Hexavalent chromium exposure activates the non-canonical nuclear factor kappa B pathway to promote immune checkpoint protein programmed death-ligand 1 expression and lung carcinogenesis.

Lung cancer is the leading cause of cancer-related death worldwide; however, the mechanism of lung carcinogenesis has not been clearly defined. Chronic exposure to hexavalent chromium [Cr(VI)], a common environmental and occupational pollutant, causes lung cancer, representing an important lung cancer etiology factor. The mechanism of how chronic Cr(VI) exposure causes lung cancer remains largely unknown. By using cell culture and mouse models and bioinformatics analyses of human lung cancer gene expression profiles, this study investigated the mechanism of Cr(VI)-induced lung carcinogenesis. A new mouse model of Cr(VI)-induced lung carcinogenesis was developed as evidenced by the findings showing that a 16-week Cr(VI) exposure (CaCrO4, 100 µg per mouse once per week) via oropharyngeal aspiration induced lung adenocarcinomas in male and female A/J mice, whereas none of the sham-exposed control mice had lung tumors. Mechanistic studies revealed that chronic Cr(VI) exposure activated the non-canonical NFκB pathway through the long non-coding RNA (lncRNA) ABHD11-AS1/deubiquitinase USP15-mediated tumor necrosis factor receptor-associated factor 3 (TRAF3) down-regulation. The non-canonical NFκB pathway activation increased the interleukin 6 (IL-6)/Janus kinase (Jak)/signal transducer and activator of transcription 3 (Stat3) signaling. The activation of the IL-6/Jak signaling axis by Cr(VI) exposure not only promoted inflammation but also stabilized the immune checkpoint molecule programmed death-ligand 1 (PD-L1) protein in the lungs, reducing T lymphocyte infiltration to the lungs. Given the well-recognized critical role of PD-L1 in inhibiting anti-tumor immunity, these findings suggested that the lncRNA ABHD11-AS1-mediated non-canonical NFκB pathway activation and PD-L1 up-regulation may play important roles in Cr(VI)-induced lung carcinogenesis.

Stabilization of MOF (KAT8) by USP10 promotes esophageal squamous cell carcinoma proliferation and metastasis through epigenetic activation of ANXA2/Wnt signaling.

Dysregulation of MOF (also known as MYST1, KAT8), a highly conserved H4K16 acetyltransferase, plays important roles in human cancers. However, its expression and function in esophageal squamous cell carcinoma (ESCC) remain unknown. Here, we report that MOF is highly expressed in ESCC tumors and predicts a worse prognosis. Depletion of MOF in ESCC significantly impedes tumor growth and metastasis both in vitro and in vivo, whereas ectopic expression of MOF but not catalytically inactive mutant (MOF-E350Q) promotes ESCC progression, suggesting that MOF acetyltransferase activity is crucial for its oncogenic activity. Further analysis reveals that USP10, a deubiquitinase highly expressed in ESCC, binds to and deubiquitinates MOF at lysine 410, which protects it from proteosome-dependent protein degradation. MOF stabilization by USP10 promotes H4K16ac enrichment in the ANXA2 promoter to stimulate ANXA2 transcription in a JUN-dependent manner, which subsequently activates Wnt/ß-Catenin signaling to facilitate ESCC progression. Our findings highlight a novel USP10/MOF/ANXA2 axis as a promising therapeutic target for ESCC.

Transcriptome Analysis Reveals Anti-Cancer Effects of Isorhapontigenin (ISO) on Highly Invasive Human T24 Bladder Cancer Cells.

