LRRC8A Is a Promising Prognostic Biomarker and Therapeutic Target for Pancreatic Adenocarcinoma

Xu, Rong; Hu, Yaohua; Xie, Qinghua; Zhang, Caiqin; Zhao, Yong; Zhang, He; Shi, Hailong; Wang, Xiaoming; Shi, Changhong

doi:10.3390/cancers14225526

Cited by 5 publications

(6 citation statements)

References 36 publications

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“…In PAAD, LRRC8A is associated with cell proliferation, migration, drug resistance, and immune infiltration [ 9 ]. Moreover, investigation of the LRRC8A gene’s co-expression and its network in PAAD patients has revealed prominent enrichment of genes situated close to LRRC8A in the PI3K-AKT and focal adhesion pathways [ 9 ]. On the contrary, detailed functions and interactions of VRAC in colon cancer are not yet clear and subjected of discussion.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, in recent years, there has been a growing interest in anion channels, i.e., chloride (Cl) channels. These channels play a vital role in various cellular processes and their abnormal expression and/or function is associated with various human diseases, such as cystic fibrosis, myotonia, epilepsy, hyperekplexia, lysosomal storage diseases, deafness, renal salt wasting, kidney stones, osteopetrosis and numerous tumour development of numerous types of tumours [ 7 – 9 ].…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Introductionmentioning

confidence: 99%

Interactomic exploration of LRRC8A in volume-regulated anion channels

Carpanese,

Festa,

Prosdocimi

et al. 2024

Cell Death Discov.

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“…VRAC has been suggested to be one of these ion channels. Indeed, while pharmacological or molecular biological inhibition of VRAC did not detectably impair migration of various cell types in a study using a wound-healing assay ( Liu and Stauber, 2019 ), other studies reported VRAC influenced the motility of a wide range of cancer cells such as colorectal cancer ( Fujii et al, 2018 ), glioblastoma ( Rubino et al, 2018 ; Wong et al, 2018 ), human colon cancer ( Zhang et al, 2018 ), hepatocellular carcinoma ( Lu et al, 2019 ), pancreatic adenocarcinoma ( Xu et al, 2022 ) and breast cancer ( Zhang et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, when either LRRC8A or LRRC8D is knocked out, cancer cells exhibit a higher tolerance towards these platinum-based medications ( Planells-Cases et al, 2015 ). LRRC8 genes have been implicated in drug resistance and prognosis in various cancer types ( Sørensen et al, 2016 ; Xu et al, 2020 ; Siemer et al, 2021 ; Widmer et al, 2022 ; Xu et al, 2022 ).…”

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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“…Leucine-rich repeat protein A (LRRC8A), also known as SWELL1, is a core component of anionic channels (VRAC) [50]. LRRC8A is closely associated with the occurrence of multiple tumors [51][52][53].…”

Section: Discussionmentioning

confidence: 99%

HERVK-mediated regulation of neighboring genes: implications for breast cancer prognosis

Liang,

Yan,

Wei

et al. 2024

Retrovirology

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Human endogenous retroviruses (HERVs) are the remnants of ancient retroviral infections integrated into the human genome. Although most HERVs are silenced or rendered inactive by various regulatory mechanisms, they retain the potential to influence the nearby genes. We analyzed the regulatory map of 91 HERV-Ks on neighboring genes in human breast cancer and investigated the impact of HERV-Ks on the tumor microenvironment (TME) and prognosis of breast cancer. Nine RNA-seq datasets were obtained from GEO and NCBI SRA. Differentially expressed genes and HERV-Ks were analyzed using DESeq2. Validation of high-risk prognostic candidate genes using TCGA data. These included Overall survival (multivariate Cox regression model), immune infiltration analysis (TIMER), tumor mutation burden (maftools), and drug sensitivity analysis (GSCA). A total of 88 candidate genes related to breast cancer prognosis were screened, of which CD48, SLAMF7, SLAMF1, IGLL1, IGHA1, and LRRC8A were key genes. Functionally, these six key genes were significantly enriched in some immune function-related pathways, which may be associated with poor prognosis for breast cancer (p = 0.00016), and the expression levels of these genes were significantly correlated with the sensitivity of breast cancer treatment-related drugs. Mechanistically, they may influence breast cancer development by modulating the infiltration of various immune cells into the TME. We further experimentally validated these genes to confirm the results obtained from bioinformatics analysis. This study represents the first report on the regulatory potential of HERV-K in the neighboring breast cancer genome. We identified three key HERV-Ks and five neighboring genes that hold promise as novel targets for future interventions and treatments for breast cancer.

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LRRC8A Is a Promising Prognostic Biomarker and Therapeutic Target for Pancreatic Adenocarcinoma

Cited by 5 publications

References 36 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

HERVK-mediated regulation of neighboring genes: implications for breast cancer prognosis

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