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1.
Biochem Biophys Res Commun ; 672: 103-112, 2023 09 10.
Artículo en Inglés | MEDLINE | ID: mdl-37343316

RESUMEN

Estrogen receptor alpha (ERα)-mediated estrogen signaling has also shown to prevent hepatic tumorigenesis in mice. Consistent with this, hormone replacement therapy with estrogen supplementation dramatically reduced the risk of hepatocellular carcinoma. Silencing of ERα is also a key event for the transformation of ERα-positive breast cancer cells into malignant triple-negative breast cancer cells. However, the mechanisms underlying ERα-mediated prevention of both hepatic and mammary tumorigenesis in humans are still unclear. Here, we present a functional genomics study of ERα targeting by comparing human liver cancer cells with human breast cancer cells using "loss or gain of function" genetic assays of ERα in vitro and in vivo. We discover that cellular communication network factor 5 (CCN5) is a direct downstream target of ERα; ERα suppresses growth and prevents tumorigenesis and malignant transformation of both liver and breast cancer cells through CCN5 in humans. The ERα-CCN5 regulatory axis functions as suppressors for both hepatic and mammary tumors, which is a common mechanism of preventing tumorigenesis for both liver cancer and breast cancer in humans.


Asunto(s)
Neoplasias de la Mama , Neoplasias Hepáticas , Animales , Femenino , Humanos , Ratones , Neoplasias de la Mama/patología , Carcinogénesis , Transformación Celular Neoplásica/genética , Receptor alfa de Estrógeno/genética , Estrógenos
2.
BMC Genomics ; 20(1): 541, 2019 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-31266464

RESUMEN

BACKGROUND: Defining histone modification at single-nucleosome resolution provides accurate epigenomic information in individual nucleosomes. However, most of histone modification data deposited in current databases, such as ENCODE and Roadmap, have low resolution with peaks of several kilo-base pairs (kb), which due to the technical defects of regular ChIP-Seq technology. RESULTS: To generate histone modification data at single-nucleosome resolution, we developed a novel approach, NUCLIZE, using synergistic analyses of histone modification data from ChIP-Seq and high-resolution nucleosome mapping data from native MNase-Seq. With this approach, we generated quantitative epigenomics data of single and multivalent histone modification marks in each nucleosome. We found that the dominant trivalent histone mark (H3K4me3/H3K9ac/H3K27ac) and others showed defined and specific patterns near each TSS, indicating potential epigenetic codes regulating gene transcription. CONCLUSIONS: Single-nucleosome histone modification data render epigenomic data become quantitative, which is essential for investigating dynamic changes of epigenetic regulation in the biological process or for functional epigenomics studies. Thus, NUCLIZE turns current epigenomic mapping studies into genuine functional epigenomics studies with quantitative epigenomic data.


Asunto(s)
Biología Computacional/métodos , Epigenómica/métodos , Código de Histonas/genética , Nucleosomas/genética , Programas Informáticos , Inmunoprecipitación de Cromatina , Epigénesis Genética , Regulación de la Expresión Génica , Células Hep G2 , Histonas/genética , Histonas/metabolismo , Humanos , Flujo de Trabajo
3.
BMC Cancer ; 19(1): 684, 2019 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-31299933

RESUMEN

BACKGROUND: Sex differences in the incidences of cancers become a critical issue in both cancer research and the development of precision medicine. However, details in these differences have not been well reported. We provide a comprehensive analysis of sexual dimorphism in human cancers. METHODS: We analyzed four sets of cancer incidence data from the SEER (USA, 1975-2015), from the Cancer Registry at Mayo Clinic (1970-2015), from Sweden (1970-2015), and from the World Cancer Report in 2012. RESULTS: We found that all human cancers had statistically significant sexual dimorphism with male dominance in the United States and mostly significant in the Mayo Clinic, Sweden, and the world data, except for thyroid cancer, which is female-dominant. CONCLUSIONS: Sexual dimorphism is a clear but mostly neglected phenotype for most human cancers regarding the clinical practice of cancer. We expect that our study will facilitate the mechanistic studies of sexual dimorphism in human cancers. We believe that fully addressing the mechanisms of sexual dimorphism in human cancers will greatly benefit current development of individualized precision medicine beginning from the sex-specific diagnosis, prognosis, and treatment.


