Ana Gamero - Academia.edu (original) (raw)

Papers by Ana Gamero

An experimental study on the asymmetry of the Balmer H{sub } profile in plasmas produced by micro... more An experimental study on the asymmetry of the Balmer H{sub } profile in plasmas produced by microwaves at atmospheric pressure is presented. The asymmetry of the whole profile is studied with the help of one function that quantified this characteristic. The asymmetry and shape of the central valley is also studied with the definition of several parameters. The study shows

The Journal of Immunology, May 1, 2014

The Journal of Immunology, May 1, 2012

Clinical Cancer Research

We set out to determine whether advanced epithelial ovarian cancer (EOC) is associated with eleva... more We set out to determine whether advanced epithelial ovarian cancer (EOC) is associated with elevated serum and ascitic concentrations of the angiogenic factors angiogenin (ANG), basic fibroblastic growth factor (bFGF), and vascular endothelial growth factor (VEGF), and whether the expression of angiogenic factors was associated with tumor vascularity. Serum and ascitic samples were collected from previously untreated patients with FIGO stage III and IV EOC and stored at -70 degreesC. Levels of the three factors were determined by enzyme-linked immunoassay. Histological sections from paraffin blocks of ovarian cancers were stained immunochemically for factor VIII, CD34, and VEGF. Thirty-nine patients were studied, although not all had paired serum and ascitic samples. For each angiogenic factor, the following findings were noted: (a) there was a wide range in serum and ascitic fluid concentrations; (b) the mean serum concentration was higher (P < 0.05) than the mean concentration in normal serum; and (c) the mean serum concentration was lower (P < 0. 05) than the mean ascitic concentration. Overall, the most consistent pattern of elevated serum and ascitic concentrations was with bFGF. With serum samples, 38.9% of patients had a normal VEGF concentration, as did 15.3% for ANG and 7.7% for bFGF. In ascites, the VEGF concentration was in the range for normal serum in 24.5% of samples, compared to 39.4% for ANG and 2.8% for bFGF. In paired samples, both VEGF and bFGF showed higher ascitic concentrations in 100 and 88.3% of samples, compared to 53.3% for ANG. There was no correlation between the serum and/or ascitic concentration of one factor and that of another, suggesting that these factors are independently regulated. Staining with anti-CD34 was more sensitive and reliable than with anti-factor VIII. VEGF staining was most prominent in poorly differentiated tumors and was observed only on tumor cells. There was no correlation between the serum or ascitic concentrations of angiogenic factors and tumor vascularity. Advanced EOC is associated with raised serum and ascitic bFGF concentrations and with markedly elevated ascitic VEGF in most cases. Serum VEGF and serum and ascitic ANG are less often elevated. There was no correlation between the angiogenic profile in serum and ascites and tumor vascularity.

Journal of immunology (Baltimore, Md. : 1950), Jan 21, 2015

Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease, characterized by ... more Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease, characterized by a spectrum of autoantibodies that target multiple cellular components. Glomerulonephritis is a major cause of morbidity in patients with SLE. Little is known about the pathogenesis of SLE renal damage and compromised renal function. Activation of both Stat1 and Stat3 has been reported in lupus and lupus nephritis. The reciprocal activation of these two transcription factors may have a major impact on renal inflammation. To study the role of Stat1 in a lupus model, we induced lupus-like chronic graft-versus-host disease (cGVHD) in Stat1-knockout (KO) and wild-type (WT) mice by i.p. injection of class II-disparate bm12 splenocytes. WT recipients of these alloreactive cells developed anti-dsDNA autoantibodies starting at week 2 as expected, with a decline after week 4. In contrast, Stat1-KO hosts exhibited a prolonged and significant increase of anti-dsDNA autoantibody responses compared wi...

Journal of leukocyte biology, 2014

TLR agonists such as LPS and poly(I:C) induce expression of type I IFNs, such as IFN-α and -β, by... more TLR agonists such as LPS and poly(I:C) induce expression of type I IFNs, such as IFN-α and -β, by macrophages. To examine the role of IFN-β in the induction of ISGs by LPS, we compared the ability of LPS to induce ISGF3 activity and ISG expression in bone marrow-derived macrophages from WT and Ifnb1(-/-) mice. We found that LPS treatment activated ISGF3 and induced expression of ISGs such as Oas1, Mx1, Ddx58 (RIG-I), and Ifih1 (MDA5) in WT macrophages, but not in macrophages derived from Ifnb1(-/-) mice or Ifnar1(-/-) mice. The inability of LPS to induce activation of ISGF3 and ISG expression in Ifnb1(-/-) macrophages correlated with the failure of LPS to induce activation of STAT1 and -2 in these cells. Consistent with these findings, LPS treatment also failed to induce ISG expression in bone marrow-derived macrophages from Stat2 KO mice. Although activation of ISGF3 and induction of ISG expression by LPS was abrogated in Ifnb1(-/-) and Ifnar1(-/-) macrophages, activation of NF-κB ...

