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Ebrahim T, Ebrahim AS, Kandouz M. Diversity of Intercellular Communication Modes: A Cancer Biology Perspective. Cells 2024; 13:495. [PMID: 38534339 PMCID: PMC10969453 DOI: 10.3390/cells13060495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 02/27/2024] [Accepted: 03/10/2024] [Indexed: 03/28/2024] Open
Abstract
From the moment a cell is on the path to malignant transformation, its interaction with other cells from the microenvironment becomes altered. The flow of molecular information is at the heart of the cellular and systemic fate in tumors, and various processes participate in conveying key molecular information from or to certain cancer cells. For instance, the loss of tight junction molecules is part of the signal sent to cancer cells so that they are no longer bound to the primary tumors and are thus free to travel and metastasize. Upon the targeting of a single cell by a therapeutic drug, gap junctions are able to communicate death information to by-standing cells. The discovery of the importance of novel modes of cell-cell communication such as different types of extracellular vesicles or tunneling nanotubes is changing the way scientists look at these processes. However, are they all actively involved in different contexts at the same time or are they recruited to fulfill specific tasks? What does the multiplicity of modes mean for the overall progression of the disease? Here, we extend an open invitation to think about the overall significance of these questions, rather than engage in an elusive attempt at a systematic repertory of the mechanisms at play.
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Affiliation(s)
- Thanzeela Ebrahim
- Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48202, USA
| | - Abdul Shukkur Ebrahim
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48202, USA
| | - Mustapha Kandouz
- Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48202, USA
- Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48202, USA
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2
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Murugan NJ, Cariba S, Abeygunawardena S, Rouleau N, Payne SL. Biophysical control of plasticity and patterning in regeneration and cancer. Cell Mol Life Sci 2023; 81:9. [PMID: 38099951 PMCID: PMC10724343 DOI: 10.1007/s00018-023-05054-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 10/12/2023] [Accepted: 11/13/2023] [Indexed: 12/18/2023]
Abstract
Cells and tissues display a remarkable range of plasticity and tissue-patterning activities that are emergent of complex signaling dynamics within their microenvironments. These properties, which when operating normally guide embryogenesis and regeneration, become highly disordered in diseases such as cancer. While morphogens and other molecular factors help determine the shapes of tissues and their patterned cellular organization, the parallel contributions of biophysical control mechanisms must be considered to accurately predict and model important processes such as growth, maturation, injury, repair, and senescence. We now know that mechanical, optical, electric, and electromagnetic signals are integral to cellular plasticity and tissue patterning. Because biophysical modalities underly interactions between cells and their extracellular matrices, including cell cycle, metabolism, migration, and differentiation, their applications as tuning dials for regenerative and anti-cancer therapies are being rapidly exploited. Despite this, the importance of cellular communication through biophysical signaling remains disproportionately underrepresented in the literature. Here, we provide a review of biophysical signaling modalities and known mechanisms that initiate, modulate, or inhibit plasticity and tissue patterning in models of regeneration and cancer. We also discuss current approaches in biomedical engineering that harness biophysical control mechanisms to model, characterize, diagnose, and treat disease states.
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Affiliation(s)
- Nirosha J Murugan
- Department of Health Sciences, Wilfrid Laurier University, Waterloo, ON, Canada.
- Allen Discovery Center, Tufts University, Medford, MA, USA.
| | - Solsa Cariba
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
| | | | - Nicolas Rouleau
- Department of Health Sciences, Wilfrid Laurier University, Waterloo, ON, Canada
- Allen Discovery Center, Tufts University, Medford, MA, USA
- Department of Biomedical Engineering, Tufts University, Medford, MA, USA
| | - Samantha L Payne
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
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3
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León-Fuentes IM, Salgado-Gil MG, Novoa MS, Retamal MA. Connexins in Cancer, the Possible Role of Connexin46 as a Cancer Stem Cell-Determining Protein. Biomolecules 2023; 13:1460. [PMID: 37892142 PMCID: PMC10604234 DOI: 10.3390/biom13101460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/15/2023] [Accepted: 09/22/2023] [Indexed: 10/29/2023] Open
Abstract
Cancer is a widespread and incurable disease caused by genetic mutations, leading to uncontrolled cell proliferation and metastasis. Connexins (Cx) are transmembrane proteins that facilitate intercellular communication via hemichannels and gap junction channels. Among them, Cx46 is found mostly in the eye lens. However, in pathological conditions, Cx46 has been observed in various types of cancers, such as glioblastoma, melanoma, and breast cancer. It has been demonstrated that elevated Cx46 levels in breast cancer contribute to cellular resistance to hypoxia, and it is an enhancer of cancer aggressiveness supporting a pro-tumoral role. Accordingly, Cx46 is associated with an increase in cancer stem cell phenotype. These cells display radio- and chemoresistance, high proliferative abilities, self-renewal, and differentiation capacities. This review aims to consolidate the knowledge of the relationship between Cx46, its role in forming hemichannels and gap junctions, and its connection with cancer and cancer stem cells.
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Affiliation(s)
| | | | | | - Mauricio A. Retamal
- Programa de Comunicación Celular en Cáncer, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, República de Honduras 12740, Las Condes, Santiago 7610496, Chile; (I.M.L.-F.); (M.G.S.-G.); (M.S.N.)
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4
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Song L, Yang J, Qin Z, Ou C, Luo R, Yang W, Wang L, Wang N, Ma S, Wu Q, Gong C. Multi-Targeted and On-Demand Non-Coding RNA Regulation Nanoplatform against Metastasis and Recurrence of Triple-Negative Breast Cancer. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2207576. [PMID: 36905244 DOI: 10.1002/smll.202207576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 02/06/2023] [Indexed: 06/08/2023]
Abstract
Dysregulation of microRNAs (miRs) is the hallmark of triple-negative breast cancer (TNBC), which is closely involved with its growth, metastasis, and recurrence. Dysregulated miRs are promising targets for TNBC therapy, however, targeted and accurate regulation of multiple disordered miRs in tumors is still a great challenge. Here, a multi-targeting and on-demand non-coding RNA regulation nanoplatform (MTOR) is reported to precisely regulate disordered miRs, leading to dramatical suppression of TNBC growth, metastasis, and recurrence. With the assistance of long blood circulation, ligands of urokinase-type plasminogen activator peptide and hyaluronan located in multi-functional shells enable MTOR to actively target TNBC cells and breast cancer stem cell-like cells (BrCSCs). After entering TNBC cells and BrCSCs, MTOR is subjected to lysosomal hyaluronidase-induced shell detachment, leading to an explosion of the TAT-enriched core, thereby enhancing nuclear targeting. Subsequently, MTOR could precisely and simultaneously downregulate microRNA-21 expression and upregulate microRNA-205 expression in TNBC. In subcutaneous xenograft, orthotopic xenograft, pulmonary metastasis, and recurrence TNBC mouse models, MTOR shows remarkably synergetic effects on the inhibition of tumor growth, metastasis, and recurrence due to its on-demand regulation of disordered miRs. This MTOR system opens a new avenue for on-demand regulation of disordered miRs against growth, metastasis, and recurrence of TNBC.
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Affiliation(s)
- Linjiang Song
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Jin Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Zeyi Qin
- Department of Biology, Brandeis University, Waltham, MA, 02453, USA
| | - Chunqing Ou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Rui Luo
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Wen Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Li Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Ning Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Shuang Ma
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Qinjie Wu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Changyang Gong
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
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5
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Lukowicz-Bedford RM, Farnsworth DR, Miller AC. Connexinplexity: the spatial and temporal expression of connexin genes during vertebrate organogenesis. G3 (BETHESDA, MD.) 2022; 12:jkac062. [PMID: 35325106 PMCID: PMC9073686 DOI: 10.1093/g3journal/jkac062] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 02/24/2022] [Indexed: 11/28/2022]
Abstract
Animal development requires coordinated communication between cells. The Connexin family of proteins is a major contributor to intercellular communication in vertebrates by forming gap junction channels that facilitate the movement of ions, small molecules, and metabolites between cells. Additionally, individual hemichannels can provide a conduit to the extracellular space for paracrine and autocrine signaling. Connexin-mediated communication is widely used in epithelial, neural, and vascular development and homeostasis, and most tissues likely use this form of communication. In fact, Connexin disruptions are of major clinical significance contributing to disorders developing from all major germ layers. Despite the fact that Connexins serve as an essential mode of cellular communication, the temporal and cell-type-specific expression patterns of connexin genes remain unknown in vertebrates. A major challenge is the large and complex connexin gene family. To overcome this barrier, we determined the expression of all connexins in zebrafish using single-cell RNA-sequencing of entire animals across several stages of organogenesis. Our analysis of expression patterns has revealed that few connexins are broadly expressed, but rather, most are expressed in tissue- or cell-type-specific patterns. Additionally, most tissues possess a unique combinatorial signature of connexin expression with dynamic temporal changes across the organism, tissue, and cell. Our analysis has identified new patterns for well-known connexins and assigned spatial and temporal expression to genes with no-existing information. We provide a field guide relating zebrafish and human connexin genes as a critical step toward understanding how Connexins contribute to cellular communication and development throughout vertebrate organogenesis.
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Affiliation(s)
| | - Dylan R Farnsworth
- Institute of Neuroscience, Department of Biology, University of Oregon, Eugene, OR 97403, USA
| | - Adam C Miller
- Institute of Neuroscience, Department of Biology, University of Oregon, Eugene, OR 97403, USA
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6
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Gong K, Hong Q, Wu H, Wang F, Zhong L, Shen L, Xu P, Zhang W, Cao H, Zhan YY, Hu T, Hong X. Gap junctions mediate glucose transfer to promote colon cancer growth in three-dimensional spheroid culture. Cancer Lett 2022; 531:27-38. [DOI: 10.1016/j.canlet.2022.01.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 01/18/2022] [Accepted: 01/18/2022] [Indexed: 11/02/2022]
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Connexin Expression Is Altered in Liver Development of Yotari ( dab1 -/-) Mice. Int J Mol Sci 2021; 22:ijms221910712. [PMID: 34639052 PMCID: PMC8509723 DOI: 10.3390/ijms221910712] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/26/2021] [Accepted: 09/29/2021] [Indexed: 01/05/2023] Open
Abstract
Disabled-1 (Dab1) protein is an intracellular adaptor of reelin signaling required for prenatal neuronal migration, as well as postnatal neurotransmission, memory formation and synaptic plasticity. Yotari, an autosomal recessive mutant of the mouse Dab1 gene is recognizable by its premature death, unstable gait and tremor. Previous findings are mostly based on neuronal abnormalities caused by Dab1 deficiency, but the role of the reelin signaling pathway in nonneuronal tissues and organs has not been studied until recently. Hepatocytes, the most abundant cells in the liver, communicate via gap junctions (GJ) are composed of connexins. Cell communication disruption in yotari mice was examined by analyzing the expression of connexins (Cxs): Cx26, Cx32, Cx37, Cx40, Cx43 and Cx45 during liver development at 13.5 and 15.5 gestation days (E13.5 and E15.5). Analyses were performed using immunohistochemistry and fluorescent microscopy, followed by quantification of area percentage covered by positive signal. Data are expressed as a mean ± SD and analyzed by one-way ANOVA. All Cxs examined displayed a significant decrease in yotari compared to wild type (wt) individuals at E13.5. Looking at E15.5 we have similar results with exception of Cx37 showing negligible expression in wt. Channels formation triggered by pathological stimuli, as well as propensity to apoptosis, was studied by measuring the expression of Pannexin1 (Panx1) and Apoptosis-inducing factor (AIF) through developmental stages mentioned above. An increase in Panx1 expression of E15.5 yotari mice, as well as a strong jump of AIF in both phases suggesting that yotari mice are more prone to apoptosis. Our results emphasize the importance of gap junction intercellular communication (GJIC) during liver development and their possible involvement in liver pathology and diagnostics where they can serve as potential biomarkers and drug targets.
