MMP‐10 (Stromelysin‐2) and MMP‐21 in human and murine squamous cell cancer

Abstract: The squamous cell cancers (SCC) of renal transplant recipients are more aggressive and metastasize earlier than those of the non‐immunocompromised population. Matrix metalloproteinases (MMPs) have a central role in tumor initiation, invasion and metastasis. Our aim was to compare the expression of MMPs‐10, ‐12 and ‐21 in SCCs from immunosuppressed (IS) and control patients and the contribution of MMPs‐10 and ‐21 to SCC development in the FVB/N‐Tg(KRT5‐Nfkbia)3Rto mouse line. Immunohistochemical analysis of 25 matched pairs of SCCs, nine of Bowen’s disease and timed back skin biopsies of mice with selective inhibition of Rel/NF‐κB signalling were performed. Semiquantitatively assessed stromal MMP‐10 expression was higher (P = 0.009) in the control group when compared with IS patients. Tumor cell‐derived MMP‐10, ‐12 and ‐21 expression did not differ between the groups but stromal fibroblasts of the control SCCs tended to express MMP‐21 more abundantly. MMP‐10 expression was observed already in Bowen’s disease while MMP‐21 was absent. MMP‐10 and ‐21 were present in inflammatory or stromal cells in ageing mice while dysplastic keratinocytes and invasive cancer were negative. Our results suggest that MMP‐10 may be important in the initial stages of SCC progression and induced in the stroma relating to the general host‐response reaction to skin cancer. MMP‐21 does not associate with invasion of SCC but may be involved in keratinocyte differentiation.     

Comparison of morphologic criteria for actinic keratosis and squamous cell carcinoma using in vivo multiphoton tomography

The routine diagnostic procedure of actinic keratosis (AK) and invasive squamous cell carcinoma (SCC) is a histological examination after taking a biopsy. In the past decades, non‐invasive optical methods for skin examination have been developed. Patients with clinical diagnosis of AK or SCC were examined. The morphological criteria were determined for healthy, AK and SCC skin and compared for statistically significant differences. In this study, the applicability of multiphoton tomography (MPT) as an in vivo diagnostic tool for AK and SCC was evaluated. Changes in the morphology of the keratinocytes such as broadened epidermis, large intercellular spaces, enlarged nucleus and a large variance in cell shape could easily be recognized. The cell nuclei of AK and SCC were significantly larger compared to healthy skin cells in all cell layers. The nucleus–cytoplasm ratio was also significantly higher for AK and SCC than for the healthy skin cells. It was even higher in SCC compared to spinous and basal cell layer of AK. The cell density in AK and SCC was significantly lower than in the basal and spinous cell layers of healthy skin. In SCC, the cell density was significantly lower than in AK. Concerning the intercellular spaces, significant differences were found for AK and healthy skin in spinous and basal cell layer and for SCC compared to AK and healthy skin. In this study, MPT proved to be a valuable non‐invasive imaging method for in vivo detection and discrimination of AK and SCC from healthy skin.     

Validation of a diagnostic algorithm for the discrimination of actinic keratosis from normal skin and squamous cell carcinoma by means of high‐definition optical coherence tomography

Actinic keratoses (AKs) commonly arise on sun‐damaged skin. Visible lesions are often associated with subclinical lesions on surrounding skin, giving rise to field cancerization. To avoid multiple biopsies to diagnose subclinical/early invasive lesions, there is an increasing interest in non‐invasive diagnostic tools, such as high‐definition optical coherence tomography (HD‐OCT). We previously developed a HD‐OCT‐based diagnostic algorithm for the discrimination of AK from squamous cell carcinoma (SCC) and normal skin. The aim of this study was to test the applicability of HD‐OCT for non‐invasive discrimination of AK from SCC and normal skin using this algorithm. Three‐dimensional (3D) HD‐OCT images of histopathologically proven AKs and SCCs and images of normal skin were collected. All images were shown in a random sequence to three independent observers with different experience in HD‐OCT, blinded to the clinical and histopathological data and with different experience with HD‐OCT. Observers classified each image as AK, SCC or normal skin based on the diagnostic algorithm. A total of 106 (38 AKs, 16 SCCs and 52 normal skin sites) HD‐OCT images from 71 patients were included. Sensitivity and specificity for the most experienced observer were 81.6% and 92.6% for AK diagnosis and 93.8% and 98.9% for SCC diagnosis. A moderate interobserver agreement was demonstrated. HD‐OCT represents a promising technology for the non‐invasive diagnosis of AKs. Thanks to its high potential in discriminating SCC from AK, HD‐OCT could be used as a relevant tool for second‐level examination, increasing diagnostic confidence and sparing patients unnecessary excisions.     

