Squamous Cell Carcinoma Antigen 2 Research Articles

Potential biomarkers of atopic dermatitis.

Atopic dermatitis (AD) is a chronic, recurrent inflammatory skin disease with a wide range of heterogeneity. Accurate biomarkers or predictors are the keys to instructing personalized tailored precise treatment. The development of technology such as transcriptomics, genomics, and proteomics provides novel insights into the possibility to find potential biomarkers. Meanwhile, emerging minimally invasive methods such as tape stripping were used to reveal different profiles of patients' skin without biopsy. Several potential biomarkers or predictors have been found. In this review, we summarized the current development of potential biomarkers of AD. Nitric oxide synthase 2/inducible nitric oxide synthase (NOS2/iNOS), human beta-defensin-2 (hBD-2), and matrix metalloproteinases 8/9 (MMP8/9) may be the candidate biomarkers for AD diagnosis. Filaggrin (FLG) gene mutation increased the occurrence risk of AD. Fatty-acid-binding protein 5 (FABP5) may serve as an effective biomarker for the atopic march (AM). Squamous cell carcinoma antigen 2 (SCCA2), serum thymus and activation-regulated chemokine (TARC), cutaneous T-cell-attracting chemokine (CTACK), eosinophil-derived neurotoxin (EDN), macrophage-derived chemokine (MDC), lactate dehydrogenase (LDH), and interleukin (IL)-18 can be the candidate biomarkers for disease severity monitoring. IL-17, IL-23, IL-33, and indoleamine 2,3-dioxygenase (IDO1) can be used as predictive biomarkers for AD comorbidities. LDH, TARC, pulmonary and activation-regulated chemokine (PARC), periostin, IL-22, eotaxin-1/3, and IL-8 may be the candidate biomarkers for monitoring treatment effects. There are still unmet needs and a long way to go for more convenient, non-invasive, and effective predictors and biomarkers to better guide personalized precise treatment.

Differences in Thymus and Activation-Regulated Chemokine and Squamous Cell Carcinoma Antigen 2 Levels in Food Protein-Induced Enterocolitis Syndrome and Atopic Dermatitis

Introduction: We previously reported that thymus and activation-regulated chemokine (TARC) levels measured after vomiting are useful predictors of a food protein-induced enterocolitis syndrome (FPIES) diagnosis. However, interpreting TARC levels in patients with eczema is difficult, as the levels are similarly elevated in patients with eczema caused by atopic dermatitis (AD). Therefore, we aimed to investigate whether it is possible to predict whether FPIES or AD is responsible for elevated TARC levels by simultaneously measuring TARC and squamous cell carcinoma antigen 2 (SCCA2), another T-helper type 2 biomarker. Methods: Twenty-one episodes in 11 patients with FPIES (FPIES group) and 42 age-matched patients with AD (AD group) were included in this study. Serum TARC and SCCA2 levels were measured, and those values and relative ratios were compared between groups. Results: The median age was 1.1 years in the FPIES group and 1.6 years in the AD group (p = 0.492). The median (interquartile range [IQR]) serum TARC concentration was significantly higher in the FPIES group than in the AD group (2,486 [1,815–4,097] pg/mL and 1,451 [1,201–1,751] pg/mL, respectively; p = 0.002). The median (IQR) SCCA2 concentration was significantly higher in the AD group than in the FPIES group (1.9 [1.3–2.9] pg/mL and 0.8 [0.6–1.5] pg/mL, respectively; p < 0.001). After matching, the analysis using stratified TARC values revealed no significant difference in TARC values between the FPIES and AD groups; however, the TARC/SCCA2 ratio was significantly higher in the FPIES group. Conclusion: Assessing the relative TARC/SCCA2 ratio may help predict whether elevated TARC levels measured after vomiting are caused by FPIES or AD.