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Ray A, Mehta PP. Cysteine residues in the C-terminal tail of connexin32 regulate its trafficking. Cell Signal 2021; 85:110063. [PMID: 34146657 DOI: 10.1016/j.cellsig.2021.110063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 05/26/2021] [Accepted: 06/14/2021] [Indexed: 12/24/2022]
Abstract
Gap junctions (GJs) are formed by the assembly of constituent transmembrane proteins called connexins (Cxs). Aberrations in this assembly of Cxs are observed in several genetic diseases as well as in cancers. Hence it becomes imperative to understand the molecular mechanisms underlying such assembly defect. The polarized cells in the epithelia express Connexin32 (Cx32). The C-terminal tail (CT) of Cx32 orchestrates several aspects of GJ dynamics, function and growth. The study here was aimed at determining if post-translational modifications, specifically, palmitoylation of cysteine residues, present in the CT of Cx32, has any effect on GJ assembly. The CT of Cx32 was found to harbor three cysteine residues, which are likely to be modified by palmitoylation. The study here has revealed for the first time that Cx32 is palmitoylated at cysteine 217 (C217) in cell line derived from prostate tumors. However, it was found that mutating C217 to alanine affected neither the trafficking nor the ability of Cx32 to assemble into GJs. Intriguingly, it was discovered that mutating cysteine 280 and 283, only in combination, blocked the trafficking of Cx32 from the trans-Golgi network to the cell surface. The mutants showed reduced stability due to enhanced lysosomal degradation. Overall, the findings reveal the importance of the two C-terminal cysteine residues of Cx32 in regulating its trafficking and stability and hence its ability to assemble into GJs.
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Affiliation(s)
- Anuttoma Ray
- Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
| | - Parmender P Mehta
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
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9
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Scatolini M, Patel A, Grosso E, Mello-Grand M, Ostano P, Coppo R, Vitiello M, Venesio T, Zaccagna A, Pisacane A, Sarotto I, Taverna D, Poliseno L, Bergamaschi D, Chiorino G. GJB5 association with BRAF mutation and survival in cutaneous malignant melanoma. Br J Dermatol 2021; 186:117-128. [PMID: 34240406 DOI: 10.1111/bjd.20629] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/03/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND Gap junctional intercellular communication is crucial for epidermal cellular homeostasis. Inability to establish melanocyte-keratinocytes contacts and loss of intercellular junction's integrity may contribute to melanoma development. Connexins, laminins and desmocollins have been implicated in the control of melanoma growth, where their reduced expression has been reported in metastatic lesions. OBJECTIVES The aim of this study was to investigate Connexin 31.1 (GJB5) expression and identify any association with BRAF mutational status, melanoma patient prognosis and MAPK inhibitors (MAPKi) treatment. MATERIAL AND METHODS GJB5 expression was measured at RNA and protein level in melanoma clinical samples and established cell lines treated or not with BRAF and MEK inhibitors, as well as in cell lines which developed MAPK inhibitors resistance. Findings were further validated and confirmed by analysis of independent datasets. RESULTS Our analysis reveals significant downregulation of GJB5 expression in metastatic melanoma lesions compared to primary ones and in BRAF mutated versus BRAF wild-type melanomas. Likewise, GJB5 expression is significantly lower in BRAFV600E compared with BRAFWT cell lines and increases upon MAPKi treatment. MAPKi-resistant melanoma cells display a similar expression pattern compared to BRAFWT cells, with increased GJB5 expression associated with morphological changes. Enhancement of BRAFV600E expression in BRAFWT melanoma cells significantly upregulates miR-335-5p expression with consequent downregulation of GJB5, one of its targets. Furthermore, overexpression of miR-335-5p in two BRAFWT cell lines confirms specific GJB5 protein downregulation. RT-qPCR analysis also revealed upregulation of miR-335 in BRAFV600E melanoma cells, which is significantly downregulated in cells resistant to MEK inhibitors. Our data were further validated using the TCGA-SKCM dataset, where BRAF mutations associate with increased miR-335 expression and inversely correlate with GJB5 expression. In clinical samples, GJB5 underexpression is also associated with patient overall worse survival, especially at early stages. CONCLUSION We identified a significant association between metastases / BRAF mutation and low GJB5 expression in melanoma. Our results identify a novel mechanism of Gap-junctional protein regulation, suggesting a prognostic role for GJB5 in cutaneous melanoma.
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Affiliation(s)
- M Scatolini
- Molecular Oncology Laboratory, Fondazione Edo ed Elvo Tempia, 13875, Ponderano, BI, Italy
| | - A Patel
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London SMD, QMUL, London, E1 2AT, UK
| | - E Grosso
- Molecular Oncology Laboratory, Fondazione Edo ed Elvo Tempia, 13875, Ponderano, BI, Italy
| | - M Mello-Grand
- Cancer Genomics Laboratory, Fondazione Edo ed Elvo Tempia, 13900, Biella, Italy
| | - P Ostano
- Cancer Genomics Laboratory, Fondazione Edo ed Elvo Tempia, 13900, Biella, Italy
| | - R Coppo
- Molecular Biotechnology Centre, 10126, Torino, Italy.,Department of Clinical Bio-Resource Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - M Vitiello
- Oncogenomics Unit, Core Research Laboratory, Istituto Toscano Tumori, Institute of Clinical Physiology, CNR, 56124, Pisa, Italy
| | - T Venesio
- Pathology and Dermosurgery Units, Candiolo Cancer Institute (FPO-IRCCS), 10060, Candiolo, Turin, Italy
| | - A Zaccagna
- Pathology and Dermosurgery Units, Candiolo Cancer Institute (FPO-IRCCS), 10060, Candiolo, Turin, Italy
| | - A Pisacane
- Pathology and Dermosurgery Units, Candiolo Cancer Institute (FPO-IRCCS), 10060, Candiolo, Turin, Italy
| | - I Sarotto
- Pathology and Dermosurgery Units, Candiolo Cancer Institute (FPO-IRCCS), 10060, Candiolo, Turin, Italy
| | - D Taverna
- Molecular Biotechnology Centre, 10126, Torino, Italy
| | - L Poliseno
- Oncogenomics Unit, Core Research Laboratory, Istituto Toscano Tumori, Institute of Clinical Physiology, CNR, 56124, Pisa, Italy
| | - D Bergamaschi
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London SMD, QMUL, London, E1 2AT, UK
| | - G Chiorino
- Cancer Genomics Laboratory, Fondazione Edo ed Elvo Tempia, 13900, Biella, Italy
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10
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Nilsson R, Liu NA. Nuclear DNA damages generated by reactive oxygen molecules (ROS) under oxidative stress and their relevance to human cancers, including ionizing radiation-induced neoplasia part II: Relation between ROS-induced DNA damages and human cancer. RADIATION MEDICINE AND PROTECTION 2020. [DOI: 10.1016/j.radmp.2020.11.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
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11
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Connexins-Therapeutic Targets in Cancers. Int J Mol Sci 2020; 21:ijms21239119. [PMID: 33266154 PMCID: PMC7730856 DOI: 10.3390/ijms21239119] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 11/24/2020] [Accepted: 11/26/2020] [Indexed: 12/11/2022] Open
Abstract
Connexins (Cx) are members of a protein family that forms intercellular channels localised in gap junction (GJ) plaques and single transmembrane channels called hemichannels. They participate in intercellular communication or communication between the intracellular and extracellular environments. Connexins affect cell homeostasis, growth and differentiation by enabling the exchange of metabolites or by interfering with various signalling pathways. Alterations in the functionality and the expression of connexins have been linked to the occurrence of many diseases. Connexins have been already linked to cancers, cardiac and brain disorders, chronic lung and kidney conditions and wound healing processes. Connexins have been shown either to suppress cancer tumour growth or to increase tumorigenicity by promoting cancer cell growth, migration and invasiveness. A better understanding of the complexity of cancer biology related to connexins and intercellular communication could result in the design of novel therapeutic strategies. The modulation of connexin expression may be an effective therapeutic approach in some types of cancers. Therefore, one important challenge is the search for mechanisms and new drugs, selectively modulating the expression of various connexin isoforms. We performed a systematic literature search up to February 2020 in the electronic databases PubMed and EMBASE. Our search terms were as follows: connexins, hemichannels, cancer and cancer treatment. This review aims to provide information about the role of connexins and gap junctions in cancer, as well as to discuss possible therapeutic options that are currently being studied.
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12
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Yang L, Liu B, Chen H, Gao R, Huang K, Guo Q, Li F, Chen W, He J. Progress in the application of organoids to breast cancer research. J Cell Mol Med 2020; 24:5420-5427. [PMID: 32283573 PMCID: PMC7214171 DOI: 10.1111/jcmm.15216] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 02/13/2020] [Accepted: 03/06/2020] [Indexed: 12/17/2022] Open
Abstract
Breast cancer is the most common cancer diagnosed in women. Breast cancer research is currently based mainly on animal models and traditional cell culture. However, the inherent species gap between humans and animals, as well as differences in organization between organs and cells, limits research advances. The breast cancer organoid can reproduce many of the key features of human breast cancer, thereby providing a new platform for investigating the mechanisms underlying the development, progression, metastasis and drug resistance of breast cancer. The application of organoid technology can also promote drug discovery and the design of individualized treatment strategies. Here, we discuss the latest advances in the use of organoid technology for breast cancer research.
