not only for inside-out and outside-in signaling, but also for establishing mechanical and biochemical properties of skin. Already minor modulations of this multifactorial cross-talk can lead to severe and systemic diseases. In this review, major epidermal and dermal cell surface receptors will be addressed with respect to their interactions with matrix components as well as their roles in fibrotic, inflammatory or tumorigenic skin diseases. Full article

(This article belongs to the Special Issue Desiphering the Network of Cell Receptors and Matrix in Health and Disease)

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