Overexpression of phosphorylated-ATF2 and STAT3 in cutaneous squamous cell carcinoma, Bowen's disease and basal cell carcinoma

Chen, Si Yuan; Takeuchi, Satoshi; Moroi, Yoichi; Hayashida, Shinsaku; Kido, M.; Chen, Shan Juan; Tomoeda, Hiroto; Uenotsuchi, Takeshi; Tu, Yuexing; Furue, Masutaka; Urabe, Kazunori

doi:10.1016/j.jdermsci.2008.04.008

Cited by 15 publications

(12 citation statements)

References 9 publications

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“…Chen et al . showed increased expression of phosphorylated (p‐)STAT3 in cutaneous squamous cell carcinoma, Bowen disease and, to a lesser extent, in BCC . Similar results were presented by Suiqing et al ., who showed increased expression of p‐STAT3 in SCC and BCC, compared with normal skin and seborrhoeic keratosis.…”

Section: Discussionsupporting

confidence: 84%

STAT 3, STAT 5A, STAT 5B and STAT 6 proteins are overexpressed in human basal cell carcinoma

et al. 2019

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Summary Background The molecular pathogenesis of basal cell carcinoma (BCC) is still not precisely described and is the subject of ongoing studies. The role of signal transducers and activators of transcription (STATs) in human epithelial carcinogenesis has been poorly investigated, but in the era of studies on inhibitors targeting STAT proteins this topic seems worth exploring. Increased expression of STAT3 in human nonmelanoma skin cancer (NMSC) has been confirmed in a few studies, but to our knowledge, expression of STAT5A, STAT5B and STAT6 in BCC has not been previously evaluated. Aim To measure expression of STAT3, STAT5A, STAT5B and STAT6 expression in different histopathological subtypes of human BCC and its correlation with selected clinical variables. Methods Immunohistochemistry was used to assess 60 BCC tumour specimens [20 superficial (s)BCCs, 20 nodular (n)BCCs and 20 infiltrative (i)BCCs] and to compare with specimens of healthy skin. There was no significant difference in age or sex between the three groups of patients with BCC. As many tumours showed heterogeneity of staining, the H‐score system was applied to calculate the intensity of immunoexpression. Results Expression of STAT3, STAT5A, STAT5B and STAT6 was observed in all histopathological subtypes of BCC, and was stronger than the expression within the adjacent epidermis and also stronger than the expression within the epidermis in the healthy control group. Statistical analysis revealed no significant differences in mean H‐scores calculated for sBCCs, nBCCs and iBCCs. There were no statistically significant associations between STAT3, STAT5A, STAT5B and STAT6 expression and patient sex/age, and tumour size/site. Conclusion Our results confirm a possible role of STATs in the pathogenesis of BCC and should encourage future investigations on the possible therapeutic implications of this finding.

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Section: Discussionsupporting

confidence: 84%

STAT 3, STAT 5A, STAT 5B and STAT 6 proteins are overexpressed in human basal cell carcinoma

et al. 2019

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“…Immunohistochemical studies have demonstrated an upregulation and activation of ATF2 in the nuclear compartment in certain cancer types75,117–119. Furthermore, immunohistochemical analysis of patient-derived tumour tissue microarrays found enriched nuclear localization of ATF2 in advanced metastatic melanoma samples, which correlated with poor prognosis and survival120.…”

Section: Jun Fos and Atf2 In Tumorigenesismentioning

confidence: 99%

“…Overexpression and activation (phosphorylation) of ATF2, altered subcellular localization and enhanced interaction with other AP1 proteins, in particular with oncogenic JUN, is observed in many cancer types and transformation models46,117. Such increased expression of ATF2 might be of diagnostic value in the clinic118.…”