Heat shock protein 105 is overexpressed in squamous cell carcinoma and extramammary Paget disease but not in basal cell carcinoma

BACKGROUND: Heat shock protein (HSP) 105 is a 105-kDa protein, recently discovered by serological analysis of recombinant cDNA expression libraries prepared from tumour cells (SEREX), and is still undergoing intensive research. SEREX can define strongly immunogenic tumour antigens that elicit both cellular and humoral immunity. Previous studies have shown that HSP105 is a cancer testis antigen and is overexpressed in various internal malignancies. The expression of HSP105 has not been studied in skin cancers. OBJECTIVES: To assess the expression of HSP105 in skin cancers including extramammary Paget disease (EMPD), cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). METHODS: Samples of EMPD (n = 25), SCC (n = 23, of which three were metastatic lesions) and BCC (n = 23) were collected from patients treated in our department between January 2002 and December 2004. Western blot and immunohistochemical staining methods were used to investigate the expression of HSP105. RESULTS: Results of Western blot analysis showed overexpression of HSP105 in EMPD and SCC, and minimal expression in BCC. Immunohistochemistry results showed that 56% of EMPD, 60% of primary and 100% of metastatic SCC highly expressed HSP105 while only 13% of BCC lesions showed increased staining. CONCLUSIONS: EMPD and SCC overexpress HSP105 while BCC does not. Tumours overexpressing HSP105 present ideal candidates for vaccination by HSP105-derived peptides or DNA.     

Autoantigens ADAMTSL5 and LL37 are significantly upregulated in active Psoriasis and localized with keratinocytes,dendritic cells and other leukocytes

Psoriasis is a common immune‐mediated disease that affects 2%‐4% of individuals in North America and Europe. In the past decade, advances in research have led to an improved understanding of immune pathways involved in the pathogenesis of psoriasis and has spurred the development of targeted therapeutics. Recently, three psoriasis autoantigens have been described: cathelicidin (LL37), a disintegrin and metalloprotease domain containing thrombospondin type 1 motif‐like 5 (ADAMTSL5), and lipid antigens generated by phospholipase A2 (PLA2) group IVD (PLA2G4D). It is important to establish the expression, regulation and therapeutic modulation of these psoriasis autoantigens. In this study, we performed immunohistochemistry and two‐colour immunofluorescence on non‐lesional and lesional psoriasis skin to characterize ADAMTSL5 and LL37, and their co‐expression with T cells, dendritic cells, neutrophils and macrophages, which are the main immune cells that drive this disease. Our results showed that ADAMTSL5 and LL37 are significantly (P<.05) increased in lesional skin and are co‐expressed by many dendritic cells, macrophages and some T cells in the dermis. Gene expression analysis showed significant (P<.05) upregulation of LL37 in lesional skin and significant downregulation following treatment with etanercept. ADAMTSL5 and LL37 are also significantly decreased by IL‐17 or TNF‐α blockade, suggesting feed‐forward induction of psoriasis autoantigens by disease‐related cytokines.     

Expression of Antimicrobial Peptides Such as LL‐37 and hBD‐2 in Nonlesional Skin of Atopic Individuals

Abstract: Recurrent skin infection is one of the major complications of atopic dermatitis and can be partly explained by decreased expression of antimicrobial peptides such as human β‐defensin‐2 and cathelicidin (LL‐37). In the human epidermis, human β‐defensin‐2 is packed in the lamellar body and LL‐37 is co‐localized with intercellular lipid lamellae of the stratum corneum; together, these antimicrobial peptides constitute the primary defense system. IL‐1α, a potent inducer of LL‐37 and human β‐defensin‐2, is also secreted from the disrupted epidermis for barrier homeostasis. In this study, we investigated whether expression of human β‐defensin‐2 and LL‐37 is constitutively decreased in the skin of atopic individuals. Nonlesional foreskins from atopic (n = 7) and nonatopic (n = 7) individuals were analyzed. The expression of LL‐37, human β‐defensin‐2 and IL‐1α was analyzed using immunohistochemical staining, Western blot, and real‐time polymerase chain reaction. Lamellar body density and secretion were evaluated by electron microscope. Quantitative analysis showed that the expression of each parameter was not significantly different between groups. Thus, basal expression of LL‐37 and human β‐defensin‐2 was not changed in atopic individuals. These results indicate that the expression of antimicrobial peptides at baseline was not different between nonlesional skin of atopic individuals and normal skin of nonatopic individuals.     