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Affiliation(s)
- Liping Yang
- Department of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, China.,Department of Breast Surgery, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Baoer Liu
- Department of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, China.,Department of Breast Surgery, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Haodong Chen
- Department of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Rui Gao
- Department of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Kanghua Huang
- Department of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Qiuyi Guo
- Department of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Feng Li
- Department of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Weicai Chen
- Department of Breast Surgery, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Jinsong He
- Department of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, China
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13
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Hernández-Guerra M, Hadjihambi A, Jalan R. Gap junctions in liver disease: Implications for pathogenesis and therapy. J Hepatol 2019; 70:759-772. [PMID: 30599172 DOI: 10.1016/j.jhep.2018.12.023] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Revised: 12/03/2018] [Accepted: 12/12/2018] [Indexed: 02/07/2023]
Abstract
In the normal liver, cells interact closely through gap junctions. By providing a pathway for the trafficking of low molecular mass molecules, these channels contribute to tissue homeostasis and maintenance of hepatic function. Thus, dysfunction of gap junctions affects a wide variety of liver processes, such as differentiation, cell death, inflammation and fibrosis. In fact, dysfunctional gap junctions have been implicated, for more than a decade, in cholestatic disease, hepatic cancer and cirrhosis. Additionally, in recent years there is an increasing body of evidence that these channels are also involved in other relevant and prevalent liver pathological processes, such as non-alcoholic fatty liver disease, acute liver injury and portal hypertension. In parallel to these new clinical implications the available data include controversial observations. Thus, a comprehensive overview is required to better understand the functional complexity of these pores. This paper will review the most recent knowledge concerning gap junction dysfunction, with a special focus on the role of these channels in the pathogenesis of relevant clinical entities and on potential therapeutic targets that are amenable to modification by drugs.
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Affiliation(s)
| | | | - Rajiv Jalan
- UCL Institute for Liver and Digestive Health, Royal Free Medical School, London, UK
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14
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Phosphorylation-Dependent Intra-Domain Interaction of the Cx37 Carboxyl-Terminus Controls Cell Survival. Cancers (Basel) 2019; 11:cancers11020188. [PMID: 30736283 PMCID: PMC6406260 DOI: 10.3390/cancers11020188] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 02/01/2019] [Accepted: 02/02/2019] [Indexed: 02/07/2023] Open
Abstract
Differential phosphorylation of the carboxyl-terminus of connexin 37 (Cx37-CT) regulates phenotypic switching between cell growth phenotypes (cell death, cell cycle arrest, proliferation). The specific phosphorylation events in the Cx37-CT that are necessary for these growth regulatory effects are currently unknown. Through the combined use of deletion and site specific (de)phospho-mimetic Cx37-CT mutants, our data suggest a phosphorylation-dependent interaction between the mid-tail (aa 273⁻317) and end-tail (aa 318⁻333) portions of the Cx37-CT that regulates cell survival. As detected by mass spectrometry, Cx37 was phosphorylated at serines 275, 321, and 328; phosphomimetic mutations of these sites resulted in cell death when expressed in rat insulinoma cells. Alanine substitution at S328, but not at S275 or S321, also triggered cell death. Cx37-S275D uniquely induced the death of only low density, non-contact forming cells, but neither hemichannel open probability nor channel conductance distinguished death-inducing mutants. As channel function is necessary for cell death, together the data suggest that the phosphorylation state of the Cx37-CT controls an intra-domain interaction within the CT that modifies channel function and induces cell death.
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Trease AJ, Li H, Spagnol G, Zheng L, Stauch KL, Sorgen PL. Regulation of Connexin32 by ephrin receptors and T-cell protein-tyrosine phosphatase. J Biol Chem 2019; 294:341-350. [PMID: 30401746 PMCID: PMC6322898 DOI: 10.1074/jbc.ra118.003883] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 10/25/2018] [Indexed: 11/06/2022] Open
Abstract
Gap junctions are intercellular conduits that permit the passage of ions, small metabolites, and signaling molecules between cells. Connexin32 (Cx32) is a major gap junction protein in the liver and brain. Phosphorylation is integral to regulating connexin assembly, degradation, and electrical and metabolic coupling, as well as to interactions with molecular partners. Cx32 contains two intracellular tyrosine residues, and tyrosine phosphorylation of Cx32 has been detected after activation of the epidermal growth factor receptor; however, the specific tyrosine residue and the functional implication of this phosphorylation remain unknown. To address the limited available information on Cx32 regulation by tyrosine kinases, here we used the Cx32 C-terminal (CT) domain in an in vitro kinase-screening assay, which identified ephrin (Eph) receptor family members as tyrosine kinases that phosphorylate Cx32. We found that EphB1 and EphA1 phosphorylate the Cx32CT domain residue Tyr243 Unlike for Cx43, the tyrosine phosphorylation of the Cx32CT increased gap junction intercellular communication. We also demonstrated that T-cell protein-tyrosine phosphatase dephosphorylates pTyr243 The data presented above along with additional examples throughout the literature of gap junction regulation by kinases, indicate that one cannot extrapolate the effect of a kinase on one connexin to another.
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Affiliation(s)
| | - Hanjun Li
- Department of Biochemistry and Molecular Biology; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198
| | | | - Li Zheng
- Department of Biochemistry and Molecular Biology
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16
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Sinyuk M, Mulkearns-Hubert EE, Reizes O, Lathia J. Cancer Connectors: Connexins, Gap Junctions, and Communication. Front Oncol 2018; 8:646. [PMID: 30622930 PMCID: PMC6308394 DOI: 10.3389/fonc.2018.00646] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Accepted: 12/10/2018] [Indexed: 12/21/2022] Open
Abstract
Despite concerted clinical and research efforts, cancer is a leading cause of death worldwide. Surgery, radiation, and chemotherapy have remained the most common standard-of-care strategies against cancer for decades. However, the side effects of these therapies demonstrate the need to investigate adjuvant novel treatment modalities that minimize the harm caused to healthy cells and tissues. Normal and cancerous cells require communication amongst themselves and with their surroundings to proliferate and drive tumor growth. It is vital to understand how intercellular and external communication impacts tumor cell malignancy. To survive and grow, tumor cells, and their normal counterparts utilize cell junction molecules including gap junctions (GJs), tight junctions, and adherens junctions to provide contact points between neighboring cells and the extracellular matrix. GJs are specialized structures composed of a family of connexin proteins that allow the free diffusion of small molecules and ions directly from the cytoplasm of adjacent cells, without encountering the extracellular milieu, which enables rapid, and coordinated cellular responses to internal and external stimuli. Importantly, connexins perform three main cellular functions. They enable direct gap junction intercellular communication (GJIC) between cells, form hemichannels to allow cell communication with the extracellular environment, and serve as a site for protein-protein interactions to regulate signaling pathways. Connexins themselves have been found to promote tumor cell growth and invasiveness, contributing to the overall tumorigenicity and have emerged as attractive anti-tumor targets due to their functional diversity. However, connexins can also serve as tumor suppressors, and therefore, a complete understanding of the roles of the connexins and GJs in physiological and pathophysiological conditions is needed before connexin targeting strategies are applied. Here, we discuss how the three aspects of connexin function, namely GJIC, hemichannel formation, and connexin-protein interactions, function in normal cells, and contribute to tumor cell growth, proliferation, and death. Finally, we discuss the current state of anti-connexin therapies and speculate which role may be most amenable for the development of targeting strategies.
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Affiliation(s)
- Maksim Sinyuk
- Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH, United States
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Erin E. Mulkearns-Hubert
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Ofer Reizes
- Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH, United States
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
- Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH, United States
- Case Comprehensive Cancer Center, Case Western University, Cleveland, OH, United States
| | - Justin Lathia
- Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH, United States
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
- Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH, United States
- Case Comprehensive Cancer Center, Case Western University, Cleveland, OH, United States
- Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
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17
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Wang H, Tian L, Liu J, Goldstein A, Bado I, Zhang W, Arenkiel BR, Li Z, Yang M, Du S, Zhao H, Rowley DR, Wong STC, Gugala Z, Zhang XHF. The Osteogenic Niche Is a Calcium Reservoir of Bone Micrometastases and Confers Unexpected Therapeutic Vulnerability. Cancer Cell 2018; 34:823-839.e7. [PMID: 30423299 PMCID: PMC6239211 DOI: 10.1016/j.ccell.2018.10.002] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 07/10/2018] [Accepted: 10/02/2018] [Indexed: 02/06/2023]
Abstract
The fate of disseminated tumor cells is largely determined by microenvironment (ME) niche. The osteogenic niche promotes cancer cell proliferation and bone metastasis progression. We investigated the underlying mechanisms using pre-clinical models and analyses of clinical data. We discovered that the osteogenic niche serves as a calcium (Ca) reservoir for cancer cells through gap junctions. Cancer cells cannot efficiently absorb Ca from ME, but depend on osteogenic cells to increase intracellular Ca concentration. The Ca signaling, together with previously identified mammalian target of rapamycin signaling, promotes bone metastasis progression. Interestingly, effective inhibition of these pathways can be achieved by danusertib, or a combination of everolimus and arsenic trioxide, which provide possibilities of eliminating bone micrometastases using clinically established drugs.
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Affiliation(s)
- Hai Wang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Lin Tian
- Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Jun Liu
- Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Amit Goldstein
- Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Igor Bado
- Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Weijie Zhang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Benjamin R Arenkiel
- Department of Human and Molecular Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; McNair Medical Institute, Baylor College of Medicine, BCM600, One Baylor Plaza, Houston, TX 77030, USA
| | - Zonghai Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, P.R. China
| | - Meng Yang
- Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Shiyu Du
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Hong Zhao
- Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, TX 77030, USA
| | - David R Rowley
- Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Stephen T C Wong
- Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, TX 77030, USA
| | - Zbigniew Gugala
- Department of Orthopaedic Surgery & Rehabilitation, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Xiang H-F Zhang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; McNair Medical Institute, Baylor College of Medicine, BCM600, One Baylor Plaza, Houston, TX 77030, USA.
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Abstract
The connexin family of channel-forming proteins is present in every tissue type in the human anatomy. Connexins are best known for forming clustered intercellular channels, structurally known as gap junctions, where they serve to exchange members of the metabolome between adjacent cells. In their single-membrane hemichannel form, connexins can act as conduits for the passage of small molecules in autocrine and paracrine signalling. Here, we review the roles of connexins in health and disease, focusing on the potential of connexins as therapeutic targets in acquired and inherited diseases as well as wound repair, while highlighting the associated clinical challenges.
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19
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Alaei SR, Abrams CK, Bulinski JC, Hertzberg EL, Freidin MM. Acetylation of C-terminal lysines modulates protein turnover and stability of Connexin-32. BMC Cell Biol 2018; 19:22. [PMID: 30268116 PMCID: PMC6162937 DOI: 10.1186/s12860-018-0173-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 09/17/2018] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The gap junction protein, Connexin32 (Cx32), is expressed in various tissues including liver, exocrine pancreas, gastrointestinal epithelium, and the glia of the central and peripheral nervous system. Gap junction-mediated cell-cell communication and channel-independent processes of Cx32 contribute to the regulation of physiological and cellular activities such as glial differentiation, survival, and proliferation; maintenance of the hepatic epithelium; and axonal myelination. Mutations in Cx32 cause X-linked Charcot-Marie-Tooth disease (CMT1X), an inherited peripheral neuropathy. Several CMT1X causing mutations are found in the cytoplasmic domains of Cx32, a region implicated in the regulation of gap junction assembly, turnover and function. Here we investigate the roles of acetylation and ubiquitination in the C-terminus on Cx32 protein function. Cx32 protein turnover, ubiquitination, and response to deacetylase inhibitors were determined for wild-type and C-terminus lysine mutants using transiently transfected Neuro2A (N2a) cells. RESULTS We report here that Cx32 is acetylated in transfected N2a cells and that inhibition of the histone deacetylase, HDAC6, results in an accumulation of Cx32. We identified five lysine acetylation targets in the C-terminus. Mutational analysis demonstrates that these lysines are involved in the regulation of Cx32 ubiquitination and turnover. While these lysines are not required for functional Cx32 mediated cell-cell communication, BrdU incorporation studies demonstrate that their relative acetylation state plays a channel-independent role in Cx32-mediated control of cell proliferation. CONCLUSION Taken together these results highlight the role of post translational modifications and lysines in the C-terminal tail of Cx32 in the fine-tuning of Cx32 protein stability and channel-independent functions.