The ubiquitous plasma membrane transcobalamin II receptor (TC II-R) mediates uptake of cobalamin ... more The ubiquitous plasma membrane transcobalamin II receptor (TC II-R) mediates uptake of cobalamin (Cbl; vitamin B12), an essential micronutrient. Tumors often require more Cbl than normal tissue, and increased Cbl uptake may result from increased TC II-R expression. To examine whether Cbl could therefore be used as a carrier molecule to target a chemotherapy drug, we tested an analogue of Cbl with nitric oxide as a ligand, nitrosylcobalamin (NO-Cbl). Because interferon ␤ (IFN-␤) has antitumor effects and increases expression of some membrane receptors, we examined whether it may enhance the effects of NO-Cbl.

Journal of leukocyte biology, 2014

Mutations in the Trex1 are associated with a spectrum of type I IFN-dependent autoimmune diseases... more Mutations in the Trex1 are associated with a spectrum of type I IFN-dependent autoimmune diseases. Trex1 plays an essential role in preventing accumulation of excessive cytoplasmic DNA, avoiding cell-intrinsic innate DNA sensor activation and suppressing activation of type I IFN-stimulated and -independent antiviral genes. Trex1 also helps HIV to escape cytoplasmic detection by DNA sensors. However, regulation of Trex1 in innate immune cells remains elusive. We report that murine cDCs have high constitutive expression of Trex1 in vitro and in vivo in the spleen. In resting bone marrow-derived cDCs, type I IFNs up-regulate Trex1 expression via the IFNAR-mediated signaling pathway (STAT1- and STAT2-dependent). DC activation induced by TLR3, -4, -7, and -9 ligands also augments Trex1 expression through autocrine IFN-β production and triggering of the IFN signaling pathway, whereas TLR4 ligand LPS also stimulates an early expression of Trex1 through IFN-independent NF-κB-dependent signa...

Proceedings of the National Academy of Sciences of the United States of America, Jan 5, 2014

Myeloid cells play a critical role in perpetuating inflammation during various chronic diseases. ... more Myeloid cells play a critical role in perpetuating inflammation during various chronic diseases. Recently the death of macrophages through programmed necrosis (necroptosis) has emerged as an important mechanism in inflammation and pathology. We evaluated the mechanisms that lead to the induction of necrotic cell death in macrophages. Our results indicate that type I IFN (IFN-I) signaling is a predominant mechanism of necroptosis, because macrophages deficient in IFN-α receptor type I (IFNAR1) are highly resistant to necroptosis after stimulation with LPS, polyinosinic-polycytidylic acid, TNF-α, or IFN-β in the presence of caspase inhibitors. IFN-I-induced necroptosis occurred through both mechanisms dependent on and independent of Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) and led to persistent phosphorylation of receptor-interacting protein 3 (Rip3) kinase, which resulted in potent necroptosis. Although various IFN-regulatory factors (IRFs) facilitated the i...

The Cancer Handbook, 2005

Molecular Biology of the Cell, 2007

Here we describe a mutation in STAT2 that confers an apoptotic effect in tumor cells in response ... more Here we describe a mutation in STAT2 that confers an apoptotic effect in tumor cells in response to type I IFNs. This mutation was introduced in a conserved motif, PYTK, located in the STAT SH2 domain, which is shared by STAT1, STAT2, and STAT3. To test whether the tyrosine in this motif might be phosphorylated and affect signaling, Y631 of STAT2 was mutated to phenylalanine (Y631F). Although it was determined that Y631 was not phosphorylated, the Y631F mutation conferred sustained signaling and induction of IFN-stimulated genes. This prolonged IFN response was associated with sustained tyrosine phosphorylation of STAT1 and STAT2 and their mutual association as heterodimers, which resulted from resistance to dephosphorylation by the nuclear tyrosine phosphatase TcPTP. Finally, cells bearing the Y631F mutation in STAT2 underwent apoptosis after IFN-␣ stimulation compared with wild-type STAT2. Therefore, this mutation reveals that a prolonged response to IFN-␣ could account for one difference between tumor cell lines that undergo IFN-␣-induced apoptosis compared with those that display an antiproliferative response but do not die.

