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The fascinating role of SPRR3 in various malignant tumors has prompted extensive research to unravel its expression patterns and prognostic significance. To comprehensively investigate SPRR3, we leveraged multiple datasets containing invaluable biomedical information, specifically focusing on the comparative analysis of SPRR3 gene expression levels across different cancer types. Meticulous examination of lung adenocarcinoma allowed us to delve deeper into the correlation between SPRR3 expression and its molecular biological functions. Our comprehensive analysis encompassed 33 malignant tumors, and the results unveiled significant differential expression of SPRR3 across a range of malignancies. Moreover, this aberrant expression of SPRR3 was observed to be closely associated with poorer prognosis in these malignant tumors. Notably, our investigation also unearthed a compelling link between SPRR3 and immune infiltrating cells in lung adenocarcinoma. The utilization of receiver operating characteristic (ROC) curves and survival curves in our study illustrated the immense potential of SPRR3 as a highly accurate predictor of cancer. These findings further emphasize the possibility of SPRR3 serving as a promising diagnostic and prognostic biomarker for a diverse array of cancers., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The prevalence of squamous cell carcinoma is increasing, and efforts that aid in an early and accurate diagnosis are crucial to improve clinical outcomes for patients. Cornulin, a squamous epithelium-specific protein, has recently garnered attention due to its implications in the progression of squamous cell carcinoma developed in several tissues. As an epidermal differentiation marker, it is involved in skin anchoring, regulating cellular proliferation, and is a putative tumor suppressor. The physiologically healthy squamous epithelium displays a considerable level of Cornulin, whereas squamous cell carcinomas have marked downregulation, suggesting that Cornulin expression levels can be utilized for the early detection and follow-up on the progression of these types of cancer. Cornulin's expression patterns in cervical cancer have been examined, and findings support the stepwise downregulation of Cornulin levels that accompanies the progression to neoplasia in the cervix. Additional studies documented a similar trend in expression in other types of cancer, such as cutaneous, esophageal, and oropharyngeal squamous cell carcinomas. The consistent and predictable pattern of Cornulin expression across several squamous cell carcinomas and its correlation with key clinicopathological parameters make it a reliable biomarker for assessing the transformation and progression events in the squamous epithelium, thus potentially contributing to the early detection, definitive diagnosis, and more favorable prognosis for these cancer patients.

In sexual assault cases, it is crucial to discriminate between peripheral blood and menstrual blood to provide evidence for vaginal intercourse with traumatic injury. In this study, the menstrual blood mRNA markers progestagen-associated endometrial protein (PAEP), matrix metallopeptidase 7 (MMP7), and left-right determination factor 2 (LEFTY2) were evaluated by quantitative RT-PCR (RT-qPCR) for the discrimination of menstrual blood from peripheral blood and vaginal fluid. As a result, all markers with cutoff delta cycle quantification (ΔCq) values were specifically determined in menstrual blood among forensically relevant body fluids. Even though the changes in the expression levels of each marker differed during the menstrual cycle, all markers were determined to be positive in most of the randomly collected menstrual blood samples that were analyzed. Additionally, the markers with proposed cutoff ΔCq values could discriminate between menstrual blood and peripheral blood-mixed vaginal fluid samples. The determination of positive markers was less affected by storage temperature under dry conditions than under wet conditions, while PAEP was detectable in samples stored below room temperature under wet conditions. The detectability of PAEP was considered to be the result of its higher expression level compared with MMP7 and LEFTY2. In conclusion, menstrual blood markers for the RT-qPCR procedure evaluated in this study were highly specific for menstrual blood. The proposed procedure could be useful for discriminating between menstruation and traumatic bleeding in the female genital tract. In particular, PAEP is expected to be applicable to forensic casework samples because of its high specificity and robustness., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: SPRR1B , a member of the small proline-rich protein family, is implicated in various epithelial cancers as a potential oncogene linked to tumour growth and poor survival outcomes. However, its role in urothelial bladder carcinoma (UBC) remains to be fully elucidated., Methods: Transcriptional profiling data from The Cancer Genome Atlas grouped UBC samples in accordance with SPRR1B expression. Bioinformatic analysis was conducted to evaluate whether SPRR1B is a prognostic factor and a survival factor in UBC. Gene set enrichment analysis (GSEA) was performed to study immune cells and pathways. Reverse transcription quantitative real-time polymerase chain reaction detected gene expression. Immunohistochemistry assessed protein expression. Spearman correlation test analysed the correlation between SPRR1B and the protein p53., Results: The bioinformatics results indicated that the expression level of SPRR1B in UBC tissues was significantly increased compared with that in normal bladder tissues, correlating with clinical characteristics. A high expression predicted poor prognosis and survival. Univariate Cox statistics showed that a high expression level of SPRR1B was correlated with UBC patients having poor overall survival (OS) ( p < 0.05). In addition, on the basis of the multivariate Cox analysis, SPRR1B expression was independently correlated with OS ( p = 0.005). GSEA analysis revealed enrichment in the p53, apoptosis, and cell cycle signalling pathways, and an association with B cells, lymphocytes, and natural killer cells. In addition, SPRR1B was found to be associated with immune infiltration based on the analysis of immune cell infiltration. Performing corresponding verification on a small number of tissues collected from bladder cancer patients revealed that the expression of this protein was negatively correlated with the expression of p53., Conclusions: SPRR1B overexpression predicts poor UBC outcomes, suggesting its role as a prognostic marker and therapeutic target. Further research is necessary to elucidate its role in UBC progression., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s).)