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Affiliation(s)
- Sarah R. Alaei
- Department of Molecular Genetics & Microbiology, Stony Brook University, Stony Brook, NY 11794 USA
| | - Charles K. Abrams
- Department of Neurology & Rehabilitation, University of Illinois at Chicago, Chicago, IL 60612 USA
| | - J. Chloë Bulinski
- Department of Cell & Molecular Biology, Columbia University, New York, NY 10032 USA
| | - Elliot L. Hertzberg
- Department of Cell & Molecular Biology, Columbia University, New York, NY 10032 USA
| | - Mona M. Freidin
- Department of Neurology & Rehabilitation, University of Illinois at Chicago, Chicago, IL 60612 USA
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20
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Delmar M, Laird DW, Naus CC, Nielsen MS, Verselis VK, White TW. Connexins and Disease. Cold Spring Harb Perspect Biol 2018; 10:cshperspect.a029348. [PMID: 28778872 DOI: 10.1101/cshperspect.a029348] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Inherited or acquired alterations in the structure and function of connexin proteins have long been associated with disease. In the present work, we review current knowledge on the role of connexins in diseases associated with the heart, nervous system, cochlea, and skin, as well as cancer and pleiotropic syndromes such as oculodentodigital dysplasia (ODDD). Although incomplete by virtue of space and the extent of the topic, this review emphasizes the fact that connexin function is not only associated with gap junction channel formation. As such, both canonical and noncanonical functions of connexins are fundamental components in the pathophysiology of multiple connexin related disorders, many of them highly debilitating and life threatening. Improved understanding of connexin biology has the potential to advance our understanding of mechanisms, diagnosis, and treatment of disease.
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Affiliation(s)
- Mario Delmar
- The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York 10016
| | - Dale W Laird
- Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A5C1, Canada
| | - Christian C Naus
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
| | - Morten S Nielsen
- Department of Biological Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Vytautas K Verselis
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, New York 10461
| | - Thomas W White
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York 11790
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21
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Connexins and Pannexins: Important Players in Tumorigenesis, Metastasis and Potential Therapeutics. Int J Mol Sci 2018; 19:ijms19061645. [PMID: 29865195 PMCID: PMC6032133 DOI: 10.3390/ijms19061645] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Revised: 05/25/2018] [Accepted: 05/28/2018] [Indexed: 12/15/2022] Open
Abstract
Since their characterization more than five decades ago, gap junctions and their structural proteins-the connexins-have been associated with cancer cell growth. During that period, the accumulation of data and molecular knowledge about this association revealed an apparent contradictory relationship between them and cancer. It appeared that if gap junctions or connexins can down regulate cancer cell growth they can be also implied in the migration, invasion and metastatic dissemination of cancer cells. Interestingly, in all these situations, connexins seem to be involved through various mechanisms in which they can act either as gap-junctional intercellular communication mediators, modulators of signalling pathways through their interactome, or as hemichannels, which mediate autocrine/paracrine communication. This complex involvement of connexins in cancer progression is even more complicated by the fact that their hemichannel function may overlap with other gap junction-related proteins, the pannexins. Despite this complexity, the possible involvements of connexins and pannexins in cancer progression and the elucidation of the mechanisms they control may lead to use them as new targets to control cancer progression. In this review, the involvements of connexins and pannexins in these different topics (cancer cell growth, invasion/metastasis process, possible cancer therapeutic targets) are discussed.
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22
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Moore D, Walker SI, Levin M. Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem. CONVERGENT SCIENCE PHYSICAL ONCOLOGY 2017. [DOI: 10.1088/2057-1739/aa8548] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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23
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Boucher J, Monvoisin A, Vix J, Mesnil M, Thuringer D, Debiais F, Cronier L. Connexins, important players in the dissemination of prostate cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2017; 1860:202-215. [PMID: 28693897 DOI: 10.1016/j.bbamem.2017.06.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 06/22/2017] [Accepted: 06/29/2017] [Indexed: 12/25/2022]
Abstract
Over the past 50years, increasing experimental evidences have established that connexins (Cxs) and gap junctional intercellular communication (GJIC) ensure an important role in both the onset and development of cancerous processes. In the present review, we focus on the impact of Cxs and GJIC during the development of prostate cancer (PCa), from the primary growth mainly localized in acinar glands and ducts to the distant metastasis mainly concentrated in bone. As observed in several other types of solid tumours, Cxs and especially Cx43 exhibit an ambivalent role with a tumour suppressor effect in the early stages and, conversely, a rather pro-tumoural profile for most of invasion and dissemination steps to secondary sites. We report here the current knowledge on the function of Cxs during PCa cells migration, cytoskeletal dynamics, proteinases activities and the cross talk with the surrounding stromal cells in the microenvironment of the tumour and the bones. In addition, we discuss the role of Cxs in the bone tropism even if the prostate model is rarely used to study the complete sequence of cancer dissemination compared to breast cancer or melanoma. Even if not yet fully understood, these recent findings on Cxs provide new insights into their molecular mechanisms associated with progression and bone targeted behaviour of PCa. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.
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Affiliation(s)
- Jonathan Boucher
- Laboratory Signalisation et Transports Ioniques Membranaires (STIM), ERL7368 - CNRS, University of Poitiers, Poitiers, France
| | - Arnaud Monvoisin
- Laboratory Signalisation et Transports Ioniques Membranaires (STIM), ERL7368 - CNRS, University of Poitiers, Poitiers, France
| | - Justine Vix
- Laboratory Signalisation et Transports Ioniques Membranaires (STIM), ERL7368 - CNRS, University of Poitiers, Poitiers, France; Department of Rheumatology, C.H.U. la Milétrie, Poitiers, France
| | - Marc Mesnil
- Laboratory Signalisation et Transports Ioniques Membranaires (STIM), ERL7368 - CNRS, University of Poitiers, Poitiers, France
| | | | - Françoise Debiais
- Laboratory Signalisation et Transports Ioniques Membranaires (STIM), ERL7368 - CNRS, University of Poitiers, Poitiers, France; Department of Rheumatology, C.H.U. la Milétrie, Poitiers, France
| | - Laurent Cronier
- Laboratory Signalisation et Transports Ioniques Membranaires (STIM), ERL7368 - CNRS, University of Poitiers, Poitiers, France.
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24
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Mesnil M, Aasen T, Boucher J, Chépied A, Cronier L, Defamie N, Kameritsch P, Laird DW, Lampe PD, Lathia JD, Leithe E, Mehta PP, Monvoisin A, Pogoda K, Sin WC, Tabernero A, Yamasaki H, Yeh ES, Dagli MLZ, Naus CC. An update on minding the gap in cancer. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2017; 1860:237-243. [PMID: 28655619 DOI: 10.1016/j.bbamem.2017.06.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 06/22/2017] [Accepted: 06/23/2017] [Indexed: 01/08/2023]
Abstract
This article is a report of the "International Colloquium on Gap junctions: 50Years of Impact on Cancer" that was held 8-9 September 2016, at the Amphitheater "Pôle Biologie Santé" of the University of Poitiers (Poitiers, France). The colloquium was organized by M Mesnil (Université de Poitiers, Poitiers, France) and C Naus (University of British Columbia, Vancouver, Canada) to celebrate the 50th anniversary of the seminal work published in 1966 by Loewenstein and Kanno [Intercellular communication and the control of tissue growth: lack of communication between cancer cells, Nature, 116 (1966) 1248-1249] which initiated studies on the involvement of gap junctions in carcinogenesis. During the colloquium, 15 participants presented reviews or research updates in the field which are summarized below.
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Affiliation(s)
- Marc Mesnil
- STIM Laboratory ERL 7368 CNRS - Faculté des Sciences Fondamentales et Appliquées, Université de Poitiers, Poitiers 86073, cedex 09, France.
| | - Trond Aasen
- Translational Molecular Pathology, Vall d'Hebron Institute of Research (VHIR), Autonomous University of Barcelona, CIBERONC, 08035 Barcelona, Spain
| | - Jonathan Boucher
- STIM Laboratory ERL 7368 CNRS - Faculté des Sciences Fondamentales et Appliquées, Université de Poitiers, Poitiers 86073, cedex 09, France
| | - Amandine Chépied
- STIM Laboratory ERL 7368 CNRS - Faculté des Sciences Fondamentales et Appliquées, Université de Poitiers, Poitiers 86073, cedex 09, France
| | - Laurent Cronier
- STIM Laboratory ERL 7368 CNRS - Faculté des Sciences Fondamentales et Appliquées, Université de Poitiers, Poitiers 86073, cedex 09, France
| | - Norah Defamie
- STIM Laboratory ERL 7368 CNRS - Faculté des Sciences Fondamentales et Appliquées, Université de Poitiers, Poitiers 86073, cedex 09, France
| | - Petra Kameritsch
- Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität München and Munich University Hospital, München, Germany
| | - Dale W Laird
- Department of Anatomy and Cell Biology, University of Western Ontario, Dental Science Building, London, Ontario N6A 5C1, Canada
| | - Paul D Lampe
- Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Justin D Lathia
- Cleveland Clinic, Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA
| | - Edward Leithe
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, and Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, NO-0424 Oslo, Norway
| | - Parmender P Mehta
- Department of Biochemistry and Molecular Biology, University of Nebraska, Medical Center, Omaha, NE 68198, USA
| | - Arnaud Monvoisin
- STIM Laboratory ERL 7368 CNRS - Faculté des Sciences Fondamentales et Appliquées, Université de Poitiers, Poitiers 86073, cedex 09, France
| | - Kristin Pogoda
- Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität München and Munich University Hospital, München, Germany
| | - Wun-Chey Sin
- Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Arantxa Tabernero
- Departamento de Bioquímica y Biología Molecular, Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, Salamanca 37007, Spain
| | | | - Elizabeth S Yeh
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29412, USA
| | - Maria Lucia Zaidan Dagli
- Laboratory of Experimental and Comparative Oncology, School of Veterinary Medicine and Animal Science of the University of São Paulo, São Paulo, SP CEP 05508-900, Brazil
| | - Christian C Naus
- Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
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25
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Mathews J, Levin M. Gap junctional signaling in pattern regulation: Physiological network connectivity instructs growth and form. Dev Neurobiol 2017; 77:643-673. [PMID: 27265625 PMCID: PMC10478170 DOI: 10.1002/dneu.22405] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 05/27/2016] [Accepted: 05/31/2016] [Indexed: 12/19/2022]
Abstract
Gap junctions (GJs) are aqueous channels that allow cells to communicate via physiological signals directly. The role of gap junctional connectivity in determining single-cell functions has long been recognized. However, GJs have another important role: the regulation of large-scale anatomical pattern. GJs are not only versatile computational elements that allow cells to control which small molecule signals they receive and emit, but also establish connectivity patterns within large groups of cells. By dynamically regulating the topology of bioelectric networks in vivo, GJs underlie the ability of many tissues to implement complex morphogenesis. Here, a review of recent data on patterning roles of GJs in growth of the zebrafish fin, the establishment of left-right patterning, the developmental dysregulation known as cancer, and the control of large-scale head-tail polarity, and head shape in planarian regeneration has been reported. A perspective in which GJs are not only molecular features functioning in single cells, but also enable global neural-like dynamics in non-neural somatic tissues has been proposed. This view suggests a rich program of future work which capitalizes on the rapid advances in the biophysics of GJs to exploit GJ-mediated global dynamics for applications in birth defects, regenerative medicine, and morphogenetic bioengineering. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 643-673, 2017.
