Trivalent arsenic (As(III)) is recently found to be an immunomodulatory agent. As(III) has therapeutic potential in several autoimmune and inflammatory diseases in vivo. In vitro, it selectively induces apoptosis of immune cells due to different sensitivity. At a non-toxic level, As(III) shows its multifaceted nature by inducing either pro- or anti-inflammatory functions of immune subsets. These effects are exerted by either As(III)-protein interactions or as a consequence of As(III)-induced homeostasis imbalance. The immunomodulatory properties also show synergistic effects of As(III) with cancer immunotherapy. In this review, we summarize the immunomodulatory effects of As(III), focusing on the effects of As(III) on immune subsets in vitro, on mouse models of immune-related diseases, and the role of As(III) in cancer immunotherapy. Updates of the mechanisms of action, the pioneer clinical trials, dosing, and adverse events of therapeutic As(III) are also provided.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.15011

Old dog, new trick: Trivalent arsenic as an immunomodulatory drug.

Arsenic is a toxic metalloid, which also compromises immunity and causes various immunological disorders. Exposure to arsenic exerts the immunosuppressive properties of dendritic cells (DCs). Autophagy is a self-renewal process of cells, which degrades damaged macromolecules and organelles through the lysosomal pathway. Thus, herein, we attempt to clarify the impacts of autophagy and the autophagy-lysosome pathway on arsenic-exposed DCs. Bone marrow-derived dendritic cells (BMDCs) were exposed to different concentrations of arsenic (0.25, 0.5 and 1 μM) with or without LPS stimulation. Initially, we observed that arsenic induced autophagosome accumulation, significantly enhanced the LC3 II and p62 expressions and down-regulated the p-mTOR protein levels. We also determined that arsenic-induced autophagy occurred via an mTOR pathway. The results further revealed that arsenic inhibited autophagic flux in LPS-stimulated BMDCs using the autophagy inhibitor chloroquine (CQ). Meanwhile, arsenic significantly decreased the number of lysosomes, protein expression of lysosomal-specific markers LAMP1 and LAMP2, and the protein levels of lysosomal cysteine cathepsins (CTSD and CTSL). Moreover, the overexpression of transcription factor EB (TFEB), the master transcriptional regulator of autophagy and lysosome biogenesis, partially relieved arsenic-inhibited lysosomal CTSD and CTSL expressions, recovered the disorder of autophagic flux, promoted the production of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-12, and reduced anti-inflammatory cytokine IL-10 secretion. In summary, our results support the idea that arsenic induces autophagy through an mTOR-dependent pathway in cultured BMDCs. Meanwhile, arsenic weakens the process of autophagic flux, which may be partially due to lysosomal dysfunction. Furthermore, we also suggest that TFEB can positively act on the autophagy-lysosome pathway and influence the expression of immunocytokines in DCs.

Arsenic induces mTOR-dependent autophagy, whereas it impairs the autophagy-lysosome pathway and the potential role of TFEB in cultured dendritic cells.

Arsenic trioxide (As2O3) is a promising effective chemotherapeutic agent for cancer treatment; however, how and through what molecular mechanisms the oxidative damage of As2O3 is controlled remains poorly understood. Recently, the involvement of dysregulated long noncoding RNA ovarian tumor domain containing 6B antisense RNA1 (lncRNA OTUD6B-AS1) in tumorigenesis is established. Here, for the first time, we characterize the regulation of As2O3 in the oxidative damage against bladder cancer via lncRNA OTUD6B-AS1. As2O3 could activate lncRNA OTUD6B-AS1 transcription in bladder cancer cells, and these findings were validated in a xenograft tumor model. Functional assays showed that lncRNA OTUD6B-AS1 dramatically exacerbated As2O3-mediated oxidative damage by inducing oxidative stress. Mechanistically, As2O3 increased levels of metal-regulatory transcription factor 1 (MTF1), which regulates lncRNA OTUD6B-AS1, in response to oxidative stress. Further, lncRNA OTUD6B-AS1 inhibited mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2) expression by stabilizing miR-6734-5p, which contributed to cytotoxicity by enhancing oxidative stress. Together, our findings offer new insights into the mechanism of As2O3-induced oxidative damage and identify important factors in the pathway, As2O3/lncRNA OTUD6B-AS1/miR-6734-5p/IDH2, expanding the knowledge of activity of As2O3 as cancer treatment.