Bladder cancer, the most common malignancy of the urinary tract, has a poor overall survival rate when the tumor becomes muscle invasive. The discovery and evaluation of new alternative medications targeting high-grade muscle invasive bladder cancer (MIBC) are of tremendous importance in reducing bladder cancer mortality. Isorhapontigenin (ISO), a stilbene derivative from the Chinese herb Gnetum cleistostachyum, exhibits a strong anti-cancer effect on MIBCs. Here, we report the whole transcriptome profiling of ISO-treated human bladder cancer T24 cells. A total of 1047 differentially expressed genes (DEGs) were identified, including 596 downregulated and 451 upregulated genes. Functional annotation and pathway analysis revealed that ISO treatment induced massive changes in gene expression associated with cell movement, migration, invasion, metabolism, proliferation, and angiogenesis. Additionally, ISO treatment-activated genes involved in the inflammatory response but repressed genes involved in hypoxia signaling, glycolysis, the actin cytoskeleton, and the tumor microenvironment. In summary, our whole transcriptome analysis demonstrated a shift in metabolism and altered actin cytoskeleton in ISO-treated T24 cells, which subsequently contribute to tumor microenvironment remodeling that suppresses tumor growth and progression.

Chronic nickel exposure alters extracellular vesicles to mediate cancer progression via sustained NUPR1 expression.

Cancer cells release extracellular vesicles (EVs) that participate in altering the proximal tumor environment and distal tissues to promote cancer progression. Chronic exposure to nickel (Ni), a human group I carcinogen, results in epigenetic changes that promotes epithelial to mesenchymal transition (EMT). Cells that undergo EMT demonstrate various molecular changes, including elevated levels of the mesenchymal cadherin N-cadherin (N-CAD) and the transcription factor Zinc finger E-box binding homeobox 1 (ZEB1). Moreover, the molecular changes following EMT induce changes in cellular behavior, including anchorage-independent growth, which contributes to cancer cells detaching from tumor bulk during the metastatic process. Here, we present data demonstrating that EVs from Ni-exposed cells induce EMT in recipient BEAS-2B cells in the absence of Ni. Moreover, we show evidence that the EVs from Ni-altered cells package the transcription factor nuclear protein 1 (NUPR1), a transcription factor associated with Ni exposure and cancer progression. Moreover, our data demonstrates that the NUPR1 in the EVs becomes part of the recipient cell proteomic milieu and carry the NUPR1 to the nuclear space of the recipient cell. Interestingly, knockdown of NUPR1 in Ni-transformed cells suppressed NUPR1 packaging in the EVs, and nanoparticle tracking analysis (NTA) demonstrated decreased EV release. Reduction of NUPR1 in EVs resulted in diminished EMT capacity that resulted in decreased anchorage independent growth. This study is the first to demonstrate the role of NUPR1 in extracellular vesicle-mediate cancer progression.

Hexavalent chromium inhibits myogenic differentiation and induces myotube atrophy.

Hexavalent chromium [Cr(VI)] is extensively used in many industrial processes. Previous studies reported that Cr(VI) exposures during early embryonic development reduced body weight with musculoskeletal malformations in rodents while exposures in adult mice increased serum creatine kinase activity, a marker of muscle damage. However, the impacts of Cr(VI) on muscle differentiation remain largely unknown. Here, we report that acute exposures to Cr(VI) in mouse C2C12 myoblasts inhibit myogenic differentiation in a dose-dependent manner. Exposure to 2 µM of Cr(VI) resulted in delayed myotube formation, as evidenced by a significant decrease in myotube formation and expression of muscle-specific markers, such as muscle creatine kinase (Mck), Myocyte enhancer factor 2 (Mef2), Myomaker (Mymk) and Myomixer (Mymx). Interestingly, exposure to 5 µM of Cr(VI) completely abolished myotube formation in differentiating C2C12 cells. Moreover, the expression of key myogenic regulatory factors (MRFs) including myoblast determination protein 1 (MyoD), myogenin (MyoG), myogenic factor 5 (Myf5), and myogenic factor 6 (Myf6) were significantly altered in Cr(VI)-treated cells. The inhibitory effect of Cr(VI) on myogenic differentiation was further confirmed in freshly isolated mouse satellite cells, a stem cell population essential for adult skeletal muscle regeneration. Furthermore, Cr(VI) exposure to fully differentiated C2C12 myotubes resulted in a decrease in myotube diameter, which was exacerbated upon co-treatment with dexamethasone. Together, our results demonstrate that Cr(VI) inhibits myogenic differentiation and induces myotube atrophy in vitro.