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Affiliation(s)
- Juanita Mathews
- Department of Biology, Tufts Center for Regenerative and Developmental Biology, Tufts University, Medford, MA
| | - Michael Levin
- Department of Biology, Tufts Center for Regenerative and Developmental Biology, Tufts University, Medford, MA
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Abstract
Being critical mediators of liver homeostasis, connexins and their channels are frequently involved in liver toxicity. In the current paper, specific attention is paid to actions of hepatotoxic drugs on these communicative structures. In a first part, an overview is provided on the structural, regulatory and functional properties of connexin-based channels in the liver. In the second part, documented effects of acetaminophen, hypolipidemic drugs, phenobarbital and methapyriline on connexin signaling are discussed. Furthermore, the relevance of this subject for the fields of clinical and in vitro toxicology is demonstrated. Relevance for patients: The role of connexin signaling in drug-induced hepatotoxicity may be of high clinical relevance, as it offers perspectives for the therapeutic treatment of such insults by interfering with connexin channel opening.
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Affiliation(s)
- Michaël Maes
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
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27
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Abstract
Fifty years ago, tumour cells were found to lack electrical coupling, leading to the hypothesis that loss of direct intercellular communication is commonly associated with cancer onset and progression. Subsequent studies linked this phenomenon to gap junctions composed of connexin proteins. Although many studies support the notion that connexins are tumour suppressors, recent evidence suggests that, in some tumour types, they may facilitate specific stages of tumour progression through both junctional and non-junctional signalling pathways. This Timeline article highlights the milestones connecting gap junctions to cancer, and underscores important unanswered questions, controversies and therapeutic opportunities in the field.
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Affiliation(s)
- Trond Aasen
- (Co-corresponding authors) Correspondence to
T.A. () and D.W.L.
()
| | - Marc Mesnil
- STIM Laboratory ERL 7368 CNRS - Faculté des Sciences
Fondamentales et Appliquées, Université de Poitiers, Poitiers,
France
| | - Christian C. Naus
- Department of Cellular and Physiological Sciences, The Life
Sciences Institute, University of British Columbia, Vancouver, British
Columbia, Canada
| | - Paul D. Lampe
- Translational Research Program, Fred Hutchinson Cancer Research
Center, Seattle, United States
| | - Dale W. Laird
- (Co-corresponding authors) Correspondence to
T.A. () and D.W.L.
()
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Non-coding RNA as mediators in microenvironment–breast cancer cell communication. Cancer Lett 2016; 380:289-95. [PMID: 26582656 DOI: 10.1016/j.canlet.2015.11.016] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Revised: 11/04/2015] [Accepted: 11/06/2015] [Indexed: 12/18/2022]
Abstract
The tumor microenvironment has a critical role in the survival and decision of the cancer cells. These include support by enhanced angiogenesis, and metastasis or adaptation of dormancy. This article discusses methods by which the microenvironment sustains the tumor. This process is important as it will identify avenues of drug targets. Non-coding RNAs (ncRNAs) are evolving as key mediators in the interaction between the cancer cells and the microenvironment. Thus, the question is how to develop methods to effectively block the effects of the ncRNA and/or to introduce them to prevent metastasis, dormancy or to reverse dormancy. We focused on the advantages of using mesenchymal stem cells (MSCs) for RNA delivery. MSCs can be available as "off-the-shelf" cells. Thus far, MSCs are shown to be safe when transplanted across allogeneic barriers. We discussed the various methods by which MSCs can interact with cancer cells to deliver ncRNA or antagomirs. We also include the advances and possible confounds of using these methods. Overall, this review article provides a potential method by which MSCs can be used for effective delivery of nucleic acid to treat cancer.
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Cogliati B, Crespo Yanguas S, da Silva TC, Aloia TP, Nogueira MS, Real-Lima MA, Chaible LM, Sanches DS, Willebrords J, Maes M, Pereira IV, de Castro IA, Vinken M, Dagli ML. Connexin32 deficiency exacerbates carbon tetrachloride-induced hepatocellular injury and liver fibrosis in mice. Toxicol Mech Methods 2016; 26:362-370. [PMID: 27268753 PMCID: PMC5417356 DOI: 10.1080/15376516.2016.1190991] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Liver fibrosis results from the perpetuation of the normal wound healing response to several types of injury. Despite the wealth of knowledge regarding the involvement of intracellular and extracellular signaling pathways in liver fibrogenesis, information about the role of intercellular communication mediated by gap junctions is scarce. METHODS In this study, liver fibrosis was chemically induced by carbon tetrachloride in mice lacking connexin32, the major liver gap junction constituent. The manifestation of liver fibrosis was evaluated based on a series of read-outs, including collagen morphometric and mRNA analysis, oxidative stress, apoptotic, proliferative and inflammatory markers. RESULTS More pronounced liver damage and enhanced collagen deposition were observed in connexin32 knockout mice compared to wild-type animals in experimentally triggered induced liver fibrosis. No differences between both groups were noticed in apoptotic signaling nor in inflammation markers. However, connexin32 deficient mice displayed decreased catalase activity and increased malondialdehyde levels. CONCLUSION These findings could suggest that connexin32-based signaling mediates tissue resistance against liver damage by the modulation of the antioxidant capacity. In turn, this could point to a role for connexin32 signaling as a therapeutic target in the treatment of liver fibrosis.
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Affiliation(s)
- Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Sara Crespo Yanguas
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Tereza C. da Silva
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Thiago P.A. Aloia
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Marina S. Nogueira
- Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Mirela A. Real-Lima
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Lucas M. Chaible
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Daniel S. Sanches
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Joost Willebrords
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Michaël Maes
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Isabel V.A. Pereira
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Inar A. de Castro
- Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Maria L.Z. Dagli
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
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Leithe E. Regulation of connexins by the ubiquitin system: Implications for intercellular communication and cancer. Biochim Biophys Acta Rev Cancer 2016; 1865:133-46. [DOI: 10.1016/j.bbcan.2016.02.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Revised: 01/15/2016] [Accepted: 02/04/2016] [Indexed: 12/31/2022]
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Cogliati B, Mennecier G, Willebrords J, Da Silva TC, Maes M, Pereira IVA, Crespo-Yanguas S, Hernandez-Blazquez FJ, Dagli MLZ, Vinken M. Connexins, Pannexins, and Their Channels in Fibroproliferative Diseases. J Membr Biol 2016; 249:199-213. [PMID: 26914707 DOI: 10.1007/s00232-016-9881-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 02/16/2016] [Indexed: 12/13/2022]
Abstract
Cellular and molecular mechanisms of wound healing, tissue repair, and fibrogenesis are established in different organs and are essential for the maintenance of function and tissue integrity after cell injury. These mechanisms are also involved in a plethora of fibroproliferative diseases or organ-specific fibrotic disorders, all of which are associated with the excessive deposition of extracellular matrix components. Fibroblasts, which are key cells in tissue repair and fibrogenesis, rely on communicative cellular networks to ensure efficient control of these processes and to prevent abnormal accumulation of extracellular matrix into the tissue. Despite the significant impact on human health, and thus the epidemiologic relevance, there is still no effective treatment for most fibrosis-related diseases. This paper provides an overview of current concepts and mechanisms involved in the participation of cellular communication via connexin-based pores as well as pannexin-based channels in the processes of tissue repair and fibrogenesis in chronic diseases. Understanding these mechanisms may contribute to the development of new therapeutic strategies to clinically manage fibroproliferative diseases and organ-specific fibrotic disorders.
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Affiliation(s)
- Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Brazil
| | - Gregory Mennecier
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Brazil
| | - Joost Willebrords
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Tereza Cristina Da Silva
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Brazil
| | - Michaël Maes
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
| | | | - Sara Crespo-Yanguas
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
| | | | - Maria Lúcia Zaidan Dagli
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Brazil
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
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32
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Maes M, McGill MR, da Silva TC, Lebofsky M, de Araújo CMM, Tiburcio T, Pereira IVA, Willebrords J, Yanguas SC, Farhood A, Dagli MLZ, Jaeschke H, Cogliati B, Vinken M. Connexin32: a mediator of acetaminophen-induced liver injury? Toxicol Mech Methods 2016; 26:88-96. [PMID: 26739117 PMCID: PMC4965445 DOI: 10.3109/15376516.2015.1103000] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 09/29/2015] [Indexed: 01/14/2023]
Abstract
Connexin32 is the building block of hepatocellular gap junctions, which control direct intercellular communication and thereby act as goalkeepers of liver homeostasis. This study was set up to investigate whether connexin32 is involved in hepatotoxicity induced by the analgesic and antipyretic drug acetaminophen. To this end, whole body connexin32 knock-out mice were overdosed with acetaminophen followed by sampling at different time points within a 24-h time frame. Evaluation was done based upon a series of clinically and mechanistically relevant read-outs, including protein adduct formation, histopathological examination, measurement of alanine aminotransferase activity, cytokine production, levels of reduced and oxidized glutathione and hepatic protein amounts of proliferating cell nuclear antigen. In essence, it was found that genetic ablation of connexin32 has no influence on several key events in acetaminophen-induced hepatotoxicity, including cell death, inflammation or oxidative stress, yet it does affect production of protein adducts as well as proliferating cell nuclear antigen steady-state protein levels. This outcome is not in line with previous studies, which are contradicting on their own, as both amplification and alleviation of this toxicological process by connexin32 have been described. This could question the suitability of the currently available models and tools to investigate the role of connexin32 in acetaminophen-triggered hepatotoxicity.