Cornulin (CRNN) and repetin (RPTN) belong to the fused-type S100 protein family. Although these proteins have been reported to be expressed in the granular layer of the epidermis and have been suggested to be associated with barrier formation in the epidermis, their exact function remains unclear. This study examined the effects of ultraviolet B (UVB) irradiation on CRNN and RPTN expression in human skin xenotransplantation. The CRNN expression increased in the granular layer of UVB-irradiated skin 2 days after UVB irradiation compared to that in sham-irradiated skin. Interestingly, CRNN signals were observed not only in the cytoplasm, but also in the peripheral regions of granular keratinocytes. In contrast, RPTN was rarely expressed in sham-irradiated skin; however, RPTN signals were markedly increased in the granular layer of the UVB-irradiated skin. In addition, activation of ERK1/2 and STAT3 was observed in UVB-irradiated skin. Accordingly, the present study demonstrated that CRNN and RPTN are novel proteins whose expression can be increased by UVB irradiation. The activation of ERK1/2 and STAT3 may be associated with the regeneration of a UVB-damaged epidermis, and CRNN and RPTN may be induced to repair any dysfunction in the epidermal barrier during this regeneration process., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Late cornified envelope (LCE) proteins are small cationic epidermal proteins with antimicrobial properties, and the combined deletion of LCE3B and LCE3C genes is a risk factor for psoriasis that affects skin microbiome composition. In a yeast two-hybrid screen, we identified CYSRT1 as an interacting partner of members of all LCE groups except LCE6. These interactions were confirmed in a mammalian cell system by coimmunoprecipitation. CYSRT1 is a protein of unknown function that is specifically expressed in cutaneous and oral epithelia and spatially colocalizes with LCE proteins in the upper layers of the suprabasal epidermis. Constitutive CYSRT1 expression is present in fully differentiated epidermis and can be further induced in vivo by disruption of the skin barrier upon stratum corneum removal. Transcriptional regulation correlates to keratinocyte terminal differentiation but not to skin bacteria exposure. Similar to LCEs, CYSRT1 was found to have antibacterial activity against Pseudomonas aeruginosa. Comparative gene sequence analysis and protein amino acid alignment indicate that CYSRT1 is highly conserved among vertebrates and has putative antimicrobial activity. To summarize, we identified CYSRT1 in the outer skin layer, where it colocalizes with LCE proteins and contributes to the constitutive epidermal antimicrobial host defense repertoire., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Particulate matter (PM2.5) is an environmental pollutant causing skin inflammatory diseases via epidermal barrier damage. However, the mechanism and related gene expression induced by PM2.5 remains unclear. Our aim was to determine the effect of PM2.5 on human skin tissue ex vivo, and elucidate the mechanism of T helper 17 cell-related inflammatory cytokine and skin barrier function. We verified the expression levels of gene in PM2.5-treated human skin tissue using Quantseq (3' mRNA-Seq), and Gene Ontology (GO) terms and protein-protein interaction (PPI) networks were performed. The PM2.5 treatment significantly enhanced the expression of Th 1, 2, 17 and 22 cell-related genes (cut-off value: │1.2 │ > fold change and p < 0.05). Most of all, Th17 cell-related genes are upregulated and those genes are associated with skin epidermal barrier function and Aryl hydrocarbon receptor (AhR), a xenobiotic receptor, pathway. In human keratinocyte cell lines, AhR-regulated genes (e.g. AhRR, CYP1A1, IL6 and IL36G), Th17 cell-related genes (e.g. IL17C) and epidermal barrier-related genes (e.g. SPRR2A and KRT71) are significantly increased after PM2.5. In the protein level, the secretion of IL-6 and IL-36G was increased in human skin tissue following PM2.5 treatment, and the expression of SPRR2A and KRT71 was significantly increased. PM2.5 exposure could ruin the skin epidermal barrier function via AhR- and Th17 cell-related inflammatory pathway., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Late cornified envelope proteins are predominantly expressed in the skin and other cornified epithelia. On the basis of sequence similarity, this 18-member homologous gene family has been subdivided into six groups. The LCE3 proteins have been the focus of dermatological research because the combined deletion of LCE3B and LCE3C genes (LCE3B/C-del) is a risk factor for psoriasis. We previously reported that LCE3B/C-del increases the expression of the LCE3A gene and that LCE3 proteins exert antibacterial activity. In this study, we analyzed the antimicrobial properties of other family members and the role of LCE3B/C-del in the modulation of microbiota composition of the skin and oral cavity. Differences in killing efficiency and specificity between the late cornified envelope proteins and their target microbes were found, and the amino acid content rather than the order of the well-conserved central domain of the LCE3A protein was found responsible for its antibacterial activity. In vivo, LCE3B/C-del correlated with a higher beta-diversity in the skin and oral microbiota. From these results, we conclude that all late cornified envelope proteins possess antimicrobial activity. Tissue-specific and genotype-dependent antimicrobial protein profiles impact skin and oral microbiota composition, which could direct toward LCE3B/C-del‒associated dysbiosis and a possible role for microbiota in the pathophysiology of psoriasis., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Oral lichen planus (OLP) is a chronic autoimmune oral mucosal disease that seriously affects the life quality of the patients. But till now, the exact etiology and pathogenesis of OLP remain unclear. Our study is aimed at finding the key molecules and pathways involved in the pathogenesis mechanisms of OLP, providing more effective therapeutic strategies for OLP., Methods: Data from GSE52130 were downloaded from GEO datasets for analysis. Then, we carried out enrichment analysis of the differentially expressed genes (DEGs) using Gene Ontology (GO) and KEGG pathway analyses. Next, the CIBERSORT algorithm was used to assess immune cell infiltration in OLP patients. Furthermore, we also constructed a protein-protein interaction network using STRING and Cytoscape and simultaneously sought potential transcription factors plug-in including MCODE CytoHubba and iRegulon. In addition, ROC analysis was employed to assess the diagnostic performance of these hub genes. Lastly, we identified 6 promising novel drugs to treat OLP through Connectivity Map., Results: We illustrated that 255 DEGs were mainly enriched in the focal adhesion pathway and metabolism pathways. Besides, Cibersort analysis showed that M1 macrophages, T follicular helper cells, and T regulatory cells are more infiltrated in OLP samples. In addition, ROC analysis demonstrated that these hub genes owned higher diagnostic value in OLP, in which SPRR1B had the highest diagnostic value. And we also predicted that SOX7 was the most relevant transcription factor of those hub genes. Lastly, through the CMap database, we identified 6 small molecules as possible treatment drugs of OLP., Conclusion: Our research identified that SPRR1B could be used as potential biomarkers for the early diagnosis of OLP. In addition, as a chronic autoimmune oral mucosal disease, OLP has different infiltration types of immune cells. Furthermore, 6 small molecules were proposed as promising novel treatment drugs for OLP patients. Therefore, our research may provide new impetus for the development of effective OLP biological treatment options., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lou Geng et al.)

Purpose: Cervical squamous cell carcinoma (CESC) is the most common cancer type of cervical cancer, which threatens women's life seriously. LncRNA DGUOK-AS1has been reported to promote the biologic processes of CESC. We aim to figure out the role of DGUOK-AS1-miR-499a-5p-SPRR1B axis in modulating the CESC progression in vitro., Methods: The levels of DGUOK-AS1, miR-499a-5p, and SPRR1B in CESC tissues and cells were examined by RT-qPCR. The interaction of DGUOK-AS1-miR-499a-5p-SPRR1B was verified by luciferase assay. Inhibition of DGUOK-AS1, miR-499a-5p, and SPRR1B was applied for exploring the biological function based on detection of cell viability, proliferation, migration, and apoptosis in CESC SiHa and HeLa cells., Results: DGUOK-AS1 and SPRR1B expressions were obviously elevated, whereas the expression of miR-499a-5p was reduced in both CESC tissues and cells. Silencing of DGUOK-AS1 attenuated cell growth and boosted apoptosis of CESC cells. Notably, DGUOK-AS1 inhibited miR-499a-5p to release SPRR1B, which significantly accelerated the development of CESC., Conclusion: DGUOK-AS1sponging miR-499a-5p facilitated CESC cells progression by releasing SPRR1B in vitro. It provides a new sight for the treatment of CESC patients involving DGUOK-AS1-miR-499a-5p-SPRR1B., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interests., (Copyright © 2021. Published by Elsevier Inc.)

BACKGROUND Psoriasis is a chronic, immune-mediated and hyperproliferative skin disease with both genetic and environmental components. Copy number variations (CNV) of IL22 and LCE3C-LCE3B deletion have been confirmed to be predisposed to psoriasis vulgaris (PsV) in several ethnic groups. However, it remains to be clarified whether CNVs of IL22 and LCE3C are associated with different subtypes of psoriasis (psoriatic arthritis, PsA; erythrodermic psoriasis, EP; and generalized pustular psoriasis, GPP). MATERIAL AND METHODS We enrolled 897 Han Chinese individuals, including 478 patients and 419 healthy controls, and detected CNVs of IL22 and LCE3C using the comparative CT method by real-time PCR, and Pearson's χ² test was used to evaluated the copy number difference among subtypes. RESULTS CNVs of IL22 were significantly higher in PsV than in healthy controls (P<0.001). CNV of LCE3C in PsV, PsA, and GPP groups were significantly lower compared to healthy controls. When linked with clinical parameters, mild psoriasis carried less IL22 copy numbers than that in severe psoriasis (P=0.043). Neither IL22 or LCE3C CNVs were associated with age of onset. CONCLUSIONS CNVs of LCE3C and IL22 might differentially contribute to subtypes of psoriasis. These findings suggest complex and diverse genetic variations in and among different clinical subtypes of psoriasis.

