Identification of clinical prognostic factors and analysis of ferroptosis-related gene signatures in the bladder cancer immune microenvironment.

BACKGROUND: Bladder cancer (BLCA) is a prevalent malignancy affecting the urinary system and poses a significant burden in terms of both incidence and mortality rates on a global scale. Among all BLCA cases, non-muscle invasive bladder cancer constitutes approximately 75% of the total. In recent years, the concept of ferroptosis, an iron-dependent form of regulated cell death marked by the accumulation of lipid peroxides, has captured the attention of researchers worldwide. Nevertheless, the precise involvement of ferroptosis-related genes (FRGs) in the anti-BLCA response remains inadequately elucidated. METHODS: The integration of BLCA samples from the TCGA and GEO datasets facilitated the quantitative evaluation of FRGs, offering potential insights into their predictive capabilities. Leveraging the wealth of information encompassing mRNAsi, gene mutations, CNV, TMB, and clinical features within these datasets further enriched the analysis, augmenting its robustness and reliability. Through the utilization of Lasso regression, a prediction model was developed, enabling accurate prognostic assessments within the context of BLCA. Additionally, co-expression analysis shed light on the complex relationship between gene expression patterns and FRGs, unraveling their functional relevance and potential implications in BLCA. RESULTS: FRGs exhibited increased expression levels in the high-risk cohort of BLCA patients, even in the absence of other clinical indicators, suggesting their potential as prognostic markers. GSEA revealed enrichment of immunological and tumor-related pathways specifically in the high-risk group. Furthermore, notable differences were observed in immune function and m6a gene expression between the low- and high-risk groups. Several genes, including MYBPH, SOST, SPRR2A, and CRNN, were found to potentially participate in the oncogenic processes underlying BLCA. Additionally, CYP4F8, PDZD3, CRTAC1, and LRTM1 were identified as potential tumor suppressor genes. Significant discrepancies in immunological function and m6a gene expression were observed between the two risk groups, further highlighting the distinct molecular characteristics associated with different prognostic outcomes. Notably, strong correlations were observed among the prognostic model, CNVs, SNPs, and drug sensitivity profiles. CONCLUSIONS: FRGs are associated with the onset and progression of BLCA. A FRGs signature offers a viable alternative to predict BLCA, and these FRGs show a prospective research area for BLCA targeted treatment in the future.

Idiopathic Subglottic Stenosis Is Associated With More Frequent and Abnormal Squamous Metaplasia.

OBJECTIVES: Gain insights into the pathophysiology of idiopathic subglottic stenosis (iSGS) by investigating differences in transcriptome of subglottic mucosal tissue between patients with iSGS and controls, and between tracheal and subglottic tissue within patients. METHODS: RNA sequencing was conducted on biopsied mucosal samples collected from subglottic and tracheal (in-patient control) regions in iSGS patients, and from subglottis in controls. The gene expression differences were validated on a protein level by (1) staining the tissue samples obtained from a second cohort of patients and controls; and (2) in vitro functional assays using primary subglottic epithelial cells from both iSGS patients and healthy donors. RESULTS: We found 7 upregulated genes in the subglottic region of iSGS patients relative to both the tracheal mucosa and subglottic region of controls. A gene ontology enrichment analysis found that the epithelial cell differentiation and cornification pathways are significant, involving specifically 3 of the genes: involucrin (IVL), small proline rich protein 1B (SPRR1B), and keratin 16 (KRT16). Involvement of these pathways suggests squamous metaplasia of the epithelium. Histological analyses of epithelium in subglottic mucosal biopsies revealed squamous metaplasia in 41% of the samples from iSGS patients and in 25% from controls. Immunohistochemical evaluation of the samples presented with squamous epithelium revealed increased expression of the protein encoded by SPRR1B, hyperproliferative basal cells, shedding of apical layers, and accompanying lesions in iSGS compared to CTRL. Cultured primary subglottic epithelial cells from iSGS patients had higher proliferation rates compared to healthy donors and squamous metaplastic differentiation formed thinner epithelia with increased expression proteins encoded by INV, SPRR1B, and KRT16, suggesting intrinsic dysfunction of basal cells in iSGS. CONCLUSIONS: Abnormal squamous differentiation of epithelial cells may contribute to the pathogenesis of iSGS. Patients having metaplastic epithelial phenotype may be sensitive to drugs that reverse it to a normal phenotype.

CYSRT1: An Antimicrobial Epidermal Protein that Can Interact with Late Cornified Envelope Proteins.

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.