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Affiliation(s)
- Michaël Maes
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Mitchell R. McGill
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Tereza Cristina da Silva
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
| | - Margitta Lebofsky
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | | | - Taynã Tiburcio
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
| | - Isabel Veloso Alves Pereira
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
| | - Joost Willebrords
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Sara Crespo Yanguas
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Anwar Farhood
- Department of Pathology, St. David's North Austin Medical Center, Austin, Texas, United States of America
| | - Maria Lucia Zaidan Dagli
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
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Sagawa H, Naiki-Ito A, Kato H, Naiki T, Yamashita Y, Suzuki S, Sato S, Shiomi K, Kato A, Kuno T, Matsuo Y, Kimura M, Takeyama H, Takahashi S. Connexin 32 and luteolin play protective roles in non-alcoholic steatohepatitis development and its related hepatocarcinogenesis in rats. Carcinogenesis 2015; 36:1539-49. [PMID: 26494227 DOI: 10.1093/carcin/bgv143] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Accepted: 09/20/2015] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) has the potential to lead to the development of cirrhosis and hepatocellular carcinoma (HCC). Connexin (Cx) 32, a hepatocyte gap-junction protein, plays a preventive role in hepatocarcinogenesis. However, the precise contribution of Cx32 in the development of NASH has not been established. In this study, we aimed to clarify the role of Cx32 and the chemopreventive effect of luteolin, an antioxidant flavonoid, on the progression of NASH and NASH-related hepatocarcinogenesis. Cx32 dominant negative transgenic (Cx32ΔTg) and wild-type (Wt) rats at 10 weeks of age were given diethylnitrosamine and fed methionine-choline-deficient diet (MCDD) or MCDD with luteolin for 12 weeks. MCDD induced steatohepatitis and fibrosis along with increased inflammatory cytokine expression and reactive oxygen species in the liver. These effects were more severe in Cx32ΔTg rats as compared with Wt rats, and significantly suppressed by luteolin in both genotypes. Concerning NASH-related hepatocarcinogenesis, the number of glutathione S-transferase placental form (GST-P)-positive foci was greater in Cx32ΔTg versus Wt rats, and significantly reduced by luteolin in Cx32ΔTg rats. Microarray analysis identified brain expressed, X-linked 1 (Bex1) as an upregulated gene in Cx32ΔTg rat liver. Quantitative RT-PCR and in situ hybridization revealed that increased Bex1 mRNA was localized in GST-P-positive foci in Cx32ΔTg rats, and the expression level was significantly decreased by luteolin. Moreover, Bex1 knockdown resulted in significant growth inhibition of the rat HCC cell lines. These results show that Cx32 and luteolin have suppressive roles in inflammation, fibrosis and hepatocarcinogenesis during NASH progression, suggesting a potential therapeutic application for NASH.
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Affiliation(s)
- Hiroyuki Sagawa
- Department of Experimental Pathology and Tumor Biology, Department of Gastroenterological Surgery and
| | - Aya Naiki-Ito
- Department of Experimental Pathology and Tumor Biology,
| | - Hiroyuki Kato
- Department of Experimental Pathology and Tumor Biology
| | - Taku Naiki
- Department of Experimental Pathology and Tumor Biology
| | | | - Shugo Suzuki
- Department of Experimental Pathology and Tumor Biology
| | - Shinya Sato
- Department of Experimental Pathology and Tumor Biology
| | - Kosuke Shiomi
- Department of Experimental Pathology and Tumor Biology
| | - Akihisa Kato
- Department of Experimental Pathology and Tumor Biology, Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-cho, Mizuho-ku 467-8601, Nagoya, Japan
| | - Toshiya Kuno
- Department of Experimental Pathology and Tumor Biology
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34
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Kim D, Seo Y, Kwon S. Role of gap junction communication in hepatocyte/fibroblast co-cultures: Implications for hepatic tissue engineering. BIOTECHNOL BIOPROC E 2015. [DOI: 10.1007/s12257-014-0595-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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35
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Chernet BT, Fields C, Levin M. Long-range gap junctional signaling controls oncogene-mediated tumorigenesis in Xenopus laevis embryos. Front Physiol 2015; 5:519. [PMID: 25646081 PMCID: PMC4298169 DOI: 10.3389/fphys.2014.00519] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 12/18/2014] [Indexed: 11/21/2022] Open
Abstract
In addition to the immediate microenvironment, long-range signaling may be an important component of cancer. Molecular-genetic analyses have implicated gap junctions-key mediators of cell-cell communication-in carcinogenesis. We recently showed that the resting voltage potential of distant cell groups is a key determinant of metastatic transformation and tumor induction. Here, we show in the Xenopus laevis model that gap junctional communication (GJC) is a modulator of the long-range bioelectric signaling that regulates tumor formation. Genetic disruption of GJC taking place within tumors, within remote host tissues, or between the host and tumors significantly lowers the incidence of tumors induced by KRAS mutations. The most pronounced suppression of tumor incidence was observed upon GJC disruption taking place farther away from oncogene-expressing cells, revealing a role for GJC in distant cells in the control of tumor growth. In contrast, enhanced GJC communication through the overexpression of wild-type connexin Cx26 increased tumor incidence. Our data confirm a role for GJC in tumorigenesis, and reveal that this effect is non-local. Based on these results and on published data on movement of ions through GJs, we present a quantitative model linking the GJC coupling and bioelectrical state of cells to the ability of oncogenes to initiate tumorigenesis. When integrated with data on endogenous bioelectric signaling during left-right patterning, the model predicts differential tumor incidence outcomes depending on the spatial configurations of gap junction paths relative to tumor location and major anatomical body axes. Testing these predictions, we found that the strongest influence of GJ modulation on tumor suppression by hyperpolarization occurred along the embryonic left-right axis. Together, these data reveal new, long-range aspects of cancer control by the host's physiological parameters.
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Affiliation(s)
- Brook T. Chernet
- Department of Biology, Tufts Center for Regenerative and Developmental Biology, Tufts UniversityMedford, MA, USA
| | | | - Michael Levin
- Department of Biology, Tufts Center for Regenerative and Developmental Biology, Tufts UniversityMedford, MA, USA
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36
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Abdulrahman Almatrrouk S, Oliver AW, Hampson L, Hampson IN. Targeting gap junction intercellular communication as a potential therapy for HCV-related carcinogenesis. Future Virol 2014. [DOI: 10.2217/fvl.14.50] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
ABSTRACT: Worldwide, at least 170 million people are infected with hepatitis C virus (HCV), which is associated with hepatocellular carcinoma (HCC). With the recent success of Sofosbuvir (and other agents) antiviral therapy may be used as a future early-stage HCC treatment; however, in the short term, a cost-effective solution is needed to treat patients with viral-associated HCC. Here, we emphasize the potential of targeting gap junction intercellular communication (GJIC) as a therapeutic approach for HCC as HCV perturbs GJIC, which is linked to cellular transformation. We review the ROCK inhibitor Y-27632 and structurally related compounds that may inhibit the carcinogenic properties of HCV.
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Affiliation(s)
| | - Anthony W Oliver
- University of Manchester, Viral Oncology, Research Floor, St Mary's Hospital, Manchester, UK
| | - Lynne Hampson
- University of Manchester, Viral Oncology, Research Floor, St Mary's Hospital, Manchester, UK
| | - Ian N Hampson
- University of Manchester, Viral Oncology, Research Floor, St Mary's Hospital, Manchester, UK
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Mones S, Bordignon B, Peiretti F, Landrier JF, Gess B, Bourguignon JJ, Bihel F, Fontés M. CamKII inhibitors reduce mitotic instability, connexon anomalies and progression of the in vivo behavioral phenotype in transgenic animals expressing a mutated Gjb1 gene. Front Neurosci 2014; 8:151. [PMID: 24982612 PMCID: PMC4056282 DOI: 10.3389/fnins.2014.00151] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Accepted: 05/24/2014] [Indexed: 11/30/2022] Open
Abstract
Mutation in the Gjb1 gene, coding for a connexin (Cx32), is associated with an inherited peripheral neuropathic disorder (X-linked Charcot-Marie-Tooth, CMTX). Our previous work reported that transgenic animals expressing a human Gjb1 transgene present polyploidy and abnormal over-duplication of the centrosome, suggesting a role for Gjb1 in mitotic stability. In this article, we propose mechanisms by which mutations in Gjb1 induce mitotic instability and discuss its potential relation with the CMTX phenotype. We showed that transgenic cells exhibit CamKII over-stimulation, a phenomenon that has been linked to mitotic instability (polyploidy, nuclear volume and centrosome over-duplication), that is reversed by CamKII inhibitors. We also demonstrate that connexon activity is partially restored in transgenic cells with CamKII inhibitors. Our model supports the role for Pim1, a kinase that has been associated with genomic instability in cancers, in genomic instability in Cx32 mutations. Regarding in vivo phenotype, we showed that degradation on the rotarod test in our transgenic mice is significantly lowered by treatment with a CamKII inhibitor (KN93). This effect was seen in two lines with different point mutations in GJB1, and stopping the treatment led to degradation of the phenotype.
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Affiliation(s)
- Saleh Mones
- Therapy of Genetic Disorders, Faculté de Médecine, EA 4263, Aix-Marseille Université Marseille, France ; INSERM, UMR1062, Nutrition, Obesity and Risk of Thrombosis, Faculté de Médecine Marseille, France ; INRA, UMR1260, Faculté de Médecine Marseille, France
| | - Benoit Bordignon
- Therapy of Genetic Disorders, Faculté de Médecine, EA 4263, Aix-Marseille Université Marseille, France ; INSERM, UMR1062, Nutrition, Obesity and Risk of Thrombosis, Faculté de Médecine Marseille, France ; INRA, UMR1260, Faculté de Médecine Marseille, France
| | - Franck Peiretti
- INSERM, UMR1062, Nutrition, Obesity and Risk of Thrombosis, Faculté de Médecine Marseille, France ; INRA, UMR1260, Faculté de Médecine Marseille, France
| | - Jean F Landrier
- INSERM, UMR1062, Nutrition, Obesity and Risk of Thrombosis, Faculté de Médecine Marseille, France ; INRA, UMR1260, Faculté de Médecine Marseille, France
| | - Burkhardt Gess
- Department of Sleep Medicine and Neuromuscular Disorders, University Hospital Münster Münster, Germany
| | - Jean J Bourguignon
- Laboratoire d'Innovation Thérapeutique, Faculté de Pharmacie, CNRS, UMR7200, Université de Strasbourg Illkirch Graffenstaden, France
| | - Frédéric Bihel
- Laboratoire d'Innovation Thérapeutique, Faculté de Pharmacie, CNRS, UMR7200, Université de Strasbourg Illkirch Graffenstaden, France
| | - Michel Fontés
- Therapy of Genetic Disorders, Faculté de Médecine, EA 4263, Aix-Marseille Université Marseille, France ; INSERM, UMR1062, Nutrition, Obesity and Risk of Thrombosis, Faculté de Médecine Marseille, France ; INRA, UMR1260, Faculté de Médecine Marseille, France
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Abstract
SUMMARY Melanoma cells interact with and depend on seemingly normal cells in their tumour microenvironment to allow the acquisition of the hallmarks of solid cancer. In general, there are three types of interaction of melanoma cells with their microenvironment. First, there is bilateral communication between melanoma cells and the stroma, which includes fibroblasts, endothelial cells, immune cells, soluble molecules, and the extracellular matrix. Second, while under normal conditions keratinocytes control localisation and proliferative behaviour of melanocytes in the epidermis, once this balance is disturbed and a melanoma has developed, melanoma cells may take over the control of their epidermal tumour microenvironment. Finally, there are subcompartments within tumours with different microenvironmental milieu defined by their access to oxygen and nutrients. Therefore, different melanoma cells within a tumour face different microenvironments. Interactions between melanoma cells among each other and with the cell types in their microenvironment happen through endocrine and paracrine communication and/or through direct contact via cell-cell and cell-matrix adhesion, and gap junctional intercellular communication (GJIC). Connexins have been identified as key molecules for direct cell-cell communication and are also thought to be important for the release of signalling molecules from cells to the microenvironment. In this review we provide an update of the alterations in cell-cell communication in melanoma and the tumour microenvironment associated with melanoma development and progression.