CancerSpectrum Knowledge Environment, 2002

Background-The ubiquitous plasma membrane transcobalamin II receptor (TC II-R) mediates uptake of... more Background-The ubiquitous plasma membrane transcobalamin II receptor (TC II-R) mediates uptake of cobalamin (Cbl; vitamin B12), an essential micronutrient. Tumors often require more Cbl than normal tissue, and increased Cbl uptake may result from increased TC II-R expression. To examine whether Cbl could therefore be used as a carrier molecule to target a chemotherapy drug, we tested an analogue of Cbl with nitric oxide as a ligand, nitrosylcobalamin (NO-Cbl). Because interferon β (IFN-β) has antitumor effects and increases expression of some membrane receptors, we examined whether it may enhance the effects of NO-Cbl.

International Journal of Gynecological Cancer, 1998

Objective: To determine the levels of interleukin 12 (IL-12) in the ascites from patients diagnos... more Objective: To determine the levels of interleukin 12 (IL-12) in the ascites from patients diagnosed with advanced epithelial ovarian cancer. Methods: Ascites samples from advanced ovarian cancer patients and peritoneal fluid from normal controls and ...

Current Medicinal Chemistry, 2007

Interferons (IFNs) are a family of pleiotropic cytokines that typically exhibit antiviral, antipr... more Interferons (IFNs) are a family of pleiotropic cytokines that typically exhibit antiviral, antiproliferative, antitumor, and immunomodulatory properties. While their complex mechanisms of action remain unclear, IFNs are used clinically in the treatment of viral infections, such as hepatitis B and hepatitis C, and remain the primary treatment for a limited number of malignancies, such as melanoma, hairy cell leukemia, and non-Hodgkin's lymphoma and in autoimmune diseases such as multiple sclerosis. IFNs not only regulate somatic cell growth and division but also influence cell survival through the modulation of apoptosis. Paradoxically, IFNs are described to be both pro- and anti-apoptotic in nature. The biological effects of IFNs are primarily mediated via activation of the JAK/STAT pathway, formation of the ISGF3 and STAT1:STAT1 protein complexes, and the subsequent induction of IFN-stimulated genes. However, the activation of JAK/STAT-independent signal transduction pathways also contribute to IFN-mediated responses. To further demonstrate the complexity of the downstream events following stimulation, oligonucleotide microarray studies have shown that in excess of 300 genes are induced following treatment with IFN, some of which are crucial to the induction of apoptosis and cell growth control. In this review we describe the recent advances made in elucidating the various signaling pathways that are activated by IFNs and how these diverse signals contribute to the regulation of cell growth and apoptosis and inhibition of viral replication. Furthermore, we highlight the role of specific signaling molecules and the function(s) of particular IFN-stimulated genes that have been implicated in determining cell fate in response to IFN, as well as the clinical experience of IFN immunotherapy.

Cancer Prevention Research, 2010

Cancer Prevention Research, 2010

STAT2 is an essential transcription factor in the type I interferon (IFN-α/β) signal transduction... more STAT2 is an essential transcription factor in the type I interferon (IFN-α/β) signal transduction pathway and known for its role in mediating antiviral immunity and cell growth inhibition. Unlike other members of the STAT family, IFNs are the only cytokines known to date that can activate STAT2. Given the inflammatory and antiproliferative dual nature of IFNs, we hypothesized that STAT2 prevents inflammation-induced colorectal and skin carcinogenesis by altering the inflammatory immune response. Contrary to our hypothesis, deletion of STAT2 inhibited AOM/ DSS-induced colorectal carcinogenesis as measured by prolonged survival, lower adenoma incidence, smaller polyps, and less chronic inflammation. STAT2 deficiency also inhibited DMBA/ TPA-induced skin carcinogenesis as indicated by reduced papilloma multiplicity. A potential mechanism by which STAT2 promotes carcinogenesis is through activation of pro-inflammatory mediators. Deletion of STAT2 decreased AOM/DSS-induced expression and release of proinflammatory mediators such as interleukin 6 and CCL2 and decreased interleukin-6 release from skin carcinoma cells, which then decreased STAT3 activation. Our findings identify STAT2 as a novel contributor to colorectal and skin carcinogenesis that may act to increase the gene expression and secretion of pro-inflammatory mediators, which in turn activate the oncogenic STAT3 signaling pathway.

