ATP Citrate Lyase is a General Tumour Biomarker and Contributes to the Development of Cutaneous Squamous Cell Carcinoma.

ATP citrate lyase, the first rate-limiting enzyme in de novo lipogenesis, plays a crucial role in tumour progression. This study explores ATP citrate lyase's potential as a tumour biomarker and its role in cutaneous squamous cell carcinoma. ATP citrate lyase expression patterns were analysed using TCGA and TIMER databases, and patient skin specimens were collected for immunohistochemistry to determine ATP citrate lyase levels. Cell proliferation, cell cycle, apoptosis, and c-Myc expression were assessed in A431 and SCL-1 cells. Stable cell lines with reduced ATP citrate lyase expression were obtained and subcutaneously implanted into nude mice to evaluate in vivo tumour growth. Ki67, c-Myc expression and TUNEL staining were analysed in subcutaneous tumours. ATP citrate lyase exhibited upregulation in various tumours, and showed significant associations with prognosis and immune infiltrate. Moreover, ATP citrate lyase was highly expressed in cutaneous squamous cell carcinoma. After ATP citrate lyase silencing, cutaneous squamous cell carcinoma cell growth decelerated, the cell cycle halted, cell apoptosis increased, and c-Myc expression decreased. Animal experiments revealed that, following ATP citrate lyase knockdown, tumour tissue growth slowed down, and there was a reduction in Ki-67 and c-Myc expression, accompanied by enhanced TUNEL staining. In conclusion, ATP citrate lyase may serve as a tumour biomarker. It is highly expressed in cutaneous squamous cell carcinoma and may serve as a therapeutic target.

TAZ acting as a potential pathogenic biomarker to promote the development of lichen planus.

BACKGROUND: Lichen planus is a chronic inflammatory disorder. Transcriptional coactivator with PDZ-binding motif (TAZ/WWTR1) is an important downstream effector of the Hippo pathway which regulates organ size and tissue homeostasis. But little is known about the role of TAZ in lichen planus so far. OBJECTIVE: To explore the expression of TAZ in lichen planus and normal skin, and to discover the relationship between TAZ expression and the clinical characteristics of lichen planus patients. METHODS: The method of immunohistochemistry was performed to quantify the expression of TAZ in 262 patients with lichen planus and 90 control tissues. Western blot and quantitative real-time reverse transcriptase-PCR (qRT-PCR) analysis were performed to examine and compare TAZ expression in 4 cases of fresh lichen planus lesions and normal skin tissues. RESULTS: TAZ was weakly expressed in the basal layers of the epidermis in normal skin tissues with a positive rate of 52.22% (47/90). But in lichen planus, TAZ was strongly expressed in almost the entire epidermis with a positive rate of 81.30% (213/262), and the difference between the two groups was statistically significant (p<0.05). Additionally, TAZ expression was significantly related to the location of the lichen planus, clinical phenotype, smoking, and alcohol preference (p<0.05). Western blot and qRT-PCR showed that the expression of TAZ in protein and mRNA levels in four cases of lichen planus lesions was significantly higher than that in normal skin tissues. CONCLUSION: TAZ may play a regulatory role in the occurrence and development of lichen planus, which might provide a new perspective for studying pathogenesis and theoretical treatment targets.

UBE2C promotes malignancy of cutaneous squamous cell carcinoma.

BACKGROUND: Our study aimed to study the involvement of ubiquitin-conjugating enzyme E2C (UBE2C) in cutaneous squamous cell carcinoma (cSCC). As the second most common malignancy with a rising incidence, understanding the molecular mechanisms driving cSCC is crucial for improved diagnosis and treatment. METHODS: We combined multiple datasets of cSCC in Gene Expression Omnibus (GEO) repository to investigate its expression and diagnostic value. We collected patient specimens and performed immunohistochemistry to examine its expression in patients and its correlation with tumor histological grade. Moreover, we compared UBE2C expression between cSCC cells and primary human epidermal keratinocytes. Subsequently, we explored the effects of UBE2C inhibition on tumor cell proliferation, migration and apoptosis through CCK8, wound healing, Transwell, and flow cytometry assay. RESULTS: The integrated analysis revealed an upregulation of UBE2C level in cSCC. Immunohistochemistry demonstrated high UBE2C expression was associated with poorer tumor histological grade. Cell experiments further supported the crucial role of UBE2C in promoting the malignant behavior of cSCC cells. CONCLUSION: Our findings indicate UBE2C is up-regulated in cSCC and contributes to its malignant behavior. These results suggest UBE2C has the potential to serve as both a cSCC biomarker and a therapeutic target.