SPRR3 Contributes to Aggressiveness of Pancreatic Cancer Cells via NF-κB Signaling Pathway.

Pancreatic cancer remains a deadly solid tumor with worst survival, and a better understanding of the mechanisms of carcinogenesis of pancreatic cancer is critical to promote the survival of patients with pancreatic cancer. qPCR and western blot assay were used to determine the expression of SPRR3 in pancreatic cancer. Anchorage-independent growth ability, BrdU labeling, Transwell assay, and in vivo experiment were used to examine the functions of SPRR3 in aggressiveness of pancreatic cancer. Luciferase reporter assay, nucleoplasmic-separation technique, qPCR, and western blot assay were used to investigate the mechanism of SPRR3 regulating aggressiveness of pancreatic cancer. Our results showed that SPRR3 was significantly increased in pancreatic cancer, which resulted in poor survival for patients with pancreatic cancer. Further analysis showed that overexpression of SPRR3 contributed to anchorage-independent growth ability, growth rate, and invasion ability of pancreatic cancer cells. While, knockdown of SPRR3 showed the reverse results. Mechanistically, overexpression of SPRR3 can promote the transcription of NF-κB pathway, nuclear accumulation of p65, and mRNA levels of NF-κB pathway downstream genes. But, knockdown of SPRR3 induced the reverse results. The above findings clarified the important roles of SPRR3 in the progression of pancreatic cancer through NF-κB pathway. And targeting SPRR3 might be an effective strategy to therapy pancreatic cancer.

Beyond keratinocyte differentiation: emerging new biology of small proline-rich proteins.

Small proline-rich proteins (SPRRPs) are traditionally known for their function in keratinocyte homeostasis. Recent evidence demonstrates their involvement in additional diverse physiological processes ranging from p53 signaling and direct prevention of DNA damage to bactericidal activities. We highlight these novel, intriguing roles of SPRRPs and discuss them in the context of relevant pathological conditions.

Particulate matter 2.5 induces the skin barrier dysfunction and cutaneous inflammation via AhR- and T helper 17 cell-related genes in human skin tissue as identified via transcriptome analysis.

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.

Corneal epithelium in keratoconus underexpresses active NRF2 and a subset of oxidative stress-related genes.

Keratoconus (KC) is a multifactorial progressive ectatic disorder characterized by local thinning of the cornea, leading to decreased visual acuity due to irregular astigmatism and opacities. Despite the evolution of advanced imaging methods, the exact etiology of KC remains unknown. Our aim was to investigate the involvement of corneal epithelium in the pathophysiology of the disease. Corneal epithelial samples were collected from 23 controls and from 2 cohorts of patients with KC: 22 undergoing corneal crosslinking (early KC) and 6 patients before penetrating keratoplasty (advanced KC). The expression of genes involved in the epidermal terminal differentiation program and of the oxidative stress pathway was assessed by real time PCR analysis. Presence of some of the differentially expressed transcripts was confirmed at protein level using immunofluorescence on controls and advanced KC additional corneal samples. We found statistically significant under-expression in early KC samples of some genes known to be involved in the mechanical resistance of the epidermis (KRT16, KRT14, SPRR1A, SPRR2A, SPRR3, TGM1 and TGM5) and in oxidative stress pathways (NRF2, HMOX1 and HMOX2), as compared to controls. In advanced KC samples, expression of SPRR2A and HMOX1 was reduced. Decreased expression of keratin (KRT)16 and KRT14 proteins was observed. Moreover, differential localization was noted for involucrin, another protein involved in the epidermis mechanical properties. Finally, we observed an immunofluorescence staining for the active form of NRF2 in control epithelia that was reduced in KC epithelia. These results suggest a defect in the mechanical resistance and the oxidative stress defense possibly mediated via the NRF2 pathway in the corneal keratoconic epithelium.

Corneal Neuro-Regenerative Effect of Transcutaneous Electrical Stimulation in Rabbit Lamellar Keratectomy Model.

