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Overexpression of transcription factor sp2 inhibits epidermal differentiation and increases susceptibility to wound- and carcinogen-induced tumorigenesis.

ABSTRACT: Sp proteins are evolutionarily conserved transcription factors required for the expression of a wide variety of genes that are critical for development and cell cycle progression. Deregulated expression of certain Sp proteins is associated with the formation of a variety of human tumors; however, direct evidence that any given Sp protein is oncogenic has been lacking. Here, we report that Sp2 protein abundance in mice increases in concert with the progression of carcinogen-induced murine squamous cell carcinomas. Transgenic mice specifically overexpressing murine Sp2 in epidermal basal keratinocytes were highly susceptible to wound- and carcinogen-induced papillomagenesis. Transgenic animals that were homozygous rather than hemizygous for the Sp2 transgene exhibited a striking arrest in the epidermal differentiation program, perishing within 2 weeks of birth. Our results directly support the likelihood that Sp2 overexpression occurring in various human cancers has significant functional effect.

SUBMITTER: Kim TH

PROVIDER: S-EPMC2970695 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Overexpression of transcription factor sp2 inhibits epidermal differentiation and increases susceptibility to wound- and carcinogen-induced tumorigenesis.

Kim Tae-Hyung TH Chiera Shannon L SL Linder Keith E KE Trempus Carol S CS Smart Robert C RC Horowitz Jonathan M JM

Cancer research 20101019 21

Sp proteins are evolutionarily conserved transcription factors required for the expression of a wide variety of genes that are critical for development and cell cycle progression. Deregulated expression of certain Sp proteins is associated with the formation of a variety of human tumors; however, direct evidence that any given Sp protein is oncogenic has been lacking. Here, we report that Sp2 protein abundance in mice increases in concert with the progression of carcinogen-induced murine squamou ...[more]

PMID: 20959487

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Project description:Among the processes involved in the breast tumor microenvironment, angiogenesis and inflammation play a central role, and the main factors of these processes are the vascular endothelial growth factor (VEGF), cyclooxygenase 2 (COX-2) and macrophages. Recently, the extract of Euterpe oleracea (açaí), a fruit that is widely found in the Amazon region, already showed antitumorigenic effects in vitro in human breast cancer cell lines. The present study aimed to investigate the effect of açaí on breast cancer using a chemically DMBA (7,12-dimethylbenzanthracene) experimental model.One day after initiation of treatment with açaí, mammary carcinogenesis was induced in female Wistar rats using a subcutaneous injection of 25 mg/kg of DMBA in the mammary gland. Forty rats were randomized into two groups: treated with 200 mg/kg of either açaí extract or vehicle, via gastric tube for 16 consecutive weeks. After treatment, the tumor was collected for macroscopic, histological and immunohistochemical (VEGF, vascular endothelial growth factor receptor 2 -VEGFR-2, COX-2 and matrix metalloproteinase -MMP-9) analyses; peritoneal fluid was subjected to flow cytometry (F4-80/MAC-2+) and ELISA immunoassay (VEGF, prostaglandin E2 -PGE2 and interleukin-10 -IL-10). Heart, liver and kidney samples were collected for histological analysis.After 16 weeks of induction, the mammary carcinoma was confirmed by macroscopic and histological evaluation. Survival analysis indicates that açaí increased the survival (P?=?.0002, long-rank test) and reduced the deaths number (P?=?.0036, Chi-square test). Açaí treatment decreased the number of inflammatory cells and macrophage positive cells (Mac-2?+?F4-80+), as well as promoting a reduction in immunostaining of VEGF, VEGFR-2 and COX-2. The açaí group also exhibited lower concentrations of PGE2, VEGF and IL-10 compared to the control. The histopathological results of the liver and kidneys showed protective effect of açaí, since in the control group, there was an increase in fibrosis, atypical cells and hemorrhagic microenvironment.The results of this study demonstrated the antiangiogenic and anti-inflammatory potential of açaí, like due to the decreases of the number of activated macrophages, resulting in the inhibition of DMBA carcinogenicity in breast cancer.

Dataset Information

Overexpression of transcription factor sp2 inhibits epidermal differentiation and increases susceptibility to wound- and carcinogen-induced tumorigenesis.

Publications

Overexpression of transcription factor sp2 inhibits epidermal differentiation and increases susceptibility to wound- and carcinogen-induced tumorigenesis.

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