A diverse group of antimicrobial proteins (AMPs) helps protect the mammalian intestine from varied microbial challenges. We show that small proline-rich protein 2A (SPRR2A) is an intestinal antibacterial protein that is phylogenetically unrelated to previously discovered mammalian AMPs. In this study, SPRR2A was expressed in Paneth cells and goblet cells and selectively killed Gram-positive bacteria by disrupting their membranes. SPRR2A shaped intestinal microbiota composition, restricted bacterial association with the intestinal surface, and protected against Listeria monocytogenes infection. SPRR2A differed from other intestinal AMPs in that it was induced by type 2 cytokines produced during helminth infection. Moreover, SPRR2A protected against helminth-induced bacterial invasion of intestinal tissue. Thus, SPRR2A is a distinctive AMP triggered by type 2 immunity that protects the intestinal barrier during helminth infection.

Functional studies to delineate the molecular mechanisms of causal genetic variants are the main focus in the post-GWAS era. Previous GWASs have identified >50 susceptibility loci associated with psoriasis. Functional understanding of the biology underlying the disease risk of most of these associated loci is unclear. In this study, we identified a regulatory SNP at the putative enhancer of the LCE3A gene within the epidermal differentiation complex that showed epistatic interaction with HLA-Cw6. The variant allele disrupted signal transducer and activator of transcription 3 binding to the region, thereby regulating the expression of the downstream LCE3A gene. Electrophoretic mobility shift and pulldown assay confirmed the preferential binding of signal transducer and activator of transcription 3 to the DNA with a wild-type allele compared with the DNA with a variant allele. The reporter assay further validated the IL-6‒stimulated phosphorylated signal transducer and activator of transcription 3‒mediated LCE3A activation in the presence of the wild-type allele. Interestingly, the presence of the HLA-Cw6 allele leads to IL-6‒mediated phosphorylation of signal transducer and activator of transcription 3, followed by its nuclear localization in the epidermal keratinocytes of psoriatic skin, suggesting indirect interaction of the HLA-Cw6 allele and a regulatory SNP upstream of the LCE3A gene. This study reflects an interesting approach to dissecting the molecular mechanism underlying the genetic interaction observed between HLA-Cw6 and LCE3A in psoriasis pathogenesis., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

MicroRNA-150 (miR-150) is downregulated in patients with multiple cardiovascular diseases and in diverse mouse models of heart failure (HF). miR-150 is significantly associated with HF severity and outcome in humans. We previously reported that miR-150 is activated by β-blocker carvedilol (Carv) and plays a protective role in the heart using a systemic miR-150 KO mouse model. However, mechanisms that regulate cell-specific miR-150 expression and function in HF are unknown. Here, we demonstrate that potentially novel conditional cardiomyocyte-specific (CM-specific) miR-150 KO (miR-150 cKO) in mice worsens maladaptive cardiac remodeling after myocardial infarction (MI). Genome-wide transcriptomic analysis in miR-150 cKO mouse hearts identifies small proline-rich protein 1a (Sprr1a) as a potentially novel target of miR-150. Our studies further reveal that Sprr1a expression is upregulated in CMs isolated from ischemic myocardium and subjected to simulated ischemia/reperfusion, while its expression is downregulated in hearts and CMs by Carv. We also show that left ventricular SPRR1A is upregulated in patients with HF and that Sprr1a knockdown in mice prevents maladaptive post-MI remodeling. Lastly, protective roles of CM miR-150 are, in part, attributed to the direct and functional repression of proapoptotic Sprr1a. Our findings suggest a crucial role for the miR-150/SPRR1A axis in regulating CM function post-MI.

Chronic postsurgical pain (CPSP) is a serious problem. We developed a mouse model of CPSP induced by electrocautery and examined the mechanism of CPSP. In this mouse model, while both incision and electrocautery each produced acute allodynia, persistent allodynia was only observed after electrocautery. Under these conditions, we found that the mRNA levels of Small proline rich protein 1A (Sprr1a) and Annexin A10 (Anxa10), which are the key modulators of neuropathic pain, in the spinal cord were more potently and persistently increased by electrocautery than by incision. Furthermore, these genes were overexpressed almost exclusively in chronic postsurgical pain-activated neurons. This event was associated with decreased levels of tri-methylated histone H3 at Lys27 and increased levels of acetylated histone H3 at Lys27 at their promoter regions. On the other hand, persistent allodynia and overexpression of Sprr1a and Anxa10 after electrocautery were dramatically suppressed by systemic administration of GSK-J4, which is a selective H3K27 demethylase inhibitor. These results suggest that the effects of electrocautery contribute to CPSP along with synaptic plasticity and epigenetic modification., (© 2021. The Author(s).)

The turnover of the epidermis beginning with the progenitor cells in the basal layer to the fully differentiated corneocytes is tightly regulated by calcium. Calcium more than anything else promotes the differentiation of keratinocytes which implies the need for a calcium gradient with low concentrations in the stratum basale and high concentrations in the stratum granulosum. One of the hallmarks of skin aging is a collapse of this gradient that has a direct impact on the epidermal fitness. The rise of calcium in the stratum basale reduces cell proliferation, whereas the drop of calcium in the stratum granulosum leads to a changed composition of the cornified envelope. We showed that keratinocytes respond to the calcium induced block of cell division by a large increase of the expression of several miRNAs (hsa-mir542-5p, hsa-mir125a, hsa-mir135a-5p, hsa-mir196a-5p, hsa-mir491-5p and hsa-mir552-5p). The pitfall of this rescue mechanism is a dramatic change in gene expression which causes a further impairment of the epidermal barrier. This effect is attenuated by a pseudogene (SPRR2C) that gives rise to a lncRNA. SPRR2C specifically resides in the stratum granulosum/corneum thus acting as a sponge for miRNAs.

Purpose: Transport and Golgi organization protein 1 (TANGO) promotes angiogenesis and lymphangiogenesis in oral squamous cell carcinoma (OSCC). To elucidate the underlying mechanisms, this study aims to identify and characterize elements downstream of TANGO that mediate its involvement in OSCC., Methods: In this study, microarray analysis compared gene expression between control and TANGO-repressed HSC3 cells. Protein expression in 213 OSCC tissue samples was analyzed immunohistochemically., Results: TANGO repression decreased or increased expression of Mucin 20 (MUC20) and small proline-rich protein 1B (SPRR1B), respectively. MUC20 increased the growth and invasiveness of OSCC cells via altered matrix metalloproteinase (MMP)-2 and E-cadherin expression and c-met phosphorylation. MUC20 induced angiogenesis and lymphangiogenesis by activating vascular endothelial growth factors A and C. In well-differentiated OSCC, SPRR1B expression was high (P = 0.0091) and correlated with keratinization markers and promoted proliferation by inducing mitogen-activated protein kinase p38 phosphorylation. MUC20 expression correlated significantly with clinical stage (P = 0.0024), lymph node metastasis (P = 0.0036), and number of blood and lymph vessels (P < 0.0001). MUC20-expressing cases had a significantly worse prognosis than non-expressing cases (P < 0.0001)., Conclusion: MUC20 and SPRR1B located downstream of TANGO may be useful molecular markers for OSCC.

Cutaneous squamous cell carcinoma (cSCC) is prevalent in the world, accounting for a huge part of non-melanoma skin cancer. Most cSCCs are associated with a distinct pre-cancerous lesion, the actinic keratosis (AK). However, the progression trajectory from normal skin to AK and cSCC has not been fully demonstrated yet. To identify genes involved in this progression trajectory and possible therapeutic targets for cSCC, here we constructed a UV-induced cSCC mouse model covering the progression from normal skin to AK to cSCC, which mimicked the solar UV radiation perfectly using the solar-like ratio of UVA and UVB, firstly. Then, transcriptome analysis and a series of bioinformatics analyses and cell experiments proved that Rorα is a key transcript factor during cSCC progression. Rorα could downregulate the expressions of S100a9 and Sprr2f in cSCC cells, which can inhibit the proliferation and migration in cSCC cells, but not the normal keratinocyte. Finally, further animal experiments confirmed the inhibitory effect of cSCC growth by Rorα in vivo. Our findings showed that Rorα would serve as a potential novel target for cSCC, which will facilitate the treatment of cSCC in the future.

