Cooperation between NRF2-mediated transcription and MDIG-dependent epigenetic modifications in arsenic-induced carcinogenesis and cancer stem cells

Environmental exposure to arsenic, a well-established carcinogen linked to a number of human cancers, is a public health concern in many areas of the world. Despite extensive studies on the molecular mechanisms of arsenic-induced carcinogenesis, how initial cellular responses, such as activation of stress kinases and the generation of reactive oxygen species, converge to affect the transcriptional and/or epigenetic reprogramming required for the malignant transformation of normal cells or normal stem cells remains to be elucidated. In this review, we discuss some recent discoveries showing how the transcription factor NRF2 and an epigenetic regulator, MDIG, contribute to the arsenic-induced generation of cancer stem-like cells (CSCs) as determined by applying CRISPR-Cas9 gene editing and chromosome immunoprecipitation followed by DNA sequencing (ChIP-seq)

The Effect Of Acute And Chronic Arsenic Exposure On Malignant Transformation Of The Human Bronchial Epithelial Cell (beas-2b)

Arsenic (As3+), a metalloid abundant in the environment, is classified as a group I carcinogen associated with several common human cancers, including cancers in the lung, skin, bladder, liver, and prostate (Wei, Zhang & Tao, 2019b). The mechanisms of As3+-induced carcinogenesis had been extensively studied, and different mechanisms might be involved in various types of cancer (Wei, Zhang & Tao, 2019b). Recent studies showed that exposure to a high dose of arsenic is able to induce lung cancer. Moreover, arsenic activates oncogenic signaling pathways such as MAPKs, EGFR/RAS/RAF, PI3K/AKT, and JNK/STAT3 pathways as well as epigenetic alterations such as miRNAs expression to regulate the carcinogenesis. Meanwhile, prolonged exposure to a low concentration of arsenic can increase the risk of lung cancer also (Fernández, López, Vivaldi & Coz, 2012; Liao et al., 2009). Emerging evidence indicated that prolonged exposure to arsenic promotes malignant transformation and induces normal cells to have cancer-stem-like properties (Ngalame, Tokar, Person & Waalkes, 2014). In the present report, we revealed that exposure to As3+ for a short time period inhibited tyrosine-705 phosphorylation of signal transducer and activator of transcription 3 (pSTAT3Y705) and induced Src homology region 2 domain-containing phosphatase-1 (SHP-1). In addition, we found that long-term exposure of the cells to As3+ activates phosphorylation of STAT3 at serine 727 (pSTAT3S727) as well as pSTAT3Y705. Moreover, As3+ is able to induce the expression of miRNA-21 (miR-21) and decrease the expression of PDCD4. Taken together, our data suggest that activation of STAT3 and induction of miR-21 are responsible for the reduced expression of PDCD4, which may play a significant role in the As3+-induced transformation of BEAS-2B cells

New Discoveries and Ambiguities of Nrf2 and ATF3 Signaling in Environmental Arsenic-Induced Carcinogenesis

Environment exposure to arsenic had been linked to increased incidents of human cancers. In cellular and animal experimental systems, arsenic has been shown to be highly capable of activating several signaling pathways that play critical roles in cell growth regulation, malignant transformation and the stemness of cancer stem-like cells. Emerging evidence indicates certain oncogenic properties of the Nrf2 transcription factor that can be activated by arsenic and many other environmental hazards. In human bronchial epithelial cells, our most recent data suggested that arsenic-activated Nrf2 signaling fosters metabolic reprogramming of the cells through shifting mitochondrial TCA cycle to cytosolic glycolysis, and some of the metabolites in glycolysis shunt the hexosamine biosynthesis and serine-glycine pathways important for the energy metabolism of the cancer cells. In the current report, we further demonstrated direct regulation of oncogenic signals by arsenic-activated Nrf2 and connection of Nrf2 with ATF3 stress transcription factor. Meanwhile, we also highlighted some unanswered questions on the molecular characteristics of the Nrf2 protein, which warrants further collaborative efforts among scientists for understanding the important role of Nrf2 in human cancers either associated or not to environmental arsenic exposure

Arsenic Activates the ER Stress-Associated Unfolded Protein Response via the Activating Transcription Factor 6 in Human Bronchial Epithelial Cells

Arsenic is a well-known human carcinogen associated with a number of cancers, including lung cancers. We have previously shown that long-term exposure to an environmentally relevant concentration of inorganic arsenic (As3+) leads to the malignant transformation of the BEAS2B cells, and some of the transformed cells show cancer stem-like features (CSCs) with a significant upregulation of glycolysis and downregulation of mitochondrial oxidative phosphorylation. In the present report, we investigate the short-term effect of As3+ on the endoplasmic reticulum (ER) stress response—the “unfolded protein response (UPR)” and metabolism in human bronchial epithelial cell line BEAS-2B cells. Treatment of the cells with inorganic As3+ upregulated both glycolysis and mitochondrial respiration. Analysis of ER UPR signaling pathway using a real-time human UPR array revealed that As3+ induced a significant up-regulation of some UPR genes, including ATF6, CEBPB, MAPK10, Hsp70, and UBE2G2. Additional tests confirmed that the induction of ATF6, ATF6B and UBE2G2 mRNAs and/or proteins by As3+ is dose dependent. Chromosome immunoprecipitation and global sequencing indicated a critical role of Nrf2 in mediating As3+-induced expression of these UPR genes. In summary, our data suggest that As3+ is able to regulate the ER stress response, possibly through activating the ATF6 signaling

Exploring interprofessional communication and collaboration among pharmacists, nurses, and laboratories enhancing patient safety and healthcare outcomes

Background: The efficiency of healthcare delivery is closely connected to the quality of interprofessional communication and cooperation among healthcare workers. The purpose of this research is to examine the diverse effects of interprofessional cooperation including pharmacists, nurses, and laboratory experts on patient safety and healthcare outcomes. Aim: This extensive study aims to consolidate current literature, empirical data, and theoretical models to provide a clear comprehension of the importance of efficient interprofessional communication and cooperation in healthcare environments. The objective of the evaluation is to assess the influence of cohesive teamwork, communication, and cooperation among healthcare professionals on several aspects of healthcare, including patient safety, medication management, care coordination, diagnostic accuracy, and overall healthcare quality. Method: A methodical search technique was used to locate relevant studies in electronic databases, such as PubMed, MEDLINE, and Cochrane Library. The inclusion criteria include research that provide insights into the influence of interprofessional cooperation on patient safety, healthcare outcomes, and the involvement of pharmacists, nurses, and laboratory experts in improving healthcare delivery. Results: The analysis emphasizes the crucial significance of pharmacists, nurses, and laboratory experts in improving patient safety and healthcare results by means of efficient interprofessional communication and cooperation.