Abstract
BackgroundRetinoic acid (RA) is a critical regulator of cell differentiation, proliferation, and apoptosis in various cell types. Recently, the RA-metabolizing enzyme CYP26A1 (cytochrome P450, family 26, subfamily A, polypeptide 1) has been shown to have an oncogenic function in breast carcinogenesis. However, the relevance of elevated CYP26A1 expression in human cancers remains to be clarified.MethodsWe immunohistochemically examined the expression of CYP26A1 in cervical squamous cell carcinoma (SCC) and its precursors, including low- and high-grade squamous intraepithelial lesions (LSIL and HSIL, respectively), as well as head and neck cancer (HNC). The association between CYP26A1 expression and a number of clinicopathological parameters was also evaluated.ResultsCYP26A1 was not expressed in normal cervical epithelium. CYP26A1 expression was present in LSIL but limited to basal and parabasal cells. HSIL cases exhibited strong nuclear expression of CYP26A1 and mixed cytoplasmic expression patterns with widely distributed expression toward the epithelial surface. Importantly, strong cytoplasmic staining of CYP26A1 was observed in 19 of 50 (38%) patients with cervical SCC. Elevated expression of CYP26A1 was significantly associated with younger age (<50 years) and lymph node involvement (pN). Similarly, CYP26A1 was not expressed in non-neoplastic tissues of the head and neck, but strong cytoplasmic staining of CYP26A1 was observed in 52 of 128 (41%) HNC cases. Such strong CYP26A1 expression was significantly associated with the primary tumor stage of carcinomas (pT) and the pathological tumor-node-metastasis (pTNM) stage in HNC.ConclusionOur results indicated an elevated CYP26A1 expression in malignant and precancerous dysplastic lesions of the human cervix, which also increased with the progression of cervical squamous neoplasia. In addition, this report is the first to demonstrate the increased expression of CYP26A1 in HNC and its significant correlation with primary tumor growth. These data suggested that CYP26A1 overexpression might contribute to the development and progression of cervical malignancies and squamous neoplasia of the head and neck.Electronic supplementary materialThe online version of this article (doi:10.1186/1756-0500-7-697) contains supplementary material, which is available to authorized users.
Highlights
Retinoic acid (RA) is a critical regulator of cell differentiation, proliferation, and apoptosis in various cell types
Constitutive expression of CYP26A1 was observed in LSIL (n = 14), but it was restricted to basal and parabasal cells, as well as in the cells with koilocytosis
CYP26A1 was strongly expressed in all HSIL samples (n = 38), in dysplasia with atypical cells occupying more than twothird of the epithelium thickness
Summary
Retinoic acid (RA) is a critical regulator of cell differentiation, proliferation, and apoptosis in various cell types. Cervical carcinoma is the second most common cancer in women worldwide [1] This malignant neoplasm develops from basal cells originating in the uterine cervix, and squamous cell carcinoma (SCC) is the most common presentation of cervical cancer, accounting for approximately 80–85% of all cases [1]. Chronic infection with human papilloma virus (HPV), especially the high-risk variants HPV16 and 18, is the single most important etiologic factor in the pathogenesis of cervical carcinoma and its precursors [1,2]. Multiple risk factors, such as sexual activity at an early age, high parity, smoking, and use of oral contraceptives, are associated with cervical carcinoma. A number of clinical studies have shown that topical application of a vitamin A derivative to the cervix completely reverses cervical dysplasia in 50% of cases [6]
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