乳房外Paget病皮损中黏蛋白1和黏蛋白2的表达

目的 探讨黏蛋白1(MUC1)和黏蛋白2(MUC2)在乳房外Paget病(EMPD)中的表达情况.方法 生物素蛋白免疫组化法(SP法)检测19例EMPD皮损及19例美容切除术后正常皮肤组织上MUC1与MUC2的表达.结果 19例EMPD皮损常规HE染色显示,3例伴低分化腺癌,6例呈浸润性,10例为上皮内.MUC1在3例伴腺癌Paget病中有2例呈阳性表达,6例浸润性和10例上皮内Paget病均呈阳性表达.MUC2在3例伴腺癌Paget病和6例浸润性Paget病均呈阳性表达,在10例上皮内Paget病中有2例呈阳性表达.MUC1与MUC2在正常皮肤组织呈阴性表达.MUC1在上皮内Paget病中的表达显著高于伴腺癌Paget病和浸润性Paget病(P＜0.05).MUC2在伴腺癌Paget病和浸润性Paget病中的表达显著高于上皮内Paget病(P＜0.05).MUC1和MUC2的表达无明显相关性(r=-0.5,P＞0.05).结论 MUC1在EMPD中呈普遍表达,MUC2在伴有腺癌和浸润性EMPD中呈阳性表达.

Abstract：

Objective To study the expressions of mucin (MUC) 1 and 2 in extramammary Paget's disease(EMPD) lesions. Methods Tissue specimens were obtained from the lesions of 19 patients with EMPD and normal skin of 19 human controls during cosmetic surgery. Streptavidin-perosidase (SP) technique was used to detect the expressions of MUC1 and MUC2 in these specimens. Results As haematoxylin-eosin (HE) staining showed, 3 cases were accompanied by poorly differentiated adenocarcinoma, 6 were invasive Paget's disease and 10 were intraepithelial EMPD. MUC1 was expressed in 2 cases accompanied by poorly differentiated adenocarcinoma, and in all the cases of invasive and intraepithelial EMPD; MUC2 was observed in all the cases of adenocarcinoma-complicated EMPD and invasive EMPD, but only in 2 of 10 cases of intraepithelial EMPD.Neither MUC1 nor MUC2 was observed in normal control specimens. A significant increase was observed in the expression of MUC1 in lesions of intraepithelial EMPD compared with invasive EMPD and adenocarcinoma-complicated EMPD (both P ＜ 0.05), and in the expression of MUC2 in lesions of invasive EMPD and adenocarcinoma-complicated EMPD compared with intraepithelial EMPD (both P ＜ 0.05). The expression of MUC1 was uncorrelated to that of MUC2 (r= -0.5, P＞ 0.05). Conclusions MUC1 is generally expressed in the lesions of EMPD, while MUC2 is expressed in those of adenocarcinoma-complicated EMPD and invasive EMPD.     

Expression of laminin-5 γ2 chain in cutaneous pseudocarcinomatous hyperplasia

Background: Since the use of laminin‐5 as a marker of invasiveness has been proposed by several authors, our objective was to compare the expression of this protein in pseudocarcinomatous hyperplasia and squamous cell carcinoma (SCC). Methods: Sixty‐four paraffin‐embedded skin biopsy samples with diagnosis of epidermal hyperplasia (non‐pseudocarcinomatous), pseudocarcinomatous hyperplasia, actinic keratosis/carcinoma in situ, microinvasive and frankly invasive SCC were obtained for immunohistochemical study. Results: Adjacent normal epithelium and epidermal hyperplasia (non‐pseudocarcinomatous) showed no staining. In pseudocarcinomatous hyperplasia, laminin‐5 was positive, at least focally, in 14 of 16 (87.5%) samples and was concentrated in peripheral cells of elongated rete pegs and in migrating cells in dermis. In samples of microinvasive carcinoma (n = 7), the expression was observed in all cases and was concentrated in the leading edge of the tumor. All cases (n = 21) of frankly invasive SCC showed cells expressing laminin‐5, at least focally. Well‐differentiated areas of the tumor presented a pattern of expression in peripheral cells of tumor nests while a diffuse pattern of expression was observed in less differentiated areas. Conclusion: We showed that cytoplasmic laminin‐5 expression should not be used as a criterion of malignancy and is not useful in distinguishing pseudocarcinomatous hyperplasia from microinvasive and well‐differentiated SCC. dos Santos AM, Carneiro FP, Queiroz AJR, Damasceno EAM, de Castro TMML, de Amorim RFB, Takano GHS, Junqueira MIMB, de Magalhães AV. Expression of laminin‐5 γ2 chain in cutaneous pseudocarcinomatous hyperplasia.     

