Dataset Information

Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells.

ABSTRACT: Chronic arsenic exposure remains a human health risk; however a clear mode of action to understand gene signaling-driven arsenic carcinogenesis is currently lacking. This study chronically exposed human lung epithelial BEAS-2B cells to low-dose arsenic trioxide to elucidate cancer promoting gene signaling networks associated with arsenic-transformed (B-As) cells. Following a 6month exposure, exposed cells were assessed for enhanced cell proliferation, colony formation, invasion ability and in vivo tumor formation compared to control cell lines. Collected mRNA was subjected to whole genome expression microarray profiling followed by in silico Ingenuity Pathway Analysis (IPA) to identify lung carcinogenesis modes of action. B-As cells displayed significant increases in proliferation, colony formation and invasion ability compared to BEAS-2B cells. B-As injections into nude mice resulted in development of primary and secondary metastatic tumors. Arsenic exposure resulted in widespread up-regulation of genes associated with mitochondrial metabolism and increased reactive oxygen species protection suggesting mitochondrial dysfunction. Carcinogenic initiation via reactive oxygen species and epigenetic mechanisms was further supported by altered DNA repair, histone, and ROS-sensitive signaling. NF-?B, MAPK and NCOR1 signaling disrupted PPAR?/?-mediated lipid homeostasis. A 'pro-cancer' gene signaling network identified increased survival, proliferation, inflammation, metabolism, anti-apoptosis and mobility signaling. IPA-ranked signaling networks identified altered p21, EF1?, Akt, MAPK, and NF-?B signaling networks promoting genetic disorder, altered cell cycle, cancer and changes in nucleic acid and energy metabolism. In conclusion, transformed B-As cells with their whole genome expression profile provide an in vitro arsenic model for future lung cancer signaling research and data for chronic arsenic exposure risk assessment.

SUBMITTER: Stueckle TA

PROVIDER: S-EPMC3358533 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells.

Stueckle Todd A TA Lu Yongju Y Davis Mary E ME Wang Liying L Jiang Bing-Hua BH Holaskova Ida I Schafer Rosana R Barnett John B JB Rojanasakul Yon Y

Toxicology and applied pharmacology 20120413 2

Chronic arsenic exposure remains a human health risk; however a clear mode of action to understand gene signaling-driven arsenic carcinogenesis is currently lacking. This study chronically exposed human lung epithelial BEAS-2B cells to low-dose arsenic trioxide to elucidate cancer promoting gene signaling networks associated with arsenic-transformed (B-As) cells. Following a 6month exposure, exposed cells were assessed for enhanced cell proliferation, colony formation, invasion ability and in vi ...[more]

PMID: 22521957

Similar Datasets

Project description:This study chronically exposed human lung epithelial BEAS-2B cells to low-dose arsenic trioxide in vitro to elucidate cancer promoting gene signaling networks (GSNs) associated with As-transformed (B-As) cells. Following a six month exposure, exposed cells were assessed for enhanced cell proliferation, colony formation, invasion ability and in vivo tumor formation compared to control cell lines. Collected mRNA was subjected to whole genome expression microarray profiling followed by in silico Ingenuity Pathway Analysis (IPA) to identify lung carcinogenesis modes of action. B-As cells displayed significant increases in proliferation, colony formation and invasion ability compared to BEAS-2B cells. B-As injections into nude mice resulted in development of primary and secondary metastatic tumors. As exposure resulted in widespread up-regulation of genes associated with mitochondrial metabolism and increased ROS protection suggesting mitochondrial dysfunction. Carcinogenic initiation via ROS and epigenetic mechanisms was further supported by altered DNA repair, histone, and ROS-sensitive signaling. NF-κB, MAPK and NCOR1 signaling disrupted PPARα/δ-mediated lipid homeostasis. A ‘pro-cancer’ GSN identified increased survival, proliferation, inflammation, metabolism, anti-apoptosis and mobility signaling. IPA-ranked signaling networks identified altered p21, EF1α, Akt, MAPK, and NF-κB signaling networks promoting genetic disorder, altered cell cycle, cancer and changes in nucleic acid and energy metabolism. In conclusion, transformed B-As cells with their whole genome GSN profile provide an in vitro As model for future lung cancer signaling research and data for chronic As exposure risk assessment. Whole genome expression profiling was conducted on arsenic (III) oxide-exposed human immortalized lung epithelial cells (BEAS-2B) following 6 month in vitro chronic exposure. As2O3 exposed cells (B-As) gene expression were compared to unexposed, passage control (B-Control) cell gene expression. Three B-As and four B-Control biological replicate cDNA samples were analyzed.