Bioinformatics analysis to reveal the potential comorbidity mechanism in psoriasis and nonalcoholic steatohepatitis.

PURPOSE: An increasing amount of evidence suggests that psoriasis and nonalcoholic steatohepatitis (NASH) may occur simultaneously, whereas the underlying mechanisms remain unclear. Our research aims to explore the potential comorbidity mechanism in psoriasis and nonalcoholic steatohepatitis. MATERIALS AND METHODS: The expression profiles of psoriasis (GSE30999, GSE13355) and NASH (GSE24807, GSE17470) were downloaded from GEO datasets. Next, common differently expressed genes (DEGs) of psoriasis and NASH were investigated. Then, GO and KEGG enrichment, protein interaction network (PPI) construction, and hub gene identification for DEGs were performed. Finally, immune cells expression, target genes predicted by common miRNAs, and transcription factors interaction analysis for hub genes were carried out. RESULTS: Twenty DEGs were identified in totally. GO analysis revealed response to the virus was the most enriched term, and hepatitis C and coronavirus disease-COVID-19 infection-associated pathways were mainly enriched in KEGG. A total of eight hub genes were collected, including IFIT1, IFIT3, OAS1, HPGDS, IFI27, IFI44, CXCL10, IRF9, and 11 TFs were predicted. Then, neutrophils and monocytes were identified as immune cells that express the most hub genes. Moreover, five common miRNAs for psoriasis and NASH and one common miRNAs (hsa-miR-1305)-mRNAs (CHL1, MBNL2) network were presented. CONCLUSION: CHL1 and MBNL2 may participate in the process of psoriasis and NASH via regulating hsa-miR-1305, and together with eight hub genes may be potential therapeutic targets for future treatment for the co-occurrence of these two diseases. This comprehensive bioinformatic analysis provides new insights on molecular pathogenesis and identification of potential therapeutic targets for the co-occurrence of them.

The causal relationship between pure hypercholesterolemia and psoriasis: A bidirectional, two-sample Mendelian randomization study.

BACKGROUND: Several studies have reported the association between pure hypercholesterolemia (PH) and psoriasis, but the causal effect remains unclear. METHODS: We explored the causal effect between PH and psoriasis using two-sample bidirectional Mendelian randomization (MR) analysis using data from genome-wide association studies. Single nucleotide polymorphisms related with exposures at the genome-wide significance level (p < 5×10-8 ) and less than the linkage disequilibrium level (r2  < 0.001) were chosen as instrumental variables. Subsequently, we used inverse variance weighting (IVW), MR-Egger and weighted median (WM) methods for causal inference. p < 0.05 was considered statistically significant. Heterogeneity was tested using Cochran's Q-test, and horizontal pleiotropy was examined using the MR-Egger intercept. Leave-one-out analyses were performed to assess the robustness and reliability of the results. RESULTS: MR results showed a positive causal effect of PH on psoriasis [IVW: odds ratios (OR): 1.139, p = 0.032; MR-Egger: OR: 1.434, p = 0.035; WM: OR: 1.170, p = 0.045] and psoriatic arthritis (PsA) (IVW: OR: 1.210, p = 0.049; MR-Egger regression: OR: 1.796, p = 0.033; WM: OR: 1.317, p = 0.028). However, there is no causal relationship between PH and psoriasis vulgaris as well as other unspecified psoriasis. Inverse MR results suggested a negative causal relationship between PsA and PH (IVW: OR: 0.950, p = 0.037). No heterogeneity and horizontal pleiotropy exist, and these results were confirmed to be robust. CONCLUSION: PH has a positive casual effect on psoriasis and PsA, and PsA may reduce the risk of having PH.