Squamous cell carcinoma antigens are sensitive biomarkers for atopic dermatitis in children and adolescents: a cross-sectional study

BackgroundWe recently reported that squamous cell carcinoma antigen 2 (SCCA2) is a reliable biomarker for atopic dermatitis (AD).ObjectiveTo further clarify its utility, we investigated for effects of comorbid allergies and AD treatment on serum SCCA levels.MethodsVolunteers <18 years old were recruited through our website. Their allergic status was elucidated using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. We also recruited pediatric patients who were hospitalized because of severe AD. The serum levels of SCCA1 and SCCA2 were measured by enzyme-linked immunosorbent assays. In the severe AD patients, the levels of thymus and activation-regulated chemokine (TARC), SCCA1, and SCCA2 were measured before and after hospitalization. The severity of AD was assessed using the severity scoring of atopic dermatitis (SCORAD).ResultsA total of 576 participants (547 volunteers and 29 patients) were enrolled in the study. The levels of SCCA1 and SCCA2 were significantly higher in volunteers with mild AD and patients with severe AD than in healthy volunteers without allergic diseases. The levels were not elevated in those who had mild bronchial asthma or allergic rhinitis without AD. TARC, SCCA1, and SCCA2 were decreased during the treatment in severe AD patients, reflecting clinical improvement in response to treatment. Linear regression analysis for predicting a decrease in the SCORAD index showed R2 values of 0.16, 0.38, and 0.48 for TARC, SCCA1, and SCCA2, respectively.ConclusionSCCAs, especially SCCA2, are sensitive biomarkers for detecting AD in children and adolescents and for assessing the severity and response to treatment of severe AD.

Serum squamous cell carcinoma antigen-2 is a highly sensitive biomarker for atopic dermatitis in children

Serum squamous cell carcinoma antigen-2 is a highly sensitive biomarker for atopic dermatitis in children

Antitumor potential of SLPI promoter controlled recombinant caspase-3 expression in laryngeal carcinoma

The purpose of this study is to develop a specific and efficient targeted gene therapy candidate approach for laryngeal carcinomas. Several promoters of human squamous cell carcinoma antigen 2(SCCA2), secretory leukocyte protease inhibitor (SLPI) and Survivin genes were cloned from human genomic DNA and evaluated for tumor-specific transcription potential in human laryngeal carcinoma Hep-2 cells by dual luciferase assays. One SLPI promoter fragment (677 bp) showed the highest efficiency and specificity, and was used to control the expression of a recombinant active caspases-3 (revCasp3), which could trigger apoptosis without activation of its upstream cascade elements once expressed in a cell, in an adenoviral vector (Ad-SLPI-revCasp3), and its antitumor efficacy was assessed. In vitro infection with Ad-SLPI-revCasp3 showed revCasp3 could be specifically expressed in Hep-2 cells, resulting in efficient activation of endogenous Caspase-3 and subsequent apoptosis of Hep-2 cells. In Hep-2 nude mice xenograft model, intratumoral administration of Ad-SLPI-revCasp3 significantly inhibited tumor growth without obvious loss of body weight and obvious hepatic toxicity. In summary, our study showed the specific and efficient apoptosis-inducing potential of Ad-SLPI-revCasp3, and this makes it a new candidate approach of targeted gene therapy for laryngeal squamous cell carcinoma, which needs further systematic investigation.

Conditionally replicating E1B-deleted adenovirus driven by the squamous cell carcinoma antigen 2 promoter for uterine cervical cancer therapy

Cervical cancer is the second most common type of malignant tumor among women worldwide. When the disease is confined locally, it can be controlled with surgical resection and radiotherapy. However, patients with recurrent or metastatic disease often have a poor prognosis. Measurement of serum levels of squamous cell carcinoma (SCC) antigens has been widely used as serological markers for SCC of uterine cervix. Recently, it has been demonstrated that cervical cancer patients with elevated squamous cell carcinoma antigen-2 (SCCA2) expression in tumor cells carry a poor prognosis. Here, by using a luciferase reporter assay, we show that SCCA2 promoter was active in SCCA2-producing human cervical cancer cell lines, including Cx, Cxwj, SiHa and HeLa cells, but relatively quiescent in normal cervical epithelial cells. We then developed a conditionally replicating adenovirus, designated Ad-KFH, under the transcriptional control of the SCCA2 promoter. This E1B-55 kDa-deleted oncolytic adenovirus replicated specifically in and lysed SCCA2-producing cervical cancer cells. Furthermore, in a peritoneal metastatic tumor model, Ad-KFH retarded Cxwj tumor growth in NOD/severe combined immunodeficient mice and prolonged survival of tumor-bearing mice, especially when combined with cisplatin. These results suggest that Ad-KFH may provide a new strategy of gene therapy for advanced or recurrent uterine cervical cancer.

