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ATF2 partly mediated the expressions of proliferative factors and inhibited pro-inflammatory factors' secretion in arsenite-treated human uroepithelial cells.

ABSTRACT: Inorganic arsenic (iAs) could induce the expression of activating transcription factor-2 (ATF2) in the human urinary bladder epithelial cell line (SV-HUC-1 cells). ATF2, as a member of the bZIP transcription factor family, has been implicated in a transcriptional response leading to cell growth, migration and malignant tumor progression. However, little is known about the effects of ATF2 on proliferative factors in iAs treated human urothelial cells. In this study, ATF2 siRNA was employed to investigate the relationship between ATF2 activation and the expressions of proliferative factors, such as BCL2, cyclin D1, COX-2, MMP1 and PCNA, and pro-inflammatory factors (TNF?, TGF? and IL-8) in SV-HUC-1 cells. The results showed that low concentration arsenite increased the expressions of proliferative factors BCL2, cyclin D1, COX-2, MMP1 and PCNA in SV-HUC-1 cells, and ATF2 siRNA partly decreased the expressions of BCL2, cyclin D1, and COX-2. A neutralizing antibody of IL-8 was used for attenuating the levels of IL-8 and neutralizing antibody of IL-8 did not relieve the expressions of ATF2 and proliferative factors induced by arsenite in SV-HUC-1 cells. In addition, ATF2 knockdown did not decrease the expressions of pro-inflammatory cytokines induced by arsenite in SV-HUC-1 cells, but dramatically increased mRNA expressions of TNF?, TGF? and IL-8 under arsenite and non-arsenite conditions. In conclusion, our present study indicated that ATF2, but not IL-8, played a partial role in the expressions of proliferative factors induced by arsenite in human uroepithelial cells.

SUBMITTER: Liu S

PROVIDER: S-EPMC6062379 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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ATF2 partly mediated the expressions of proliferative factors and inhibited pro-inflammatory factors' secretion in arsenite-treated human uroepithelial cells.

Liu Shengnan S Wang Fei F Liu Jieyu J Jin Peiyu P Wang Xiaoyan X Yang Li L Xi Shuhua S

Toxicology research 20170329 4

Inorganic arsenic (iAs) could induce the expression of activating transcription factor-2 (ATF2) in the human urinary bladder epithelial cell line (SV-HUC-1 cells). ATF2, as a member of the bZIP transcription factor family, has been implicated in a transcriptional response leading to cell growth, migration and malignant tumor progression. However, little is known about the effects of ATF2 on proliferative factors in iAs treated human urothelial cells. In this study, ATF2 siRNA was employed to inv ...[more]

PMID: 30090515

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Project description:This article reviews and summarizes chromosomal changes responsible for the initiation and progression of uroepithelial carcinomas. Characterization of these alterations may lead to a better understanding of the genetic mechanisms and open the door for molecular markers that can be used for better diagnosis and prognosis of the disease. Such information might even help in designing new therapeutic strategies geared towards prevention of tumor recurrences and more aggressive approach in progression-prone cases. The revision of 205 cases of uroepithelial carcinomas reported with abnormal karyotypes showed karyotypic profile characterized by nonrandom chromosomal aberrations varying from one or few changes in low-grade and early stage tumors to massively rearranged karyotypes in muscle invasive ones. In general, the karyotypic profile was dominated by losses of chromosomal material seen as loss of entire chromosome and/or deletions of genetic materials. Rearrangements of chromosome 9 resulting in loss of material from 9p, 9q, or of the entire chromosome were the most frequent cytogenetic alterations, seen in 45% of the cases. Whereas loss of material from chromosome arms 1p, 8p, and 11p, and gains of chromosome 7, and chromosome arm 1q, and 8q seem to be an early, but secondary, changes appearing in superficial and well differentiated tumors, the formation of an isochromosome for 5p and loss of material from 17p are associated with more aggressive tumor phenotypes. Upper urinary tract TCCs have identical karyotypic profile to that of bladder TCCs, indicating the same pathogenetic mechanisms are at work in both locales. Intratumor cytogenetic heterogeneity was not seen except in a few post-radiation uroepithelial carcinomas in which distinct karyotypic and clonal pattern were characterized by massive intratumor heterogeneity (cytogenetic polyclonality) with near-diploid clones and simple balanced and/or unbalanced translocations. In the vast majority of cases strong correlation between the tumors grade/stage and karyotypic complexity was seen, indicating that progressive accumulation of acquired genetic alterations is the driving force behind multistep bladder TCC carcinogenesis. Although most of these cytogenetic alterations have been identified for many years, the molecular consequences and relevant cancer genes of these alterations have not yet been identified. However, loss of TSG(s) from chromosome 9 seems to be the primary and important event(s) in uroepithelial carcinogenesis.

Project description:Oxidative stress activates the cellular kinase HRI, which then phosphorylates eIF2α, resulting in stalled translation initiation and the formation of stress granules (SGs). SG assembly redirects cellular translation to stress response mRNAs and inhibits cap-dependent viral RNA translation. Flavivirus infections were previously reported to induce oxidative stress in infected cells but flavivirus-infected cells paradoxically develop resistance to arsenite (Ars)-induced SG formation with time after infection. This resistance was previously postulated to be due to sequestration of the SG protein Caprin1 by Japanese encephalitis virus capsid protein. However, Caprin1 did not co-localize with West Nile virus (WNV) capsid protein in infected cells. Other stressors induced SGs with equal efficiency in mock- and WNV-infected cells indicating the intrinsic ability of cells to assemble SGs was not disabled. Induction of both reactive oxygen species (ROS) and the antioxidant response was detected at early times after WNV-infection. The transcription factors, Nrf2 and ATF4, which activate antioxidant genes, were upregulated and translocated to the nucleus. Knockdown of Nrf2, ATF4 or apoptosis-inducing factor (AIF), a mitochondrial protein involved in regenerating intracellular reduced glutathione (GSH) levels, with siRNA or treatment of cells with buthionine sulphoximine, which induces oxidative stress by inhibiting GSH synthesis, decreased intracellular GSH levels and increased the number of SG-positive, infected cells. Mitochondria were protected from Ars-induced damage by WNV infection until late times in the infection cycle. The results indicate that the increase in virus-induced ROS levels is counterbalanced by a virus-induced antioxidant response that is sufficient to also overcome the increase in ROS induced by Ars treatment and prevent Ars-induced SG assembly and mitochondrial damage. The virus-induced alterations in the cellular redox status appear to provide benefits for the virus during its lifecycle.

Dataset Information

ATF2 partly mediated the expressions of proliferative factors and inhibited pro-inflammatory factors' secretion in arsenite-treated human uroepithelial cells.

Publications

ATF2 partly mediated the expressions of proliferative factors and inhibited pro-inflammatory factors' secretion in arsenite-treated human uroepithelial cells.

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