Asunto(s)
Neoplasias/epidemiología , Factores Sexuales , Femenino , Salud Global , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Incidencia , Masculino , Neoplasias/historia , Vigilancia de la Población , Programa de VERF , Suecia , Estados Unidos
4.
J Genet Genomics ; 50(2): 87-98, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-35500745

RESUMEN

Human hepatocellular carcinoma (HCC) occurs almost exclusively in cirrhotic livers. Here, we report that hepatic loss of protein arginine methyltransferase 5 (PRMT5) in mice is sufficient to cause cirrhosis and HCC in a clinically relevant way. Furthermore, pathological polyploidization induced by hepatic loss of PRMT5 promotes liver cirrhosis and hepatic tumorigenesis in aged liver. The loss of PRMT5 leads to hyper-accumulation of P21 and endoreplication-dependent formation of pathological mono-nuclear polyploid hepatocytes. PRMT5 and symmetric dimethylation at histone H4 arginine 3 (H4R3me2s) directly associate with chromatin of P21 to suppress its transcription. More importantly, loss of P21 rescues the pathological mono-nuclear polyploidy and prevents PRMT5-deficiency-induced liver cirrhosis and HCC. Thus, our results indicate that PRMT5-mediated symmetric dimethylation at histone H4 arginine 3 (H4R3me2s) is crucial for preventing pathological polyploidization, liver cirrhosis and tumorigenesis in mouse liver.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Ratones , Animales , Anciano , Histonas/metabolismo , Proteína-Arginina N-Metiltransferasas/metabolismo , Carcinogénesis , Cirrosis Hepática , Arginina/metabolismo
5.
Am J Cancer Res ; 9(2): 429-433, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30906640

RESUMEN

Sexual dimorphism in the incidence of human esophageal cancer, including both esophageal adenocarcinoma and squamous cell carcinoma, shows male dominancy. However, the mechanisms that underlie sexual dimorphism of esophageal cancer have been understudied in vivo due to the lack of sex-dimorphic mouse models. Here, we developed a sex-dimorphic mouse model of esophageal squamous cell carcinoma (ESCC) using a lower amount of 4-nitroquinoline-1-oxide (4-NQO) and a shorter latency of tumorigenesis compared to the traditional carcinogenesis procedures. In this model, we found that male mice were highly sensitive to the tumorigenesis of ESCC whereas female mice were resistant to it. This model provided us an opportunity for investigating the mechanisms underlying sexual dimorphism of ESCC in vivo and for better understanding the sex-dimorphic incidence of ESCC in humans.

6.
Am J Cancer Res ; 9(2): 424-428, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30906639

RESUMEN

Risk reducing mastectomy is the only surgical approach for the prevention of breast cancer in women with deleterious genetic mutations or in those deemed to be at extremely high risk. However, up to 10.5% of these women still developed breast cancer. Thus, developing new strategies for complete prevention of breast cancer is imperative. Mammary ducts were ablated by mammary-specific ablation of forkhead box protein A1 (Foxa1). Mammary tumorigenesis was induced in control and mammary-specific Foxa1 knockout mice using carcinogens. No mammary tumors were observed in these knockout mice compared to four types of breast tumors induced in control mice. We present a promising novel strategy for the prevention of breast cancer by genetic ablation of mammary ducts via targeting Foxa1.

7.
Mol Cell Endocrinol ; 471: 33-41, 2018 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-28554805

RESUMEN

The liver plays a crucial role in a variety of physiological processes. Sexual dimorphism is markedly defined in liver disorders, such as fatty liver diseases and liver cancer, but barely addressed in the normal liver. Distinct sex hormone signaling between male and female livers is the major driving factor for hepatic sexual dimorphism. Over 6000 genes are differently expressed between male and female livers in mice. Here we address how sex hormone receptors, estrogen receptor alpha (ERα) and androgen receptor (AR), mediate sexually dimorphic gene expression in mouse livers. We identified 5192 ERα target genes and 4154 AR target genes using ChIP-Seq. Using liver-specific ERα or AR knockout mice, we further identified direct and functional target genes of ERα (123 genes) and AR (151 genes) that contribute to hepatic sexual dimorphism. We also found that the most significant sexually dimorphic gene expression was initiated at birth by comparing hepatic gene expression data from the embryonic stage E10.5 to the postnatal stage P60 during liver development. Overall, our study indicates that sex hormone receptor signaling drives sexual dimorphism of hepatic gene expression throughout liver development.


Asunto(s)
Receptor alfa de Estrógeno/genética , Genómica , Hígado/metabolismo , Receptores Androgénicos/genética , Caracteres Sexuales , Animales , Receptor alfa de Estrógeno/metabolismo , Femenino , Regulación del Desarrollo de la Expresión Génica , Masculino , Ratones , Receptores Androgénicos/metabolismo
8.
Cancer Lett ; 438: 24-31, 2018 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-30223066

RESUMEN

Gender differences in the incidences of cancers have been found in almost all human cancers. However, the mechanisms that underlie gender disparities in most human cancer types have been under-investigated. Here, we provide a comprehensive overview of potential mechanisms underlying sexual dimorphism of each cancer regarding sex hormone signaling. Fully addressing the mechanisms of sexual dimorphism in human cancers will greatly benefit current development of precision medicine. Our discussions of potential mechanisms underlying sexual dimorphism in each cancer will be instructive for future cancer research on gender disparities.


Asunto(s)
Hormonas Esteroides Gonadales/metabolismo , Neoplasias/metabolismo , Receptores de Esteroides/metabolismo , Transducción de Señal , Femenino , Humanos , Masculino , Neoplasias/patología , Medicina de Precisión/métodos , Factores Sexuales
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