An expression of squamous cell carcinoma antigen 2 in peripheral blood within the different stages of esophageal carcinogenesis

The malignant transformation of esophageal mucosa is a progressive process, which includes basal cell hyperplasia, dysplasia, carcinoma in situ, and invasive esophageal squamous cell carcinoma (ESCC). The objectives of this study were to prove the relationship of squamous cell carcinoma antigen 2 (SCCA2) mRNA expression in peripheral blood with non-malignant lesion, premalignant lesion, and carcinoma of the esophagus at the same assay, as well as to evaluate whether or not SCCA2 mRNA expression in peripheral blood may be a biomarker for monitoring the premalignant lesion of the disease. The subjects consisted of 50 patients with basal cell hyperplasia, 50 patients with dysplasia, 50 patients with ESCC (12 carcinoma in situ, 38 carcinoma in invasive stage), and 50 controls who were pathologically diagnosed to be normal and whose esophageal mucosa were stained brown by iodine. All the subjects are residents of Feicheng, China, which is considered an area with a high incidence of esophageal cancer. All subjects were diagnosed by two separate histopathologists, and the expression of SCCA2 mRNA in peripheral blood was detected by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Furthermore, SCCA2 concentration in the serum was measured using an enzyme-linked immunosorbent assay (ELISA). In the cancer group, SCCA2 mRNA expression was also detected in 20 tissues of esophageal cancer. By using the band intensity ratios of SCCA2 to beta-actin, with a positive cut-off value of > or = 0.4, the positive rates of the SCCA2 mRNA expression in peripheral blood were found to be 82% (41/50), 60% (30/50), 48% (24/50), and 36% (18/50) in the cancer, dysplasia, basal cell hyperplasia, and control groups, respectively. The positive rate of the cancer group was significantly different from the three other groups (P < 0.05), and there was also a significant difference in the SCCA2 mRNA expression between the dysplasia group and the control group (chi(2)=5.769, P= 0.016). In the multinomial logistic regression analysis, the odds ratios (ORs) were 1.71 [95% confidence interval (95% CI), 0.73-3.99] in the basal cell hyperplasia group, 2.77 (95% CI, 1.14-6.71) in the dysplasia group, and 7.87 (95% CI, 2.88-21.55) in the cancer group after being adjusted for age, gender, smoking index, drinking index, and family history of esophageal cancer. The SCCA2 mRNA expression in peripheral blood was then divided into different grades according to the band intensity ratios of SCCA2 to beta-actin. By using a positive cut-off value of > or = 0.4, the testing sensitivities in the basal cell hyperplasia, dysplasia, and cancer groups were found to be 48%, 60%, and 82%, respectively, with the same testing specificity at 64%. On the other hand, SCCA2 mRNA expression in peripheral blood had a 97.5% agreement with that in tissue, and there was a significant correlation between the ELISA SCCA2 levels in the serum and the SCCA2 mRNA expression levels in the peripheral blood (r= 0.80, P= 0.01). The results indicate that SCCA2 mRNA expression in peripheral blood is linked with the different stages of esophageal pathological changes, despite the fact that SCCA2 mRNA was not a biomarker for screening early esophageal cancer. This knowledge may be useful in monitoring the processes of change that occur in esophageal premalignant lesions among subjects who live in a high-incidence area.

