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1.
Int J Mol Sci ; 24(7)2023 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-37047583

RESUMO

Malic Enzyme 1 (ME1) supports lipogenesis, cholesterol synthesis, and cellular redox potential by catalyzing the decarboxylation of L-malate to pyruvate, and the concomitant reduction of NADP to NADPH. We examined the contribution of ME1 to the development of obesity by provision of an obesogenic diet to C57BL/6 wild type (WT) and MOD-1 (lack ME1 protein) female mice. Adiposity, serum hormone levels, and adipose, mammary gland, liver, and small intestine gene expression patterns were compared between experimental groups after 10 weeks on a diet. Relative to WT female mice, MOD-1 female mice exhibited lower body weights and less adiposity; decreased concentrations of insulin, leptin, and estrogen; higher concentrations of adiponectin and progesterone; smaller-sized mammary gland adipocytes; and reduced hepatosteatosis. MOD-1 mice had diminished expression of Lep gene in abdominal fat; Lep, Pparg, Klf9, and Acaca genes in mammary glands; Pparg and Cdkn1a genes in liver; and Tlr9 and Ffar3 genes in the small intestine. By contrast, liver expression of Cdkn2a and Lepr genes was augmented in MOD-1, relative to WT mice. Results document an integrative role for ME1 in development of female obesity, suggest novel linkages with specific pathways/genes, and further support the therapeutic targeting of ME1 for obesity, diabetes, and fatty liver disease.


Assuntos
Leptina , Hepatopatia Gordurosa não Alcoólica , Camundongos , Feminino , Animais , Leptina/metabolismo , Insulina/metabolismo , Adiposidade/genética , Camundongos Obesos , PPAR gama/metabolismo , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/metabolismo , Fígado/metabolismo , Insulina Regular Humana , Hepatopatia Gordurosa não Alcoólica/metabolismo , Dieta Hiperlipídica
2.
Carcinogenesis ; 36(9): 946-55, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26210742

RESUMO

UNLABELLED: Expression of the transcription factor Krüppel-like factor 9 (KLF9) is frequently reduced in colorectal cancers, although a tumor suppressive role has not been established. To determine if KLF9 suppresses intestinal adenoma formation, we generated mice of distinct Klf9 genotypes in the background of the Apc (Min/+) mouse and compared their adenoma burdens at 16 weeks of age. While small intestine adenoma burden remained unchanged among Klf9 genotypes, male and female Apc(Min/+)/Klf9(-/-) and Apc(Min/+)/Klf9(+/-) mice exhibited significantly more colon adenomas than their Apc(Min/+)/Klf9(+/+) counterparts. Microarray analysis showed significant increases in the expression of interferon-induced genes in the colon mucosa of female Apc (Min/+)/Klf9(+/-) and Apc(Min/+)/Klf9(-/-) compared to Apc(Min/+)/Klf9(+/+) mice, prior to overt adenoma occurrence. Gene upregulation was confirmed by qPCR of colon mucosa and by siRNA knockdown of KLF9 in human HT29 colorectal cancer cells. Increases in expression of these genes were further augmented by supplementation with Interferon ß1. Circulating levels of the cytokine, interferon-stimulated gene 15 (ISG15) were increased in Apc(Min/+)/Klf9(+/-) and Apc(Min/+)/Klf9(-/-) mice relative to Apc(Min/+)/Klf9(+/+). Additionally, colon mucosal levels of ISG15 were increased in Apc(Min/+)/Klf9(+/-) mice. Chromatin immunoprecipitation demonstrated KLF9 recruitment to the ISG15 promoter. Lastly, treatment with ISG15 suppressed apoptosis in HT29 cells, in the presence and absence of 5-fluorouracil (5FU). Results show KLF9 to be a haploinsufficient suppressor of colon tumorigenesis in Apc(Min/+) mice in part, by repression of ISG15 and the latter's antiapoptotic function. SUMMARY: Krüppel-like factor 9 (KLF9) is a haploinsufficient tumor suppressor in the ApcMin/+ mouse colon by suppressing expression of ISG15, an apoptosis-inhibiting cytokine.


Assuntos
Neoplasias Colorretais/genética , Citocinas/genética , Fatores de Transcrição Kruppel-Like/genética , Ubiquitinas/genética , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Citocinas/metabolismo , Citocinas/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica , Células HT29 , Haploinsuficiência/genética , Humanos , Interferon beta/farmacologia , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Regiões Promotoras Genéticas/genética , Interferência de RNA , RNA Interferente Pequeno , Transdução de Sinais/genética , Ubiquitinas/metabolismo , Ubiquitinas/farmacologia
3.
Biol Reprod ; 92(6): 140, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25904015

