LRRC8A is responsible for exosome biogenesis and volume regulation in colon cancer cells

Zhang, Haifeng; Cui, Shiyu; Jing, Zhenghui; Fu, Guodan; Liu, Rong; Zhao, Wenbao; Xu, Li‐Yan; Yu, Lei; Bai, Yuhui; Lv, Changsheng; Wu, Min; Wei, Yuan; Li, Liangming; Peng, Shuang

doi:10.1042/bcj20220614

Cited by 5 publications

(3 citation statements)

References 44 publications

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“…Recently, it has been revealed that LRRC8A is one of the components of the exosomes released from colon cancer HCT116 cells. Exosomes play a crucial role in intercellular communications within the microscopic tumor environment, facilitating the progression of colon cancer [ 62 ]. Additionally, compromised cellular junctions might enhance metastatic potential, leading to a more aggressive and invasive tumor phenotype.…”

Section: Discussionmentioning

confidence: 99%

Interactomic exploration of LRRC8A in volume-regulated anion channels

Carpanese,

Festa,

Prosdocimi

et al. 2024

Cell Death Discov.

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Ion channels are critical in enabling ion movement into and within cells and are important targets for pharmacological interventions in different human diseases. In addition to their ion transport abilities, ion channels interact with signalling and scaffolding proteins, which affects their function, cellular positioning, and links to intracellular signalling pathways. The study of “channelosomes” within cells has the potential to uncover their involvement in human diseases, although this field of research is still emerging. LRRC8A is the gene that encodes a crucial protein involved in the formation of volume-regulated anion channels (VRACs). Some studies suggest that LRRC8A could be a valuable prognostic tool in different types of cancer, serving as a biomarker for predicting patients’ outcomes. LRRC8A expression levels might be linked to tumour progression, metastasis, and treatment response, although its implications in different cancer types can be varied. Here, publicly accessible databases of cancer patients were systematically analysed to determine if a correlation between VRAC channel expression and survival rate exists across distinct cancer types. Moreover, we re-evaluated the impact of LRRC8A on cellular proliferation and migration in colon cancer via HCT116 LRRC8A-KO cells, which is a current topic of debate in the literature. In addition, to investigate the role of LRRC8A in cellular signalling, we conducted biotin proximity-dependent identification (BioID) analysis, revealing a correlation between VRAC channels and cell-cell junctions, mechanisms that govern cellular calcium homeostasis, kinases, and GTPase signalling. Overall, this dataset improves our understanding of LRRC8A/VRAC and explores new research avenues while identifying promising therapeutic targets and promoting inventive methods for disease treatment.

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Section: Discussionmentioning

confidence: 99%

Interactomic exploration of LRRC8A in volume-regulated anion channels

Carpanese,

Festa,

Prosdocimi

et al. 2024

Cell Death Discov.

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“…Among them, VRAC has been suggested to play a role in regulating cell growth, movement and apoptosis of tumor cells ( Fraser and Pardo, 2008 ; Arcangeli and Becchetti, 2015 ; Sirianant et al, 2016 ; Prevarskaya et al, 2018 ). Downregulation of LRRC8A subunit has been reported to suppress the growth or proliferation of different cancer cell types, including human glioblastoma cells ( Rubino et al, 2018 ), colorectal carcinoma cells ( Fujii et al, 2018 ), esophageal squamous cell carcinoma cells ( Konishi et al, 2019 ), gastric cancer ( Kurashima et al, 2021 ), colon cancer ( Zhang et al, 2018 ; Zhang et al, 2023 ) and cervical cancer ( Chen et al, 2023 ), while LRRC8A overexpression reportedly facilitated hepatocellular carcinoma cell growth ( Lu et al, 2019 ). In vivo studies in nude mouse models have also shown that LRRC8A downregulation suppressed the proliferation of colon carcinoma, hepatocellular carcinoma, and cervical cancer ( Zhang et al, 2018 ; Lu et al, 2019 ; Chen et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Trends in volume-regulated anion channel (VRAC) research: visualization and bibliometric analysis from 2014 to 2022