The increase in tryptase‐ and chymase‐positive mast cells is associated with partial inactivation of chymase and increase in protease inhibitors in basal cell carcinoma

In basal cell carcinoma (BCC), mast cells accumulate in the peritumoral stroma. The serine proteinases tryptase and chymase are the major mediators in mast cell granules and they may exert their enzymatic activity in the BCC lesion by inducing matrix remodeling and epithelial cell detachment. To analyse the numbers of mast cells showing tryptase enzyme activity, chymase enzyme activity and chymase immunoreactivity as well as the presence of chymase inhibitors alpha(1)-antichymotrypsin (alpha(1)-AC), alpha(1)-proteinase inhibitor (alpha(1)-PI) and squamous cell carcinoma antigen-2 (SCCA-2) in BCC. Eleven biopsies were taken from the lesion and healthy-looking skin of 10 patients with superficial spreading BCC. The frozen biopsies were analysed enzyme- and immunohistochemically, and a sequential double-staining method was applied. In the BCC lesion, the number of mast cells with tryptase activity and chymase immunoreactivity was significantly increased by 2.2- to 2.3-fold. Practically all tryptase-immunopositive cells contained tryptase activity although occasional tryptase-immunopositive cells (about 1% of total) revealed no activity. However, the ratio of cells with chymase activity to those with chymase immunoreactivity was significantly decreased from 49 +/- 19% in the healthy skin to 33 +/- 19% in the BCC lesion. Instead, the percentage of mast cells displaying alpha(1)-AC or alpha(1)-PI immunoreactivity was significantly increased by 1.7-fold in the BCC lesion. SCCA-2 expression was strongly increased in the malignant BCC epithelium but mostly in the suprabasal layers. Tryptase- and chymase-positive mast cells (MC(TC)) increased in the BCC lesion. However, chymase is partially inactivated, possibly by the effective chymase inhibitors alpha(1)-AC and alpha(1)-PI. SCCA-2 increased in BCC, but was localized mostly to the suprabasal layers, and thus it seems not to be crucial in inhibiting chymase.

Uteroglobin Suppresses SCCA Gene Expression Associated with Allergic Asthma

Uteroglobin (UG), the founding member of the Secretoglobin superfamily, is a potent anti-inflammatory protein constitutively expressed at a high level in the airway epithelia of all mammals. We previously reported that the lungs of UG-knock-out (UG-KO) mice express elevated levels of Th2 cytokines (e.g. interleukin (IL)-4 and IL-13), which are augmented by allergen sensitization and challenge leading to exaggerated airway inflammation. Notably, these responses are suppressed by recombinant UG treatment (Mandal, A. K., Zhang, Z., Ray, R., Choi, M. S., Chowdhury, B., Pattabiraman, N., and Mukherjee, A. B. (2004) J. Exp. Med. 199, 1317-1330). Recent reports indicate that human orthologs of murine squamous cell carcinoma antigen-2 (SCCA-2/serpinb3a), a serine protease-inhibitor, are overexpressed in the airways of asthmatic patients. We report here that compared with wild type littermates, UG-KO mouse lungs express markedly elevated levels of SCCA-2 mRNA and protein, which are augmented by allergen-challenge. Most importantly, these effects are abrogated by recombinant UG treatment. We further demonstrate that treatment of cultured human bronchial epithelial cells with IL-4 or IL-13 stimulates phosphorylation of STAT-1 and STAT-6 leading to SCCA-1 (SERPINB3) and SCCA-2 (SERPINB4) gene expression. We propose that: (i) IL-4- and IL-13-stimulated SCCA gene expression is mediated via STAT-1 and STAT-6 activation, and (ii) by suppressing the production, and most likely by interfering with the signaling of these cytokines, UG inhibits SCCA gene expression associated with airway inflammation in asthma.

Three-dimensional modeling of squamous cell carcinoma antigen 2 and its interactions with serine protease

An attempt is made to build up a three-dimensional model of squamous cell carcinoma antigen 2 (SCCA2) by means of the homology module of Insight II, where SCCA2 contains the stressed and relaxed forms, i.e. SCCA2(S) and SCCA2(R). The docking of SCCA2(S) with two different target serine proteinases, that are the cathepsin G (Cat G) and the human mast cell chymase (HMC), are studied theoretically to give two different complexes, respectively. It is shown, from the molecular surface electricity potential, that in the formation of the two complexes SCCA2(S)–Cat G and SCCA2(S)–HMC, the electrostatic interaction may play an important role. Since HMC possesses a loop to produce spatial anti-effect, the complex SCCA2(S)–HMC is less stable than the complex SCCA2(S)–Cat G. However, the reactive site loop involved in SCCA2(S) is an important factor in restraining serine proteinases.