The NRF2-p97-NRF2 negative feedback loop.

p97 is a ubiquitin-targeted ATP-dependent segregase that regulates proteostasis, in addition to a variety of other cellular functions. Previously, we demonstrated that p97 negatively regulates NRF2 by extracting ubiquitylated NRF2 from the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex, facilitating proteasomal destruction. In the current study, we identified p97 as an NRF2-target gene that contains a functional ARE, indicating the presence of an NRF2-p97-NRF2 negative feedback loop that maintains redox homeostasis. Using CRISPR/Cas9 genome editing, we generated endogenous p97 ARE-mutated BEAS-2B cell lines. These p97 ARE-mutated cell lines exhibit altered expression of p97 and NRF2, as well as a compromised response to NRF2 inducers. Importantly, we also found a positive correlation between NRF2 activation and p97 expression in human cancer patients. Finally, using chronic arsenic-transformed cell lines, we demonstrated a synergistic effect of NRF2 and p97 inhibition in killing cancer cells with high NRF2 and p97 expression. Our study suggests dual upregulation of NRF2 and p97 occurs in certain types of cancers, suggesting that inhibition of both NRF2 and p97 could be a promising treatment strategy for stratified cancer patients.

A combination of three antioxidants decreases the impact of rural particulate pollution in Normal human keratinocytes.

OBJECTIVE: It is well established that exposure of human skin to airborne pollution, particularly in the form of particulate matter sized 2.5 µm (PM2.5 ), is associated with oxidative stress, DNA damage and inflammation, leading to premature signs of skin aging. Because much of the damage results from oxidative stress, we examined the effects of a topical composition containing three antioxidants in an in vitro model system to assess the potential for amelioration of premature aging. The use of multiple antioxidants was of interest based on the typical composition of therapeutic skincare products. It is important to determine the efficacy of multiple antioxidants together and develop a short-term assay for larger scale efficacy testing. METHODS: Normal human epidermal keratinocytes were exposed to a rural-derived source of PM2.5 in the presence and absence of an antioxidant mixture of resveratrol, niacinamide and GHK peptide. Endpoints related to inflammation, premature aging and carcinogenicity were monitored after 5 h of exposure and included IL-6, CXCL10, MMP-1 and NRF2. Differentially expressed genes were monitored by RNA-seq. RESULTS: Pre-treatment of keratinocytes with the antioxidant preparation in the absence of PM2.5 reduced baseline levels of MMP-1, IL-6 and CYP1A1 and reduced PM2.5 -induced increases in all four endpoints, MMP-1, IL-6, CXCL10 and CYP1A1. Antioxidants significantly increased NRF2 protein in the presence of PM2.5 , indicating a protective response. RNA-seq interrogation of antioxidant-treated cells further showed increased expression of NRF2 inducible genes. The expression of CYP1A1 and genes related to aryl hydrocarbon activation were induced by PM2.5 and suppressed by antioxidants. CONCLUSIONS: Specific signalling pathways known to be correlated with skin inflammation and aging were examined based on their suitability for use in efficacy testing for the prevention of skin damage due to ambient hydrocarbon pollution. Endpoints examined after only 5 h of exposure provide a useful method amenable to high through-put screening. The results obtained reinforce the concept that a multiple antioxidant preparation, topically applied, may reduce pro-inflammatory signalling and cellular damage and thereby reduce premature skin aging due to exposure to rural-derived airborne pollution.