et al. 2023

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Objective: In this study, we utilized bibliometric methods to assess the worldwide scientific output and identify hotspots related to the research on the volume-regulated anion channel (VRAC) from 2014 to 2022.Methods: From Web of Science, we obtained studies related to VRAC published from 2014 to 2022. To analyzed the data, we utilized VOSviewer, a tool for visualizing network, to create networks based on the collaboration between countries, institutions, and authors. Additionally, we performed an analysis of journal co-citation, document citation, and co-occurrence of keywords. Furthermore, we employed CiteSpace (6.1. R6 Advanced) to analyzed keywords and co-cited references with the strongest burst.Results: The final analysis included a total of 278 related articles and reviews, covering the period from 2014 to 2022. The United States emerged as the leading country contributing to this field, while the University of Copenhagen stood out as the most prominent institution. The author with most publications and most citations was Thomas J. Jentsch. Among the cited references, the article by Voss et al. published in Science (2014) gained significant attention for its identification of LRRC8 heteromers as a crucial component of the volume-regulated anion channel VRAC. Pflügers Archiv European Journal of Physiology and Journal of Physiology-London were the leading journals in terms of the quantity of associated articles and citations. Through the analysis of keyword co-occurrence, it was discovered that VRAC is involved in various physiological processes including cell growth, migration, apoptosis, swelling, and myogenesis, as well as anion and organic osmolyte transport including chloride, taurine, glutamate and ATP. VRAC is also associated with related ion channels such as TMEM16A, TMEM16F, pannexin, and CFTR, and associated with various diseases including epilepsy, leukodystrophy, atherosclerosis, hypertension, cerebral edema, stroke, and different types of cancer including gastric cancer, glioblastoma and hepatocellular carcinoma. Furthermore, VRAC is involved in anti-tumor drug resistance by regulating the uptake of platinum-based drugs and temozolomide. Additionally, VRAC has been studied in the context of pharmacology involving DCPIB and flavonoids.Conclusion: The aim of this bibliometric analysis is to provide an overall perspective for research on VRAC. VRAC has become a topic of increasing interest, and our analysis shows that it continues to be a prominent area. This study offers insights into the investigation of VRAC channel and may guide researchers in identifying new directions for future research.

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“…Chloride ions are the most abundant anion and are involved in many different physiological and pathological processes. The molecular constituents of the volume-regulated anion channel (VRAC) are diverse, including LRRC8A-E, CFTR, ClCs, and more ( 3 ). The ClC-3 chloride channel, encoded by Clcn3 , is critical for several basic cellular functions, such as cell volume regulation, proliferation, apoptosis, differentiation, and β cell insulin secretion ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

Clcn3 deficiency ameliorates high-fat diet-induced obesity and improves metabolism in mice

Duan,

Li,

Cui

et al. 2024

Front. Nutr.

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ObjectiveObesity is defined as excess body fat and is a current health epidemic associated with increased risk for type 2 diabetes and cardiovascular disease. The ClC-3 chloride channel/antiporter, encoded by the Clcn3, is associated with some diseases, like carcinoma, nervous system diseases, and metabolic diseases. To verify the relationship between the Clcn3 and weight including metabolic changes, searching for a new target for metabolic therapy of obesity, we designed the experiment.MethodsThe mice were divided into 4 different groups: Clcn3+/+ mice + high-fat diet (HFD), Clcn3−/− mice + HFD, Clcn3+/+ mice + normal diet (ND), Clcn3−/− mice + ND, and fed for 16 weeks. After the glucose tolerance test and insulin tolerance test, peripheral blood and adipose tissues were collected. Moreover, we performed transcriptome sequencing for the epididymal white adipose tissue from Clcn3+/+ and Clcn3−/− mice with the high-fat diet. Western blotting verified the changes in protein levels of relevant metabolic genes.ResultsWe found that the Clcn3−/− mice had lower body weight and visceral fat, refining glucose and lipid metabolism in HFD-induced mice, but had no effect in normal diet mice. RNA-seq and Western blotting indicated that Clcn3 deficiency may inhibit obesity through the AMPK-UCP1 axis.ConclusionModulation of Clcn3 may provide an appealing therapeutic target for obesity and associated metabolic syndrome.

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LRRC8A is responsible for exosome biogenesis and volume regulation in colon cancer cells

Cited by 5 publications

References 44 publications

Interactomic exploration of LRRC8A in volume-regulated anion channels

Interactomic exploration of LRRC8A in volume-regulated anion channels

Trends in volume-regulated anion channel (VRAC) research: visualization and bibliometric analysis from 2014 to 2022

Clcn3 deficiency ameliorates high-fat diet-induced obesity and improves metabolism in mice

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