Purpose: This study aimed to evaluate the effect of transcutaneous electrical stimulation (TES) on corneal nerve regeneration in rabbits injured from superficial lamellar keratectomy (SLK). Methods: New Zealand White rabbits were used in this experimental study. To induce corneal nerve damage, SLK was performed using a 7.0-mm trephine. TES was applied for 28 days after the corneal nerve injury. Corneal sensitivity, Western blotting, real-time polymerase chain reaction (PCR), and immunofluorescence were performed to observe changes in the corneal tissue. Results: In the 2-Hz and 20-Hz electrical stimulation groups, the degree of corneal wound healing increased by more than 10% compared to the control group, but no significant difference was observed. Conversely, the electrical stimulation (2-Hz or 20-Hz) group showed significantly increased corneal sensitivity compared to the control group. Western blot analysis revealed that small proline-rich protein 1A (SPRR1a), a regeneration-associated protein was significantly increased in the 2-Hz group on days 1 and 7 compared to that in the other groups. Once again, nerve regeneration in the 2-Hz group was supported by the results of PCR, in which a significant increase in the nerve growth factor (NGF) on day 1 was observed compared with the other groups. Moreover, immunofluorescence after 28 days of electrical stimulation showed significant nerve regeneration in the 2-Hz group. Conclusions: TES promoted corneal nerve regeneration in rabbit SLK model. The application of electrical stimulation of 2-Hz frequency was more effective than the 20-Hz frequency, showing potential clinical applications for corneal diseases. Translational Relevance: This study shows how application of TES to the eyes that exhibit corneal nerve damage can improve corneal nerve regeneration examined by histologic analysis.

Role of the long non-coding RNA, SPRR2C, based on an in vitro psoriatic keratinocyte cell model

Background: Psoriasis is a chronic inflammatory disease of the skin with complex pathogenesis. Long non-coding RNAs (lncRNAs) play an important regulatory role in the occurrence and progression of many diseases, as well as psoriasis. Objectives: This study aimed to investigate the role and mechanism of the lncRNA, SPRR2C, in M5-induced psoriatic keratinocytes. Materials & Methods: SPRR2C expression and subcellular localization was detected using FISH and qRT-PCR. Ker-CT and HaCaT cells stimulated by M5 (IL-17A, tumour necrosis factor-α, IL-1α, IL-22, and oncostatin-M) were used to establish a psoriatic cell model. CCK-8 assay, CFSE proliferation assay, flow cytometry, western blotting and ELISA were used to examine the effects of SPRR2C in the keratinocyte model. Results: SPRR2C was highly expressed in psoriatic samples and M5-induced psoriatic keratinocytes, and SPRR2C was mainly localised to the cytoplasm. In keratinocytes, SPRR2C regulated proliferation, cell cycle and apoptosis, and induced the expression of IL-1ß, IL-6, IL-8, CXCL2 and CCL20. Moreover, SPRR2C cellular effects were shown to be mediated by the PI3K/AKT/mTOR signalling pathway, based on experiments with the AKT-specific inhibitor, MK-2206, which was also shown to suppress overexpression of SPRR2C. Conclusion: Our results indicate that SPRR2C plays a regulatory role and is involved in the PI3K/AKT/mTOR signalling pathway in psoriatic keratinocytes, which may provide a potential diagnostic and therapeutic target for psoriasis.

Survival-related indicators ALOX12B and SPRR1A are associated with DNA damage repair and tumor microenvironment status in HPV 16-negative head and neck squamous cell carcinoma patients.

OBJECTIVES: To investigate prognostic-related gene signature based on DNA damage repair and tumor microenvironment statue in human papillomavirus 16 negative (HPV16-) head and neck squamous cell carcinoma (HNSCC). METHODS: For the RNA-sequence matrix in HPV16- HNSCC in the Cancer Genome Atlas (TCGA) cohort, the DNA damage response (DDR) and tumor microenvironment (TM) status of each patient sample was estimated by using the ssGSEA algorithm. Through bioinformatics analysis in DDR_high/TM_high (n = 311) and DDR_high/TM_low (n = 53) groups, a survival-related gene signature was selected in the TCGA cohort. Two independent external validation cohorts (GSE65858 (n = 210) and GSE41613 (n = 97)) with HPV16- HNSCC patients validated the gene signature. Correlations among the clinical-related hub differentially expressed genes (DEGs) and infiltrated immunocytes were explored with the TIMER2.0 server. Drug screening based on hub DEGs was performed using the CellMiner and GSCALite databases. The loss-of-function studies were used to evaluate the effect of screened survival-related gene on the motility of HPV- HNSCC cells in vitro. RESULTS: A high DDR level (P = 0.025) and low TM score (P = 0.012) were independent risk factors for HPV16- HNSCC. Downregulated expression of ALOX12B or SPRR1A was associated with poor survival rate and advanced cancer stages. The pathway enrichment analysis showed the DDR_high/TM_low samples were enriched in glycosphingolipid biosynthesis-lacto and neolacto series, glutathione metabolism, platinum drug resistance, and ferroptosis pathways, while the DDR_high/TM_low samples were enriched in Th17 cell differentiation, Neutrophil extracellular trap formation, PD - L1 expression and PD - 1 checkpoint pathway in cancer. Notably, the expression of ALOX12B and SPRR1A were negatively correlated with cancer-associated fibroblasts (CAFs) infiltration and CAFs downstream effectors. Sensitivity to specific chemotherapy regimens can be derived from gene expressions. In addition, ALOX12B and SPRR1A expression was associated with the mRNA expression of insulin like growth factor 1 receptor (IGF1R), AKT serine/threonine kinase 1 (AKT1), mammalian target of rapamycin (MTOR), and eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1) in HPV negative HNSCC. Down-regulation of ALOX12B promoted HPV- HNSCC cells migration and invasion in vitro. CONCLUSIONS: ALOX12B and SPRR1A served as a gene signature for overall survival in HPV16- HNSCC patients, and correlated with the amount of infiltrated CAFs. The specific drug pattern was determined by the gene signature.

