Expression Of Dsc3 Research Articles

Experimentally validated oxidative stress -associated prognostic signatures describe the immune landscape and predict the drug response and prognosis of SKCM.

Skin Cutaneous Melanoma (SKCM) incidence is continually increasing, with chemotherapy and immunotherapy being among the most common cancer treatment modalities. This study aims to identify novel biomarkers for chemotherapy and immunotherapy response in SKCM and explore their association with oxidative stress. Utilizing TCGA-SKCM RNA-seq data, we employed Weighted Gene Co-expression Network Analysis (WGCNA) and Protein-Protein Interaction (PPI) networks to identify six core genes. Gene co-expression analysis and immune-related analysis were conducted, and specific markers associated with oxidative stress were identified using Gene Set Variation Analysis (GSVA). Single-cell analysis revealed the expression patterns of Oxidative Stress-Associated Genes (OSAG) in the tumor microenvironment. TIDE analysis was employed to explore the association between immune therapy response and OSAG, while CIBERSORT was used to analyze the tumor immune microenvironment. The BEST database demonstrated the impact of the Oxidative Stress signaling pathway on chemotherapy drug resistance. Immunohistochemical staining and ROC curve evaluation were performed to assess the protein expression levels of core genes in SKCM and normal samples, with survival analysis utilized to determine their diagnostic value. We identified six central genes associated with SKCM metastasis, among which the expression of DSC2 and DSC3 involved in the oxidative stress pathway was closely related to immune cell infiltration. DSC2 influenced drug resistance in SKMC patients. Furthermore, downregulation of DSC2 and DSC3 expression enhanced the response of SKCM patients to immunotherapy. This study identified two Oxidative Stress-Associated genes as novel biomarkers for SKCM. Additionally, targeting the oxidative stress pathway may serve as a new strategy in clinical practice to enhance SKCM chemotherapy and sensitivity.

Abstract 881: Desmocollin-3 and tumor immune microenvironment: Bioinformatics evaluation

Abstract Desmocollin-3 (DSC3) is a desmosomal adhesion molecule responsible for integrity and cell adhesion under normal physiological condition. Its expression is altered during carcinogenesis. DSC3 is a p53 responsive gene. Like other adhesion molecules, it is described to provide barrier for immune infiltration of tumor. To identify a specific immune gene signature related to DSC3, spearman correlation coefficient was determined for 207 immune related genes using Cbioportal in cancer having high and low level of DSC3 gene expression .We classified renal adenocarcinoma lung, hepatocellular carcinoma and renal cancer as DSC3low and squamous lung cancer, cervical cancer and head and Neck cancer as DSC3high based on DSC3 gene expression level. In DSC3high group, six genes were found to be correlated (Spearman correlation ≥ 0.3) with DSC3 expression (Table), while none of the 207 immune related genes were correlated with DSC3low expression. Of genes with positive correlation, CD44 is a marker for stem cell and is associated with resistance to chemotherapy while S100A12 and TOLLIP are associated with carcinogenesis and inflammation. Of immune genes with negative correlation, GATA6 is a tumor suppressive gene, IL-12A is responsible for T-cell-independent induction of IFNγ and CD63 is associated with survival as described in lung cancer. This findings suggests DSC3high expression may be associated with poor prognosis compared DSC3low . DSC3 expression is specific for squamous lung cancer and is used to differentiate it from adenocarcinoma lung. Squamous lung cancer is also known to have poor prognosis compared to adenocarcinoma of lung. We will be presenting full details about 207 selected genes and their correlation with DSC3 in our presentation. Table: Spearman’s correlation of DSC3 with Immune genes DSC3 expression Immune genes with positive spearman’s correlation Immune genes with negative spearman’s correlation Cancer Median RSEM (N) CD44 S100A12 TOLLIP CD63 GATA6 IL12A LUSC 6208 (n=501) 0.4 0.3 0.4 -0.4 -0.3 -0.3 CESC 10086 (n=306) 0.6 0.6 0.6 -0.6 -0.4 -0.4 HNSC 15287(n=522) 0.3 0.3 0.3 -0.5 -0.3 -0.4 KIPAN 1.5 (n=720) < 0.3 < 0.3 < 0.3 < 0.3 < 0.3 < 0.3 LIHC 2.0 (n=231) < 0.3 < 0.3 < 0.3 < 0.3 < 0.3 < 0.3 LUAD 10 (n=496) < 0.3 < 0.3 < 0.3 < 0.3 < 0.3 < 0.3 Citation Format: Arpit Dheeraj, Bakulesh M. Khamar, Chandreshwar P. Shukla, Nayan K. Jain, Rajiv I. Modi. Desmocollin-3 and tumor immune microenvironment: Bioinformatics evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 881.