An experimental study on the asymmetry of the Balmer H{sub } profile in plasmas produced by micro... more An experimental study on the asymmetry of the Balmer H{sub } profile in plasmas produced by microwaves at atmospheric pressure is presented. The asymmetry of the whole profile is studied with the help of one function that quantified this characteristic. The asymmetry and shape of the central valley is also studied with the definition of several parameters. The study shows

The Journal of Immunology, May 1, 2014

The Journal of Immunology, May 1, 2012

Clinical Cancer Research

We set out to determine whether advanced epithelial ovarian cancer (EOC) is associated with eleva... more We set out to determine whether advanced epithelial ovarian cancer (EOC) is associated with elevated serum and ascitic concentrations of the angiogenic factors angiogenin (ANG), basic fibroblastic growth factor (bFGF), and vascular endothelial growth factor (VEGF), and whether the expression of angiogenic factors was associated with tumor vascularity. Serum and ascitic samples were collected from previously untreated patients with FIGO stage III and IV EOC and stored at -70 degreesC. Levels of the three factors were determined by enzyme-linked immunoassay. Histological sections from paraffin blocks of ovarian cancers were stained immunochemically for factor VIII, CD34, and VEGF. Thirty-nine patients were studied, although not all had paired serum and ascitic samples. For each angiogenic factor, the following findings were noted: (a) there was a wide range in serum and ascitic fluid concentrations; (b) the mean serum concentration was higher (P < 0.05) than the mean concentration in normal serum; and (c) the mean serum concentration was lower (P < 0. 05) than the mean ascitic concentration. Overall, the most consistent pattern of elevated serum and ascitic concentrations was with bFGF. With serum samples, 38.9% of patients had a normal VEGF concentration, as did 15.3% for ANG and 7.7% for bFGF. In ascites, the VEGF concentration was in the range for normal serum in 24.5% of samples, compared to 39.4% for ANG and 2.8% for bFGF. In paired samples, both VEGF and bFGF showed higher ascitic concentrations in 100 and 88.3% of samples, compared to 53.3% for ANG. There was no correlation between the serum and/or ascitic concentration of one factor and that of another, suggesting that these factors are independently regulated. Staining with anti-CD34 was more sensitive and reliable than with anti-factor VIII. VEGF staining was most prominent in poorly differentiated tumors and was observed only on tumor cells. There was no correlation between the serum or ascitic concentrations of angiogenic factors and tumor vascularity. Advanced EOC is associated with raised serum and ascitic bFGF concentrations and with markedly elevated ascitic VEGF in most cases. Serum VEGF and serum and ascitic ANG are less often elevated. There was no correlation between the angiogenic profile in serum and ascites and tumor vascularity.

Journal of immunology (Baltimore, Md. : 1950), Jan 21, 2015

Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease, characterized by ... more Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease, characterized by a spectrum of autoantibodies that target multiple cellular components. Glomerulonephritis is a major cause of morbidity in patients with SLE. Little is known about the pathogenesis of SLE renal damage and compromised renal function. Activation of both Stat1 and Stat3 has been reported in lupus and lupus nephritis. The reciprocal activation of these two transcription factors may have a major impact on renal inflammation. To study the role of Stat1 in a lupus model, we induced lupus-like chronic graft-versus-host disease (cGVHD) in Stat1-knockout (KO) and wild-type (WT) mice by i.p. injection of class II-disparate bm12 splenocytes. WT recipients of these alloreactive cells developed anti-dsDNA autoantibodies starting at week 2 as expected, with a decline after week 4. In contrast, Stat1-KO hosts exhibited a prolonged and significant increase of anti-dsDNA autoantibody responses compared wi...

Journal of leukocyte biology, 2014

TLR agonists such as LPS and poly(I:C) induce expression of type I IFNs, such as IFN-α and -β, by... more TLR agonists such as LPS and poly(I:C) induce expression of type I IFNs, such as IFN-α and -β, by macrophages. To examine the role of IFN-β in the induction of ISGs by LPS, we compared the ability of LPS to induce ISGF3 activity and ISG expression in bone marrow-derived macrophages from WT and Ifnb1(-/-) mice. We found that LPS treatment activated ISGF3 and induced expression of ISGs such as Oas1, Mx1, Ddx58 (RIG-I), and Ifih1 (MDA5) in WT macrophages, but not in macrophages derived from Ifnb1(-/-) mice or Ifnar1(-/-) mice. The inability of LPS to induce activation of ISGF3 and ISG expression in Ifnb1(-/-) macrophages correlated with the failure of LPS to induce activation of STAT1 and -2 in these cells. Consistent with these findings, LPS treatment also failed to induce ISG expression in bone marrow-derived macrophages from Stat2 KO mice. Although activation of ISGF3 and induction of ISG expression by LPS was abrogated in Ifnb1(-/-) and Ifnar1(-/-) macrophages, activation of NF-κB ...