RESUMO

Krüppel-like Factor (KLF) 13 and the closely related KLF9 are members of the Sp/KLF family of transcription factors that have collectively emerged as essential regulators of tissue development, differentiation, proliferation, and programmed cell death. Steroid hormone-responsive tissues express multiple KLFs that are linked to progesterone receptor (PGR) and estrogen receptor (ESR) actions either as integrators or as coregulators. Endometriosis is a chronic disease characterized by progesterone resistance and dysregulated estradiol signaling; nevertheless, distinct KLF members' contributions to endometriosis remain largely undefined. We previously demonstrated promotion of ectopic lesion establishment by Klf9 null endometrium in a mouse model of endometriosis. Here we evaluated whether KLF13 loss of expression in endometrial cells may equally contribute to lesion formation. KLF13 transcript levels were lower in the eutopic endometria of women with versus women without endometriosis at menstrual midsecretory phase. In wild-type (WT) mouse recipients intraperitoneally administered WT or Klf13 null endometrial fragments, lesion incidence did not differ with donor genotype. No differences were noted for lesion volume, number, proliferation status, and apoptotic index as well. Klf13 null lesions displayed reduced total PGR and ESR1 (RNA and immunoreactive protein) and altered expression of several PGR and ESR1 target genes, relative to WT lesions. Unlike for Klf9 null lesions, changes in transcript levels for PGR-A, ESR1, and Notch/Hedgehog-associated pathway components were not observed for Klf13 null lesions. Results demonstrate lack of a causative relationship between endometrial KLF13 deficiency and lesion establishment in mice, and they support the broader participation of multiple signaling pathways, besides those mediated by steroid receptors, in the pathology of endometriosis.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Endometriose/metabolismo , Endométrio/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais/genética , Animais , Apoptose/genética , Proteínas de Ciclo Celular/genética , Diferenciação Celular/genética , Modelos Animais de Doenças , Endometriose/genética , Endometriose/patologia , Endométrio/patologia , Estradiol/sangue , Feminino , Humanos , Fatores de Transcrição Kruppel-Like/genética , Camundongos , Camundongos Knockout , Progesterona/sangue , Proteínas Repressoras/genética
4.
Carcinogenesis ; 35(9): 2102-12, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24832086

RESUMO

Many adult chronic diseases are thought to be influenced during early life by maternal nutrition; however, the underlying mechanisms remain largely unknown. Obesity-related diseases may be due partly to high fat consumption. Herein, we evaluated mammary tumor risk in female mouse mammary tumor virus-Wnt-1 transgenic (Tg) offspring exposed to high-fat diet (HFD) or control diet (CD) (45% and 17% kcal from fat, respectively) during gestation and lactation, with CD provided to progeny at weaning. In Tg offspring, maternal HFD exposure increased mammary tumor incidence and decreased tumor latency without affecting tumor volume. Tumor risk was associated with higher tumor necrosis factor-α and insulin and altered oxidative stress biomarkers in sera and with early changes in mammary expression of genes linked to tumor promotion [interleukin 6 (Il6)] or inhibition [phosphatase and tensin homolog deleted on chromosome 10 (Pten), B-cell lymphoma 2 (Bcl2)]. Corresponding wild-type progeny exposed to maternal HFD displayed accelerated mammary development, higher mammary adiposity, increased insulin resistance and early changes in Pten, Bcl2 and Il6, than CD-exposed offspring. Dams-fed HFD showed higher serum glucose and oxidative stress biomarkers but comparable adiposity compared with CD-fed counterparts. In human breast cancer MCF-7 cells, sera from maternal HFD-exposed Tg offspring elicited changes in PTEN, BCL2 and IL6 gene expression, mimicking in vivo exposure; increased cell viability and mammosphere formation and induced measures [insulin receptor substrate-1 (IRS-1), IRS-2] of insulin sensitivity. Serum effects on IRS-1 were recapitulated by exogenous insulin and the PTEN-specific inhibitor SF1670. Hyperinsulinemia and PTEN loss-of-function may thus, couple maternal HFD exposure to enhanced insulin sensitivity via increased mammary IRS-1 expression in progeny, to promote breast cancer risk.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Neoplasias Mamárias Experimentais/etiologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Proteína Wnt1/fisiologia , Animais , Animais Lactentes , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Lactação , Células MCF-7 , Masculino , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Estresse Oxidativo , Fenótipo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Fenômenos Fisiológicos da Nutrição Pré-Natal , Fatores de Risco , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
5.
Am J Physiol Lung Cell Mol Physiol ; 306(3): L269-76, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24285265

RESUMO

A hallmark of cigarette smoking is a shift in the protease/antiprotease balance, in favor of protease activity. However, it has recently been shown that smokers have increased expression of a key antiprotease, secretory leukoprotease inhibitor (SLPI), yet the mechanisms involved in SLPI transcriptional regulation and functional activity of SLPI remain unclear. We examined SLPI mRNA and protein secretion in differentiated nasal epithelial cells (NECs) and nasal lavage fluid (NLF) from nonsmokers and smokers and demonstrated that SLPI expression is increased in NECs and NLF from smokers. Transcriptional regulation of SLPI expression was confirmed using SLPI promoter reporter assays followed by chromatin immunoprecipitation. The role of STAT1 in regulating SLPI expression was further elucidated using WT and stat1(-/-) mice. Our data demonstrate that STAT1 regulates SLPI transcription in epithelial cells and slpi protein in the lungs of mice. Additionally, we reveal that NECs from smokers have increased STAT1 mRNA/protein expression. Finally, we demonstrate that SLPI contained in the nasal mucosa of smokers is proteolytically cleaved but retains functional activity against neutrophil elastase. These results demonstrate that smoking enhances expression of SLPI in NECs in vitro and in vivo, and that this response is regulated by STAT1. In addition, despite posttranslational cleavage of SLPI, antiprotease activity against neutrophil elastase is enhanced in smokers. Together, our findings show that SLPI regulation and activity is altered in the nasal mucosa of smokers, which could have broad implications in the context of respiratory inflammation and infection.