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Sirnes S, Lind GE, Bruun J, Fykerud TA, Mesnil M, Lothe RA, Rivedal E, Kolberg M, Leithe E. Connexins in colorectal cancer pathogenesis. Int J Cancer 2014; 137:1-11. [PMID: 24752574 DOI: 10.1002/ijc.28911] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Accepted: 03/11/2014] [Indexed: 12/17/2022]
Abstract
The connexins constitute a family of integral membrane proteins that form channels between adjacent cells. These channels are assembled in plasma membrane domains known as gap junctions and enable cells to directly exchange ions and small molecules. Intercellular communication via gap junctions plays important roles in regulating cell growth and differentiation and in maintaining tissue homeostasis. This type of cell communication is often impaired during cancer development, and several members of the connexin protein family have been shown to act as tumor suppressors. Emerging evidence suggests that the connexin protein family has important roles in colorectal cancer development. In the normal colonic epithelial tissue, three connexin isoforms, connexin 26 (Cx26), Cx32 and Cx43, have been shown to be expressed at the protein level. Colorectal cancer development is associated with loss of connexin expression or relocalization of connexins from the plasma membrane to intracellular compartments. Downregulation of connexins in colorectal carcinomas at the transcriptional level involves cancer-specific promoter hypermethylation. Recent studies suggest that Cx43 may constrain growth of colon cancer cells by interfering with the Wnt/β-catenin pathway. There is also increasing evidence that the connexins may have potential as prognostic markers in colorectal cancer. This review discusses the role of connexins in colorectal cancer pathogenesis, as well as their potential as prognostic markers and targets in the prevention and treatment of the disease.
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Affiliation(s)
- Solveig Sirnes
- Department of Cancer Prevention, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway
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Igarashi I, Maejima T, Kai K, Arakawa S, Teranishi M, Sanbuissho A. Role of connexin 32 in acetaminophen toxicity in a knockout mice model. EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY : OFFICIAL JOURNAL OF THE GESELLSCHAFT FUR TOXIKOLOGISCHE PATHOLOGIE 2014; 66:103-10. [PMID: 24263089 DOI: 10.1016/j.etp.2013.10.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2013] [Revised: 09/03/2013] [Accepted: 10/21/2013] [Indexed: 01/28/2023]
Abstract
Gap junctional intercellular communication (GJIC), by which glutathione (GSH) and inorganic ions are transmitted to neighboring cells, is recognized as being largely involved in toxic processes of chemicals. We examined acetaminophen (APAP)-induced hepatotoxicity clinicopathologically using male wild-type mice and mice lacking the gene for connexin32, a major gap junction protein in the liver [knockout (Cx32KO) mice]. When APAP was intraperitoneally administered at doses of 100, 200, or 300mg/kg, hepatic centrilobular necrosis with elevated plasma aminotransferase activities was observed in wild-type mice receiving 300mg/kg, and in Cx32KO mice given 100mg/kg or more. At 200mg/kg or more, hepatic GSH and GSSG contents decreased significantly and the effect was more severe in wild-type mice than in Cx32KO mice. On the other hand, markedly decreased GSH staining was observed in the hepatic centrilobular zones of Cx32KO mice compared to that of wild-type mice. These results demonstrate that Cx32KO mice are more susceptible to APAP hepatotoxicity than wild-type mice, and indicate that the distribution of GSH of the centrilobular zones in the hepatic lobules, rather than GSH and GSSG contents in the liver, is important in APAP hepatotoxicity. In conclusion, Cx32 protects against APAP-induced hepatic centrilobular necrosis in mice, which may be through the GSH transmission to neighboring hepatocytes by GJIC.
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Affiliation(s)
- Isao Igarashi
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co. Ltd., Fukuroi, Shizuoka 437-0065, Japan.
| | - Takanori Maejima
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co. Ltd., Fukuroi, Shizuoka 437-0065, Japan
| | - Kiyonori Kai
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co. Ltd., Fukuroi, Shizuoka 437-0065, Japan
| | - Shingo Arakawa
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co. Ltd., Fukuroi, Shizuoka 437-0065, Japan
| | - Munehiro Teranishi
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co. Ltd., Fukuroi, Shizuoka 437-0065, Japan
| | - Atsushi Sanbuissho
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co. Ltd., Fukuroi, Shizuoka 437-0065, Japan
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Maes M, Decrock E, Cogliati B, Oliveira AG, Marques PE, Dagli MLZ, Menezes GB, Mennecier G, Leybaert L, Vanhaecke T, Rogiers V, Vinken M. Connexin and pannexin (hemi)channels in the liver. Front Physiol 2014; 4:405. [PMID: 24454290 PMCID: PMC3887319 DOI: 10.3389/fphys.2013.00405] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Accepted: 12/23/2013] [Indexed: 01/14/2023] Open
Abstract
The liver was among the first organs in which connexin proteins have been identified. Hepatocytes harbor connexin32 and connexin26, while non-parenchymal liver cells typically express connexin43. Connexins give rise to hemichannels, which dock with counterparts on adjacent cells to form gap junctions. Both hemichannels and gap junctions provide pathways for communication, via paracrine signaling or direct intercellular coupling, respectively. Over the years, hepatocellular gap junctions have been shown to regulate a number of liver-specific functions and to drive liver cell growth. In the last few years, it has become clear that connexin hemichannels are involved in liver cell death, particularly in hepatocyte apoptosis. This also holds true for hemichannels composed of pannexin1, a connexin-like protein recently identified in the liver. Moreover, pannexin1 hemichannels are key players in the regulation of hepatic inflammatory processes. The current paper provides a concise overview of the features of connexins, pannexins and their channels in the liver.
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Affiliation(s)
- Michaël Maes
- Department of Toxicology, Center for Pharmaceutical Research, Vrije Universiteit Brussel Brussels, Belgium
| | - Elke Decrock
- Physiology Group, Department of Basic Medical Sciences, Ghent University Ghent, Belgium
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo Sao Paulo, Brazil
| | - André G Oliveira
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais Belo Horizonte, Brazil
| | - Pedro E Marques
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais Belo Horizonte, Brazil
| | - Maria L Z Dagli
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo Sao Paulo, Brazil
| | - Gustavo B Menezes
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais Belo Horizonte, Brazil
| | - Gregory Mennecier
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo Sao Paulo, Brazil
| | - Luc Leybaert
- Physiology Group, Department of Basic Medical Sciences, Ghent University Ghent, Belgium
| | - Tamara Vanhaecke
- Department of Toxicology, Center for Pharmaceutical Research, Vrije Universiteit Brussel Brussels, Belgium
| | - Vera Rogiers
- Department of Toxicology, Center for Pharmaceutical Research, Vrije Universiteit Brussel Brussels, Belgium
| | - Mathieu Vinken
- Department of Toxicology, Center for Pharmaceutical Research, Vrije Universiteit Brussel Brussels, Belgium
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Ableser MJ, Penuela S, Lee J, Shao Q, Laird DW. Connexin43 reduces melanoma growth within a keratinocyte microenvironment and during tumorigenesis in vivo. J Biol Chem 2013; 289:1592-603. [PMID: 24297173 DOI: 10.1074/jbc.m113.507228] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Connexins (Cx) have been identified as tumor suppressors or enhancers, a distinction that appears to be dependent on the type and stage of disease. However, the role of connexins in melanoma tumorigenesis and their status during cancer onset and progression remain controversial and unclear. Here, we show that the aggressive B16-BL6 mouse melanoma cell line expresses low basal levels of Cx26 and Cx43, rendering them gap junctional intercellular communication-deficient as elucidated by immunofluorescence, Western blotting, and dye transfer studies. Following ectopic expression of green fluorescent protein-tagged Cx26 and Cx43 in these connexin-deficient melanomas, punctate gap junction-like plaques were evident at sites of cell-cell apposition, and the incidence of dye transfer was significantly increased similar to connexin-rich keratinocytes. We found that the expression of Cx43, but not Cx26, significantly reduced cellular proliferation and anchorage-independent growth from control melanomas, whereas migration was unaffected. Additionally, melanomas expressing Cx43 displayed significantly reduced growth within the in situ-like microenvironment of keratinocytes, despite a lack of heterocellular gap junctional intercellular communication between the two cell types. Furthermore, when grown in vivo in the chicken chorioallantoic membrane, primary tumors derived from Cx43-expressing melanomas were significantly smaller than controls, whereas Cx26-expressing melanomas produced tumors similar to controls. Collectively, these results suggest that Cx43, and not Cx26, can act as a tumor suppressor during melanoma tumorigenesis.
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43
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Gap junctions and blood-tissue barriers. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2013; 763:260-80. [PMID: 23397629 DOI: 10.1007/978-1-4614-4711-5_13] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Gap junction is a cell-cell communication junction type found in virtually all mammalian epithelia and endothelia and provides the necessary "signals" to coordinate physiological events to maintain the homeostasis of an epithelium and/or endothelium under normal physiological condition and following changes in the cellular environment (e.g., stimuli from stress, growth, development, inflammation, infection). Recent studies have illustrated the significance of this junction type in the maintenance of different blood-tissue barriers, most notably the blood-brain barrier and blood-testis barrier, which are dynamic ultrastructures, undergoing restructuring in response to stimuli from the environment. In this chapter, we highlight and summarize the latest findings in the field regarding how changes at the gap junction, such as the result of a knock-out, knock-down, knock-in, or gap junction inhibition and/or its activation via the use of inhibitors and/or activators, would affect the integrity or permeability of the blood-tissue barriers. These findings illustrate that much research is needed to delineate the role of gap junction in the blood-tissue barriers, most notably its likely physiological role in mediating or regulating the transport of therapeutic drugs across the blood-tissue barriers.