Differential expression of two new members of the p53 family, p63 and p73, in extramammary Paget's disease

Background.  The proteins p53, p63 and p73 are known to be overexpressed and to play important roles in the pathogenesis of many tumours, but the expression of p63 and p73 has not previously been investigated in extramammary Paget's disease (EMPD).
Aim.  To investigate the potential contribution of p53, p63 and p73 in the pathogenesis of EMPD.
Methods.  In total, 35 paraffin wax-embedded tissue samples from patients with EMPD were examined using immunohistochemical staining for p53, p63 and p73.
Results.  All of the 35 EMPD specimens, including all 6 invasive EMPD and 2 metastatic lymph-node specimens, showed nuclear overexpression of both p53 and p73. The expression levels (percentage of positive cells) of p53 and p73 (90.66 ± 12.53% and 80.20 ± 13.07%) in EMPD were significantly higher than those of normal skin. There was a significant correlation between the expression levels of p53 and p73 in EMPD. In 29 of 35 EMPD specimens, there was no nuclear expression of p63, and weak or moderate staining was found in only 6 specimens. The expression level of p63 in EMPD was significantly less than that in normal skin.
Conclusions.  Our study shows that the concordant overexpression of p53 and p73 and the decreased expression of p63 may play a pivotal role in the pathogenesis of EMPD. The decreased expression of p63 may play a more important role in the pathogenesis of EMPD than the overexpression of p53 and p73.     

Immunohistochemical analysis of the mammalian target of rapamycin signalling pathway in extramammary Paget's disease

Background We have previously observed that persistent activation of the serine/threonine kinase, protein kinase B (AKT) is a frequent event in extramammary Paget’s disease (EMPD). AKT promotes cell proliferation by its ability to coordinate mitogenic signalling with energy‐ and nutrient‐sensing pathways that control protein synthesis through the atypical serine/threonine kinase, mammalian target of rapamycin (mTOR). CDK2, a member of the serine/threonine kinase family of cyclin‐dependent kinases, is a key regulator of G₁–S cell cycle progression, and has recently been shown to be one of the targets of AKT. The AKT–mTOR–p70 ribosomal protein S6 kinase (p70S6K) pathway has been described in some human malignancies, but not in EMPD. Objective To investigate the immunohistochemical staining of the AKT–mTOR–p70S6K pathway in EMPD and to evaluate the relationships among the components. Methods Samples of primary EMPD tissue were subjected to immunohistological staining with phosphorylated (p)‐AKT, p‐mTOR, p‐4E‐binding protein 1 (p‐4EBP1), p‐p70S6K/S6K1, p‐ribosomal protein S6 (p‐S6) and CDK2. Ten normal skin samples served as a control. Results Of the 32 EMPD tissue samples, 29, 27, 26, 29, 26 and 32 samples were positive for p‐AKT, p‐mTOR, p‐4EBP1, p‐p70S6K/S6K1, p‐S6 and CDK2 staining, respectively. All these cell signalling molecules showed higher positivity in invasive EMPD than in EMPD in situ. There were significant correlations between p‐AKT, p‐mTOR, p‐4EBP1, p‐p70S6K/S6K1 and p‐S6 and CDK2. Conclusions The activation of the AKT–mTOR–p70S6K pathway may play an important role in the pathogenesis of EMPD. The high expression of the components of the pathway was highly correlated with CDK2 expression, suggesting that the AKT/mTOR pathway may induce the malignant transition through CDK2 in EMPD. The AKT–mTOR–p70S6K pathway might be a potential therapeutic target in EMPD.     