/pdf/lncrna-otud6b-as1-exacerbates-as2o3-induced-oxidative-damage-4n3vtd4lh4.pdf

lncRNA OTUD6B-AS1 Exacerbates As2O3-Induced Oxidative Damage in Bladder Cancer via miR-6734-5p-Mediated Functional Inhibition of IDH2.

Arsenic is an environmental contaminant, its multiple effects on human tend to increase the rate of disease, cancer and other health problems. Some of long non-coding RNAs (lncRNAs) can be induced in major cellular processes such as necrosis, proliferation, and mutation. While the toxicity of arsenic is well established, the association between arsenic exposure and long non-coding RNAs has not been studied enough. This study investigated the association between arsenic and the expression of HOTAIR and LincRNA-p21 in vivo and vitro. In epidemiological studies, the expression of HOTAIR and LincRNA-p21 was increased after long-term arsenic exposure. HOTAIR and LincRNA-p21 expression were positively linked to monomethylarsenic acid (MMA), dimethylarsenic acid (DMA), inorganic arsenic (iAs), total arsenic (tAs), and MMA% and negatively linked to secondary methylation index (SMI). In A549 cells, arsenic exposure resulted in enhanced HOTAIR and LincRNA-p21 expression dose-dependently. The expression of HOTAIR was considerably high in the presence of NaAsO2 and MMA but showed no difference in DMA compared with control group. And LincRNA-p21 expression was increased in the presence of NaAsO2, MMA, and DMA. The expression of HOTAIR and LincRNA-p21 induced by iAs was much higher than that induced by MMA and DMA. Compared with the control group, treatment of A549 cells with NaAsO2/S-adenosylmethionine (SAM) and NaAsO2/glutathione (GSH) combination increased HOTAIR and LincRNA-p21 expression. The expression of LincRNA-p21 in combination of NaAsO2/GSH was significantly decreased compared with NaAsO2 alone. Besides, in the presence of arsenic, both of HOTAIR and LincRNA-p21 were upregulated significantly when P53 was knocked down. We revealed that inorganic arsenic, its methylated metabolites, and arsenic metabolism efficiency affect the expression of HOTAIR and LincRNA-p21.

Arsenic exposure increased expression of HOTAIR and LincRNA-p21 in vivo and vitro

Simple Summary Long noncoding RNAs (lncRNAs) were proposed as novel tumor prognostic markers, including for predicting bladder cancer progression, and the competing endogenous RNA (ceRNA) hypothesis conceived an accessible entry point to discover potential lncRNA candidates. This study indicated that LINC02470 promotes bladder cancer cell viability, migration, invasion, and in vivo tumorigenicity by sponging miR-143-3p and consequently rescuing SMAD3 translation to activate the TGF-β-induced EMT process. These data demonstrate that the LINC02470–miR-143-3p–SMAD3 ceRNA axis directly regulates the major transcription factor of TGF-β signaling, SMAD3, thereby inducing the EMT process in bladder cancer and enhancing the aggressiveness of bladder cancer cells. Abstract Bladder cancer progression and metastasis have become major threats in clinical practice, increasing mortality and therapeutic refractoriness; recently, epigenetic dysregulation of epithelial-to-mesenchymal transition (EMT)-related signaling pathways has been explored. However, research in the fields of long noncoding RNA (lncRNA) and competing endogenous RNA (ceRNA) regulation in bladder cancer progression is just beginning. This study was designed to determine potential EMT-related ceRNA regulation in bladder cancer progression and elucidate the underlying mechanisms that provoke aggressiveness. After screening the intersection of bioinformatic pipelines, LINC02470 was identified as the most upregulated lncRNA during bladder cancer initiation and progression. Both in vitro and in vivo biological effects indicated that LINC02470 promotes bladder cancer cell viability, migration, invasion, and tumorigenicity. On a molecular level, miR-143-3p directly targets and reduces both LINC02470 and SMAD3 RNA expression. Therefore, the LINC02470–miR-143-3p–SMAD3 ceRNA axis rescues SMAD3 translation upon LINC02470 sponging miR-143-3p, and SMAD3 consequently activates the TGF-β-induced EMT process. In conclusion, this is the first study to demonstrate that LINC02470 plays a pivotally regulatory role in the promotion of TGF-β-induced EMT through the miR-143-3p/SMAD3 axis, thereby aggravating bladder cancer progression. Our study warrants further investigation of LINC02470 as an indicatively prognostic marker of bladder cancer.