Assuntos
Inibidor Secretado de Peptidases Leucocitárias/biossíntese , Fumar/genética , Adulto , Animais , Células Epiteliais/metabolismo , Feminino , Humanos , Elastase de Leucócito/antagonistas & inibidores , Pulmão/metabolismo , Masculino , Camundongos , Líquido da Lavagem Nasal , Mucosa Nasal/metabolismo , Fator de Transcrição STAT1/biossíntese
6.
Carcinogenesis ; 34(2): 464-74, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23144318

RESUMO

Despite the well-accepted notion that early maternal influences persist beyond fetal life and may underlie many adult diseases, the risks imposed by the maternal environment on breast cancer development and underlying biological mechanisms remain poorly understood. In this study, we investigated whether early exposure to blueberry (BB) via maternal diet alters oncogene Wnt1-induced mammary tumorigenesis in offspring. Wnt1-transgenic female mice were exposed to maternal Casein (CAS, control) or blueberry-supplemented (CAS + 3%BB) diets throughout pregnancy and lactation. Offspring were weaned to CAS and mammary tumor development was followed until age 8 months. Tumor incidence and latency were similar for both groups; however, tumor weight at killing and tumor volume within 2 weeks of initial detection were lower (by 50 and 60%, respectively) in offspring of BB- versus control-fed dams. Dietary BB exposure beginning at weaning did not alter mammary tumor parameters. Tumors from maternal BB-exposed offspring showed higher tumor suppressor (Pten and Cdh1) and lower proproliferative (Ccnd1), anti-apoptotic (Bcl2) and proangiogenic (Figf, Flt1 and Ephb4) transcript levels, and displayed attenuated microvessel density. Expression of Pten and Cdh1 genes was also higher in mammary tissues of maternal BB-exposed offspring. Mammary tissues and tumors of maternal BB-exposed offspring showed increased chromatin-modifying enzyme Dnmt1 and Ezh2 transcript levels. Body weight, serum insulin and serum leptin/adiponectin ratio were lower for maternal BB-exposed than control tumor-bearing offspring. Tumor weights and serum insulin were positively correlated. Results suggest that dietary influences on the maternal environment contribute to key developmental programs in the mammary gland to modify breast cancer outcome in adult progeny.


Assuntos
Mirtilos Azuis (Planta) , Dieta , Insulina/sangue , Neoplasias Mamárias Animais/prevenção & controle , Fitoterapia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Proteína Wnt1/fisiologia , Animais , Western Blotting , Feminino , Humanos , Técnicas Imunoenzimáticas , Lactação , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Transgênicos , Gravidez , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais
7.
Int J Mol Sci ; 14(8): 16240-57, 2013 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-23924944

RESUMO

Thyroid hormones play a critical role in the growth and development of the alimentary tract in vertebrates. Their effects are mediated by nuclear receptors as well as the cell surface receptor integrin αVß3. Systemic thyroid hormone levels are controlled via activation and deactivation by iodothyronine deiodinases in the liver and other tissues. Given that thyroid hormone signaling has been characterized as a major effector of digestive system growth and homeostasis, numerous investigations have examined its role in the occurrence and progression of cancers in various tissues of this organ system. The present review summarizes current findings regarding the effects of thyroid hormone signaling on cancers of the esophagus, stomach, liver, pancreas, and colon. Particular attention is given to the roles of different thyroid hormone receptor isoforms, the novel integrin αVß3 receptor, and thyroid hormone-related nutrients as possible protective agents and therapeutic targets. Future investigations geared towards a better understanding of thyroid hormone signaling in digestive system cancers may provide preventive or therapeutic strategies to diminish risk, improve outcome and avert recurrence in afflicted individuals.


Assuntos
Neoplasias do Sistema Digestório/metabolismo , Neoplasias do Sistema Digestório/prevenção & controle , Integrina alfaVbeta3/metabolismo , Hormônios Tireóideos/metabolismo , Humanos , Iodeto Peroxidase/metabolismo , Fígado/metabolismo , Isoformas de Proteínas/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Transdução de Sinais , Glândula Tireoide/metabolismo
8.
Cancers (Basel) ; 15(23)2023 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-38067370