Intestinal insulin/IGF1 signalling through FoxO1 regulates epithelial integrity and susceptibility to colon cancer.

Obesity promotes the development of insulin resistance and increases the incidence of colitis-associated cancer (CAC), but whether a blunted insulin action specifically in intestinal epithelial cells (IECs) affects CAC is unknown. Here, we show that obesity impairs insulin sensitivity in IECs and that mice with IEC-specific inactivation of the insulin and IGF1 receptors exhibit enhanced CAC development as a consequence of impaired restoration of gut barrier function. Blunted insulin signalling retains the transcription factor FOXO1 in the nucleus to inhibit expression of Dsc3, thereby impairing desmosome formation and epithelial integrity. Both IEC-specific nuclear FoxO1ADA expression and IEC-specific Dsc3 inactivation recapitulate the impaired intestinal integrity and increased CAC burden. Spontaneous colonic tumour formation and compromised intestinal integrity are also observed upon IEC-specific coexpression of FoxO1ADA and a stable Myc variant, thus suggesting a molecular mechanism through which impaired insulin action and nuclear FOXO1 in IECs promotes CAC.

SOX30 is a key regulator of desmosomal gene suppressing tumor growth and metastasis in lung adenocarcinoma

BackgroundThe expression of desmosomal genes in lung adenocarcinoma and lung squamous carcinoma is different. However, the regulatory mechanism of desmosomal gene expression in lung adenocarcinoma and lung squamous carcinoma remains unknown.MethodsThe correlation between expression of desmosomal gene expression and SOX30 expression were analyzed by bioinformatics. The expression of SOX30, DSP, JUP and DSC3 were detected in lung cancer cell lines, lung tissues of mice and patients’ tissues by qPCR, WB, Immunofluorescence and Immunohistochemistry. A chromatin Immunoprecipitation assay was used to investigate the mechanisms of the SOX30 regulation on desmosomal gene expression. In vitro proliferation, migration and invasion assays, and an in vivo nude mice model were utilized to assess the important role of desmosomal genes on SOX30-induced tumor suppression. A WB assay and TOP/FOP flash reporter assay was used to investigate the downstream pathway regulated by the SOX30-desmosomal gene axis. A chemical carcinogenic model of SOX30-knockout mice was generated to confirm the role of the SOX30-desmosomal gene axis in tumorigenesis.ResultsThe expression of desmosomal genes were upregulated by SOX30 in lung adenocarcinoma but not in lung squamous carcinoma. Further mechanism studies showed that SOX30 acts as a key transcriptional regulator of desmosomal genes by directly binding to the ACAAT motif of desmosomal genes promoter region and activating their transcription in lung adenocarcinoma. Knockdown of the expression of related desmosomal genes by miRNA significantly attenuated the inhibitory effect of SOX30 on cell proliferation, migration and invasion in vitro and on tumor growth and metastasis in vivo. In addition, knockout of SOX30 promotes lung tumor development and loss the inhibition of desmosomal genes on downstream Wnt and ERK signal in urethane-induced lung carcinogenesis in SOX30-knockout mice.ConclusionsOverall, these findings demonstrate for the first time that SOX30 acts as a master switch of desmosomal genes, inhibits lung adenocarcinoma cell proliferation, migration and invasion by activating the transcription of desmosomal genes. This study provides novel insights on the regulatory mechanism of desmosomal genes in lung adenocarcinoma.

Desmocollin 3 mediates follicle stimulating hormone-induced ovarian epithelial cancer cell proliferation by activating EGFR/Akt signaling pathway

