Arginase 2 and nitric oxide synthase: Pathways associated with the pathogenesis of thyroid tumors

Sousa, Maria Sharmila Alina de; Latini, Flávia Roche Moreira; Monteiro, Hugo P.; Cerutti, Janete M.

doi:10.1016/j.freeradbiomed.2010.06.006

Cited by 31 publications

(23 citation statements)

References 34 publications

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“…Arginase expression is positively correlated to expression of nitric oxide synthase (NOS), and, therefore, increased production of nitric oxide. Nitric oxide plays regulatory roles on various physiological and pathophysiological properties, including vascular and neurological functions (Sousa et al , 2010). We observed significantly decreased expression of arg2 at 48 hpf following exposure to all seven NPAHs tested, and significantly increased expression at 120 hpf following exposure to 1,6-dinitropyrene, 5-nitroacenaphthalene, and 7-nitrobenzo[k]fluoranthene.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Investigations Into the Developmental Toxicity of Nitrated and Heterocyclic PAHs

Chlebowski

Garcia

et al. 2017

Toxicological Sciences

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Nitrated polycyclic aromatic hydrocarbons (NPAHs) and heterocyclic PAHs (HPAHs) are recognized environmental pollutants. However, the health risks of NPAHs and HPAHs to humans and environmental systems are not well-studied. The developmental zebrafish (Danio rerio) model was used to evaluate the toxicity of a structurally diverse set of 27 NPAHs and 10 HPAHs. The individual activity of each compound towards the aryl hydrocarbon receptor (AHR), including the role of the AHR in observed toxicity, and genetic markers of oxidative stress and cardiac toxicity were evaluated. Zebrafish embryos were exposed from 6 to 120 hours post fertilization (hpf), to a broad concentration range of individual compounds, and evaluated for 22 developmental endpoints. The potential role of AHR was determined using the transgenic Tg(cyp1a:nls-egfp) reporter zebrafish line. All compounds were screened computationally through molecular docking using a previously developed AHR models of zebrafish isoforms 1A, 1B, and 2. Some compounds did not induce observable developmental toxic responses, whereas others produced statistically significant concentration-dependent toxicity. The tested compounds also exhibited a range of predicted AHR binding and cyp1a/GFP induction patterns, including cyp1a expression in the liver, vasculature, skin, and yolk, which we determined to be due to distinct isoforms of the AHR, using morpholino oligonucleotide knockdown. Furthermore, we investigated mRNA expression of oxidative and cardiac stress genes at 48 and 120 hpf, which indicated several potential mechanisms-of-action for NPAHs. Overall, we observed a range of developmental toxicities, cyp1a/GFP expression patterns, and gene expression profiles, suggestive of several potential mechanisms of action.

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Section: Discussionmentioning

confidence: 99%

Mechanistic Investigations Into the Developmental Toxicity of Nitrated and Heterocyclic PAHs

Chlebowski

Garcia

et al. 2017

Toxicological Sciences

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“…Among miR-199a-3p targets predicted by integrated analysis, there are indeed genes involved in macropinocytosis, such as ABI1 [52], and other genes worthy of further investigation due to their oncogenic relevance in PTC (listed in supplementary informations). These include C8orf4, also known as thyroid cancer 1 (TC-1) [53], DUSP5, involved in ERK1/2 pathway attenuation [54], and ARG2, whose over-expression has been associated with the thyroid cancer pathogenesis [55]. It would be also interesting to investigate whether the other members of the miR-199a-2/214 cluster (miR-199a-5p and miR-214), down-regulated by RET/PTC1 , might cooperate in the regulation of the same networks.…”