LPCAT1 promotes melanoma cell proliferation via Akt signaling.

Melanoma is the most lethal type of skin cancer with an increasing cutaneous cancer­related mortality rate worldwide. Despite therapeutic advances in targeted therapy and immunotherapy, the overall survival of patients with melanoma remains unsatisfactory. Thus, a further understanding of the pathogenesis of melanoma may aid towards the development of therapeutic strategies. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) is a key enzyme that converts lysophosphatidylcholine into phosphatidylcholine in lipid remodeling. In the present study, LPCAT1 was found to play a pro­proliferative role in melanoma. Firstly, the expression of LPCAT1 was found to be upregulated in tissues from patients with melanoma compared with that in benign nevi. Subsequently, LPCAT1 knockdown was performed, utilizing short hairpin RNA, which induced melanoma cell cycle arrest at the G1/S transition and promoted cell death. Moreover, LPCAT1 facilitated melanoma cell growth in an Akt­dependent manner. In summary, the results of the present study indicate that targeting LPCAT1 may impede cell proliferation by inhibiting Akt signaling, thus providing a promising therapeutic strategy for melanoma in clinical practice.

FOXE1 Contributes to the Development of Psoriasis by Regulating WNT5A.

Psoriasis is a common, chronic, and relapsing inflammatory skin disease characterized by hyperproliferation of keratinocytes (KCs) and infiltration of immune cells. The pathogenesis of psoriasis is complex, and the exact mechanism remains partially understood. In this study, we showed that the forkhead box family protein, FOXE1, had increased expression in lesional skins compared with nonlesional skin from patients with psoriasis. FOXE1 expression was also increased in an imiquimod-induced psoriatic mouse model as well as in M5-stimulated KCs. Using combinational approaches of knockdown and overexpression of FOXE1, we demonstrated that FOXE1 may promote the proliferation of KCs by facilitating G1/S transition and activating extracellular signal-regulated kinase 1/2 signaling pathway. In addition, knockdown of FOXE1 reduced the production of IL-1ß, IL-6, and TNF-α by KCs. RNA-sequencing profiling identified WNT5A as a potential downstream effector of FOXE1. Knockdown of WNT5A inhibited the proliferation of KCs; reduced the production of IL-1ß, IL-6, and TNF-α by KCs; and mitigated the growth-promoting effect of FOXE1 in FOXE1-overexpressed KCs. Finally, depletion of FOXE1 by lentiviral delivery of small hairpin RNAs or genetic approach ameliorated dermatitis symptoms in imiquimod-induced psoriasis-like mouse models. Taken together, our results indicated that FOXE1 participates in the pathogenesis of psoriasis and can serve as a target of psoriasis treatment.

The effects of unsaturated fatty acids on psoriasis: A two-sample Mendelian randomization study.

