Connexins and Gap Junctions in Cancer of the Urinary Tract

Tschernig, Thomas

doi:10.3390/cancers11050704

Cited by 12 publications

(6 citation statements)

References 66 publications

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“…Multiparametric SL-DT assay is suitable for different cell types. To set up the multiparametric SL-DT assay, WB-F344 cell line was employed as one of the most widely used model for the in vitro assessment of GJIC 9,10 . Nevertheless, multiparametric microplate-based SL-DT assay is suitable also for other cell types, as demonstrated in this study.…”

mentioning

confidence: 99%

Improved multiparametric scrape loading-dye transfer assay for a simultaneous high-throughput analysis of gap junctional intercellular communication, cell density and viability

Dydowiczová

Brózman

Babica

et al. 2020

Sci Rep

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Gap junctional intercellular communication (GJic) is a vital cellular process required for maintenance of tissue homeostasis. In vitro assessment of GJic represents valuable phenotypic endpoint that could be effectively utilized as an integral component in modern toxicity testing, drug screening or biomedical in vitro research. However, currently available methods for quantifying GJic with higher-throughputs typically require specialized equipment, proprietary software and/or genetically engineered cell models. to overcome these limitations, we present here an innovative adaptation of traditional, fluorescence microscopy-based scrape loading-dye transfer (SL-DT) assay, which has been optimized to simultaneously evaluate GJic, cell density and viability. this multiparametric method was demonstrated to be suitable for various multiwell microplate formats, which facilitates an automatized image acquisition. The assay workflow is further assisted by an open source-based software tools for batch image processing, analysis and evaluation of GJic, cell density and viability. our results suggest that this approach provides a simple, fast, versatile and cost effective way for in vitro high-throughput assessment of GJic and other related phenotypic cellular events, which could be included into in vitro screening and assessment of pharmacologically and toxicologically relevant compounds. Gap junctional intercellular communication (GJIC) allows an exchange of low molecular weight molecules (<1.2 kDa) between adjacent cells in both vertebrates and invertebrates 1. GJIC is mediated through intercellular channels build from connexin proteins in vertebrates and from innexin proteins in invertebrates 1,2. GJIC plays a central role in coordinating cell-to-cell communication and integration of signal transduction pathways controlling gene expression and cell behaviour in order to receive coordinated and collective responses from the cells across a tissue of multicellular organism 3,4. Dysregulation of GJIC and GJIC-dependent signal integration, for example by drugs or environmental contaminants, can disrupt the normal homeostatic control of a cell behaviour and lead to numerous adverse outcomes such as cardiovascular 5 , pulmonary 6 or reproductive system 7,8 diseases and cancer 4,9,10. On the other hand, timed and targeted upregulation or downregulation of GJIC, connexin channel or hemichannel activity, induced by pharmacological agents, is currently widely discussed as potential therapeutic approach for treatment of various diseases 10-12. Accordingly, GJIC can be effectively utilized in the modern toxicological and pharmacological research, and GJIC analysis could be a valuable component of any biological study. However, in vitro assessment of GJIC has been used relatively less frequently in the modern research in comparison to other and more traditional phenotypic assays, such as evaluation of cellular metabolic activity, cell proliferation, cell cycle, autophagy, apoptosis, cell migration, cytoskeletal rearangements 13. This m...

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mentioning

confidence: 99%

Improved multiparametric scrape loading-dye transfer assay for a simultaneous high-throughput analysis of gap junctional intercellular communication, cell density and viability

Dydowiczová

Brózman

Babica

et al. 2020

Sci Rep

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“…Besides, Bacillus Calmette-Guerin (BCG) was considered as an agonist of TLR2 and TLR4 and has been widely used in intravesical BCa therapy [41]. Connexins is of great importance for gap junctional intercellular communication and might facilitate the occurrence and metastases of cancer [42]. Ai et al [43] revealed that GAP junction protein CX43 could be a promising therapeutic target for BCa.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitination-Related Molecular Subtypes and a Novel Prognostic Index for Bladder Cancer Patients

Cai¹,

Chen²,

Huang³

et al. 2021

Pathol. Oncol. Res.