Background: With the ongoing development of targeted therapy and immunotherapy in recent years, the overall five-year survival rate of NSCLC patients has not improved, and the search for novel diagnostic and prognostic markers for lung adenocarcinoma continues., Methods: Lung adenocarcinoma (LUAD) gene expression data and relevant clinical information were obtained from the TCGA. Hub genes were identified with weighted gene co-expression network analysis (WGCNA) and protein-protein interaction network (PPI). Survival analyses were also performed using GEPIA. The 536 LUAD patients were divided into two groups according to the SPRR1B expression level and analyzed by gene set enrichment analysis (GSEA) and verified by immunoblotting. The effects of SPRR1B on cell proliferation and cell metastasis and apoptosis were evaluated by 5-ethynyl-2'-deoxyuridine (EdU) staining, colony formation assay, transwell migration and invasion assay, and flow cytometry, respectively., Results: A total of 2269 DEGs were analyzed by WGCNA and five hub genes (CCK, FETUB, PCSK9, SPRR1B, and SPRR2D) were identified. Among them, SPRR1B was selected as one of the most significant prognostic genes in LUAD. SPRR1B was found to be highly expressed in lung adenocarcinoma cells compared with that in normal bronchial epithelial cells. In addition, silencing of SPRR1B could inhibit the cell proliferation, invasion, and migration of lung adenocarcinoma cells, but induced cell apoptosis and G2/M phase arrest in vitro. The result of GSEA and immunoblotting revealed that SPRR1B activated the MAPK signaling pathway involved in the proliferation and metastasis of lung cancer., Conclusions: Our findings demonstrate that SPRR1B may function as a prognosis predictor in lung adenocarcinoma., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Objective: Atopic eczema (AE) is a chronic relapsing inflammatory skin disease. This study aims to identify key genes related to the development of AE., Materials and Methods: The GSE6012 dataset was obtained from the Gene Expression Omnibus (GEO) database. The limma package was used to analyze differentially expressed genes (DEGs). Then, the weighted gene co-expression network analysis (WGCNA) package was utilized to generate weighted correlation networks of up-and downregulated genes. Additionally, the WGCNA package was used for enrichment analyses to explore the underlying functions of DEGs in modules (weighted correlation sub-networks) significantly associated with AE., Results: A total of 515 DEGs were identified between lesional and non-lesional skin samples. For the upregulated genes, the blue module was found to have a significant positive correlation with AE. Importantly, small proline-rich protein 2C (SPRR2C) and defensin, beta 4A (DEFB4A) exhibited higher |log fold change (FC) values and were the key nodes of the network. Moreover, KEGG pathway analysis revealed that the upregulated genes in the blue module were primarily involved in cytokine-cytokine receptor interaction. Additionally, for the downregulated genes, the brown module was found to have a significant positive correlation with AE. Further, WNT inhibitory factor 1 (WIF1), cryptochrome 2 (CRY2), and keratin 19 (KRT19) had higher |log FC| values and were key nodes of the network., Conclusions: SPRR2C, DEFB4A, WIF1, CRY2, KRT19 and cytokine-cytokine receptor interaction might be correlated with the development of AE.

Psoriasis is a chronic inflammatory disease of the skin with highly complex pathogenesis. In this study, we identified lncRNA SPRR2C (small proline-rich protein 2C) as a hub gene with a critical effect on the pathogenesis of psoriasis and response to treatment using both weighted gene coexpression network analysis (WGCNA) and differential expression analysis. SPRR2C expression was significantly upregulated in both psoriatic lesion samples and HaCaT cell lines in response to IL-22 treatment. After SPRR2C knockdown, IL-22-induced suppression of HaCaT proliferation, changes in the KRT5/14/1/10 protein levels, and suppression of the IL-1β, IL-6, and TNF-α mRNA levels were dramatically reversed. In the coexpression network with SPRR2C based on GSE114286, miR-330 was significantly negatively correlated with SPRR2C, while STAT1 and S100A7 were positively correlated with SPRR2C. By binding to miR-330, SPRR2C competed with STAT1 and S100A7 to counteract miR-330-mediated suppression of STAT1 and S100A7. MiR-330 overexpression also reversed the IL-22-induced changes in HaCaT cell lines; in response to IL-22 treatment, miR-330 inhibition significantly attenuated the effects of SPRR2C knockdown. STAT1 and S100A7 expression was significantly upregulated in psoriatic lesion samples. The expression of miR-330 had a negative correlation with the expression of SPRR2C, while the expression of SPRR2C had a positive correlation with the expression of STAT1 and S100A7. Thus, SPRR2C modulates the IL-22-stimulated HaCaT cell phenotype through the miR-330/STAT1/S100A7 axis. WGCNA might uncover additional biological pathways that are crucial in the pathogenesis and response to the treatment of psoriasis.

The aim of this study was to examine the effects of carba cyclic phosphatidic acid (ccPA) on cornified envelope (CE) formation and keratinocyte differentiation. ccPA-treated keratinocytes showed higher mRNA and protein levels of differentiation markers and CE components than untreated cells. These results suggest that ccPA could serve as therapeutic targets for treating skin barrier dysfunction because of their roles in upregulating genes and proteins associated with CE formation and keratinocyte differentiation.

Differentiation of normal human keratinocytes (NHK) grown in vitro as a monolayer to confluency can be triggered with an acute increase in concentration of extracellular Ca ++ . Over several days, induced by Ca ++ , the cells form pseudostratified sheets that somewhat resemble the basic organization of the intact skin. This experimental system is widely used in studies of keratinocyte biology and skin pathology. However, expression pattern of the genes considered as markers for cells in specific layers of epidermis in vivo does not always match the specific pattern observed in vitro and might lead to misinterpretation of data. Here, we demonstrate that among 18 markers of terminally differentiated keratinocytes of stratum granulosum (SG) and stratum corneum (SC) in vivo, only four (CDSN, KPRP, LCE1C and SPRR4) have reproduced their expression pattern in vitro. Our data suggest that findings based on two-dimensional (2D) Ca ++ -induced terminal differentiation of NHK in vitro should be subjected to additional scrutiny before conclusions could be made and, if possible, verified in other experimental system that might more faithfully represent the in vivo microenvironment., (© 2020 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

Renal injury leads to chronic kidney disease, with which women are not only more likely to be diagnosed than men but have poorer outcomes as well. We have previously shown that expression of small proline-rich region 2f ( Sprr2f ), a member of the small proline-rich region ( Sprr ) gene family, is increased several hundredfold after renal injury using a unilateral ureteral obstruction (UUO) mouse model. To better understand the role of Sprr2f in renal injury, we generated a Sprr2f knockout ( Sprr2f -KO) mouse model using CRISPR-Cas9 technology. Sprr2f -KO female mice showed greater renal damage after UUO compared with wild-type ( Sprr2f -WT) animals, as evidenced by higher hydroxyproline levels and denser collagen staining, indicating a protective role of Sprr2f during renal injury. Gene expression profiling by RNA sequencing identified 162 genes whose expression levels were significantly different between day 0 and day 5 after UUO in Sprr2f -KO mice. Of the 162 genes, 121 genes were upregulated after UUO and enriched with those involved in oxidation-reduction, a phenomenon not observed in Sprr2f -WT animals, suggesting a protective role of Sprr2f in UUO through defense against oxidative damage. Consistently, bilateral ischemia-reperfusion injury resulted in higher serum blood urea nitrogen levels and higher tissue reactive oxygen species in Sprr2f -KO compared with Sprr2f -WT female mice. Moreover, cultured renal epithelial cells from Sprr2f -KO female mice showed lower viability after oxidative damage induced by menadione compared with Sprr2f -WT cells that could be rescued by supplementation with reduced glutathione, suggesting that Sprr2f induction after renal damage acts as a defense against reactive oxygen species.