Objective To explore whether desmocollin 3( Dsc3) mediates follicle stimulating hormone( FSH)-induced ovarian epithelial cancer cell proliferation by activating EGFR / Akt signaling pathway, thereby promoting tumor growth. Methods Immunohistochemical staining was used to detect the expression of Dsc3 in ovarian tumor tissues; Western blotting analysis was used to detect Dsc3 protein expression in 6 ovarian tumor cell lines and immortalized ovarian epithelial cells,and Dsc3,EGFR expression after FSH treatment. After knock-down Dsc3 and EGFR expression by siRNA and after treatment with PI3K / Akt signaling pathway inhibitor, Western blotting analysis was used to detect the expression of Dsc3,EGFR,Akt and pAkt; MTT assay was used to determine cellular growth. Results( 1) The positive expression rates of Dsc3 in ovarian cancer tissues and borderline ovarian tumor tissues were significantly higher than that in benign ovarian cyst tissues( P 0. 05); and the positive rates were similar between the former two tissues. The expression of Dsc3 in some ovarian cancer cells,such as Hey and HO8910 and borderline ovarian tumor cells MCV152, was higher than that in immortalized ovarian epithelial cells( Moody).( 2) FSH up-regulated expression of Dsc3 and EGFR in a doseand time-dependent manner.( 3) Inhibition of Dsc3 by RNA interference inhibited the expression of EGFR and pAkt,but not Akt. Inhibition of EGFR by RNA interference inhibited the expression of Dsc3 and pAkt,but not Akt. Inhibition of PI3K / Akt signalingpathway inhibited the expression of Dsc3 and pAkt,but not Akt. The above three methods could all reduce the regulation role of FSH for PI3K / Akt signaling pathway.( 4) Inhibition of Dsc3,EGFR and PI3K / Akt signaling pathway could significantly reduce FSHinduced cell proliferation( P 0. 05). Conclusion Dsc3 can mediate FSH-induced ovarian epithelial cancer cell proliferation by activating EGFR / Akt signaling pathway,and thereby promoting tumor growth.

The influence of desmocollin 1–3 expression on prognosis after curative resection of colorectal liver metastases

Prognosis after curative resection of colorectal liver metastases is hard to determine based on clinical parameters; biomarkers are therefore needed. The purpose of this study was to determine the value of desmocollins (DSC) as potential biomarkers. Desmocollins are responsible for cell-cell adhesion in epithelial tissue; their loss may lead to reduced cellular adhesion and facilitate cellular migration, enabling tumor cells to form distant metastases. We analyzed DSC expression in colorectal liver metastases with respect to the risk of recurrence following liver resection. Tissue microarrays from 257 consecutive patients who underwent R0-resection of colorectal liver metastases were constructed. Low expression of DSC 1, 2, and 3 was observed in 55, 54, and 79 % of liver metastases. There was no correlation between site or stage of the primary tumor, presence of extrahepatic tumor, grading, size or number of metastases, and desmocollin expression. Primary tumor stage I or II (p = 0.005) and no or few lymph node metastases (p < 0.001) were associated with a significantly better disease-free survival on univariate analysis. These parameters reached only marginal significance on multivariate analysis (p = 0.059 and p = 0.052, respectively), as did desmocollin 3 expression (p = 0.050). In the subgroup of patients with stages III-IV primary tumors, however, multivariate analysis showed a significant correlation between DSC 3 expression and disease-free survival after liver resection (p = 0.009). Reduced expression of DSC3 correlated with an increased risk of developing tumor recurrence after resection of liver metastases. These findings may be helpful in selecting high-risk patients who might benefit from multimodal therapy.

Diagnostic and prognostic impact of desmocollins in human lung cancer

ObjectiveDesmosomes are intercellular junctions that confer strong cell–cell adhesion. Two main members of desmosomal cadherins, desmogleins (DSGs) and desmocollins (DSCs), are involved in carcinogenesis. However, their role in human lung...

Loss of desmocollin 3 in skin tumor development and progression

Desmocollin 3 (DSC3) is a desmosomal cadherin that is required for maintaining cell adhesion in the epidermis as demonstrated by the intra-epidermal blistering observed in Dsc3 null skin. Recently, it has been suggested that deregulated expression of DSC3 occurs in certain human tumor types. It is not clear whether DSC3 plays a role in the development or progression of cancers arising in stratified epithelia such as the epidermis. To address this issue, we generated a mouse model in which Dsc3 expression is ablated in K-Ras oncogene-induced skin tumors. Our results demonstrate that loss of Dsc3 leads to an increase in K-Ras-induced skin tumors. We hypothesize that acantholysis-induced epidermal hyperplasia in the Dsc3 null epidermis facilitates Ras-induced tumor development. Further, we demonstrate that spontaneous loss of DSC3 expression is a common occurrence during human and mouse skin tumor progression. This loss occurs in tumor cells invading the dermis. Interestingly, other desmosomal proteins are still expressed in tumor cells that lack DSC3, suggesting a specific function of DSC3 loss in tumor progression. While loss of DSC3 on the skin surface leads to epidermal blistering, it does not appear to induce loss of cell-cell adhesion in tumor cells invading the dermis, most likely due to a protection of these cells within the dermis from mechanical stress. We thus hypothesize that DSC3 can contribute to the progression of tumors both by cell adhesion-dependent (skin surface) and likely by cell adhesion-independent (invading tumor cells) mechanisms.