RESUMO

Specificity Proteins/Krüppel-like Factors (SP/KLF family) are a conserved family of transcriptional regulators. These proteins share three highly conserved, contiguous zinc fingers in their carboxy-terminus, requisite for binding to cis elements in DNA. Each SP/KLF protein has unique primary sequence within its amino-terminal and carboxy-terminal regions, and it is these regions which interact with co-activators, co-repressors, and chromatin-modifying proteins to support the transcriptional activation and repression of target genes. Krüppel-like Factor 9 (KLF9) and Krüppel-like Factor 13 (KLF13) are two of the smallest members of the SP/KLF family, are paralogous, emerged early in metazoan evolution, and are highly conserved. Paradoxically, while most similar in primary sequence, KLF9 and KLF13 display many distinct roles in target cells. In this article, we summarize the work that has identified the roles of KLF9 (and to a lesser degree KLF13) in tumor suppression or promotion via unique effects on differentiation, pro- and anti-inflammatory pathways, oxidative stress, and tumor immune cell infiltration. We also highlight the great diversity of miRNAs, lncRNAs, and circular RNAs which provide mechanisms for the ubiquitous tumor-specific suppression of KLF9 mRNA and protein. Elucidation of KLF9 and KLF13 in cancer biology is likely to provide new inroads to the understanding of oncogenesis and its prevention and treatments.

9.
Reprod Sci ; 30(8): 2429-2438, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36788175

RESUMO

Endometriosis (ENDO) is a chronic estrogen-dependent gynecological condition that affects reproductive-age women, causing pelvic pain, infertility, and increased risk for ovarian cancer. Diabetes mellitus (DM) is a metabolic disease with significant morbidity and mortality and rising incidence worldwide. The occurrence of DM among ENDO patients remains understudied, despite commonalities in these conditions' immune, inflammatory, and metabolic dysfunctions. This pilot study evaluated whether a subset of women with ENDO manifests DM co-morbidity and if so, whether DM promotes ENDO status. Archived ectopic lesions obtained at ENDO surgery from non-diabetic (ENDO-N; n = 11) and diabetic (ENDO-DM; n = 15) patients were identified by a search of an electronic health database. Retrieved samples were analyzed by immunohistochemistry for markers of proliferation (Ki67, PTEN), steroid receptor signaling (ESR, PGR) and macrophage infiltration (CD68). Immunostaining data were expressed as percentages of immune-positive cells in lesion stroma and epithelium. In lesion stroma, the percentages of nuclear immune-positive cells were higher for ESR2 and lower for PGR-T, in ENDO-DM than ENDO-N patients. The percentages of nuclear immune-positive cells for ESR1 and PTEN tended to be higher and lower, respectively, in ENDO-DM than ENDO-N groups. In lesion glandular epithelium, the percentages of nuclear immune-positive cells were higher for ESR1 and ESR2, in ENDO-DM than ENDO-N groups. ENDO-N lesions had lower percentages of stromal CD68 immune-positive cells than ENDO-DM Type 1 lesions. Findings demonstrate DM in a subset of women with ENDO, which was associated with significant changes in lesion stromal and epithelial nuclear steroid hormone receptor levels, suggestive of disease progression.


Assuntos
Diabetes Mellitus , Endometriose , Humanos , Feminino , Endometriose/metabolismo , Projetos Piloto , Regulação da Expressão Gênica , Estrogênios/metabolismo , Transdução de Sinais , Receptores Citoplasmáticos e Nucleares , Endométrio/metabolismo , Diabetes Mellitus/metabolismo
10.
Carcinogenesis ; 33(3): 652-60, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22219179

RESUMO

Mammary stem cells are undifferentiated epithelial cells, which initiate mammary tumors and render them resistant to anticancer therapies, when deregulated. Diets rich in fruits and vegetables are implicated in breast cancer risk reduction, yet underlying mechanisms are poorly understood. Here, we addressed whether dietary factors selectively target mammary epithelial cells that display stem-like/progenitor subpopulations with previously recognized tumor-initiating potential. Using estrogen receptor-positive MCF-7 and estrogen receptor-negative MDA-MB-231 human breast cancer cell lines and freshly isolated epithelial cells from MMTV-Wnt-1 transgenic mouse mammary tumors, we demonstrate that sera of adult mice consuming soy isoflavone genistein (GEN) or blueberry (BB) polyphenol-containing diets alter the population of stem-like/progenitor cells, as measured by their functional ability to self-renew and form anchorage-independent spheroid cultures in vitro at low frequency (1-2%). Serum effects on mammosphere formation were dose-dependently replicated by GEN (40 nM >2 µM) and targeted the basal stem-like CD44+/CD24-/ESA+ and the luminal progenitor CD24+ subpopulations in MDA-MB-231 and MCF-7 cells. GEN inhibition of mammosphere formation was mimicked by the Akt inhibitor perifosine and was associated with enhanced tumor suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN) expression. In contrast, a selected mixture of BB phenolic acids was only active in MDA-MD-231 cells and its CD44+/CD24-/ESA+ subpopulation, and this activity was independent of induction of PTEN expression. These findings delineate a novel and selective function of distinct dietary factors in targeting stem/progenitor cell populations in estrogen receptor-dependent and -independent breast cancers.


