Abstract
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. 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. 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. 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.
Highlights
Skin cancer, categorized as melanoma and nonmelanoma skin carcinoma, is the common and life-risky type of cancer in the world and the incidence of skin cancer has reached epidemic proportions (Boni et al, 2002; Diepgen and Mahler, 2002; Gordon, 2013)
We found that Activating transcription factor 3 (ATF3) was upregulated in skin cancer tissues from patients and that ATF3 promoted skin cancer cell proliferation through activating Stat3 phosphorylation, which is the hallmark of various cancers development (Hodge et al, 2005; Yu et al, 2009; Kamran et al, 2013)
Western blot were performed to p53, p-Stat3 and total Stat3. (B) Control or ATF3 overexpressed cells were treated with Stat3 inhibitor Stattic or DMSO for
Summary
Skin cancer, categorized as melanoma and nonmelanoma (basal and squamous cell carcinoma) skin carcinoma, is the common and life-risky type of cancer in the world and the incidence of skin cancer has reached epidemic proportions (Boni et al, 2002; Diepgen and Mahler, 2002; Gordon, 2013). The precise molecular mechanism of skin cancer remains unclear, which make it difficult for treatment of the disease. ATF3 is expressed at low levels in normal cells but can be rapidly induced by multiple and diverse extracellular signals including growth factors, cytokines and some genotoxic stress agents (Chen et al, 1996; Hai et al, 1999; Hai and Hartman, 2001; Fan et al, 2002; Taketani et al, 2012, Wang et al, 2012; Lee et al, 2013). ATF3 has been reported to promote skin tumor formation through suppression of p53-dependent senescence (Wu et al, 2010), the precise role of ATF3 and the underlying molecular mechanism in skin cancer remain unclear
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