Nondenaturing two-dimensional electrophoretic analysis of loop-sheet polymerization of serpin, squamous cell carcinoma antigen-2.

Two homologous serine proteinase inhibitors (serpins), squamous cell carcinoma (SCC) antigen-1 and -2 were separated by nondenaturing two-dimensional electrophoresis combined with immunostaining to acquire further information on these proteins under physiological conditions. Polymers of SCC antigen-2 were detected in cytosolic extracts prepared from tumor tissues. The polymer formation of SCC antigen-2 was apparently decreased and the SCC antigen-2-synthetic peptide binary complexes were newly formed by the addition of synthetic peptide with sequences corresponding to residues from P14 to P2 in the reactive center loop of SCC antigen-2. On the other hand, the incubation with synthetic peptides having the sequence of the reactive center loop of SCC antigen-1 or antithrombin had no effect on polymerization of SCC antigen-2. These data suggest that the polymerization of SCC antigen-2 may occur spontaneously in vivo by the loop-sheet mechanism of serpin.

Cloning and characterization of hurpin (protease inhibitor 13): a new skin-specific, UV-repressible serine proteinase inhibitor of the ovalbumin serpin family

Epidermal keratinocytes are the primary target of the midrange ultraviolet part (UVB, 280–320 nm) of terrestrial sunlight. Analysis of the resulting UV response at the transcriptional level by differential display PCR identified a formerly unrecognized large group of repressed genes. Among those UV-repressible genes, a novel serine proteinase inhibitor (serpin) termed hurpin (HaCaT UV-repressible serpin) has been identified. The isolated full-length cDNAs harbour a 1176 bp open reading frame encoding a potential protein with 391 amino acid residues and a predicted molecular mass of ∼44 kDa. The novel serpin has nearly 59% amino acid identity with the squamous cell carcinoma antigen 1 (SCCA1) and squamous cell carcinoma antigen 2 (SCCA2). In addition, it displays all of the structural features unique to the ovalbumin family of serpins (ov-serpins). The amino acid sequence of the hinge region in the reactive site loop suggests that hurpin has the potential for protease inhibition. The putative reactive center P 1-P 1′ residues were identified as Thr356-Ser357 by alignment with other ov-serpins. The physiological target protease is unknown and the in vitro translated hurpin does not form SDS-stable complexes with a variety of known serine proteases. Expression of hurpin is restricted to epidermal cells where two distinct transcripts of 3.0 and 3.4 kb are detectable. Furthermore, expression of hurpin appears to be related to the activation or proliferation state of keratinocytes, since hurpin transcripts are more abundant in immortalized keratinocytes (HaCaT) and in cultured normal human keratinocytes, compared to the expression in normal skin. Moreover, in psoriasis, a skin disease characterized by hyperproliferation of keratinocytes and responsive to therapeutic UV irradiation, overexpression of hurpin is noted in psoriatic skin lesions compared to non-lesional skin.

Identification of squamous cell carcinoma antigen-2 in tumor tissue by two-dimensional electrophoresis.

The aim of this study was to identify two homologous serine proteinase inhibitor (serpin) molecules, squamous cell carcinoma (SCC) antigen-1 and -2, by two-dimensional electrophoresis (2-DE), combined with immunoblotting, and examine their expression in tumor tissue. The recombinant SCC (rSCC) antigen-1 showed four spots with p/ 6.5, 6.4, 6.3 and 6.0, whereas rSCC antigen-2 showed a more acidic spot with p/5.95. SCC antigen in tumor tissue appeared in three new acidic spots (p/5.7-5.5, M(r) 44 500), numbered 5, 6 and 7, besides the previously reported four spots numbered 1 to 4. These new acidic spots of SCC antigen apparently increased in SCC tissue. Treatment of tissue extract by carboxymethyl (CM)-papain agarose matrix extinguished spots 1 to 4 encoded on the SCCA1 gene, but not 5 to 7 on the SCCA2 gene. Overexpression of the SCCA2 gene may play an important role in the malignant behavior of tumor cells.