Assuntos
Mirtilos Azuis (Planta) , Neoplasias da Mama/tratamento farmacológico , Genisteína/farmacologia , Isoflavonas/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Neoplasias da Mama/patologia , Antígeno CD24/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , PTEN Fosfo-Hidrolase/metabolismo , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Polifenóis/química , Polifenóis/farmacologia , Proteínas de Soja/farmacologia
11.
Biol Reprod ; 87(5): 115, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22993382

RESUMO

The ovarian hormones estrogen and progesterone promote uterine receptivity and successful pregnancy through their cognate receptors functioning in concert with context-dependent nuclear coregulators. Previously, we showed that the transcription factor Krüppel-like factor (KLF) 9 is a progesterone receptor (PGR) coactivator in the uterus and that mice null for Klf9 exhibit subfertility and reduced progesterone sensitivity. The highly related family member KLF13 displays increased expression in uteri of pregnant and nonpregnant Klf9 null mice and similarly regulates PGR-mediated transactivation in endometrial stromal cells. However, a uterine phenotype with loss of Klf13 has not been reported. In the present study, we demonstrate that Klf13 deficiency in mice did not compromise female fertility and pregnancy outcome. Klf13 null females had litter sizes, numbers of implanting embryos, uterine morphology, and ovarian steroid hormone production comparable to those of wild-type (WT) counterparts. Further, pregnant WT and Klf13 null females at Day Postcoitum (DPC) 3.5 had similar uterine Pgr, estrogen receptor, and Wnt-signaling component transcript levels. Nuclear levels of KLF9 were higher in Klf13 null than in WT uteri at DPC 3.5, albeit whole-tissue KLF9 protein and transcript levels did not differ between genotypes. The lack of a similar induction of nuclear KLF9 levels in uteri of virgin Klf13((-/-)) mice relative to WT uteri was associated with lower stromal PGR expression. In differentiating human endometrial stromal cells, coincident KLF9/KLF13 knockdown by small interfering RNA targeting reduced decidualization-associated PRL expression, whereas KLF9 and KLF13 knockdowns alone reduced transcript levels of WNT4 and BMP2, respectively. Results suggest that KLF9 and KLF13 functionally compensate in peri-implantation uterus for pregnancy success.


Assuntos
Proteínas de Ciclo Celular/fisiologia , Implantação do Embrião/fisiologia , Fatores de Transcrição Kruppel-Like/fisiologia , Proteínas Repressoras/fisiologia , Reprodução/genética , Útero/fisiologia , Fosfatase Alcalina/metabolismo , Animais , Proteínas de Ciclo Celular/deficiência , Proteínas de Ciclo Celular/genética , Diferenciação Celular , Feminino , Expressão Gênica , Fatores de Transcrição Kruppel-Like/deficiência , Fatores de Transcrição Kruppel-Like/genética , Camundongos , Camundongos Knockout , Fenótipo , Gravidez , RNA Interferente Pequeno/farmacologia , Proteínas Repressoras/deficiência , Proteínas Repressoras/genética , Células Estromais
12.
Cancers (Basel) ; 14(7)2022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35406507

RESUMO

Obesity, oxidative stress, and inflammation are risk factors for hepatocellular carcinoma (HCC). We examined, in mice, the effects of Krüppel-like factor 9 (KLF9) knockout on: adiposity, hepatic and systemic oxidative stress, and hepatic expression of pro-inflammatory and NOX/DUOX family genes, in a high-fat diet (HFD) context. Male and female Klf9+/+ (wild type, WT) and Klf9-/- (knockout, KO) mice were fed HFD (beginning at age 35 days) for 12 weeks, after which liver and adipose tissues were obtained, and serum adiponectin and leptin levels, liver fat content, and markers of oxidative stress evaluated. Klf9-/- mice of either sex did not exhibit significant alterations in weight gain, adipocyte size, adipokine levels, or liver fat content when compared to WT counterparts. However, Klf9-/- mice of both sexes had increased liver weight/size (hepatomegaly). This was accompanied by increased hepatic oxidative stress as indicated by decreased GSH/GSSG ratio and increased homocysteine, 3-nitrotyrosine, 3-chlorotyrosine, and 4HNE content. Decreased GSH to GSSG ratio and a trend toward increased homocysteine levels were observed in the corresponding Klf9-/- mouse serum. Gene expression analysis showed a heightened pro-inflammatory state in livers from Klf9-/- mice. KLF9 suppresses hepatic oxidative stress and inflammation, thus identifying potential mechanisms for KLF9 suppression of HCC and perhaps cancers of other tissues.