Altered expression of desmocollin 3, desmoglein 3, and β-catenin in oral squamous cell carcinoma: correlation with lymph node metastasis and cell proliferation

Desmocollin 3 (Dsc3) and desmoglein 3 (Dsg3) are both transmembrane glycoproteins that belong to the cadherin family of calcium-dependent cell adhesion molecules. beta-Catenin is a member of the cadherin-catenin complex that mediates homotypic cell-cell adhesion and is also an important molecule in the wnt signaling pathway. In this study, we examined the simultaneous expression level of Dsc3, Dsg3, and beta-catenin in oral squamous cell carcinomas (OSCCs) and normal oral epithelia using immunohistochemistry. There was a significant correlation (p < 0.05) among the following variables in OSCCs: reduced or loss of expression of Dsc3, Dsg3, and beta-catenin compared to normal oral epithelium, reduced or loss of expression of Dsc3 and histological grade (moderately or poorly differentiated), and reduced or loss of expression of beta-catenin and lymph node metastasis. Furthermore, a positive correlation was found between reduced or loss of beta-catenin staining and reduced or loss of Dsc3 staining in lymph node metastatic cancer tissue (r = 0.734, p < 0.05). These results suggest an abnormal expression of Dsc3, Dsg3, and beta-catenin induced in the progression of oral carcinomas and that the Dsc3 expression level might be related to the regulation of beta-catenin in lymph node metastasis and cell proliferation in OSCCs.

Desmocollin switching in colorectal cancer

The desmocollins are members of the desmosomal cadherin family of cell–cell adhesion molecules. They are essential constituents of desmosomes, intercellular junctions that play a critical role in the maintenance of tissue integrity in epithelia and cardiac muscle. In humans, three desmocollins (Dsc1, Dsc2 and Dsc3) have been described. The desmocollins exhibit tissue-specific patterns of expression; only Dsc2 is expressed in normal colonic epithelium. We have found switching between desmocollins in sporadic colorectal adenocarcinoma with a reduction in Dsc2 protein (in 8/16 samples analysed by immunohistochemistry) being accompanied by de novo expression of Dsc1 (16/16) and Dsc3 (7/16). Similar results were obtained by western blotting of a further 16 samples. No change was found in Dsc2 mRNA, but de novo expression of Dscs 1 and 3 was accompanied by increased message levels. Loss of Dsc2 (8/19) and de novo expression of Dsc1 (11/19) and Dsc3 (6/19) was also found in colorectal adenocarcinomas on a background of colitis. The data raise the possibility that switching of desmocollins could play an important role in the development of colorectal cancer.

Regulation of desmocollin gene expression in the epidermis: CCAAT/enhancer-binding proteins modulate early and late events in keratinocyte differentiation.

Desmocollins (Dscs) are desmosomal cadherins that exhibit differentiation-specific patterns of expression in the epidermis. Dsc3 expression is strongest in basal cell layers, whereas Dsc1 is largely confined to upper, terminally differentiating strata. To understand better the processes by which Dsc expression is regulated in the epidermis, we have isolated Dsc3 and Dsc1 5'-flanking DNAs and analysed their activity in primary keratinocytes. In the present study, we found that transcription factors of the CCAAT/enhancer-binding protein family play a role in the regulation of expression of both Dscs and, in so doing, implicate this class of transcription factors in both early and late events in keratinocyte differentiation. We show that Dscs are differentially regulated by C/EBP (CCAAT/enhancer-binding protein) family members, with Dsc3 expression being activated by C/EBPbeta but not C/EBPalpha, and the reverse being the case for Dsc1. Expression of both Dscs is activated by another family member, C/EBPdelta. These results show for the first time how desmosomal cadherin gene expression is regulated and provide a mechanism for the control of other differentiation-specific genes in the epidermis.

The differential expression of desmocollin isoforms in mammary epithelia.