p-Alkoxyphenols (AOPs) are a class of ethers that are widely used in industrial and agricultural productions and daily necessities. p-Phenoxyphenol (PhOP) and p-pentyloxyphenol (PeOP) belong to this class and have been reported to be estrogenic in vitro. However, their in vivo estrogenic activities have rarely been of concern. In this study, we performed an immature mouse uterotrophic assay and studied the estrogenic effects of these two compounds in mice. The results revealed that the uterine weights of the animals treated with PhOP significantly increased at doses of 30 and 300 mg kg -1 bw day -1 for 3 days (P < 0.05), while no significant uterotrophic effects were observed in the mice treated with PeOP. Using next-generation transcriptome sequencing (RNA-seq), we also analyzed the gene expression in the uterine tissue of mice treated with PhOP and PeOP. The observed gene regulation patterns of the PhOP- and PeOP-treated specimens were similar to those of the 17β-estradiol (E 2 )-treated specimens. In particular, some estrogen-responsive genes, such as the Sprr2 gene family, Apoa1, Prap1, and Ahsg, displayed a regulation trend similar to that of E 2 . In addition, molecule docking analysis revealed that both PhOP and PeOP could be well docked into the active site of hERα, with potential of mean force (PMF) values of - 58.68 and - 52.67 kcal mol -1 for PhOP and PeOP, respectively. The results of this study indicate that PhOP exhibits relatively strong in vivo estrogenic activity, which could be of future concern.

Skin lesions in dermatomyositis (DM) are common, are frequently refractory, and have prognostic significance. Histologically, DM lesions appear similar to cutaneous lupus erythematosus (CLE) lesions and frequently cannot be differentiated. We thus compared the transcriptional profile of DM biopsies with CLE lesions to identify unique features. Type I IFN signaling, including IFN-κ upregulation, was a common pathway in both DM and CLE; however, CLE also exhibited other inflammatory pathways. Notably, DM lesions could be distinguished from CLE by a 5-gene biomarker panel that included IL18 upregulation. Using single-cell RNA-sequencing, we further identified keratinocytes as the main source of increased IL-18 in DM skin. This study identifies a potentially novel molecular signature, with significant clinical implications for differentiating DM from CLE lesions, and highlights the potential role for IL-18 in the pathophysiology of DM skin disease.

Background: Currently the leading cause of global disability, clinical depression is a heterogeneous condition characterised by low mood, anhedonia and cognitive impairments. Its growing incidence among young people, often co-occurring with self-harm, is of particular concern. We recently reported very high rates of depression among first year university students in Northern Ireland, with over 25% meeting the clinical criteria, based on DSM IV. However, the causes of depression in such groups remain unclear, and diagnosis is hampered by a lack of biological markers. The aim of this exploratory study was to examine DNA methylation patterns in saliva samples from individuals with a history of depression and matched healthy controls., Results: From our student subjects who showed evidence of a total lifetime major depressive event (MDE, n = 186) we identified a small but distinct subgroup (n = 30) with higher risk scores on the basis of co-occurrence of self-harm and attempted suicide. Factors conferring elevated risk included being female or non-heterosexual, and intrinsic factors such as emotional suppression and impulsiveness. Saliva samples were collected and a closely matched set of high-risk cases (n = 16) and healthy controls (n = 16) similar in age, gender and smoking status were compared. These showed substantial differences in DNA methylation marks across the genome, specifically in the late cornified envelope (LCE) gene cluster. Gene ontology analysis showed highly significant enrichment for immune response, and in particular genes associated with the inflammatory skin condition psoriasis, which we confirmed using a second bioinformatics approach. We then verified methylation gains at the LCE gene cluster at the epidermal differentiation complex and at MIR4520A/B in our cases in the laboratory, using pyrosequencing. Additionally, we found loss of methylation at the PSORSC13 locus on chromosome 6 by array and pyrosequencing, validating recent findings in brain tissue from people who had died by suicide. Finally, we could show that similar changes in immune gene methylation preceded the onset of depression in an independent cohort of adolescent females., Conclusions: Our data suggests an immune component to the aetiology of depression in at least a small subgroup of cases, consistent with the accumulating evidence supporting a relationship between inflammation and depression. Additionally, DNA methylation changes at key loci, detected in saliva, may represent a valuable tool for identifying at-risk subjects.

Familial acne inversa (AI) is an autoinflammatory disorder that affects hair follicles and is caused by loss-of-function mutations in γ-secretase component genes. We and other researchers showed that nicastrin (NCSTN) is the most frequently mutated gene in familial AI. In this study, we generated a keratin 5-Cre-driven epidermis-specific Ncstn conditional knockout mutant in mice. We determined that this mutant recapitulated the major phenotypes of AI, including hyperkeratosis of hair follicles and inflammation. In Ncstn flox/flox ;K5-Cre mice, the IL-36a expression level markedly increased starting from postnatal day 0 (P0), and this increase occurred much earlier than those of TNF-α, IL-23A, IL-1β, and TLR4. RNA-Seq analysis indicated that Sprr2d, a member of the small proline-rich protein 2 family, in the skin tissues of the Ncstn flox/flox ;K5-Cre mice was also upregulated on P0. Quantitative reverse-transcription polymerase chain reaction showed that other Sprr2 genes had a similar expression pattern. Our findings suggested that IL-36a might be a key inflammatory cytokine in the pathophysiology of AI and involved in the malfunction of the skin barrier in the pathogenesis of AI.

Pashmina, the world's finest natural fiber is derived from secondary hair follicles of Changthangi goats which are domesticated in Ladakh region of Jammu and Kashmir by nomadic pastoralists. Complex epithelial-mesenchymal interactions involving numerous signal molecules and signaling pathways govern hair follicle morphogenesis and mitosis across different species. The present study involved transcriptome profiling of skin from fiber type Changthangi goats and meat type Barbari goats to unravel gene networks and metabolic pathways that might contribute to Pashmina development. In Changthangi goats, 525 genes were expressed at significantly higher levels and 54 at significantly lower levels with fold change >2 (p adj  < 0.05). Functional annotation and enrichment analysis identified significantly enriched pathways to be formation of the cornified envelope, keratinization and developmental biology. Expression of genes for keratins (KRTs) and keratin-associated proteins (KRTAPs) was observed to be much higher in Changthangi goats. A host of transcriptional regulator genes for hair follicle keratin synthesis such as GPRC5D, PADI3, HOXC13, FOXN1, LEF1 and ELF5 showed higher transcript abundance in Pashmina producing goats. Positive regulation of Wnt signaling pathway and negative regulation of Oncostatin M signaling pathway may be speculated to be important contributors to hair follicle development and hair shaft differentiation in Changthangi goats.