OBJECTIF: Il est bien établi que l'exposition de la peau humaine à la pollution atmosphérique, en particulier sous forme de particules d'une taille de 2,5 µm (PM2,5 ), est associée à un stress oxydatif, à des dommages à l'ADN et à une inflammation entraînant des signes prématurés de vieillissement cutané. Étant donné que la plupart des dommages résultent du stress oxydatif, nous avons examiné les effets d'une composition topique contenant trois antioxydants dans un système de modèle in vitro afin d'évaluer le potentiel d'amélioration du vieillissement prématuré. L'utilisation de plusieurs antioxydants a été intéressante en raison de la composition typique des produits thérapeutiques de soin de la peau. Il est important de déterminer l'efficacité de plusieurs antioxydants combinés et de développer un test à court terme pour des tests d'efficacité à plus grande échelle. MÉTHODES: Des kératinocytes épidermiques humains normaux ont été exposés à une source de PM2,5 rurale en présence et en l'absence d'un mélange antioxydant de resvératrol, de niacinamide et de peptide GHK. Les critères d'évaluation liés à l'inflammation, au vieillissement prématuré et à la carcinogénicité ont été surveillés après 5 heures d'exposition et comprenaient l'IL-6, CXCL10, MMP-1 et le NRF2. Les gènes exprimés de manière différentielle ont été surveillés par séquençage de l'ARN. RÉSULTATS: Le prétraitement des kératinocytes par la préparation antioxydante en l'absence de PM2,5 a réduit les taux initiaux de MMP-1, IL-6 et de CYP1A1 et a réduit les augmentations induites par les PM2,5 dans les quatre critères d'évaluation, MMP-1, IL-6, CXCL10 et CYP1A1. Les antioxydants ont significativement augmenté la protéine NRF2 en présence de PM2,5 , ce qui indique une réponse protectrice. L'interrogation des séquences d'ARN des cellules traitées par antioxydants a également montré une expression accrue des gènes inductibles par NRF2. L'expression du CYP1A1 et des gènes liés à l'activation des hydrocarbures aryles a été induite par les PM2,5 et supprimée par les antioxydants. CONCLUSIONS: Les voies de signalisation spécifiques connues pour être corrélées à l'inflammation cutanée et au vieillissement ont été examinées en fonction de leur adéquation à l'utilisation dans les tests d'efficacité pour la prévention des lésions cutanées dues à la pollution des hydrocarbures ambiants. Les critères d'évaluation examinés après seulement 5 heures d'exposition fournissent une méthode utile pouvant être utilisée pour un dépistage à haut débit. Les résultats obtenus renforcent le principe selon lequel une préparation antioxydante multiple, appliquée par voie topique, peut réduire la signalisation pro-inflammatoire et les dommages cellulaires et ainsi réduire le vieillissement prématuré de la peau résultant de l'exposition à la pollution atmosphérique d'origine rurale.

Toxic element contaminations of prenatal vitamins.

The detrimental effects of gestational and lactational exposure to adverse chemical agents are gathering increasing attention. In our study, the presence of toxic heavy metals in several prenatal vitamins from six brands available in supermarkets and pharmacies was measured using ICP mass spectrometry. Several toxic heavy metals were detected, some at levels that could have potential toxicity to the fetus and the mother as well. Previous studies have also detected toxic heavy metals in prenatal and other vitamins. One of the reasons for toxic heavy metals in "natural vitamins" sold to consumers is that they are produced from naturally grown material and not synthesized. They are likely exposed to the heavy metals from the ground that they are grown in and there has not been any significant attempt to get rid of them before the vitamin pill was sold to consumers. Thus, this problem is not an isolated issue and regulatory agencies should be dealing more aggressively than they have been doing. In fact, several papers have already been published showing similar findings as we are reporting here. The vitamin pills we analyzed have elevated levels of boron, aluminum, molybdenum, barium, lead, titanium, nickel, arsenic, strontium, and cadmium. The levels of total chromium were also elevated but we did not separately determine Cr(III) and the much more hazardous Cr(VI), because of the tedious procedure required to separate these two forms of Cr.

Loss of MEG3 contributes to the enhanced migration and invasion in arsenic-induced carcinogenesis through NQO1/FSCN1 pathway.