Project description:Exposure to genotoxic stresses such as radiation and tobacco smoke can cause increased cancer incidence rate as reflected in an in depth meta-analysis of data for women and breast cancer incidence. Published reports have indicated that exposures to low dose radiation and tobacco smoke are factors that contribute to the development of breast cancer. However, there is a scarcity of information on the combinatorial effects of low dose radiation and tobacco smoke on formation and progression of breast cancer. The combination of these two genotoxic insults can induce significant damage to the genetic material of the cells resulting in neoplastic transformation.To study the effects of low dose ionizing radiation and tobacco smoke on breast cells, MCF 10A cells were treated either with radiation (Rad - 0.1 Gray) or cigarette smoke condensate (Csc - 10 microgram/ml of medium) or a combination of Rad + Csc. Following treatments, cells were analyzed for cell cycle distribution patterns and the ability to extrude the Hoechst 33342 dye. In addition, in vitro invasion and migration as well as mammosphere formation assays were performed. Finally, differential gene expression profiles were generated from the individual and combination treatment.Exposure of MCF 10A cells to the combination of radiation plus cigarette smoke condensate generated a neoplastic phenotype. The transformed phenotype promoted increased mammosphere numbers, altered cell cycle phases with a doubling of the population in S phase, and increased invasion and motility. Also, exclusion of Hoechst 33342 dye, a surrogate marker for increased ABC transporters, was observed, which indicates a possible increase in drug resistance. In addition, changes in gene expression include the up regulation of genes encoding proteins involved in metabolic pathways and inflammation.The results indicate that when normal breast cells are exposed to low dose radiation in combination with cigarette smoke condensate a phenotype is generated that exhibits traits indicative of neoplastic transformation. More importantly, this is the first study to provide a new insight into a possible etiology for breast cancer formation in individuals exposed to low dose radiation and tobacco smoke.

Project description:Inorganic arsenic in the drinking water is a multisite human carcinogen that potentially targets the kidney. Recent evidence also indicates that developmental arsenic exposure impacts renal carcinogenesis in humans and mice. Emerging theory indicates that cancer may be a disease of stem cells (SCs) and that there are abundant active SCs during early life. Therefore, we hypothesized that inorganic arsenic targets SCs, or partially differentiated progenitor cells (PCs), for oncogenic transformation. Thus, a rat kidney SC/PC cell line, RIMM-18, was chronically exposed to low-level arsenite (500 nM) for up to 28 weeks. Multiple markers of acquired cancer phenotype were assessed biweekly during arsenic exposure, including secreted matrix metalloproteinase (MMP) activity, proliferation rate, colony formation in soft agar, and cellular invasiveness. Arsenic exposure by 10 weeks and after also induced marked and sustained increases in colony formation, indicative of the loss of contact inhibition, and increased invasiveness, both cancer cell characteristics. Compared to the passage-matched control, chronic arsenic exposure caused exposure-duration dependent increases in secreted MMP-2 and MMP-9 activity, Cox-2 expression, and more rapid proliferation (all >2-fold), characteristics typical of cancer cells. Dysregulation of SC maintenance genes and signaling pathways are common during oncogenesis. During arsenite exposure, expression of several genes associated with normal kidney development and SC regulation and differentiation (i.e., Wt-1, Wnt-4, Bmp-7, etc.) were aberrantly altered. Arsenic-exposed renal SCs produced more nonadherent spheroid bodies that grew much more aggressively in Matrigel, typical of cancer SCs (CSCs). The transformed cells also showed gene overexpression typical of renal SCs/CSCs (CD24, Osr1, Ncam) and arsenic adaptation such as overexpression of Mt-1, Mt2, Sod-1, and Abcc2. These data suggest that inorganic arsenic induced an acquired cancer phenotype in vitro in these rat kidney SCs potentially forming CSCs and, consistent with data in vivo, indicate that these multipotent SCs may be targets of arsenic during renal carcinogenesis.

Project description:BackgroundArsenic exposure has become a matter of worldwide concern, which is associated with immune-related diseases. However, little is known about its effect on inflammatory immune-related homeostasis. The purpose of our study was to understand the potential tuning of above responses exerted by chronic arsenic exposure.MethodsKunming mice were treated with 25 and 50 mg/L sodium arsenite for 1, 3 and 12 months via drinking water. At different endpoints of arsenic exposure, all animals and the whole spleen of the mice were weighed. The total arsenic levels of spleen were determined by the HPLC-HG-AFS method. Splenic NF-κB, MAPK and NRF2 protein levels by treatment of 25 mg/L NaAsO2 for 1, 3 and 12 months and 25 mg/L and 50 mg/L NaAsO2 for 12 months were assessed by western blot. Total RNA of spleen was isolated and relative mRNA levels of Foxp3, Il-10, Tnf-α, Il-6, Ifn-γ, Il-1β and Il-12 were measured by real-time PCR.ResultsOur results shown that NF-κB were continuously activated with treatment of 25 mg/L arsenic from 1, 3 to 12 months and 50 mg/L arsenic for 12 months. The transcription factor Foxp3 increased at 1 month but decreased at 3 and 12 months no matter 25 or 50 mg/L arsenic exposure. However, cytokine Il-10 always showed increased trend in mice treated with 25 or 50 mg/L arsenic for 1, 3 and 12 months. The transcriptional profiles of Tnf-α, Il-1β, Il-6, Ifn-γ and Il-12 revealed transient elevation at 1 and 3 months but shown significant decrease at 12 months on the whole. In addition, the sustained activation of inflammatory MAPK and anti-oxidative Nrf2 signaling pathways were observed in mice exposed to arsenic for 1, 3 and 12 months.ConclusionIn summary, our experiment in vivo suggested chronic arsenic exposure induces the time-dependent modulation of the inflammation and immunosuppression in spleen, which may be related to the activation of Tregs induced by MAPK/NF-κB as well as the increased transcription level of Foxp3 and Il-10.

Dataset Information

Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells.

Publications

Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets