The utility of ATF3 in distinguishing cutaneous squamous cell carcinoma among other cutaneous epithelial neoplasms

Department of Pathology, Section of Dermatopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Journal of Cutaneous Pathology (Impact Factor: 1.58). 07/2012; 39(8):762-8. DOI: 10.1111/j.1600-0560.2012.01938.x
Source: PubMed


The histopathologic distinction between benign and malignant cutaneous keratinocytic proliferations can pose a difficult diagnostic challenge - often with important clinical implications. Activating transcription factor 3 (ATF3) has emerged as a potential biomarker which may aid in the segregation of these lesions, and we hypothesize that ATF3 expression may be a specific marker of cutaneous squamous cell carcinoma (SCC). Using immunohistochemistry, we characterized ATF3 expression in a series of 126 cutaneous epithelial proliferations, including SCC (n = 27), basal cell carcinomas (BCC, n = 59), seborrheic keratoses with atypia (SK, n = 16), hyperplastic actinic keratoses (AK, n = 12) and prurigo nodularis cases (PN, n = 12). We showed strong, nuclear and/or nucleolar expression of ATF3 in a statistically significant number of cases of SCC compared to BCC, SK and PN. We conclude that ATF3 expression is a surrogate of malignancy (or pre-malignancy) in keratinocytic epithelial proliferations and thus helps distinguish SCC from other cutaneous epithelial neoplasms.

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    • "addressed in several cell lines that ATF3 might be involved in homeostasis, wound healing, cell adhesion, cancer cell invasion, apoptosis and signaling pathways (Chen et al., 1996; Wolfgang et al., 1997; Ishiguro and Nagawa, 2000; Ishiguro et al., 2000; Wolfgang et al., 2000; Allen-Jennings et al., 2001; Gold et al., 2012; Jang et al., 2012; Rose et al., 2012). Over-expression of ATF3 protein moderately suppresses cell growth through slowing down progression from G1/S transition in Hela cells (Fan et al., 2002). "
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    ABSTRACT: Aim: ATF3, a member of the ATF/CREB family of transcription factors, has been found to be selectively induced by calcineurin/NFAT inhibition and to enhance keratinocyte tumor formation, although the precise role of ATF3 in human skin cancer and possible mechanisms remain unknown. Methods: In this study, clinical analysis of 30 skin cancer patients and 30 normal donors revealed that ATF3 was accumulated in skin cancer tissues. Functional assays demonstrated that ATF3 significantly promoted skin cancer cell proliferation. Results: Mechanically, ATF3 activated Stat3 phosphorylation in skin cancer cell through regulation of p53 expression. Moreover, the promotion effect of ATF3 on skin cancer cell proliferation was dependent on the p53-Stat3 signaling cascade. Conclusion: Together, the results indicate that ATF3 might promote skin cancer cell proliferation and enhance skin keratinocyte tumor development through inhibiting p53 expression and then activating Stat3 phosphorylation.
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    ABSTRACT: This study aimed to investigate the expression and significance of ATF-3 in laryngeal squamous cell carcinoma (LSCC). Expression of ATF-3 was examined using immunohistochemistry methods in samples from 83 cases of LSCC carcinoma. MTT assay was used to detect proliferation of Hep-2 cells after ATF-3 knocked down by siRNA lentivirus. A mouse model was used to investigate the inhibitive role of ATF-3 siRNA in LSCC xenografts. Realtime RCR was used to detect Cyclin D1 expression after ATF-3 downregulation in Hep-2 cells. The expression of ATF-3 was positively detected in all the 83 cases of LSCC cancer tissues while Only 4 cases of adjacent non-neoplastic tissues were detected with positive ATF-3 expression. The ATF-3 expression was statistically related with T stage, neck nodal metastasis, clinical stage and prognosis of LSCC. Both cell proliferation in vitro and tumor growth in vivo were suppressed after ATF-3 knockdown. Furthermore, the expression of Cyclin D1 was decreased after ATF-3 downregulation in Hep-2 cells. ATF-3 is involved in the progress of LSCC, and may provide clinical information for evaluation of prognosis of LSCC. The oncologic role of ATF-3 may be correlated with Cyclin D1 regulation.
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    ABSTRACT: Background: High mitotic figure count (MFC) correlates with low survival rate in Merkel cell carcinoma (MCC). However, the prognostic impact of histone biomarkers as surrogates of MFC in MCC is unknown. We evaluated the prognostic significance of the immunodetection of mitotic figures and of G2+ tumor nuclei with histone-associated mitotic markers H3K79me3T80ph (H3KT) and phosphohistone H3 (PHH3) in MCC. Methods: Immunohistochemical analyses of H3KT and PHH3 and proliferative marker Ki-67 were performed in a series of 21 cases of MCC. The significance of the pathologic data and immunoreactivity with these markers was evaluated with Pearson correlation and paired Student t-test. Univariate Cox proportional hazards regression models were performed to assess the relationships between these markers and survival. Results: H3KT detected a higher number of mitotic figure (p<0.0001) and G2+ tumor nuclei (p<0.0052) than did PHH3. Furthermore, the MFC combined with G2+ tumor nuclei detected with H3KT compared to PHH3 and manual MFC was a significant predictor of impaired survival in patients with MCC (p=0.035; HR=1.0172), corresponding to a 1.72% increased risk of death for each unit increase in H3KT. Conclusions: Biomarker analysis of proliferative rates with histone markers may have relevance in stratifying risk in patients with MCC.
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