Arsenic ranks at the top among all toxic metals and poses a serious threat to human health. Inorganic arsenite and arsenate compounds have been classified as human carcinogens in various types of cancers. Maternally expressed gene 3 (MEG3), a tumor suppressor that is commonly lost in cancer, was investigated in this study for its role in the migration and invasion of arsenic-transformed cells. Our results showed that MEG3 was downregulated in both arsenic-transformed cells (As-T) and cells treated with low doses of arsenic for three months (As-treated). The analysis using TCGA dataset revealed that MEG3 expression was significantly reduced in the tumor tissues from human lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) compared to normal lung tissues. The results from the methylation-specific PCR (MSP) assay demonstrated enhanced methylation in the MEG3 promoters in both As-T and As-treated cells, indicating that increased methylation of the MEG3 promoter caused MEG3 downregulation in these cells. Moreover, As-T cells displayed increased migration and invasion and higher levels of NAD(P)H quinone dehydrogenase 1 (NQO1) and fascin actin-bundling protein 1 (FSCN1). Consistently, the results from immunohistochemistry staining showed that both NQO1 and FSCN1 are highly expressed in human lung squamous cell carcinoma tissues compared to those in normal lungs. Knockdown of MEG3 in normal BEAS-2B cells also led to increased migration and invasion, along with elevated levels of NQO1 and FSCN1. The negative regulation of MEG3 on FSCN1 was restored by NQO1 overexpression in both As-T and BEAS-2B cells. The results from immunoprecipitation assays confirmed the direct binding of NQO1 to FSCN1. Overexpression of NQO1 increased migration and invasion abilities in BEAS-2B cells, while knockdown of NQO1 by its shRNA reduced these two hallmarks of cancer. Interestingly, the reduced migration and invasion by NQO1 knockdown were restored by FSCN1. Collectively, the loss of MEG3 upregulated NQO1, which in turn stabilized FSCN1 protein through its direct binding, resulting in elevated migration and invasion in arsenic-transformed cells.

Polyadenylation of canonical histone H3.1 in carcinogenesis.

Canonical histone messenger RNAs (mRNAs) are transcribed during S phase and do not terminate with a poly(A) tail at the 3' end. Instead, the histone mRNAs display a stem-loop structure at their 3-end. Stem-loop-binding protein (SLBP) binds the stem-loop and regulates canonical histone mRNA metabolism. We previously demonstrated that exposure to arsenic, an environmental carcinogen, induces polyadenylation of canonical histone H3.1 mRNA, causing transformation of human cells in vitro. Arsenic decreased cellular levels of SLBP by inducing its proteasomal degradation and inhibiting SLBP transcription via epigenetic mechanisms. Similarly, we also reported that nickel and arsenic have similar effects on canonical histone mRNA transcription and translation. Most recently, we further demonstrated that bisphenols' exposure increased polyadenylation of canonical histone H3.1 mRNA possibly through down-regulation of SLBP expression. This facilitates the abnormal stability of at least one canonical histone isoform (H3.1), and also increases H3 protein levels. Excess expression of canonical histones have been shown to increase sensitivity to DNA damage as well as increase the frequency of missing chromosomes and induce genomic instability. Thus, polyadenylation of canonical histone mRNA following arsenic, nickel and bisphenols exposure may contribute to metal and bisphenol-induced carcinogenesis.

Long Non-Coding RNA MEG3 in Metal Carcinogenesis.

Most transcripts from human genomes are non-coding RNAs (ncRNAs) that are not translated into proteins. ncRNAs are divided into long (lncRNAs) and small non-coding RNAs (sncRNAs). LncRNAs regulate their target genes both transcriptionally and post-transcriptionally through interactions with proteins, RNAs, and DNAs. Maternally expressed gene 3 (MEG3), a lncRNA, functions as a tumor suppressor. MEG3 regulates cell proliferation, cell cycle, apoptosis, hypoxia, autophagy, and many other processes involved in tumor development. MEG3 is downregulated in various cancer cell lines and primary human cancers. Heavy metals, such as hexavalent chromium (Cr(VI)), arsenic, nickel, and cadmium, are confirmed human carcinogens. The exposure of cells to these metals causes a variety of cancers. Among them, lung cancer is the one that can be induced by exposure to all of these metals. In vitro studies have demonstrated that the chronic exposure of normal human bronchial epithelial cells (BEAS-2B) to these metals can cause malignant cell transformation. Metal-transformed cells have the capability to cause an increase in cell proliferation, resistance to apoptosis, elevated migration and invasion, and properties of cancer stem-like cells. Studies have revealed that MEG is downregulated in Cr(VI)-transformed cells, nickel-transformed cells, and cadmium (Cd)-transformed cells. The forced expression of MEG3 reduces the migration and invasion of Cr(VI)-transformed cells through the downregulation of the neuronal precursor of developmentally downregulated protein 9 (NEDD9). MEG3 suppresses the malignant cell transformation of nickel-transformed cells. The overexpression of MEG3 decreases Bcl-xL, causing reduced apoptosis resistance in Cd-transformed cells. This paper reviews the current knowledge of lncRNA MEG3 in metal carcinogenesis.