The skin barrier defect in cutaneous T-cell lymphomas (CTCL) was recently confirmed to be similar to the one observed in atopic dermatitis (AD). We have examined the expression level of cornified envelope (CE) proteins in CTCL, AD and healthy skin, to search for the differences and their relation to the courses of both diseases. The levels of FLG, FLG2, RPTN, HRNR, SPRR1A, SPRR1B, SPRR3 and LELP-1 mRNA were determined by qRT-PCR, while protein levels were examined using the ELISA method in skin samples. We have found that mRNA levels of FLG, FLG2, LOR, CRNN and SPRR3v1 were decreased ( p ≤ 0.04), whereas mRNA levels of RPTN, HRNR and SPRR1Av1 were increased in lesional and nonlesional AD skin compared to the healthy control group ( p ≤ 0.04). The levels of FLG, FLG2, CRNN, SPRR3v1 mRNA increased ( p ≤ 0.02) and RPTN, HRNR and SPRR1Av1 mRNA decreased ( p ≤ 0.005) in CTCL skin compared to the lesional AD skin. There was a strong correlation between the stage of CTCL and increased SPRR1Av1 gene expression at both mRNA (R = 0.89; p ≤ 0.05) and protein levels (R = 0.94; p ≤ 0.05). FLG, FLG2, RPTN, HRNR and SPRR1A seem to play a key role in skin barrier dysfunction in CTCL and could be considered a biomarker for differential diagnosis of AD and CTCL. SPRR1Av1 transcript levels seem to be a possible marker of CTCL stage, however, further studies on a larger study group are needed to confirm our findings.

Background: miRNAs have been involved in neural development, degeneration, and regeneration. MiR-463-3p is expressed in reproductive and nervous systems. In this study, the role of miR-463-3p in tibial nerve injury and regeneration was explored. Materials and methods: A model of tibial nerve injury was established with the crush method, and the levels of miR-463-3p were detected at days 0, 3, 7, 12, 18 and 24 post-injury. Then, primary tibial nerve cells were isolated from newborn mice, and miR-463-3p was respectively overexpressed and knocked down in cultured cells. Behaviors of tibial nerve cells were detected. Furthermore, bioinformatics technology was used to investigate the underlying mechanism. Results: The expression miR-463-3p was robustly increased in the injured tibial nerve in vivo and in tibial nerve cells treated with oxygen-glucose deprivation. The data on gain- and loss-of-function demonstrated that miR-463-3p negatively regulated including neurite length, percentage of cells with neurites, and cell branching in tibial nerve cells. Small proline-rich repeat protein 1 A (SPRR1A), an identified nerve regeneration associated genes, was identified as a target gene of miR-463-3p. Conclusion: Inhibition of miR-463-3p could increase SPRR1A expression in the tibial nerve tissue and improve regeneration of the tibial nerve post-injury in vivo .

Inorganic arsenic (As) is a toxic xenobiotic and carcinogen associated with severe health conditions. The urban population from the Atacama Desert in northern Chile was exposed to extremely high As levels (up to 600 µg/l) in drinking water between 1958 and 1971, leading to increased incidence of urinary bladder cancer (BC), skin cancer, kidney cancer, and coronary thrombosis decades later. Besides, the Andean Native-American ancestors of the Atacama population were previously exposed for millennia to elevated As levels in water (∼120 µg/l) for at least 5,000 years, suggesting adaptation to this selective pressure. Here, we performed two genome-wide selection tests-PBSn1 and an ancestry-enrichment test-in an admixed population from Atacama, to identify adaptation signatures to As exposure acquired before and after admixture with Europeans, respectively. The top second variant selected by PBSn1 was associated with LCE4A-C1orf68, a gene that may be involved in the immune barrier of the epithelium during BC. We performed association tests between the top PBSn1 hits and BC occurrence in our population. The strongest association (P = 0.012) was achieved by the LCE4A-C1orf68 variant. The ancestry-enrichment test detected highly significant signals (P = 1.3 × 10-9) mapping MAK16, a gene with important roles in ribosome biogenesis during the G1 phase of the cell cycle. Our results contribute to a better understanding of the genetic factors involved in adaptation to the pathophysiological consequences of As exposure., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Background: We aimed at identifying molecular markers predictive of clinical outcome in patients with head and neck cancer based on the expression profile of cells showing epithelial-like (EL) or mesenchymal-like (ML) phenotypes., Materials and Methods: We analyzed the association between EL and ML cells and migration, drug resistance, or tumor growth. The differential gene expression profile between cell types was used to build a model to stratify patients according to survival., Results: EL cells were sensitive to cisplatin and cetuximab, showed low migration, and generated squamous differentiated tumors in mouse. A differential 93-gene expression signature between ML and EL cells was used to build a three-gene (EFS, GPX2, and SPRR1A) survival model by analyzing the RNA-seq data of the TCGA-HNSC project. Its prognostic value was confirmed in two independent cohorts., Conclusion: EFS, GPX2, and SPRR1A are prognostic markers able to distinguish clinical outcome among subtypes sharing an EL phenotype., (© 2019 Wiley Periodicals, Inc.)

Renal ischemia/reperfusion injury (IRI) is a main risk factor for the occurrence of delayed graft function or primary graft nonfunction of kidney transplantation. However, it lacks ideal molecular markers for indicating IRI in kidney transplantation. The present study is to explore novel candidate genes involved in renal IRI. Experimental renal IRI mouse models were constructed, and the differentially expressed genes were screened using a microarray assay. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed. The expression of genes was detected using real-time qPCR assay. Western blotting and immunohistochemistry staining assays were performed for protein determination. We identified that renal IRI induced the upregulation of SPRR2F, SPRR1A, MMP-10, and long noncoding RNA (lncRNA) Malat1 in kidney tissues for 479.3-, 4.98-, 238.1-, and 3.79-fold, respectively. The expression of miR-139-5p in kidney tissues of IRI-treated mice was decreased to 40.4% compared with the sham-operated mice. These genes are associated with keratinocyte differentiation, regeneration and repair of kidney tissues, extracellular matrix degradation and remodeling, inflammation, and cell proliferation in renal IRI. Identification of novel biomarkers involved in renal IRI may provide evidences for the diagnosis and treatment of renal IRI.

Several long non-coding RNAs (lncRNAs) act as regulators of cellular homeostasis; however, few of these molecules were functionally characterized in a mature human tissue environment. Here, we report that the lncRNA LINC00941 is a crucial regulator of human epidermal homeostasis. LINC00941 is enriched in progenitor keratinocytes and acts as a repressor of keratinocyte differentiation. Furthermore, LINC00941 represses SPRR5, a previously uncharacterized molecule, which functions as an essential positive regulator of keratinocyte differentiation. Interestingly, 54.8% of genes repressed in SPRR5-deficient epidermal tissue are induced in LINC00941-depleted organotypic epidermis, suggesting a common mode of action for both molecules., (© 2019 The Authors.)

Metastases and tumor recurrence have a major prognostic impact in head and neck squamous cell carcinoma (HNSCC); however, cellular models that comprehensively characterize metastatic and recurrent HNSCC are lacking. To this end, we obtained genomic, transcriptomic, and copy number profiles of the UM-SCC cell line panel, encompassing patient-matched metastatic and recurrent cells. UM-SCC cells recapitulate the most prevalent genomic alterations described in HNSCC, featuring common TP53, PI3K, NOTCH, and Hippo pathway mutations. This analysis identified a novel F977Y kinase domain PIK3CA mutation exclusively present in a recurrent cell line (UM-SCC14B), potentially conferring resistance to PI3K inhibitors. Small proline-rich protein 2A (SPRR2A), a protein involved in epithelial homeostasis and invasion, was one of the most consistently downregulated transcripts in metastatic and recurrent UM-SCC cells. Assessment of SPRR2A protein expression in a clinical cohort of patients with HNSCC confirmed common SPRR2A downregulation in primary tumors (61.9% of cases) and lymph node metastases (31.3%), but not in normal tissue. High expression of SPRR2A in lymph node metastases was, along with nonoropharyngeal location of the primary tumor, an independent prognostic factor for regional disease recurrence after surgery and radiotherapy (HR 2.81; 95% CI, 1.16-6.79; P = 0.02). These results suggest that SPRR2A plays a dual role in invasion and therapeutic resistance in HNSCC, respectively through its downregulation and overexpression. IMPLICATIONS: The current study reveals translationally relevant mechanisms underlying metastasis and recurrence in HNSCC and represents an adjuvant tool for preclinical research in this disease setting. Underlining its discovery potential this approach identified a PIK3CA-resistant mutation as well as SPRR2A as possible theragnostic markers., (©2018 American Association for Cancer Research.)