The ubiquitous plasma membrane transcobalamin II receptor (TC II-R) mediates uptake of cobalamin ... more The ubiquitous plasma membrane transcobalamin II receptor (TC II-R) mediates uptake of cobalamin (Cbl; vitamin B12), an essential micronutrient. Tumors often require more Cbl than normal tissue, and increased Cbl uptake may result from increased TC II-R expression. To examine whether Cbl could therefore be used as a carrier molecule to target a chemotherapy drug, we tested an analogue of Cbl with nitric oxide as a ligand, nitrosylcobalamin (NO-Cbl). Because interferon ␤ (IFN-␤) has antitumor effects and increases expression of some membrane receptors, we examined whether it may enhance the effects of NO-Cbl.

Journal of leukocyte biology, 2014

Mutations in the Trex1 are associated with a spectrum of type I IFN-dependent autoimmune diseases... more Mutations in the Trex1 are associated with a spectrum of type I IFN-dependent autoimmune diseases. Trex1 plays an essential role in preventing accumulation of excessive cytoplasmic DNA, avoiding cell-intrinsic innate DNA sensor activation and suppressing activation of type I IFN-stimulated and -independent antiviral genes. Trex1 also helps HIV to escape cytoplasmic detection by DNA sensors. However, regulation of Trex1 in innate immune cells remains elusive. We report that murine cDCs have high constitutive expression of Trex1 in vitro and in vivo in the spleen. In resting bone marrow-derived cDCs, type I IFNs up-regulate Trex1 expression via the IFNAR-mediated signaling pathway (STAT1- and STAT2-dependent). DC activation induced by TLR3, -4, -7, and -9 ligands also augments Trex1 expression through autocrine IFN-β production and triggering of the IFN signaling pathway, whereas TLR4 ligand LPS also stimulates an early expression of Trex1 through IFN-independent NF-κB-dependent signa...

Proceedings of the National Academy of Sciences of the United States of America, Jan 5, 2014

Myeloid cells play a critical role in perpetuating inflammation during various chronic diseases. ... more Myeloid cells play a critical role in perpetuating inflammation during various chronic diseases. Recently the death of macrophages through programmed necrosis (necroptosis) has emerged as an important mechanism in inflammation and pathology. We evaluated the mechanisms that lead to the induction of necrotic cell death in macrophages. Our results indicate that type I IFN (IFN-I) signaling is a predominant mechanism of necroptosis, because macrophages deficient in IFN-α receptor type I (IFNAR1) are highly resistant to necroptosis after stimulation with LPS, polyinosinic-polycytidylic acid, TNF-α, or IFN-β in the presence of caspase inhibitors. IFN-I-induced necroptosis occurred through both mechanisms dependent on and independent of Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) and led to persistent phosphorylation of receptor-interacting protein 3 (Rip3) kinase, which resulted in potent necroptosis. Although various IFN-regulatory factors (IRFs) facilitated the i...

The Cancer Handbook, 2005

Molecular Biology of the Cell, 2007

Here we describe a mutation in STAT2 that confers an apoptotic effect in tumor cells in response ... more Here we describe a mutation in STAT2 that confers an apoptotic effect in tumor cells in response to type I IFNs. This mutation was introduced in a conserved motif, PYTK, located in the STAT SH2 domain, which is shared by STAT1, STAT2, and STAT3. To test whether the tyrosine in this motif might be phosphorylated and affect signaling, Y631 of STAT2 was mutated to phenylalanine (Y631F). Although it was determined that Y631 was not phosphorylated, the Y631F mutation conferred sustained signaling and induction of IFN-stimulated genes. This prolonged IFN response was associated with sustained tyrosine phosphorylation of STAT1 and STAT2 and their mutual association as heterodimers, which resulted from resistance to dephosphorylation by the nuclear tyrosine phosphatase TcPTP. Finally, cells bearing the Y631F mutation in STAT2 underwent apoptosis after IFN-␣ stimulation compared with wild-type STAT2. Therefore, this mutation reveals that a prolonged response to IFN-␣ could account for one difference between tumor cell lines that undergo IFN-␣-induced apoptosis compared with those that display an antiproliferative response but do not die.