Cadmium Activates EGFR/STAT5 Signaling to Overcome Calcium Chelation and Promote Epithelial to Mesenchymal Transition.

Cadmium (Cd) is a heavy metal found in cigarette smoke, as well as in air and drinking water due to agricultural and industrial activities, and it poses a health risk to the general population. Prolonged low-dose Cd exposure via inhalation or ingestion causes lung and kidney cancers in humans and in animal models. While high doses of Cd exposure are correlated with the occupational setting and are cytotoxic, low doses of Cd are mainly correlated with exposure in the general population and induce carcinogenesis. The mechanism by which Cd-exposed cells overcome calcium chelation and induce malignant transformation remains unclear. This study examines how cells exposed to low doses of Cd survive loss of E-cadherin cell-cell adhesion via activation of the epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 5 (STAT5), which work to upregulate genes associated with survival and proliferation. To demonstrate the role of Cd in EGFR/STAT5 activation, we exposed two epithelial cell lines, BEAS-2B and HEK293, to two different doses (0.4 µM and 1.6 µM) of Cadmium chloride hemipentahydrate (CdCl2·2.5H2O) that are environmentally relevant to levels of Cd found in food and cigarettes for 24 h (hours) and 9 weeks (wks). When comparing cells treated with Cd with control cells, the Cd treated cells exhibited faster proliferation; therefore, we studied activation of EGFR via the STAT5 pathway using immunofluorescence (IF) for protein expression and localization and, in addition, RT-qPCR to examine changes in EGFR/STAT5 inducible genes. Our results showed an increase in EGFR and phosphorylated EGFR (p-EGFR) protein, with 1.6 µM of Cadmium having the highest expression at both 24-hour (hr) and 9-week (wk) exposures. Moreover, the IF analysis also demonstrated an increase of STAT5 and phosphorylated STAT5 (pSTAT5) in both short-term and long-term exposure, with 0.4 µM having the highest expression at 24 h. Finally, via Western blot analysis, we showed that there was a dose-dependent decrease in E-cadherin protein expression and increased N-cadherin in cells treated with low doses of Cd. These data demonstrate that epithelial cells can overcome Cd-mediated toxicity via activation of EGFR pathway to induce cell proliferation and survival and promote epithelial to mesenchymal transition.

Extracellular Vesicles as Mediators of Nickel-Induced Cancer Progression.