Psoriasis (Ps) is an inflammatory skin disease caused by genetic and environmental factors. Previous studies on DNA methylation (DNAm) found genetic markers that are closely associated with Ps, and evidence has shown that DNAm mediates genetic risk in Ps. In this study, Consensus Clustering was used to analyze DNAm data, and 114 Ps patients were divided into three subclassifications. Investigation of the clinical characteristics and copy number variations (CNVs) of DEFB4, IL22, and LCE3C in the three subclassifications revealed no significant differences in gender ratio and in Ps area and severity index (PASI) score. The proportion of late-onset ( ≥ 40 years) Ps patients was significantly higher in type I than in types II and III (P = 0.035). Type III contained the smallest proportion of smokers and the largest proportion of non-smoking Ps patients (P = 0.086). The CNVs of DEFB4 and LCE3C showed no significant differences but the CNV of IL22 significantly differed among the three subclassifications (P = 0.044). This study is the first to profile Ps subclassifications based on DNAm data in the Chinese Han population. These results are useful in the treatment and management of Ps from the molecular and genetic perspectives.

Aim: The airway epithelium of smokers exhibits upregulated SPRR3, an indicator of pathogenic keratinization. The mechanisms underlying this phenomenon require investigation., Patients & Methods: Human bronchial epithelial (HBE) SPRR3 expression was analyzed by smoking status. Primary HBE cells were exposed to cigarette smoke (CS). SPRR3 expression, SPRR3 promoter activity, AP-1 factor binding and AP-1 factors' effects were analyzed., Results: Current smokers display SPRR3 upregulation relative to never smokers. CS upregulates SPRR3 transcription in an exposure-dependent manner. CS promotes c-Jun and Fra1 binding to the SPRR3-AP-1/TRE site. Wild-type c-Jun and Fra1 upregulate, whereas c-Jun and Fra1, dominant-negative mutants, suppress SPRR3 promoter activity., Conclusion: CS induces SPRR3 upregulation in HBE cells by promoting aberrant c-Jun/Fra1 dimerization.

Background: Aberrant hyperactivation of epithelial proliferation, AKT signaling, and association with unopposed estrogen (E2) exposure is the most common endometrial cancer dysfunction. In the normal uterus, progesterone (P4) inhibits proliferation by coordinating stromal-epithelial cross-talk, which we previously showed is mediated by the function of Mitogen-inducible gene 6 (Mig-6). Despite their attractive characteristics, non-surgical conservative therapies based on progesterone alone have not been universally successful. One barrier to this success has been the lack of understanding of the P4 effect on endometrial cells., Method: To further understand the role of Mig-6 and P4 in controlling uterine proliferation, we developed a Sprr2f-cre driven mouse model where Mig-6 is specifically ablated only in the epithelial cells of the uterus (Sprr2f cre+ Mig-6 f/f ). We examined P4 effect and regulation of AKT signaling in the endometrium of mutant mice., Results: Sprr2f cre+ Mig-6 f/f mice developed endometrial hyperplasia. P4 treatment abated the development of endometrial hyperplasia and restored morphological and histological characteristics of the uterus. P4 treatment reduced cell proliferation which was accompanied by decreased AKT signaling and the restoration of stromal PGR and ESR1 expression. Furthermore, our in vitro studies revealed an inhibitory effect of MIG-6 on AKT phosphorylation as well as MIG-6 and AKT protein interactions., Conclusions: These data suggest that endometrial epithelial cell proliferation is regulated by P4 mediated Mig-6 inhibition of AKT phosphorylation, uncovering new mechanisms of P4 action. This information may help guide more effective non-surgical interventions in the future.

The late cornified envelope (LCE) gene cluster is located on chromosome 1q21, including LCE1-LCE6. Several single nucleotide polymorphisms (SNPs) in the LCE cluster were associated with susceptibility to psoriasis in Chinese population. However, there is no report on the relationship in ethnic minority areas in China. This study aimed to investigate the association between the gene polymorphisms of LCE1B, LCE1C, LCE3A, LCE3D and psoriasis vulgaris among Mongolians from Inner Mongolia. Totally, 305 Mongolians with psoriasis vulgaris (PsV) and 383 healthy controls were enrolled in the study from 2006 to 2015. 7 SNPs including rs6701216, rs4112788, rs12023196, rs512208, rs4845454, rs4085613 and rs1886734, were selected for genotyping with ligase detection reaction (LDR). Statistical analysis was performed for comparisons of allele frequencies and genotype frequencies between the patient group and the control group. In this study, excluding rs4085613 and rs1886734, differences were detected in the allele frequencies of other 5 SNPs between the patients and controls. Genotype analysis showed that under the recessive inheritance model, the genotype frequencies of rs4845454, rs4112788 differed between the patients and controls (all p < 0.00 5).Under the dominant and the recessive model, the genotype frequencies of rs6701216, rs12023196 and rs512208 significantly differed between the patients and controls. The LD analysis showed that strong LD existed between rs6701216 and rs12023196, rs4845454 and rs4085613, rs4845454 and rs1886734, and rs4085613 and rs1886734. The SNPs rs6701216, rs4112788, rs12023196, rs512208 and rs4845454 in the LCE gene were associated with psoriasis vulgaris among Mongolians from Inner Mongolia.

Heart disease is associated with the accumulation of resident cardiac fibroblasts (CFs) that secrete extracellular matrix (ECM), leading to the development of pathological fibrosis and heart failure. However, the mechanisms underlying resident CF proliferation remain poorly defined. Here, we report that small proline-rich protein 2b ( Sprr2b ) is among the most up-regulated genes in CFs during heart disease. We demonstrate that SPRR2B is a regulatory subunit of the USP7/MDM2-containing ubiquitination complex. SPRR2B stimulates the accumulation of MDM2 and the degradation of p53, thus facilitating the proliferation of pathological CFs. Furthermore, SPRR2B phosphorylation by nonreceptor tyrosine kinases in response to TGF-β1 signaling and free-radical production potentiates SPRR2B activity and cell cycle progression. Knockdown of the Sprr2b gene or inhibition of SPRR2B phosphorylation attenuates USP7/MDM2 binding and p53 degradation, leading to CF cell cycle arrest. Importantly, SPRR2B expression is elevated in cardiac tissue from human heart failure patients and correlates with the proliferative state of patient-derived CFs in a process that is reversed by insulin growth factor-1 signaling. These data establish SPRR2B as a unique component of the USP7/MDM2 ubiquitination complex that drives p53 degradation, CF accumulation, and the development of pathological cardiac fibrosis., Competing Interests: Conflict of interest statement: E.M.S. is the recipient of a research grant from Novartis Pharmaceuticals.

p63, a transcriptional factor that belongs to the p53 family, regulates epidermal differentiation, stemness, cell death, tumorigenesis, metastasis, and senescence. However, its molecular mechanism remains elusive. We report here that TAp63 phosphorylated at T46/T281 specifically upregulates the late cornified envelope 1C (LCE1C) gene that is essential at a relatively late stage of epithelial development. We identified these phosphorylation sites during a search for the targets of Cyclin G-associated kinase (GAK) in vitro. LCE1C was drastically upregulated by doxycycline-dependent expression of Myc-TAp63 wild-type protein. Luciferase reporter assays using the promoter region of the LCE1C gene confirmed that the phosphorylations of TAp63-T46/T281 contributed to full transcriptional activation of the LCE1C gene. LCE1C interacted with protein arginine methyltransferase 5 (PRMT5) and translocated it from the nucleus to the cytoplasm. Mass spectrometry and co-immunoprecipitation identified importin-α as one of the association partners of LCE1C. In summary, we propose that the GAK&#95;TAp63-pT46/pT281&#95;LCE1C axis plays an important role in preventing the nuclear function of PRMT5.

