A novel role for the retinoic acid-catabolizing enzyme CYP26A1 in Barrett's associated adenocarcinoma

Cl, Chang; Hong, Eunkyoung; Lao-Sirieix, Pierre; Fitzgerald, Rebecca C.

doi:10.1038/sj.onc.1210969

Cited by 32 publications

(30 citation statements)

References 33 publications

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“…This is in line with earlier studies suggesting that VAD is associated with carcinogenesis (Wolbach and Howe, 1925), and upregulation of CYP26A1 has recently been shown in a number of cancer cell types (Sonneveld et al, 1998;Van heusden et al, 1998;Shelton et al, 2006;Chang et al, 2008). If increased RA metabolism is solely responsible for the apoptogen desensitizing effect, our results would imply that in a state of RA deficiency, cells may be less susceptible to apoptosis following the acquisition of DNA damage.…”

Section: Discussionsupporting

confidence: 92%

“…Despite the fact that the CYP26 enzymes may have a similar but separate role in limiting the consequences of fluctuations in nutritional vitamin A, the possibility that pathological conditions such as cancer might involve aberrant expression of CYP26A1 has recently emerged from several studies. Accumulating evidence has shown that enhanced RA catabolic activity has been observed in various types of cancer and elevated CYP26A1 expression has been detected in a number of cancer cell types (Sonneveld et al, 1998;Van heusden et al, 1998;Shelton et al, 2006;Chang et al, 2008). On the other hand, our previous study has shown that the cells expressing CYP26A1 gain significant resistance to apoptosis because of the state of reduced bioavailability caused by the metabolic inactivation of RA (Osanai and Petkovich, 2005).…”

Section: Introductionmentioning

confidence: 76%

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Oncogenic and cell survival properties of the retinoic acid metabolizing enzyme, CYP26A1

2009

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Vitamin A deficiency (VAD) is associated with increased susceptibility to carcinogenesis in animal models and elevated risk for a number of human cancers. Here, we found that CYP26A1, the gene encoding a cytochrome P450 enzyme specifically involved in metabolic inactivation of retinoic acid (RA), the most active vitamin A derivative, is highly expressed in 42% (27/65) of primary breast cancers. We also showed that enhanced expression of CYP26A1 suppresses cellular responses to anoikis and consequently promotes anchorage-independent growth. This transformed phenotype was sufficient to markedly increase tumorigenic and metastatic potential. Suppression of CYP26A1 significantly reversed the CYP26A1-mediated oncogenic characteristics, suggesting a direct link between intracellular RA status and tumorigenicity. Our observations provide strong evidence for oncogenic and cell survival properties of CYP26A1 in carcinogenesis, and suggest mechanisms whereby VAD might promote cancer development.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 76%

Oncogenic and cell survival properties of the retinoic acid metabolizing enzyme, CYP26A1

2009

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“…5 In addition, a number of reports have indicated that enhanced RA catabolic activity and elevated CYP26A1 expression have been observed in various types of cancer. [8][9][10] The data are consistent with evidence that vitamin A defi ciency (VAD) is associated with increased susceptibility to carcinogenesis and elevated risk for a number of human cancers. 11 Because RA is required for normal skin development and function, disruption in RA signaling resulting from CYP26A1 overexpression might result in a state of functional VAD with deleterious consequences for skin function.…”

Section: Introductionsupporting

confidence: 76%

Enhanced expression of retinoic acid-metabolizing enzyme CYP26A1 in sunlight-damaged human skin

Osanai

Lee

2011

Med Mol Morphol

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Vitamin A deficiency (VAD) is associated with increased susceptibility to carcinogenesis. CYP26A1, the gene encoding a cytochrome P450 enzyme specifically involved in metabolic inactivation of retinoic acid (RA), the most active vitamin A derivative, has been shown to result in a state of functional VAD of the cell. Recently, we demonstrated that CYP26A1 efficiently promotes cell survival properties and eventually contributes to the carcinogenic process, implying roles as an oncogene. To clarify the possible association between VAD caused by CYP26A1 expression and the development of human epithelial neoplasia, we examined whether enhanced expression of CYP26A1 might be observed in various lesions of human skin. We report here that basal keratinocytes showed only weak positivity of CYP26A1 in sunlight-nonexposed areas, whereas strong positive staining was observed in skin from chronically sunexposed body areas and in epidermis that had the dysplastic changes known as actinic keratosis. However, we found no expression of constitutive CYP26A1 in skin malignancies such as squamous cell carcinomas. Our observation suggests an involvement of enhanced CYP26A1 expression causing a functional VAD state in skin that can potentially lead to neoplastic transformation of keratinocytes in an early phase during skin carcinogenesis.

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“…The RA-metabolizing enzyme CYP26A1 has been shown to promote cell survival and contribute to the oncogenic potential of breast carcinoma cells, suggesting that this protein has an oncogenic function (10). Consistent with this finding, enhanced RA metabolism has been observed in various types of cancer and elevated levels of CYP26A1 have been reported in a number of cancer cell types (11)(12)(13). The above-mentioned studies suggested that CYP26A1 confers unique cell-survival properties on cells and modulates the expression of a variety of genes to favor cell survival.…”

Section: Introductionsupporting

confidence: 54%

The retinoic acid-metabolizing enzyme CYP26A1 upregulates fascin and promotes the malignant behavior of breast carcinoma cells

Osanai

Lee

2015

Oncology Reports

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Abstract. The retinoic acid (RA)-metabolizing enzyme CYP26A1 has been shown to efficiently enhance the oncogenic potential of breast cancer, suggesting a potential oncogenic function. We previously demonstrated that CYP26A1 confers unique cell survival properties by modulating the expression of a variety of genes and identified a number of genes that drive the cells into the oncogenic state. Accumulating evidence suggested that fascin is overexpressed in various types of cancer, primarily leading to increased cell motility. Therefore, in the present study, we examined fascin, an actinbundling protein, using immunohistochemical and SA-β-gal staining as well as TUNEL and colony forming assays. The results of the present study showed that the expression levels of fascin increased significantly in response to CYP26A1 overexpression and, conversely, treatment with all-trans RA downregulated the expression of fascin. In addition, primary breast carcinoma samples, particularly hormone receptornegative carcinomas and CYP26A1-overexpressing cancers, expressed elevated levels of fascin. Notably, fascin contributed to the ability of breast carcinoma cells to escape premature senescence and exhibit enhanced cell apoptotic resistance, promoting anchorage-independent growth properties. Fascin also promoted cell motility and the invasiveness of CYP26A1-expressing breast carcinoma cells. These data suggest that fascin expression is modulated by the intracellular RA status regulated by the expression of CYP26A1 and plays a significant role in the malignant behavior of CYP26A1-expressing breast carcinoma cells. CYP26A1 exerts oncogenic functions during breast carcinogenesis. Therefore, CYP26A1-mediated oncogenic characteristics may be partially responsible for the elevated expression of fascin.

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A novel role for the retinoic acid-catabolizing enzyme CYP26A1 in Barrett's associated adenocarcinoma

Cited by 32 publications

References 33 publications

Oncogenic and cell survival properties of the retinoic acid metabolizing enzyme, CYP26A1

Oncogenic and cell survival properties of the retinoic acid metabolizing enzyme, CYP26A1

Enhanced expression of retinoic acid-metabolizing enzyme CYP26A1 in sunlight-damaged human skin

The retinoic acid-metabolizing enzyme CYP26A1 upregulates fascin and promotes the malignant behavior of breast carcinoma cells

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