Unsaturated fatty acids have been reported to be associated with the risk of psoriasis. However, the causal relationship between them remains unclear This study aimed to explore the causal relationship between unsaturated FAs and psoriasis. Firstly, we obtained genome-wide association study (GWAS) data for psoriasis from the FINNGEN database (number of cases = 4510, number of controls = 212,242) and different FA levels (number of samples = 114,999) from the IEU OpenGWAS Project. Secondly, the genetic correlation coefficient was calculated using linkage disequilibrium fractional regression. Thirdly, a two-sample Mendelian randomization (MR) analysis was performed using independent instrumental variables (p < 5 × 10-8) to determine the direction of randomization. Finally, expression quantitative trait loci (eQTL)-related analyses of common single nucleotide polymorphisms (SNPs) were carried out to explore the potential molecular mechanisms of unsaturated FAs affecting psoriasis. We found that an increase in the ratio of monounsaturated fatty acids (MUFAs) to total fatty acids could increase the risk of psoriasis (inverse-variance weighted [IVW], adjusted odds ratio [OR] = 1.175; adjusted 95% confidence interval [CI] = 1.045-1.321; adjusted p = .007). However, an increase in the ratio of polyunsaturated fatty acids (PUFAa) to total fatty acids could decrease the risk of psoriasis (IVW, adjusted OR = 0.754; adjusted 95% CI = 0.631-0.901; adjusted p = .002). Moreover, an increase in the ratio of PUFAs to MUFAs could decrease the risk of psoriasis (IVW, adjusted OR = 0.823; adjusted 95% CI = 0.715-0.948; adjusted p = .007). The heterogeneity of data was eliminated, and pleiotropy was not detected. There was no statistical difference in the MR analysis of other fatty acids indices with psoriasis. Further, no statistically significant evidence was found to verify a causal relationship between psoriasis and fatty acid levels in reverse MR. Functional enrichment analysis showed that these eQTL related to common SNPs were mainly involved in organic ion transport, choline metabolism, and the expression of key metabolic factors mediated by PKA, ChREBP, and PP2A. Our study indicated that the ratio of MUFAs to total fatty acids had a positive causal effect on psoriasis, while the ratio of PUFAs to total fatty acids and the ratio of PUFAs to MUFAs had a negative causal effect on psoriasis. Moreover, PKA-, PP2A-, and ChREBP-mediated activation of metabolic factors may play an important role in this process.

NPTX2 Promotes Epithelial-Mesenchymal Transition in Cutaneous Squamous Cell Carcinoma through METTL3-Mediated N6-Methyladenosine Methylation of SNAIL.

Cutaneous squamous cell carcinoma (cSCC) is the second most common type of skin cancer. NPTX2, a member of the neuronal pentraxin family, is reported to play inconsistent roles in different cancers. The role and mechanism of NPTX2 in cSCC remain unclear. In this study, we found that NPTX2 was overexpressed in both skin lesions and cell lines of cSCC. In vitro studies showed that NPTX2 facilitated cell proliferation, migration, invasion, colony formation, and epithelial‒mesenchymal translation in A431 and SCL-1 cells. NPTX2 interacted with METTL3, increased METTL3 expression, and improved N6-methyladenosine modification in cSCC cell lines. Mechanistically, NPTX2 facilitated epithelial‒mesenchymal translation by promoting METTL3-mediated N6-methyladenosine of SNAIL. METTL3 knockdown and N6-methyladenosine inhibition reversed the impacts of NPTX2 overexpression on cSCC cells. In vivo studies verified the role of NPTX2 as an oncogene in cSCC. Therefore, NPTX2 may be a potential therapeutic target for cSCC.

Bioinformatic Analysis to Identify and Cellular Experiments to Validate Autophagy-related Genes in Psoriasis.

PURPOSE: To explore differentially expressed genes (DEGs) associated with autophagy in psoriasis using bioinformatics analysis and verify them in an M5-induced psoriatic cell model. METHODS: We obtained gene expression microarray data from patients with psoriasis and normal skin tissues from the dataset GSE78097 of the NCBI Gene Expression Omnibus (GEO) database. R software was used to identify DEGs associated with autophagy in psoriasis. Proteinprotein interaction (PPI) and correlation analyses were used to show interactions between certain genes. Their potential biological roles were determined using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Finally, all the DEGs associated with autophagy in psoriasis were validated in a psoriatic cell model by RT-qPCR. RESULTS: 28 DEGs associated with autophagy were identified. These genes were linked to one another, and the most connected hub gene was VEGFA, according to PPI analysis. GO and KEGG enrichment analyses revealed various biological pathways associated with autophagy. The RT-qPCR findings of the expression of 18 genes in the psoriatic cell model confirmed the bioinformatics analysis results. The five genes with the most significant differences were IL24, CCL2, NAMPT, PPP1R15A, and SPHK1. CONCLUSION: We identified DEGs associated with autophagy in patients with psoriasis. IL24, CCL2, NAMPT, PPP1R15A, and SPHK1 were identified as important genes that may influence psoriasis development through the regulation of autophagy.