Emerging evidence suggests that extracellular vesicles (EVs), which represent a crucial mode of intercellular communication, play important roles in cancer progression by transferring oncogenic materials. Nickel (Ni) has been identified as a human group I carcinogen; however, the underlying mechanisms governing Ni-induced carcinogenesis are still being elucidated. Here, we present data demonstrating that Ni exposure generates EVs that contribute to Ni-mediated carcinogenesis and cancer progression. Human bronchial epithelial (BEAS-2B) cells and human embryonic kidney-293 (HEK293) cells were chronically exposed to Ni to generate Ni-treated cells (Ni-6W), Ni-transformed BEAS-2B cells (Ni-3) and Ni-transformed HEK293 cells (HNi-4). The signatures of EVs isolated from Ni-6W, Ni-3, HNi-4, BEAS-2B, and HEK293 were analyzed. Compared to their respective untreated cells, Ni-6W, Ni-3, and HNi-4 released more EVs. This change in EV release coincided with increased transcription of the EV biogenesis markers CD82, CD63, and flotillin-1 (FLOT). Additionally, EVs from Ni-transformed cells had enriched protein and RNA, a phenotype also observed in other studies characterizing EVs from cancer cells. Interestingly, both epithelial cells and human umbilical vein endothelial (HUVEC) cells showed a preference for taking up Ni-altered EVs compared to EVs released from the untreated cells. Moreover, these Ni-altered EVs induced inflammatory responses in both epithelial and endothelial cells and increased the expression of coagulation markers in endothelial cells. Prolonged treatment of Ni-alerted EVs for two weeks induced the epithelial-to-mesenchymal transition (EMT) in BEAS-2B cells. This study is the first to characterize the effect of Ni on EVs and suggests the potential role of EVs in Ni-induced cancer progression.

The role of NUPR1 in response to stress and cancer development.

Stress contributes to the development of many human diseases, including cancer. Based on the source of stress, it can be divided into external stress, such as environmental carcinogens, chemicals, and radiation, and internal stress, like endoplasmic reticulum (ER) stress, hypoxia, and oxidative stress. Nuclear Protein 1 (NUPR1, p8 or Com-1) is a small, highly basic transcriptional regulator that participates in regulating a variety of cellular processes including DNA repair, ER stress, oxidative stress response, cell cycle, autophagy, apoptosis, ferroptosis and chromatin remodeling. A large number of studies have reported that NUPR1 expression can be stimulated rapidly in response to various stresses. Thus, NUPR1 is also known as a stress-response gene. Since the role of NUPR1 in breast cancer was identified in 1999, an increasing number of studies sought to reveal its function in cancer. High expression of NUPR1 has been identified in oral squamous cell carcinoma, breast cancer, lung cancer, multiple myeloma, liver cancer and renal cancer. In this review, we summarize current studies of NUPR1 in response to multiple external stressors and internal stressors, and its role in mediating stressors to cause different cell signaling responses. In addition, this review discusses the function of NUPR1 in carcinogenesis, tumorigenesis, metastasis, and cancer therapy. Thus, this review gives a comprehensive insight into the role of NUPR1 in mediating signals from stress to different cell responses, and this process plays a role in the development of cancer.

DNMT3A/miR-129-2-5p/Rac1 Is an Effector Pathway for SNHG1 to Drive Stem-Cell-like and Invasive Behaviors of Advanced Bladder Cancer Cells.

The stem-cell-like behavior of cancer cells plays a central role in tumor heterogeneity and invasion and correlates closely with drug resistance and unfavorable clinical outcomes. However, the molecular underpinnings of cancer cell stemness remain incompletely defined. Here, we show that SNHG1, a long non-coding RNA that is over-expressed in ~95% of human muscle-invasive bladder cancers (MIBCs), induces stem-cell-like sphere formation and the invasion of cultured bladder cancer cells by upregulating Rho GTPase, Rac1. We further show that SNHG1 binds to DNA methylation transferase 3A protein (DNMT3A), and tethers DNMT3A to the promoter of miR-129-2, thus hyper-methylating and repressing miR-129-2-5p transcription. The reduced binding of miR-129-2 to the 3'-UTR of Rac1 mRNA leads to the stabilization of Rac1 mRNA and increased levels of Rac1 protein, which then stimulates MIBC cell sphere formation and invasion. Analysis of the Human Protein Atlas shows that a high expression of Rac1 is strongly associated with poor survival in patients with MIBC. Our data strongly suggest that the SNHG1/DNMT3A/miR-129-2-5p/Rac1 effector pathway drives stem-cell-like and invasive behaviors in MIBC, a deadly form of bladder cancer. Targeting this pathway, alone or in combination with platinum-based therapy, may reduce chemoresistance and improve longer-term outcomes in MIBC patients.

Loss of MEG3 and upregulation of miR-145 play an important role in the invasion and migration of Cr(VI)-transformed cells.