In the mammary gland, cell-cell contacts influence epithelial morphogenesis during the formation of ducts and alveoli. Desmosomes are adhesive intercellular junctions that are widespread in epithelia and other tissues. Although the components of desmosomes have been characterised at the molecular level, their precise function in epithelial organisation and morphogenesis has not been determined. Desmosomal adhesion is partly mediated by one of its components, desmocollin, a family of transmembrane proteins which belongs to the cadherin superfamily of calcium-dependent adhesion molecules. To date, three desmocollin isoforms have been characterised and are called Dsc I , Dsc2 and Dsc3. In addition, each isoform can be alternatively spliced cytoplasmically to give either the “a” or “b” forms. The desmocollins have been demonstrated to have tissue-specific localisation [ I ] . We propose that desmosomes containing different desmocollin isoforms reflect differences in cell-cell adhesion An ideal system for the study of simple epithelia morphogenesis and one that can be manipulated in culture is the mammary gland. Luminal epithelial cells form monolayers when plated on tissue culture plastic, but in the presence of EHS matrix undergo striking morphogenetic events to form spherical alveolar structures. This cellular remodelling mimics developmental events occurring in vivo during alveoli formation in pregnancy [2]. In this work we demonstrate the differential distribution of desmocollin isoforms present in mammary epithelia in vivo by indirect-immunofluorescence. This has been done by using monoclonal and polyclonal antibodies specific to desmocollin isoforms. Furthermore, it has been possible to establish the localisation of the desmocollins in the different mammary epithelia. Both luminal epithelial cells and myoepithelial cells can be identified by cytoskeletal markers. Luminal epithelial cells can be detected by cytokeratins 7, 8, 18 and 19, while myoepithelial cells contain cytokeratins 5 and 14. Cryosections of bovine mammary gland were doublestained with antibodies for either Dscl, Dsc2 or Dsc3 and myoepithelial-specific cytokeratin (K14) or luminal epithelialspecific cytokeratin (K7 & K8). We show that Dsc2 is present in the luminal epithelial layer, whereas Dsc3 is restricted to the myoepithelial layer and Dsc 1 is completely absent from mammary epithelia (figure 1). In addition, the expression of Dsc2 and Dsc3, but not Dscl in mammary epithelia at the mRNA level has been confirmed by RT-PCR using desmocollin isoform specific primers. The parenchyma of both mammary ducts of alveoli consists of a layer of myoepithelial cells which surround the luminal epithelial component. We propose that differential adhesiveness between desmosomes containing Dsc2 or Dsc3 may contribute to the cellular organization of mammary epithelia, thereby contributing to the formation of luminal epithelial tubes situated within a myoepithelial sheath. A B

Distinct desmocollin isoforms occur in the same desmosomes and show reciprocally graded distributions in bovine nasal epidermis.

The adhesive core of the desmosome is composed of cadherin-like glycoproteins of two families, desmocollins and desmogleins. Three isoforms of each are expressed in a tissue-specific and developmentally regulated pattern. In bovine nasal epidermis, the three desmocollin (Dsc) isoforms are expressed in overlapping domains; Dsc3 expression is strongest in the basal layer, while Dsc2 and Dsc1 are strongly expressed in the suprabasal layers. Herein we have investigated whether different isoforms are assembled into the same or distinct desmosomes by performing double immunogold labeling using isoform-specific antibodies directed against Dsc1 and Dsc3. The results show that individual desmosomes harbor both isoforms in regions where their expression territories overlap. Quantification showed that the ratio of the proteins in each desmosome altered gradually from basal to immediately suprabasal and upper suprabasal layers, labeling for Dsc1 increasing and Dsc3 decreasing. Thus desmosomes are constantly modified as cells move up the epidermis, with continuing turnover of the desmosomal glycoproteins. Statistical analysis of the quantitative data showed a possible relationship between the distributions of the two isoforms. This gradual change in desmosomal composition may constitute a vertical adhesive gradient within the epidermis, having important consequences for cell positioning and differentiation.

The bovine desmocollin family: a new gene and expression patterns reflecting epithelial cell proliferation and differentiation.

We have discovered a third bovine desmocollin gene, DSC3, and studied expression of all three desmocollin genes, DSC1, 2, and 3, by Northern blotting, RT-PCR and in situ hybridization. DSC1 is strongly expressed in epidermis and tongue papillae, showing a "skin"-type pattern resembling that previously described for keratins 1 and 10. Expression is absent from the epidermal basal layer but appears in the immediate suprabasal layers and continues uniformly to the lower granular layer. In tongue epithelium, expression is suprabasal and strictly localized to papillae, being absent from interpapillary regions. In other epithelial low level DSC1 expression is detectable only by RT-PCR. The distribution of Dsc1 glycoproteins, detected by an isoform-specific monoclonal antibody, closely reflects mRNA distribution in epidermis and tongue. DSC2 is ubiquitously expressed in epithelia and cardiac muscle. In stratified epithelia, expression appears immediately suprabasal, continuing weakly to the lower granular layer in epidermis and to just above half epithelial thickness in interpapillary tongue, oesophageal, and rumenal epithelia. DSC3 expression is restricted to the basal and immediately suprabasal layers in stratified epithelia. In deep rete ridges DSC expression strikingly resembles the distribution of stem, transit-amplifying, and terminally differentiating cells described by others. DSC3 expression is strongly basal, DSC2 is strong in 5-10 suprabasal layers, and then weakens to be superseded by strong DSC1. These results suggest that desmocollin isoform expression has important functional consequences in epithelial proliferation, stratification, and differentiation. The data also provide a standard for nomenclature of the desmocollins.