Matrix metalloproteinase‐7 activates heparin‐binding epidermal growth factor‐like growth factor in cutaneous squamous cell carcinoma

Background Tumour‐specific expression of matrix metalloproteinase (MMP)‐7 has been noted in cutaneous squamous cell carcinomas (SCCs) in patients with recessive dystrophic epidermolysis bullosa (RDEB). Objectives To examine the potential role of MMP‐7 in shedding of heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF) in RDEB‐associated and sporadic SCCs. Methods Tissue microarrays of RDEB‐associated SCC (n = 20), non‐EB SCC (n = 60) and Bowen disease (n = 28) were immunostained for MMP‐7, CD44 variant 3 (CD44v3) and HB‐EGF. Shedding of HB‐EGF was studied in vitro using two cutaneous SCC cell lines. Results Immunohistochemical analysis showed that HB‐EGF was absent in tumour cells when MMP‐7 and CD44v3 colocalized, and that the absence of HB‐EGF was more pronounced in RDEB‐associated SCCs than in non‐EB SCCs. The loss of HB‐EGF in MMP‐7–CD44v3 double‐positive areas was interpreted to indicate shedding and activation of HB‐EGF; this was also detected in Bowen disease indicating its importance in the early phase of SCC development. Specific knockdown of MMP‐7 expression in human cutaneous SCC cells by small interfering RNA inhibited shedding of HB‐EGF and resulted in diminished activation of the EGF receptor (EGFR) and ERK1/2, and in reduced proliferation of SCC cells. Conclusions These findings provide evidence for the role of MMP‐7 in promoting the growth of cutaneous SCCs by shedding HB‐EGF, and identify EGFR signalling as a potential therapeutic target in RDEB‐associated SCC and unresectable sporadic cutaneous SCC.     

Elevated levels of the antimicrobial peptide LL‐37 in hidradenitis suppurativa are associated with a Th1/Th17 immune response

Hidradenitis suppurativa (HS) is an inflammatory skin disease with poorly understood immunopathogenic mechanisms. LL‐37 is an antimicrobial peptide, which is transcribed from the CAMP (cathelicidin antimicrobial peptide) gene. Previous reports showed upregulated levels of CAMP and LL‐37 in HS lesions, and therefore, the aim of this study was to compare levels of LL‐37 in HS to other inflammatory skin diseases and to establish immunomodulatory functions of LL‐37 in HS. We confirm an upregulation of the LL‐37 peptide in lesional HS skin with comparable levels as in psoriasis patients and are able to positively correlate the presence of LL‐37 in HS with the presence of T cells, macrophages, neutrophils, IFN‐γ, IL‐17, IL‐23, TNF‐α, IL‐32 and IL‐1β. Mechanistically, LL‐37 boosts the proliferation of unspecifically activated CD4⁺ T cells via an increased calcium signalling independent of antigen‐presenting cells. Targeting LL‐37 may therefore represent a new therapeutic option for the treatment of this recalcitrant disease, but it has to be kept in mind that LL‐37 also has an antimicrobial function.     

Imiquimod 5% cream as a therapeutic option for extramammary Paget's disease

A wide local excision is the standard treatment for extramammary Paget's disease (EMPD), though this treatment often leads to permanent anogenital mutilation and functional impairment. The purpose of our study is to evaluate the efficacy and safety of the topical application of imiquimod 5% cream for non‐invasive EMPD. We examined nine patients with EMPD. Eight of the nine patients were treated with imiquimod 5% cream three times per week for 16 weeks; one case was treated for 6 weeks. The response rate was 100% including five complete remissions. Local irritation was observed in three patients, which was controlled by a provisional withdrawal of the treatment. These results suggest that imiquimod 5% cream may be considered an alternative therapeutic option for the treatment of non‐invasive EMPD.     

七种细胞角蛋白在皮肤上皮性肿瘤中的表达

目的 观察7种细胞角蛋白在皮肤上皮性肿瘤中的表达,并探讨其意义.方法 应用免疫组化S-P法对54例不同的皮肤上皮性肿瘤和20例正常皮肤进行细胞角蛋白7(K72.2)、细胞角蛋白8(C-51)、细胞角蛋白10(DE-K10)、细胞角蛋白14(LL002)、细胞角蛋白17(E3)、细胞角蛋白18(DC10)、细胞角蛋白19(KS19.1)标记,观察不同细胞角蛋白的表达.结果 54例皮肤上皮性肿瘤包括,鳞状细胞癌10例、基底细胞癌10例、毛发肿瘤19例、皮脂腺癌2例、汗腺肿瘤13例.皮肤上皮性肿瘤中7种细胞角蛋白的表达和分布有所不同.鳞状细胞癌、基底细胞癌和毛发分化的肿瘤中细胞角蛋白多数呈弥漫表达;而汗腺分化的肿瘤中,不同部位表达不同细胞角蛋白,每种肿瘤各有特点.结论 选择地检测一组细胞角蛋白的联合表达,有助于皮肤上皮性肿瘤的诊断和鉴别诊断.     