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Objective: To develop and validate ubiquitination-related molecular subtypes and a novel prognostic index using ubiquitination-related genes (URGs) for patients with bladder cancer (BCa).Materials and Methods: We downloaded the clinical data and transcriptome data of BCa from TCGA and GEO database. Consensus clustering analysis was conducted to identify ubiquitination-related molecular subtypes for BCa. Besides, we performed univariate and multivariate Cox regression analysis to develop a novel prognostic URGs-related index for BCa. We conducted internal and external verification in TCGA cohort and GEO cohort, respectively. Furthermore, the associations of ubiquitination-related molecular subtypes and prognostic index with tumor immune environment were also investigated.Results: A total of four ubiquitination-related molecular subtypes of BCa were finally identified. These four molecular subtypes had significantly different clinical characteristics, prognosis, PD-L1 expression level and tumor microenvironment. Besides, we developed a novel prognostic index using six URGs (including HLA-A, TMEM129, UBE2D1, UBE2N, UBE2T and USP5). The difference in OS between high and low-risk group was statistically significant in training cohort, testing cohort, and validating cohort. The area under ROC curve (AUC) for OS prediction was 0.736, 0.723, and 0.683 in training cohort, testing cohort, and validating cohort, respectively. Multivariate survival analysis showed that this index was an independent predictor for OS. This prognostic index was especially suitable for subtype 1 and 3, older, male, high grade, AJCC stage III-IV, stage N0, stage T3-4 BCa patients.Conclusions: This study identified a total of four ubiquitination-related molecular subtypes with significantly different tumor microenvironment, prognosis, clinical characteristics and PD-L1 expression level. Besides, a novel ubiquitination-related prognostic index for BCa patients was developed and successfully verified, which performed well in predicting prognosis of BCa.

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“…However, since the last decade, the scientific community’s understanding of Gj and connexins in cancer has grown considerably, and it is now accepted that Gj and connexins have multiple functions in cancer development, from primary tumor growth to metastatic progression [ 12 , 46 , 47 ]. There are many connexins (21 in humans), and they have differential roles in tumor initiation, progression or metastasis [ 12 , 46 , 47 , 48 , 49 , 50 , 51 ]; this review focuses on the role of connexin43 in cancer development.…”

Section: Brief Overview Of the Role Of Connexin43 In Solid Cancer mentioning

confidence: 99%

Antagonistic Functions of Connexin 43 during the Development of Primary or Secondary Bone Tumors

et al. 2020

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Despite research and clinical advances during recent decades, bone cancers remain a leading cause of death worldwide. There is a low survival rate for patients with primary bone tumors such as osteosarcoma and Ewing’s sarcoma or secondary bone tumors such as bone metastases from prostate carcinoma. Gap junctions are specialized plasma membrane structures consisting of transmembrane channels that directly link the cytoplasm of adjacent cells, thereby enabling the direct exchange of small signaling molecules between cells. Discoveries of human genetic disorders due to genetic mutations in gap junction proteins (connexins) and experimental data using connexin knockout mice have provided significant evidence that gap-junctional intercellular communication (Gj) is crucial for tissue function. Thus, the dysfunction of Gj may be responsible for the development of some diseases. Gj is thus a main mechanism for tumor cells to communicate with other tumor cells and their surrounding microenvironment to survive and proliferate. If it is well accepted that a low level of connexin expression favors cancer cell proliferation and therefore primary tumor development, more evidence is suggesting that a high level of connexin expression stimulates various cellular process such as intravasation, extravasation, or migration of metastatic cells. If so, connexin expression would facilitate secondary tumor dissemination. This paper discusses evidence that suggests that connexin 43 plays an antagonistic role in the development of primary bone tumors as a tumor suppressor and secondary bone tumors as a tumor promoter.

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Connexins and Gap Junctions in Cancer of the Urinary Tract

Cited by 12 publications

References 66 publications

Improved multiparametric scrape loading-dye transfer assay for a simultaneous high-throughput analysis of gap junctional intercellular communication, cell density and viability

Improved multiparametric scrape loading-dye transfer assay for a simultaneous high-throughput analysis of gap junctional intercellular communication, cell density and viability

Ubiquitination-Related Molecular Subtypes and a Novel Prognostic Index for Bladder Cancer Patients

Antagonistic Functions of Connexin 43 during the Development of Primary or Secondary Bone Tumors

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