Chronic exposure of human bronchial epithelial BEAS-2B cells to hexavalent chromium (Cr(VI)) causes malignant cell transformation. These transformed cells exhibit increases in migration and invasion. Neuronal precursor of developmentally downregulated protein 9 (NEDD9) is upregulated in Cr(VI)-transformed cells compared to that of passage-matched normal BEAS-2B cells. Knockdown of NEDD9 by its shRNA reduced invasion and migration of Cr(VI)-transformed cells. Maternally expressed gene 3 (MEG3), a long noncoding RNA, was lost and microRNA 145 (miR-145) was upregulated in Cr(VI)-transformed cells. MEG3 was bound to miR-145 and this binding reduced its activity. Overexpression of MEG3 or inhibition of miR-145 decreased invasion and migration of Cr(VI)-transformed cells. Overexpression of MEG3 was able to decrease miR-145 level and NEDD9 protein level in Cr(VI)-transformed cells. Ectopic expression of MEG3 was also shown to reduce ß-catenin activation. Inhibition of miR-145 in Cr(VI)-transformed cells decreased Slug, an important transcription factor that regulates epithelial-to-mesenchymal transition (EMT). Inhibition of miR-145 was found to increase MEG3 in Cr(VI)-transformed cells. Further studies showed that mutation of MEG3 at the binding site for miR-145 did not change NEDD9 and failed to decrease invasion and migration. The present study demonstrated that loss of MEG3 and upregulation of miR-145 elevated NEDD9, resulting in activation of ß-catenin and further upregulation of EMT, leading to increased invasion and migration of Cr(VI)-transformed cells.

Index Coding with Multiple Interpretations.

The index coding problem consists of a system with a server and multiple receivers with different side information and demand sets, connected by a noiseless broadcast channel. The server knows the side information available to the receivers. The objective is to design an encoding scheme that enables all receivers to decode their demanded messages with a minimum number of transmissions, referred to as an index code length. The problem of finding the minimum length index code that enables all receivers to correct a specific number of errors has also been studied. This work establishes a connection between index coding and error-correcting codes with multiple interpretations from the tree construction of nested cyclic codes. The notion of multiple interpretations using nested codes is as follows: different data packets are independently encoded, and then combined by addition and transmitted as a single codeword, minimizing the number of channel uses and offering error protection. The resulting packet can be decoded and interpreted in different ways, increasing the error correction capability, depending on the amount of side information available at each receiver. Motivating applications are network downlink transmissions, information retrieval from datacenters, cache management, and sensor networks.

Longitudinal Impact of WTC Dust Inhalation on Rat Cardiac Tissue Transcriptomic Profiles.

First responders (FR) exposed to the World Trade Center (WTC) Ground Zero air over the first week after the 9/11 disaster have an increased heart disease incidence compared to unexposed FR and the general population. To test if WTC dusts were causative agents, rats were exposed to WTC dusts (under isoflurane [ISO] anesthesia) 2 h/day on 2 consecutive days; controls received air/ISO or air only. Hearts were collected 1, 30, 240, and 360 d post-exposure, left ventricle total RNA was extracted, and transcription profiles were obtained. The data showed that differentially expressed genes (DEG) for WTC vs. ISO rats did not reach any significance with a false discovery rate (FDR) < 0.05 at days 1, 30, and 240, indicating that the dusts did not impart effects beyond any from ISO. However, at day 360, 14 DEG with a low FDR were identified, reflecting potential long-term effects from WTC dust alone, and the majority of these DEG have been implicated as having an impact on heart functions. Furthermore, the functional gene set enrichment analysis (GSEA) data at day 360 showed that WTC dust could potentially impact the myocardial energy metabolism via PPAR signaling and heart valve development. This is the first study showing that WTC dust could significantly affect some genes that are associated with the heart/CV system, in the long term. Even > 20 years after the 9/11 disaster, this has potentially important implications for those FR exposed repeatedly at Ground Zero over the first week after the buildings collapsed.