Small proline-rich protein 1A promotes lung adenocarcinoma progression and indicates unfavorable clinical outcomes.

Small proline-rich protein 1A (SPRR1A) plays a critical role in regulating squamous cell differentiation. SPRR1A overexpression was reported to be closely related to the progression of some tumors, such as gastric cancer and colon cancer. However, the function of SPRR1A in lung adenocarcinoma (LUAD) has not been elucidated. Here, we first examined the expression pattern of SPRR1A in LUAD tissues, which indicated that the SPRR1A expression level was significantly elevated in LUAD tissues compared with normal lung tissues. High expression of SPRR1A was closely related to larger tumor size. LUAD patients with higher SPRR1A expression had poorer overall survival and SPRR1A was identified as an independent unfavorable prognosis factor. In addition, the effects of SPRR1A on lung cancer cells were tested through cellular experiments and the result demonstrated that knockdown of SPRR1A can suppress the proliferation and invasion capacities of tumor cells, while overexpressing SPRR1A exerted opposite effects. Finally, our findings were substantiated by the data obtained from in vivo xenografts using a mice model. In conclusion, LUAD patients with higher SPRR1A expression were more predisposed to poorer clinical outcomes and unfavorable prognoses, indicating the potential role of SPRR1A as a novel clinical biomarker and therapeutic target.

Small proline-rich proteins (SPRRs) are epidermally produced antimicrobial proteins that defend the cutaneous barrier by direct bacterial membrane disruption.

Human skin functions as a physical barrier, preventing the entry of foreign pathogens while also accommodating a myriad of commensal microorganisms. A key contributor to the skin landscape is the sebaceous gland. Mice devoid of sebocytes are prone to skin infection, yet our understanding of how sebocytes function in host defense is incomplete. Here, we show that the small proline-rich proteins, SPRR1 and SPRR2 are bactericidal in skin. SPRR1B and SPPR2A were induced in human sebocytes by exposure to the bacterial cell wall component lipopolysaccharide (LPS). Colonization of germ-free mice was insufficient to trigger increased SPRR expression in mouse skin, but LPS injected into mouse skin stimulated increased expression of the mouse SPRR orthologous genes, Sprr1a and Sprr2a, through activation of MYD88. Both mouse and human SPRR proteins displayed potent bactericidal activity against MRSA (methicillin-resistant Staphylococcus aureus), Pseudomonas aeruginosa, and skin commensals. Thus, Sprr1a-/-;Sprr2a-/- mice are more susceptible to MRSA and P. aeruginosa skin infection. Lastly, mechanistic studies demonstrate that SPRR proteins exert their bactericidal activity through binding and disruption of the bacterial membrane. Taken together, these findings provide insight into the regulation and antimicrobial function of SPRR proteins in skin and how the skin defends the host against systemic infection.

Identification of Potential Key Biomarkers and Immune Infiltration in Oral Lichen Planus.

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.

Antimicrobial Late Cornified Envelope Proteins: The Psoriasis Risk Factor Deletion of LCE3B/C Genes Affects Microbiota Composition.

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.

Copy Number Variation Analysis of IL22 and LCE3C in Different Subtypes of Psoriasis in a Chinese Han Population.

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.

Small proline-rich protein 2A is a gut bactericidal protein deployed during helminth infection.

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.

DGUOK-AS1 promotes cervical squamous cell carcinoma progression by suppressing miR-499a-5p that targets SPRR1B in vitro.

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.

Histone modification of pain-related gene expression in spinal cord neurons under a persistent postsurgical pain-like state by electrocautery.

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.

The life in a gradient: calcium, the lncRNA SPRR2C and mir542/mir196a meet in the epidermis to regulate the aging process.

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.