Section: Discussionmentioning

confidence: 99%

miR-199a-3p displays tumor suppressor functions in papillary thyroid carcinoma

et al. 2014

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Thyroid cancer incidence is rapidly increasing. Papillary Thyroid Carcinoma (PTC), the most frequent hystotype, usually displays good prognosis, but no effective therapeutic options are available for the fraction of progressive PTC patients. BRAF and RET/PTC are the most frequent driving genetic lesions identified in PTC. We developed two complementary in vitro models based on RET/PTC1 oncogene, starting from the hypothesis that miRNAs modulated by a driving PTC-oncogene are likely to have a role in thyroid neoplastic processes. Through this strategy, we identified a panel of deregulated miRNAs. Among these we focused on miR-199a-3p and showed its under-expression in PTC specimens and cell lines. We demonstrated that miR-199a-3p restoration in PTC cells reduces MET and mTOR protein levels, impairs migration and proliferation and, more interesting, induces lethality through an unusual form of cell death similar to methuosis, caused by macropinocytosis dysregulation. Silencing MET or mTOR, both involved in survival pathways, does not recapitulate miR-199a-3p-induced cell lethality, thus suggesting that the cooperative regulation of multiple gene targets is necessary. Integrated analysis of miR-199a-3p targets unveils interesting networks including HGF and macropinocytosis pathways. Overall our results indicate miR-199a-3p as a tumor suppressor miRNA in PTC.

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“…IDO has become a gene of interest because expansion of Tregs has previously been shown to be induced in the presence of IDO, leading to immune tolerance against TAA (40). Arg-2 is known to be highly elevated in cancer patients with aggressive tumors (39,41,42); therefore, reduction in both IDO and Arg-2 expression can potentiate a better prognosis. Although we saw a reduction in Arg-2 and IDO in the Ad-LIGHT treated group, we conclude this is an adenovirus-mediated effect because vector controls also displayed a decreased expression of Arg-2 and IDO.…”

Section: Discussionmentioning

confidence: 99%

Forced LIGHT expression in prostate tumors overcomes Treg mediated immunosuppression and synergizes with a prostate tumor therapeutic vaccine by recruiting effector T lymphocytes

et al. 2014

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Background LIGHT, a ligand for lymphotoxin-β receptor (LTβR) and herpes virus entry mediator, is predominantly expressed on activated immune cells and LTβR signaling leads to the recruitment of lymphocytes. The interaction between LIGHT and LTβR has been previously shown in a virus induced tumor model to activate immune cells and result in tumor regression, but the role of LIGHT in tumor immunosuppression or in a prostate cancer setting, where self antigens exist, has not been explored. We hypothesized that forced expression of LIGHT in prostate tumors would shift the pattern of immune cell infiltration, would inhibit T regulatory cells (Tregs) and would induce prostate cancer tumor associated antigen (TAA) specific T cells that would eradicate tumors. Methods Real Time PCR was used to evaluate expression of forced LIGHT and various other genes in prostate tumors samples. Adenovirus encoding murine LIGHT was injected intratumorally into TRAMP C2 prostate cancer cell tumor bearing mice for in vivo studies. Chemokine and cytokine concentrations were determined by multiplex ELISA. Flow cytometry was used to phenotype tumor infiltrating lymphocytes and expression of LIGHT on the tumor cell surface. Tumor specific lymphocytes were quantified via an ELISpot assay. Treg induction and Treg suppression assays determined Treg functionality after LIGHT treatment. Results LIGHT expression peaked within 48 hours of infection, recruited effector T cells into the tumor microenvironment that recognized mouse prostate stem cell antigen (PSCA) and inhibited the infiltration of Tregs. Tregs isolated from tumor draining lymph nodes had impaired suppressive capability after LIGHT treatment. LIGHT in combination with a therapeutic vaccine, PSCA TriVax, reduced tumor burden. Conclusion Forced LIGHT treatment combined with PSCA TriVax therapeutic vaccination delays prostate cancer progression in mice by recruiting effector T lymphocytes to the tumor and inhibiting Treg mediated immunosuppression.

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Arginase 2 and nitric oxide synthase: Pathways associated with the pathogenesis of thyroid tumors

Cited by 31 publications

References 34 publications

Mechanistic Investigations Into the Developmental Toxicity of Nitrated and Heterocyclic PAHs

Mechanistic Investigations Into the Developmental Toxicity of Nitrated and Heterocyclic PAHs

miR-199a-3p displays tumor suppressor functions in papillary thyroid carcinoma

Forced LIGHT expression in prostate tumors overcomes Treg mediated immunosuppression and synergizes with a prostate tumor therapeutic vaccine by recruiting effector T lymphocytes

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