Concordant overexpression of p-FAK and p-ERK1/2 in extramammary Paget’s disease

Focal adhesion kinase (FAK) is a tyrosine kinase which is at the crossroad of extracellular signal-regulated kinase-1/2 (ERK1/2), PI3K/Akt, MAPK and JAK/STAT signaling pathways. We have previously reported that p-ERK1/2, p-Akt, p38MAPK and p-STAT3 are overexpressed in extramammary Paget’s diseases (EMPD), this study aimed to examine the expression of phosphorylated (p)-FAK and p-ERK1/2 proteins in EMPD and to evaluate the relationships among them. Paraffin-embedded EMPD specimens (35 tissue samples from 33 patients with primary EMPD, including two samples of metastatic lymph nodes from two of the 33 patients) were subjected to immunohistochemical staining for p-FAK and p-ERK1/2. All of the 35 EMPD specimens, including all of six invasive EMPD and two metastatic lymph node specimens, showed cytoplasmic overexpression of p-FAK and nuclear overexpression of p-ERK1/2. The expression levels (% positive cells) of p-FAK and p-ERK1/2 (88.34 ± 14.66 and 91.26 ± 11.21%) in EMPD were significantly higher than those in normal skin (22.38 ± 2.13 and 29.00 ± 4.44%), respectively. The expression levels of p-FAK (95.38 ± 4.57%) and p-ERK1/2 (96.25 ± 5.01%) in the advanced EMPD showed slightly higher than that in the non-invasive EMPD (86.26 ± 15.99 and 89.78 ± 12.15%), respectively. There exhibited a significantly high positive correlation between expression levels of p-ERK1/2 and p-FAK in EMPD. The present study shows that the concordant overexpression of p-FAK and p-ERK1/2 in EMPD which is associated with the grade of malignancy of EMPD, indicating that p-FAK and p-ERK1/2 may play pivotal roles in the tumorigenesis and further malignant transduction of EMPD.     

Altered gene expression in squamous cell carcinoma arising from congenital unilateral linear porokeratosis

Congenital unilateral linear porokeratosis (CULP) is a rare disorder of keratinization that shares clinical and molecular similarities with psoriasis. It also has an increased risk for malignant transformation to cutaneous squamous cell carcinoma (SCC). We investigated the expression of psoriasin, human beta‐defensin‐2, cathelicidin antimicrobial peptide/LL‐37, e‐cadherin, involucrin, p16^INK4a, p53, cyclin D1 and microchromosome maintenance protein 7 in healthy skin and in lesions of psoriasis, CULP and SCC from the same patient. p16^INK4a was overexpressed in CULP but not in the subsequent SCC. Psoriasin was overexpressed in psoriasis, CULP and SCC compared with healthy skin. Speculatively, p16^INK4a and psoriasin could be involved in the pathogenesis of CULP. Moreover, psoriasin may play a role in the malignant transformation of CULP to SCC.     

NUAK2 localization in normal skin and its expression in a variety of skin tumors with YAP

BackgroundNUAK2 is a critical gene that participates in the carcinogenesis of various types of cancers including melanomas. However, the expression patterns of NUAK2 in normal skin and in various types of skin tumors have not been fully elucidated to date.ObjectivesTo elucidate the distribution and localization of NUAK2 expression in normal skin, and characterize the expression patterns of NUAK2 and YAP in various types of skin tumors.MethodsIn this study, we characterized the expression of NUAK2 in tissues by developing a novel NUAK2-specific monoclonal antibody and using that to determine NUAK2 expression patterns in normal skin and in 155 cases of various types of skin tumors, including extramammary Paget’s disease (EMPD), squamous cell carcinoma (SCC), Bowen’s disease (BD), actinic keratosis (AK), basal cell carcinoma (BCC) and angiosarcoma (AS). Further, we analyzed the expression patterns of YAP and p-Akt in those tumors.ResultsOur analyses revealed that NUAK2 is expressed at high frequencies in EMPD, SCC, BD, AK, BCC and AS. The expression of p-Akt was positively correlated with tumor size in EMPD (P = 0.001). Importantly, the expression of NUAK2 was significantly correlated with YAP in SCC (P = 0.012) and in BD (P = 0.009).ConclusionsOur results suggest that the YAP-NUAK2 axis has critical importance in the tumorigenesis of SCC and BD, and that therapeutic modalities targeting the YAP-NUAK2 axis may be an effective approach against skin tumors including SCC and BD.