/pdf/long-noncoding-rna-linc02470-sponges-microrna-143-3p-and-1bvz34d9.pdf

Long Noncoding RNA LINC02470 Sponges MicroRNA-143-3p and Enhances SMAD3-Mediated Epithelial-to-Mesenchymal Transition to Promote the Aggressive Properties of Bladder Cancer

Bladder cancer has easy recurrence characteristics, but its occurrence and development mechanism are still unclear. Non-coding RNA is a kind of RNA that exists widely and cannot be translated into proteins, which has played a key role in the regulation of biological functions of tumor cells. However, the regulation mechanism of non-coding RNA on bladder tumors is not fully understood. By microarray analysis and database analysis, we found that LINC00511 was significantly highly expressed in bladder cancer. The expressions of LINC00511, miR-143-3p, and PCMT in bladder cancer tissues and cells were detected by quantitative reverse transcription-polymerase chain reaction. The relationship between the expressions of miR-143-3p and PCMT1 and the clinicopathological parameters of the tumor was analyzed. The proliferation and invasion of bladder cancer cells were detected by MTT assay and Transwell assay. The expression levels of E-cadherin and vimentin in bladder cancer cells were detected by Western blot. Cell apoptosis was detected by flow cytometry. In vivo, TCCSUP or SW780 cells were inoculated into BALB/c nude mice to detect tumor volume and weight. Bioinformatics and dual luciferase reporter gene were used to analyze the relationship between LINC00511 and miR-143-3p and its downstream target gene PCMT1. The results showed that LINC00511 could target miR-143-3p/PCMT1 to regulate the proliferation, migration, and apoptosis of bladder cancer TCCSUP or SW780 cells and promote the occurrence and development of bladder cancer.

/pdf/linc00511-mirna-143-3p-modulates-apoptosis-and-malignant-1f4qbribm5.pdf

LINC00511/miRNA-143-3p Modulates Apoptosis and Malignant Phenotype of Bladder Carcinoma Cells via PCMT1.

Additive antitumor effect of arsenic trioxide combined with intravesical bacillus Calmette–Guerin immunotherapy against bladder cancer through blockade of the IER3/Nrf2 pathway

Abstract The neuronally expressed developmentally downregulated 4 (NEDD4) gene encodes a ubiquitin ligase that targets the epithelial sodium channel for degradation and has been implicated in tumor growth in various cancers. Hence, in this study, we intended to characterize the functional relevance of the NEDD4-mediated Kruppel-like factor 8/microRNA-132/nuclear factor E2-related factor 2 (KLF8/miR-132/NRF2) axis in the development of bladder cancer. NEDD4 and KLF8 were overexpressed in bladder cancer tissues and were associated with poorer patient survival rates. In bladder cancer cells, NEDD4 intensified the stability and transcriptional activity of KLF8 through ubiquitination to augment cell viability and migratory ability. Our investigations revealed that NEDD4 promotes the binding of KLF8 to the miR-132 promoter region and inhibits the expression of miR-132. KLF8 inhibited the expression of miR-132 to augment the viability and migratory ability of bladder cancer cells. Furthermore, miR-132 downregulated the expression of NRF2 to restrict the viability and migratory ability of bladder cancer cells. In addition, in vivo findings verified that NEDD4 regulates the KLF8/miR-132/NRF2 axis by accelerating tumor growth and lung metastasis. In conclusion, this study highlights NEDD4 as a potential therapeutic target against tumor recurrence and metastasis in bladder cancer. 

/pdf/oncogenic-e3-ubiquitin-ligase-nedd4-binds-to-klf8-and-2qox5qjt.pdf

Oncogenic E3 ubiquitin ligase NEDD4 binds to KLF8 and regulates the microRNA-132/NRF2 axis in bladder cancer

https://www.nature.com/articles/s12276-021-00663-2.pdf

Ming-Huan Mao

Papers

LINC00511/miRNA-143-3p Modulates Apoptosis and Malignant Phenotype of Bladder Carcinoma Cells via PCMT1.

Additive antitumor effect of arsenic trioxide combined with intravesical bacillus Calmette–Guerin immunotherapy against bladder cancer through blockade of the IER3/Nrf2 pathway

Oncogenic E3 ubiquitin ligase NEDD4 binds to KLF8 and regulates the microRNA-132/NRF2 axis in bladder cancer

Oncogenic E3 ubiquitin ligase NEDD4 binds to KLF8 and regulates the microRNA-132/NRF2 axis in bladder cancer

ALDH2 Hampers Immune Escape in Liver Hepatocellular Carcinoma through ROS/Nrf2-mediated Autophagy