Chronic orofacial pain is a significant health problem requiring identification of regulating processes. Involvement of epigenetic modifications that is reported for hindlimb neuropathic pain experimental models, however, is less well studied in cranial nerve pain models. Three independent observations reported here are the (1) epigenetic profile in mouse trigeminal ganglia (TG) after trigeminal inflammatory compression (TIC) nerve injury mouse model determined by gene expression microarray, (2) H3K9 acetylation pattern in TG by immunohistochemistry, and (3) efficacy of histone deacetylase (HDAC) inhibitors to attenuate development of hypersensitivity. After TIC injury, ipsilateral whisker pad mechanical sensitization develops by day 3 and persists well beyond day 21 in contrast to sham surgery. Global acetylation of H3K9 decreases at day 21 in ipsilateral TG . Thirty-four genes are significantly ( p < 0.05) overexpressed in the ipsilateral TG by at least two-fold at either 3 or 21 days post-trigeminal inflammatory compression injury. The three genes most overexpressed three days post-trigeminal inflammatory compression nerve injury are nerve regeneration-associated gene ATF3, up 6.8-fold, and two of its regeneration-associated gene effector genes, Sprr1a and Gal, up 174- and 25-fold, respectively. Although transcription levels of 25 of 32 genes significantly overexpressed three days post-trigeminal inflammatory compression return to constitutive levels by day 21, these three regeneration-associated genes remain significantly overexpressed at the later time point. On day 21, when tissues are healed, other differentially expressed genes include 39 of the top 50 upregulated and downregulated genes. Remarkably, preemptive manipulation of gene expression with two HDAC inhibitors (HDACi's), suberanilohydroxamic acid (SAHA) and MS-275, reduces the magnitude and duration of whisker pad mechanical hypersensitivity and prevents the development of a persistent pain state. These findings suggest that trigeminal nerve injury leads to epigenetic modifications favoring overexpression of genes involved in nerve regeneration and that maintaining transcriptional homeostasis with epigenetic modifying drugs could help prevent the development of persistent pain.

Many researches document long-term RNA persistence in a variety of tissues and its applicability in estimating the postmortem interval (PMI). Skin-specific mRNA marker, late cornified envelope 1C (LCE1C), was used to identified skin samples. Before using the LCE1C in criminal casework, its persistence and applicability for estimating PMI in different temperatures were tested. Twelve skin samples were collected from 6 patients, and 6 samples were kept at 24°C and others were kept at 40°C for 5 days. The expression levels of LCE1C mRNA are serially detected and quantified using real-time polymerase chain reaction. The expression levels of LCE1C were decreased with increasing the time interval in time-dependent manner, whereas changing the surrounding temperatures did not show any statistical significance. These results could suggest using LCE1C in estimation of PMI. Moreover, these encourage investigators and crime laboratories to know environmental conditions before interpreting the results.

Background: Recently, there is no effective targeted drug for to the lung squamous carcinoma, the targeted drug for the adenocarcinoma does not benefit for the patients with squamous lung cancer, and researchers have known less targets for this type of patients. The main study herein is to screen and identify the specific key genes for the lung squamous carcinoma that will provide potential novel targets to describe pathogenesis of lung cancer., Methods: Transcript sequence was used to detect the five pairs lung squamous carcinoma and normal lung tissues and bioinformatics was performed to investigate the differential coding genes between them and quantitative PCR was done to validate the key genes expression in lung cancer cell lines., Results: The results of transcriptome sequence showed that 534 genes were up-regulated in the tumor tissues compared with the corresponding normal tissues. The top ten increased genes in the tumors were GAGE12J, SPRR3, PRAME, SPRR1A, SPRR2E, MAGEA3, SPRR1B, IL36G and TMPRSS11D. Next, we identified expression of SPRR family in lung cancer cell lines H520, GLC82, A549, H1299 and PC9. And we found higher expression of SPRR family genes in H1299 cells which metastasized to the lymph node., Conclusions: SPRR family genes are identified to be highly expressed in the lung squamous carcinoma by high throughput transcript sequencing. This SPRR family genes are associated with lymph node metastasis that provide novel idea for lung cancer therapy.
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Deletion of late cornified envelope (LCE) genes LCE3B and LCE3C (LCE3B/C-del) is a psoriasis risk factor linked to the major psoriasis risk gene HLA-C*06. Niehues et al. demonstrate that LCE3B/C-del leads to increased keratinocyte LCE3A expression. They also show that LCE3A/B/C possess antimicrobial activity but do not obviously regulate epidermal barrier integrity. These findings implicate LCE proteins in psoriasis pathogenesis via a new functional role., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Terminally differentiating epidermal keratinocytes express a large number of structural and antimicrobial proteins that are involved in the physical barrier function of the stratum corneum and provide innate cutaneous host defense. Late cornified envelope (LCE) genes, located in the epidermal differentiation complex on chromosome 1, encode a family of 18 proteins of unknown function, whose expression is largely restricted to epidermis. Deletion of two members, LCE3B and LCE3C (LCE3B/C-del), is a widely-replicated psoriasis risk factor that interacts with the major psoriasis-psoriasis risk gene HLA-C*06. Here we performed quantitative trait locus analysis, utilizing RNA-seq data from human skin and found that LCE3B/C-del was associated with a markedly increased expression of LCE3A, a gene directly adjacent to LCE3B/C-del. We confirmed these findings in a 3-dimensional skin model using primary keratinocytes from LCE3B/C-del genotyped donors. Functional analysis revealed that LCE3 proteins, and LCE3A in particular, have defensin-like antimicrobial activity against a variety of bacterial taxa at low micromolar concentrations. No genotype-dependent effect was observed for the inside-out or outside-in physical skin barrier function. Our findings identify an unknown biological function for LCE3 proteins and suggest a role in epidermal host defense and LCE3B/C-del-mediated psoriasis risk., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Vascular smooth muscle cells (VSMCs) represent important modulators of plaque stability in advanced lesions. We previously reported that loss of small proline-rich repeat protein 3 (Sprr3), leads to VSMC apoptosis in a PI3K/Akt-dependent manner and accelerates lesion progression. Here, we investigated the role of Sprr3 in modulating plaque stability in hyperlipidemic ApoE-/- mice. We show that loss of Sprr3 increased necrotic core size and reduced cap collagen content of atheromas in brachiocephalic arteries with evidence of plaque rupture and development of intraluminal thrombi. Moreover, Sprr3-/-ApoE-/- mice developed advanced coronary artery lesions accompanied by intraplaque hemorrhage and left ventricle microinfarcts. SPRR3 is known to reduce VSMC survival in lesions by promoting their apoptosis. In addition, we demonstrated that Sprr3-/- VSMCs displayed reduced expression of procollagen in a PI3K/Akt dependent manner. SPRR3 loss also increased MMP gelatinase activity in lesions, and increased MMP2 expression, migration and contraction of VSMCs independently of PI3K/Akt. Consequently, Sprr3 represents the first described VSMC modulator of each of the critical features of cap stability, including VSMC numbers, collagen type I synthesis, and protease activity through Akt dependent and independent pathways.