Section: Jun Fos and Atf2 In Human Cancermentioning

confidence: 99%

Emerging roles of ATF2 and the dynamic AP1 network in cancer

López-Bergami¹,

Lau²,

Ronai³

2010

Nat Rev Cancer

273

269

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Cooperation among transcription factors is central for their ability to execute specific transcriptional programmes. The AP1 complex exemplifies a network of transcription factors that function in unison under normal circumstances and during the course of tumour development and progression. This Perspective summarizes our current understanding of the changes in members of the AP1 complex and the role of ATF2 as part of this complex in tumorigenesis.Activator protein 1 (AP1) 1,2 functions in almost all areas of eukaryotic cellular behaviour, from cell cycle proliferation and development to stress response and apoptosis. Indeed, AP1 is activated in response to a plethora of extracellular signals from cytokines and growth factors to stress and inflammation 3,4 . The expansive transcriptional repertoire executed by AP1 complexes is propagated from the diverse compositional array of homodimeric or heterodimeric combinations formed by members of the Jun, Atf, Fos and Maf transcription factor families (BOX 1). The dimeric combinations and transcriptional activity observed in vivo are largely influenced by the tissue-specific expression patterns of the individual proteins, and importantly by their specific activating mechanisms and post-translational modifications that facilitate their individual ability to dimerize with other basic leucine zipper (bZIP) domain proteins. This inherently diverse composition of AP1 complexes and their central role in transcriptional regulation places AP1 complexes at a functional epicenter for pathological signal relay in disease, particularly in the context of malignant cellular transformation in which AP1 proteins are often deregulated by oncoprotein signalling [4][5][6] . This Perspective describes the function and cooperation of Jun, Fos and Atf family members in tumour cells, and the emerging function of ATF2 as part of the dynamic AP1 complex. Competing interests statement:The authors declare no competing financial interests. The Ap1 transcription factor complexThe mammalian AP1 proteins are homodimers and heterodimers composed of proteins from the Jun (JUN, JUNB and JUND) and Fos (FOS, FOSB, FRA1 and FRA2) families, and the closely related activating transcription factor (Atf and Creb) subfamily and the Maf subfamily 5 . AP1 constituent proteins are structurally distinguished by a basic leucine zipper (bZIP) domain that is composed of leucine zipper and basic domains. It is through these domains that AP1 proteins dimerize and bind to DNA. These proteins are typically activated through phosphorylation by the indicated upstream kinases. The different AP1 dimers bind to DNA with varying affinities and differ in their transactivation efficiencies 8,15 . Jun proteins can form stable dimers that bind to the AP1 DNA recognition element 5′-TGAC/ GTCA-3′ (also known as TPA response element (TRE)) based on their ability to mediate transcriptional induction in response to the phorbol ester tumour promoter TPA 2,15 . Atf proteins, conversely, form dimers that preferentially bind to c...

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“…21 Upregulation of pStat3 has been identified in cSCC in comparison to normal skin (including a limited number of metastatic lesions), which is supportive of a role in cSCC tumorigenesis. 39,40 The effect of the deletion within PTPRD is currently unknown. As illustrated in this publication, only 15% of deletions described in the literature extend into the protein-coding region, with the remainder located in the 5 0 UTR of the gene.…”

Section: Discussionmentioning

confidence: 99%

Metastatic cutaneous squamous cell carcinoma shows frequent deletion in the protein tyrosine phosphatase receptor Type D gene

Lambert

Harwood

Purdie

et al. 2011

Intl Journal of Cancer

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Cutaneous squamous cell carcinoma (cSCC) is the second most common form of nonmelanoma skin cancer (NMSC), and its incidence is increasing rapidly. Metastatic cSCC accounts for the majority of deaths associated with NMSC, but the genetic basis for cSCC progression remains poorly understood. A previous study identified small deletions (typically <1 Mb) in the protein tyrosine phosphatase receptor Type D (PTPRD) gene that segregated with more aggressive cSCC. To investigate the apparent association between deletion within PTPRD and cSCC metastasis, a series of 74 formalin-fixed paraffin-embedded tumors from 31 patients was analyzed using a custom Illumina 384 SNP microarray. Deletions were found in 37% of patients with metastatic cSCC and were strongly associated with metastatic tumors when compared to those that had not metastasized (p 5 0.007). Subsequent mutation analysis revealed a higher mutation rate for PTPRD than has been reported in any other cancer type, with 37% of tumors harboring a somatic mutation. Conversely, bisulfite sequencing showed that methylation was not a mechanism of PTPRD disruption in cSCC. This is the first report to observe an association between deletion within PTPRD and metastatic disease and highlights the potential use of these deletions as a diagnostic biomarker for tumor progression. Combined with the high mutation rate observed in our study, PTPRD is one of the most commonly altered genes in cSCC and warrants further investigation to determine its significance for metastasis in other tumor types.Nonmelanoma skin cancer (NMSC) has a predicted prevalence equal to that of all other cancers combined and its incidence is increasing.1 There are more than 81,500 new cases of NMSC diagnosed annually in the United Kingdom alone, placing a heavy burden on both patients and healthcare resources.2 Despite accounting for only 20% of total NMSC cases, cutaneous squamous cell carcinoma (cSCC) is responsible for the majority of NMSC deaths, largely as a result of metastatic disease. A subset of immunosuppressed individuals, such as organ transplant recipients on long-term immunosuppressive drugs, develop particularly aggressive tumors with an increased risk of metastasis.3 Risk factors for metastasis include poor differentiation of the tumor cells, large tumor size, tumor depth >5 mm, immunosuppression and localization on the ear and lip. [4][5][6][7] Metastatic cSCC is currently treated by surgical intervention and/or chemotherapy or radiotherapy and is associated with a poor outcome. 8Despite the well-established role of ultraviolet radiation (UVR) in the etiology of cSCC, the molecular events underlying its development remain largely undefined. Inactivation of the tumor suppressor genes TP53 and p16INK4A is a common and early event in cSCC pathogenesis and is characteristic of all histological grades of tumor. 9,10 Recently, genotyping of 60 cSCC identified high rates of loss of heterozygosity (LOH)

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Overexpression of phosphorylated-ATF2 and STAT3 in cutaneous squamous cell carcinoma, Bowen's disease and basal cell carcinoma

Cited by 15 publications

References 9 publications

STAT 3, STAT 5A, STAT 5B and STAT 6 proteins are overexpressed in human basal cell carcinoma

STAT 3, STAT 5A, STAT 5B and STAT 6 proteins are overexpressed in human basal cell carcinoma

Emerging roles of ATF2 and the dynamic AP1 network in cancer

Metastatic cutaneous squamous cell carcinoma shows frequent deletion in the protein tyrosine phosphatase receptor Type D gene

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