13.
Biol Reprod ; 85(2): 378-85, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21543766

RESUMO

Endometrial cancer is the most commonly diagnosed female genital tract malignancy. Krüppel-like factor 9 (KLF9), a member of the evolutionarily conserved Sp family of transcription factors, is expressed in uterine stroma and glandular epithelium, where it affects cellular proliferation, differentiation, and apoptosis. Deregulated expression of a number of Sp proteins has been associated with multiple types of human tumors, but a role for KLF9 in endometrial cancer development and/or progression is unknown. Here, we evaluated KLF9 expression in endometrial tumors and adjacent uninvolved endometrium of women with endometrial carcinoma. KLF9 mRNA and protein levels were lower in endometrial tumors coincident with decreased expression of family member KLF4 and growth-regulators FBJ murine osteosarcoma viral oncogene homolog (FOS) and myelocytomatosis viral oncogene homolog (MYC) and with increased expression of telomerase reverse transcriptase (TERT) and the chromatin-modifying enzymes DNA methyltransferase 1 (DNMT1) and histone deacetylase 3 (HDAC3). Expression of estrogen receptor alpha (ESR1) and the tumor-suppressor phosphatase and tensin homolog deleted in chromosome 10 (PTEN) did not differ between tumor and normal tissue. The functional relevance of attenuated KLF9 expression in endometrial carcinogenesis was further evaluated in the human endometrial carcinoma cell line Ishikawa by siRNA targeting. KLF9 depletion resulted in loss of normal cellular response to the proliferative effects of estrogen concomitant with reductions in KLF4 and MYC and with enhancement of TERT and ESR1 gene expression. Silencing of KLF4 did not mimic the effects of silencing KLF9 in Ishikawa cells. We suggest that KLF9 loss-of-expression accompanying endometrial carcinogenesis may predispose endometrial epithelial cells to mechanisms of escape from estrogen-mediated growth regulation, leading to progression of established neoplasms.


Assuntos
Carcinoma/metabolismo , Neoplasias do Endométrio/metabolismo , Estrogênios/farmacologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Fatores de Transcrição Kruppel-Like/metabolismo , Adulto , Idoso , Carcinoma/genética , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Endométrio/citologia , Feminino , Inativação Gênica , Humanos , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Pessoa de Meia-Idade
14.
Front Physiol ; 12: 702674, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34712146

RESUMO

Endometriosis is a chronic, estrogen-dependent gynecologic disorder that affects reproductive-aged women and to a lesser extent, post-menopausal women on hormone therapy. The condition is associated with systemic and local immune dysfunctions. While its underlying mechanisms remain poorly understood, endometriosis has a genetic component and propensity for the disease is subject to environmental, nutritional, and lifestyle influences. Previously, we showed that high-fat diet (HFD) increased ectopic lesion numbers, concurrent with systemic and peritoneal changes in inflammatory and oxidative stress status, in immunocompetent recipient mice ip administered with endometrial fragments null for Krüppel-like factor 9 gene. Herein, we determined whether HFD modifies lesion parameters, when recipient peritoneal environment is challenged with ectopic wild-type (WT) endometrial fragments, the latter simulating retrograde menstruation common in women during the menstrual period. WT endometrium-recipient mice fed HFD (45% kcal from fat) showed reduced lesion incidence, numbers, and volumes, in the absence of changes in systemic ovarian steroid hormone and insulin levels, relative to those fed the control diet (CD, 17% kcal from fat). Lesions from HFD- and CD-fed recipients demonstrated comparable gene expression for steroid hormone receptors (Esr and Pgr) and cytokines (Il-6, Il-8, and CxCL4) and similar levels of DNA oxidative biomarkers. HFD moderately altered serum (3-nitrotyrosine and methionine/homocysteine) and peritoneal (reduced glutathione/oxidized glutathione) pro-oxidative status but had no effect on peritoneal inflammatory (tumor necrosis factor α and tumor necrosis factor receptor 1) mediators. Results indicate that lesion genotype modifies dietary effects on disease establishment and/or progression and if translated, could be important for provision of nutritional guidelines to women with predisposition to, or affected by endometriosis.

15.
J Mol Endocrinol ; 67(4): 173-188, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34382943

RESUMO

Epidemiological studies inversely associate BMI with breast cancer risk in premenopausal women, but the pathophysiological linkage remains ill-defined. Despite the documented relevance of the 'local' environment to breast cancer progression and the well-accepted differences in transcriptome and metabolic properties of anatomically distinct fat depots, specific breast adipose contributions to the proliferative potential of non-diseased breast glandular compartment are not fully understood. To address early breast cancer causation in the context of obesity status, we compared the cellular and molecular phenotypes of breast adipose and matched breast glandular tissue from premenopausal non-obese (mean BMI = 27 kg/m2) and obese (mean BMI = 44 kg/m2) women. Breast adipose from obese women showed higher expression levels of adipogenic, pro-inflammatory, and estrogen synthetic genes than from non-obese women. Obese breast glandular tissue displayed lower proliferation and inflammatory status and higher expression of anti-proliferative/pro-senescence biomarkers TP53 and p21 than from non-obese women. Transcript levels for T-cell receptor and co-receptors CD3 and CD4 were higher in breast adipose of obese cohorts, coincident with elevated adipose interleukin 10 (IL10) and FOXP3 gene expression. In human breast epithelial cell lines MCF10A and HMEC, recombinant human IL10 reduced cell viability and CCND1 transcript levels, increased those of TP53 and p21, and promoted (MCF10A) apoptosis. Our findings suggest that breast adipose-associated IL10 may mediate paracrine interactions between non-diseased breast adipose and breast glandular compartments and highlight how breast adipose may program the local inflammatory milieu, partly by recruiting FOXP3+ T regulatory cells, to influence premenopausal breast cancer risk.


