Colorectal cancer (CRC) has been the third most common malignancy and the second cause of cancer-related mortality. As the core of volume-sensitive chloride currents, leucine-rich repeat-containing 8A (LRRC8A) contributes to tumor progression but is not consistent, especially for whom the roles in colon carcinoma metastasis were not fully elucidated. Herein, LRRC8A proteins were found highly expressed in hematogenous metastasis from human colorectal cancer samples. The oxaliplatin-resistant HCT116 cells highly expressed LRRC8A, which was related to impaired proliferation and enhanced migration. The over-expressed LRRC8A slowed proliferation and increased migration ex vivo and in vivo. The elevated LRRC8A upregulated the focal adhesion, MAPK, AMPK, and chemokine signaling pathways via phosphorylation and dephosphorylation. Inhibition of LRRC8A impeded the TNF-α signaling cascade and TNF-α-induced migration. LRRC8A binding to PIP5K1B regulated the PIP2 formation, providing a platform for LRRC8A to mediate cell signaling transduction. Importantly, LRRC8A self-regulated its transcription via NF-κB1 and NF-κB2 pathways and the upregulation of NIK/NF-κB2/LRRC8A transcriptional axis was unfavorable for colon cancer patients. Collectively, our findings reveal that LRRC8A is a central mediator in mediating multiple signaling pathways to promote metastasis and targeting LRRC8A proteins could become a potential clinical biomarker-driven treatment strategy for colon cancer patients. 

LRRC8A as a central mediator promotes colon cancer metastasis by regulating PIP5K1B/PIP2 pathway.

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.

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

Obesity 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.The 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.We 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.Modulation of Clcn3 may provide an appealing therapeutic target for obesity and associated metabolic syndrome.

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

Exosomes are vital mediators for intercellular communications in the tumor microenvironment to accelerate colon cancer progression. Leucine-rich repeat-containing 8A (LRRC8A), the core component of the volume-regulated anion channel, is closely associated with acquiring heterogeneity for tumor cells. However, the role of LRRC8A in the exosomes remains largely unknown. Here, we reported that LRRC8A was one of the compositions in the exosomes released from colon cancer HCT116 cells. Downregulation of LRRC8A proteins inhibited ex vivo cell growth and induced apoptosis. Consistently, chloride channel blockers DCPIB and NPPB inhibited cell growth and induced cell apoptosis in a time or concentration-dependent manner. Interestingly, the total amounts and proportions of different diameter exosomes released in 6 hours were not altered by the treatment of DCPIB and NPPB in HCT116 cells. In contrast to the downregulation or inhibition of LRRC8A, overexpression of LRRC8A proteins in HCT116 cells released significantly more distinct populations of exosomes. Importantly, the switches of ratios for exosomes in a hypotonic challenge were eliminated by DCPIB treatment. Collectively, our results uncovered that LRRC8A proteins were responsible for the exosome generation and sorted into exosomes for monitoring the volume regulation.

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

Objective: To investigate the effect of auricular acupuncture on postoperative pain and gastrointestinal motility recovery after laparoscopic surgery for colorectal cancer. Methods: The clinical data of patients who underwent laparoscopic radical surgery for colorectal cancer in our hospital from April 2020 to December 2021 were collected. Based on the inclusion and exclusion criteria, 76 patients were included in the retrospective analysis. Depending on whether they received auricular acupuncture or not, the patients were divided into two groups: 46 patients in the experimental group (auricular acupuncture) and 30 patients in the control group. The differences between the two groups were analyzed. Results: The time to first flatus of the experimental group was significantly shorter than that of the control group (52.2 ± 7.36 h versus 66.3 ± 7.83 h; P < 0.001). Similarly, the time to first defecation of the experimental group was significantly shorter than that of the control group (76.3 ± 7.76 h versus 86.1 ± 10.79 h; P < 0.001). The time to first fluid intake of the auricular group was significantly shorter than that of the control group (90.4 ± 8.92 h versus 107.3 ± 9.66 h, P < 0.001). Compared with the control group, the experimental group scored significantly lower on the visual analogue scale on postoperative days 2 and 3 (P < 0.001). Conclusion: Auricular acupuncture is an effective traditional Chinese medicine external treatment method. It can promote gastrointestinal motility recovery in patients after laparoscopic radical surgery for colorectal cancer and also reduce postoperative pain and discomfort. Furthermore, this therapy is easy to operate and well-accepted by patients. Therefore, it should be strongly promoted in clinical practice.

/pdf/retrospective-analysis-of-the-effect-of-auricular-1uja1x3y.pdf

Retrospective Analysis of the Effect of Auricular Acupuncture on Pain and Gastrointestinal Motility Recovery After Laparoscopic Surgery for Colorectal Cancer

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

Retrospective Analysis of the Effect of Auricular Acupuncture on Pain and Gastrointestinal Motility Recovery After Laparoscopic Surgery for Colorectal Cancer