CancerSpectrum Knowledge Environment, 2002

Background-The ubiquitous plasma membrane transcobalamin II receptor (TC II-R) mediates uptake of... more Background-The ubiquitous plasma membrane transcobalamin II receptor (TC II-R) mediates uptake of cobalamin (Cbl; vitamin B12), an essential micronutrient. Tumors often require more Cbl than normal tissue, and increased Cbl uptake may result from increased TC II-R expression. To examine whether Cbl could therefore be used as a carrier molecule to target a chemotherapy drug, we tested an analogue of Cbl with nitric oxide as a ligand, nitrosylcobalamin (NO-Cbl). Because interferon β (IFN-β) has antitumor effects and increases expression of some membrane receptors, we examined whether it may enhance the effects of NO-Cbl.

International Journal of Gynecological Cancer, 1998

Objective: To determine the levels of interleukin 12 (IL-12) in the ascites from patients diagnos... more Objective: To determine the levels of interleukin 12 (IL-12) in the ascites from patients diagnosed with advanced epithelial ovarian cancer. Methods: Ascites samples from advanced ovarian cancer patients and peritoneal fluid from normal controls and ...

Current Medicinal Chemistry, 2007

Interferons (IFNs) are a family of pleiotropic cytokines that typically exhibit antiviral, antipr... more Interferons (IFNs) are a family of pleiotropic cytokines that typically exhibit antiviral, antiproliferative, antitumor, and immunomodulatory properties. While their complex mechanisms of action remain unclear, IFNs are used clinically in the treatment of viral infections, such as hepatitis B and hepatitis C, and remain the primary treatment for a limited number of malignancies, such as melanoma, hairy cell leukemia, and non-Hodgkin's lymphoma and in autoimmune diseases such as multiple sclerosis. IFNs not only regulate somatic cell growth and division but also influence cell survival through the modulation of apoptosis. Paradoxically, IFNs are described to be both pro- and anti-apoptotic in nature. The biological effects of IFNs are primarily mediated via activation of the JAK/STAT pathway, formation of the ISGF3 and STAT1:STAT1 protein complexes, and the subsequent induction of IFN-stimulated genes. However, the activation of JAK/STAT-independent signal transduction pathways also contribute to IFN-mediated responses. To further demonstrate the complexity of the downstream events following stimulation, oligonucleotide microarray studies have shown that in excess of 300 genes are induced following treatment with IFN, some of which are crucial to the induction of apoptosis and cell growth control. In this review we describe the recent advances made in elucidating the various signaling pathways that are activated by IFNs and how these diverse signals contribute to the regulation of cell growth and apoptosis and inhibition of viral replication. Furthermore, we highlight the role of specific signaling molecules and the function(s) of particular IFN-stimulated genes that have been implicated in determining cell fate in response to IFN, as well as the clinical experience of IFN immunotherapy.

Cancer Prevention Research, 2010

Cancer Prevention Research, 2010

STAT2 is an essential transcription factor in the type I interferon (IFN-α/β) signal transduction... more STAT2 is an essential transcription factor in the type I interferon (IFN-α/β) signal transduction pathway and known for its role in mediating antiviral immunity and cell growth inhibition. Unlike other members of the STAT family, IFNs are the only cytokines known to date that can activate STAT2. Given the inflammatory and antiproliferative dual nature of IFNs, we hypothesized that STAT2 prevents inflammation-induced colorectal and skin carcinogenesis by altering the inflammatory immune response. Contrary to our hypothesis, deletion of STAT2 inhibited AOM/ DSS-induced colorectal carcinogenesis as measured by prolonged survival, lower adenoma incidence, smaller polyps, and less chronic inflammation. STAT2 deficiency also inhibited DMBA/ TPA-induced skin carcinogenesis as indicated by reduced papilloma multiplicity. A potential mechanism by which STAT2 promotes carcinogenesis is through activation of pro-inflammatory mediators. Deletion of STAT2 decreased AOM/DSS-induced expression and release of proinflammatory mediators such as interleukin 6 and CCL2 and decreased interleukin-6 release from skin carcinoma cells, which then decreased STAT3 activation. Our findings identify STAT2 as a novel contributor to colorectal and skin carcinogenesis that may act to increase the gene expression and secretion of pro-inflammatory mediators, which in turn activate the oncogenic STAT3 signaling pathway.