Assuntos
Tecido Adiposo/metabolismo , Mama/metabolismo , Epitélio/metabolismo , Interleucina-10/metabolismo , Fenótipo , Pré-Menopausa/metabolismo , Adipócitos/imunologia , Adipócitos/metabolismo , Adiposidade , Adulto , Biomarcadores , Mama/patologia , Neoplasias da Mama/etiologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Citocinas/genética , Citocinas/metabolismo , Feminino , Expressão Gênica , Hormônios Esteroides Gonadais/sangue , Hormônios Esteroides Gonadais/metabolismo , Humanos , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Pessoa de Meia-Idade , Modelos Biológicos , Obesidade/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Telômero/genética , Telômero/metabolismo , Adulto Jovem
16.
Carcinogenesis ; 31(8): 1491-500, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20554748

RESUMO

The tumor suppressors phosphatase and tensin homologue deleted on chromosome ten (PTEN) and p53 are closely related to the pathogenesis of breast cancer, yet pathway-specific mechanisms underlying their participation in mediating the protective actions of dietary bioactive components on breast cancer risk are poorly understood. We recently showed that dietary exposure to the soy isoflavone genistein (GEN) induced PTEN expression in mammary epithelial cells in vivo and in vitro, consistent with the breast cancer preventive effects of soy food consumption. Here, we evaluated PTEN and p53 functional interactions in the nuclear compartment of mammary epithelial cells as a mechanism for mammary tumor protection by GEN. Using the non-tumorigenic human mammary epithelial cells MCF10-A, we demonstrate that GEN increased PTEN expression and nuclear localization. We show that increased nuclear PTEN levels initiated an autoregulatory loop involving PTEN-dependent increases in p53 nuclear localization, PTEN-p53 physical association, PTEN-p53 co-recruitment to the PTEN promoter region and p53 transactivation of PTEN promoter activity. The PTEN-p53 cross talk induced by GEN resulted in increased cell cycle arrest; decreased pro-proliferative cyclin D1 and pleiotrophin gene expression and the early formation of mammary acini, indicative of GEN promotion of lobuloalveolar differentiation. Our findings provide support to GEN-induced PTEN as both a target and regulator of p53 action and offer a mechanistic basis for PTEN pathway activation to underlie the antitumor properties of dietary factors, with important implications for reducing breast cancer risk.


Assuntos
Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Genisteína/farmacologia , PTEN Fosfo-Hidrolase/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Primers do DNA , Feminino , Humanos , Isoflavonas/metabolismo , Luciferases/genética , PTEN Fosfo-Hidrolase/efeitos dos fármacos , PTEN Fosfo-Hidrolase/genética , Ratos , Ratos Sprague-Dawley , Renilla , Proteínas de Soja/farmacologia , Transfecção , Proteína Supressora de Tumor p53/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética
17.
Nutr Cancer ; 62(6): 774-82, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20661826

RESUMO

Dietary contribution to breast cancer risk, recurrence, and progression remains incompletely understood. Increased consumption of soy and soy isoflavones is associated with reduced mammary cancer susceptibility in women and in rodent models of carcinogenesis. In rats treated with N-methyl-N-nitrosourea, dietary intake of soy protein isolate (SPI) reduced mammary tumor occurrence but increased incidence of more invasive tumors in tumored rats, relative to the control diet casein. Here we evaluated whether mammary tumor progression in tumor-bearing rats lifetime exposed to SPI is associated with deregulated progesterone receptor (PR) isoform expression. In histologically normal mammary glands of rats with invasive ductal carcinoma lesions, PR-A protein levels were higher for SPI- than casein-fed rats, whereas PR-B was undetectable for both groups. Increased mammary PR-A expression was associated with higher transforming growth factor-beta1, stanniocalcin-1, and CD44 transcript levels; lower E-cadherin and estrogen receptor-alpha expression; and reduced apoptotic status in ductal epithelium. Serum progesterone (ng/ml) (CAS: 25.94 +/- 3.81; SPI: 13.19 +/- 2.32) and estradiol (pg/ml) (CAS: 27.9 +/- 4.49; SPI: 68.48 +/- 23.87) levels differed with diet. However, sera from rats of both diet groups displayed comparable mammosphere-forming efficiency in human MCF-7 cells. Thus, soy-rich diets may influence the development of more aggressive tumors by enhancing PR-A-dependent signaling in premalignant breast tissues.


Assuntos
Genisteína/administração & dosagem , Isoflavonas/administração & dosagem , Neoplasias Mamárias Experimentais/etiologia , Receptores de Progesterona/fisiologia , Animais , Carcinoma Ductal de Mama/etiologia , Carcinoma Intraductal não Infiltrante/etiologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Receptores de Hialuronatos/genética , Glândulas Mamárias Animais/química , Neoplasias Mamárias Experimentais/química , Ratos , Receptores de Progesterona/análise , Fator de Crescimento Transformador beta1/genética
18.
J Mol Endocrinol ; 65(4): R77-R90, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33064660

RESUMO

Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP. Early studies identified ME1 as a mediator of intermediary metabolism primarily through its participatory roles in lipid and cholesterol biosynthesis. ME1 was one of the first identified insulin-regulated genes in liver and adipose and is a transcriptional target of thyroxine. Multiple studies have since documented that ME1 is pro-oncogenic in numerous epithelial cancers. In tumor cells, the reduction of ME1 gene expression or the inhibition of its activity resulted in decreases in proliferation, epithelial-to-mesenchymal transition and in vitro migration, and conversely, in promotion of oxidative stress, apoptosis and/or cellular senescence. Here, we integrate recent findings to highlight ME1's role in oncogenesis, provide a rationale for its nexus with metabolic syndrome and diabetes, and raise the prospects of targeting the cytosolic NADPH network to improve therapeutic approaches against multiple cancers.