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Igarashi I, Makino T, Suzuki Y, Kai K, Teranishi M, Takasaki W, Furuhama K. Background lesions during a 24-month observation period in connexin 32-deficient mice. J Vet Med Sci 2013; 75:207-10. [PMID: 23001129 DOI: 10.1292/jvms.12-0280] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Connexin 32 (Cx32) is a major gap junction protein in the liver. Neoplastic and non-neoplastic lesions were examined in Cx32-deficient (Cx32KO) mice maintained for 24-month, and compared with those in wild-type mice as a corresponding control. In neoplastic lesions, hepatocellular carcinoma increased significantly only in male Cx32KO mice, suggesting that Cx32 deficiency may be related to their pathogenesis. For females, the incidence of pituitary adenoma in the pars distalis of Cx32KO mice was lower than that of wild-type mice. No non-neoplastic lesions related to Cx32-deficiency were observed in the Cx32KO mice. In conclusion, these results demonstrate that the incidence of hepatocellular carcinoma increases only in male Cx32KO mice, presumably due to enhanced tumor promotion and progression signals associated with Cx32 deficiency.
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Affiliation(s)
- Isao Igarashi
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Fukuroi, Shizuoka, Japan.
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Jee H, Lee SH, Park JW, Lee BR, Nam KT, Kim DY. Connexin32 inhibits gastric carcinogenesis through cell cycle arrest and altered expression of p21Cip1 and p27Kip1. BMB Rep 2013; 46:25-30. [PMID: 23351380 PMCID: PMC4133826 DOI: 10.5483/bmbrep.2013.46.1.078] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2012] [Revised: 06/04/2012] [Accepted: 08/10/2012] [Indexed: 01/22/2023] Open
Abstract
Gap junctions and their structural proteins, connexins (Cxs), have been implicated in carcinogenesis. To explore the involvement of Cx32 in gastric carcinogenesis, immunochemical analysis of Cx32 and proliferation marker Ki67 using tissue-microarrayed human gastric cancer and normal tissues was performed. In addition, after Cx32 overexpression in the human gastric cancer cell line AGS, cell proliferation, cell cycle analyses, and p21(Cip1) and p27(Kip1) expression levels were examined by bromodeoxyuridine assay, flow cytometry, real-time RT-PCR, and western blotting. Immunohistochemical study noted a strong inverse correlation between Cx32 and Ki67 expression pattern as well as their location. In vitro, overexpression of Cx32 in AGS cells inhibited cell proliferation significantly. G1 arrest, up-regulation of cell cycle-regulatory proteins p21(Cip1) and p27(Kip1) was also found at both mRNA and protein levels. Taken together, Cx32 plays some roles in gastric cancer development by inhibiting gastric cancer cell proliferation through cell cycle arrest and cell cycle regulatory proteins.
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Affiliation(s)
- Hyang Jee
- Department of Veterinary Pathology and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea
| | - Su-Hyung Lee
- Department of Veterinary Pathology and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea
| | - Jun-Won Park
- Department of Veterinary Pathology and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea
| | - Bo-Ram Lee
- Department of Veterinary Pathology and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea
| | - Ki-Taek Nam
- Nashville Department of Veterans Affairs Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232-2733, USA
| | - Dae-Yong Kim
- Department of Veterinary Pathology and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea
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Lobikin M, Chernet B, Lobo D, Levin M. Resting potential, oncogene-induced tumorigenesis, and metastasis: the bioelectric basis of cancer in vivo. Phys Biol 2012. [PMID: 23196890 DOI: 10.1088/1478-3975/9/6/065002] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cancer may result from localized failure of instructive cues that normally orchestrate cell behaviors toward the patterning needs of the organism. Steady-state gradients of transmembrane voltage (V(mem)) in non-neural cells are instructive, epigenetic signals that regulate pattern formation during embryogenesis and morphostatic repair. Here, we review molecular data on the role of bioelectric cues in cancer and present new findings in the Xenopus laevis model on how the microenvironment's biophysical properties contribute to cancer in vivo. First, we investigated the melanoma-like phenotype arising from serotonergic signaling by 'instructor' cells-a cell population that is able to induce a metastatic phenotype in normal melanocytes. We show that when these instructor cells are depolarized, blood vessel patterning is disrupted in addition to the metastatic phenotype induced in melanocytes. Surprisingly, very few instructor cells need to be depolarized for the hyperpigmentation phenotype to occur; we present a model of antagonistic signaling by serotonin receptors that explains the unusual all-or-none nature of this effect. In addition to the body-wide depolarization-induced metastatic phenotype, we investigated the bioelectrical properties of tumor-like structures induced by canonical oncogenes and cancer-causing compounds. Exposure to carcinogen 4-nitroquinoline 1-oxide (4NQO) induces localized tumors, but has a broad (and variable) effect on the bioelectric properties of the whole body. Tumors induced by oncogenes show aberrantly high sodium content, representing a non-invasive diagnostic modality. Importantly, depolarized transmembrane potential is not only a marker of cancer but is functionally instructive: susceptibility to oncogene-induced tumorigenesis is significantly reduced by forced prior expression of hyperpolarizing ion channels. Importantly, the same effect can be achieved by pharmacological manipulation of endogenous chloride channels, suggesting a strategy for cancer suppression that does not require gene therapy. Together, these data extend our understanding of the recently demonstrated role of transmembrane potential in tumor formation and metastatic cell behavior. V(mem) is an important non-genetic biophysical aspect of the microenvironment that regulates the balance between normally patterned growth and carcinogenesis.
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Affiliation(s)
- Maria Lobikin
- Biology Department and Tufts Center for Regenerative and Developmental Biology, Tufts University, 200 Boston Avenue, Medford, MA 02155, USA
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Inhibition of Connexin 26/43 and Extracellular-Regulated Kinase Protein Plays a Critical Role in Melatonin Facilitated Gap Junctional Intercellular Communication in Hydrogen Peroxide-Treated HaCaT Keratinocyte Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 2012:589365. [PMID: 23243457 PMCID: PMC3518788 DOI: 10.1155/2012/589365] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/26/2012] [Accepted: 09/26/2012] [Indexed: 01/19/2023]
Abstract
Though melatonin was known to regulate gap junctional intercellular communication (GJIC) in chick astrocytes and mouse hepatocytes, the underlying mechanism by melatonin was not elucidated in hydrogen peroxide- (H2O2-) treated HaCaT keratinocyte cells until now. In the current study, though melatonin at 2 mM and hydrogen peroxide (H2O2) at 300 μM showed weak cytotoxicity in HaCaT keratinocyte cells, melatonin significantly suppressed the formation of reactive oxygen species (ROS) in H2O2-treated HaCaT cells compared to untreated controls. Also, the scrape-loading dye-transfer assay revealed that melatonin enhances the intercellular communication by introducing Lucifer Yellow into H2O2-treated cells. Furthermore, melatonin significantly enhanced the expression of connexin 26 (Cx26) and connexin 43 (Cx43) at mRNA and protein levels, but not that of connexin 30 (Cx30) in H2O2-treated HaCaT cells. Of note, melatonin attenuated the phosphorylation of extracellular signal-regulated protein kinases (ERKs) more than p38 MAPK or JNK in H2O2-treated HaCaT cells. Conversely, ERK inhibitor PD98059 promoted the intercellular communication in H2O2-treated HaCaT cells. Furthermore, combined treatment of melatonin (200 μM) and vitamin C (10 μg/mL) significantly reduced ROS production in H2O2-treated HaCaT cells. Overall, these findings support the scientific evidences that melatonin facilitates gap junctional intercellular communication in H2O2-treated HaCaT keratinocyte cells via inhibition of connexin 26/43 and ERK as a potent chemopreventive agent.
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Vinken M, de Kock J, Oliveira AG, Menezes GB, Cogliati B, Dagli MLZ, Vanhaecke T, Rogiers V. Modifications in Connexin Expression in Liver Development and Cancer. ACTA ACUST UNITED AC 2012; 19:55-62. [DOI: 10.3109/15419061.2012.712576] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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49
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Changes in connexin43 expression and localization during pancreatic cancer progression. J Membr Biol 2012; 245:255-62. [PMID: 22729649 DOI: 10.1007/s00232-012-9446-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2012] [Accepted: 06/01/2012] [Indexed: 12/11/2022]
Abstract
Gap junctions and gap junction communication have long been recognized to play roles in tissue organization and remodeling through both cell autonomous and intercellular means. We hypothesized that these processes become dysregulated during pancreas cancer progression. Molecular and histological characterization of the gap junction protein, connexin43, during progression of pancreatic ductal adenocarcinoma could yield insight into how these events may contribute to or be modulated during carcinogenesis. In a mouse model of pancreatic ductal adenocarcinoma generated through targeted endogenous expression of Kras(G12D) in the murine pancreas, we examined the evolving expression and localization of connexin43. Overall, connexin43 expression increased over time, and its localization became more widespread. At early stages, connexin43 is found almost exclusively in association with the basolateral membrane of duct cells found in invasive lesions. Connexin43 became increasingly associated with the surrounding stroma over time. Connexin43 phosphorylation was also altered during tumorigenesis, as assessed by migrational changes of the protein in immunoblots. These data suggest a potential role for gap junctions and connexin43 in mediating interactions between and amongst the stromal and epithelial cells in pancreatic ductal adenocarcinoma.
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Levin M. Morphogenetic fields in embryogenesis, regeneration, and cancer: non-local control of complex patterning. Biosystems 2012; 109:243-61. [PMID: 22542702 DOI: 10.1016/j.biosystems.2012.04.005] [Citation(s) in RCA: 152] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2012] [Revised: 04/12/2012] [Accepted: 04/12/2012] [Indexed: 12/22/2022]
Abstract
Establishment of shape during embryonic development, and the maintenance of shape against injury or tumorigenesis, requires constant coordination of cell behaviors toward the patterning needs of the host organism. Molecular cell biology and genetics have made great strides in understanding the mechanisms that regulate cell function. However, generalized rational control of shape is still largely beyond our current capabilities. Significant instructive signals function at long range to provide positional information and other cues to regulate organism-wide systems properties like anatomical polarity and size control. Is complex morphogenesis best understood as the emergent property of local cell interactions, or as the outcome of a computational process that is guided by a physically encoded map or template of the final goal state? Here I review recent data and molecular mechanisms relevant to morphogenetic fields: large-scale systems of physical properties that have been proposed to store patterning information during embryogenesis, regenerative repair, and cancer suppression that ultimately controls anatomy. Placing special emphasis on the role of endogenous bioelectric signals as an important component of the morphogenetic field, I speculate on novel approaches for the computational modeling and control of these fields with applications to synthetic biology, regenerative medicine, and evolutionary developmental biology.
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Affiliation(s)
- Michael Levin
- Department of Biology, and Center for Regenerative and Developmental Biology, Tufts University, 200 Boston Ave., Medford, MA 02155, USA.
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