Assuntos
Suscetibilidade a Doenças , Malato Desidrogenase/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Animais , Metabolismo Energético , Transição Epitelial-Mesenquimal , Humanos , Metabolismo dos Lipídeos , Malato Desidrogenase/genética , Neoplasias/patologia , Oxirredução , Estresse Oxidativo
19.
Oncol Lett ; 20(5): 249, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32994812

RESUMO

Metformin (MET) constitutes the first-line treatment against type 2 diabetes. Growing evidence linking insulin resistance and cancer risk has expanded the therapeutic potential of MET to several cancer types. However, the oncostatic mechanisms of MET are not well understood. MET has been shown to promote the expression of progesterone receptor (PGR) and other antitumor biomarkers in patients with non-diabetic endometrial cancer (EC) and in Ishikawa EC cells cultured in normal glucose (5.5 mM) media. Therefore, the present study aimed to assess the effects of MET on EC cells under conditions simulating diabetes. Ishikawa cells treated with 10 nM 17ß-estradiol (E2) and/or 100 µM MET and exposed to normal and high (17.5 mM) concentrations of glucose were evaluated for proliferative and PGR expression status. Under normal glucose conditions, MET attenuated E2-induced cell proliferation and cyclin D1 gene expression, and increased total PGR and PGR-B transcript levels. MET inhibited Ishikawa cell spheroid formation only in the absence of E2 treatment. In E2-treated cells under high glucose conditions, MET showed no effects on cell proliferation and spheroid formation, and increased total PGR but not PGR-B transcript levels. Transfection with Krüppel-like factor 9 small interfering RNA increased PGR-A transcript levels, irrespective of glucose environment. Medroxyprogesterone acetate downregulated PGR-A expression more effectively with metformin under high compared with normal glucose conditions. To evaluate the potential mechanisms underlying the targeting of PGR by MET, E2-treated cells were incubated with MET and the AMPK inhibitor Compound C, or with the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), under normal glucose conditions. Compound C abrogated the effects of MET on PGR-B while AICAR increased PGR-B transcript levels, albeit less effectively compared with MET. The present results demonstrate the glucose-dependent effects of MET on PGR-B isoform expression, which may inform the response to progestin therapy in diabetic women with EC.

20.
Carcinogenesis ; 30(2): 331-9, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19073877

RESUMO

Breast cancer risk is highly modifiable by diet; however, mechanisms underlying dietary protection against mammary tumorigenesis remain poorly understood. A proportion of breast carcinomas is associated with deregulation of beta-catenin stability and amplification of c-Myc expression. We recently showed that dietary exposure to the soy isoflavone genistein (Gen) inhibited Wnt transduction in rat mammary epithelial cells in vivo. Here, we explored the role of Gen on cell adhesion protein, E-cadherin, expression to downregulate beta-catenin proto-oncogene function. In mammary glands of female rats exposed to dietary Gen, E-cadherin and beta-catenin protein levels were increased, concurrent with higher beta-casein gene expression. In HC11 mouse mammary epithelial cells, Gen diminished basal and Wnt-1-induced cell proliferation and attenuated Wnt-1 targets c-Myc and Cyclin D1 expression. Whereas, Gen had no effect on E-cadherin transcript levels, the abundance of membrane E-cadherin protein and of E-cadherin-beta-catenin adhesion complex was increased by Gen, attendant with downregulation of Wnt-1-induced free beta-catenin accumulation in cytosol. Gen inhibition of Wnt-induced c-Myc expression was mimicked by an estrogen receptor (ER)-beta-specific but not ER-alpha-specific agonist and was attenuated with loss of ER-beta expression, concordant with decreased E-cadherin expression. E-cadherin small-interfering RNA targeting eliminated Gen inhibition of Wnt-stimulated c-Myc expression and promoted Gen induction of basal c-Myc transcript levels and subsequent proliferation. Our studies identify E-cadherin as a Gen cellular target and demonstrate that the dichotomy in mammary epithelial response to Gen may be a function of cellular E-cadherin expression.


Assuntos
Antineoplásicos/farmacologia , Caderinas/biossíntese , Células Epiteliais/efeitos dos fármacos , Genisteína/farmacologia , Glândulas Mamárias Animais/citologia , beta Catenina/fisiologia , Animais , Suplementos Nutricionais , Células Epiteliais/metabolismo , Feminino , Camundongos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Regulação para Cima , Proteína Wnt1/metabolismo
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