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Allergic rhinitis (AR) is an important risk factor for the development of asthma. The \"unified airway\" theory considers the upper and lower airways as a morphological and functional whole. However, studies exploring biomarkers linking the upper and lower airways in allergic disease are lacking, which may provide insight into the mechanisms underlying AR comorbid asthma. To integrate bioinformatics techniques to explore biomarkers in airway allergic diseases, and to provide a molecular etiology profile for preventing the development of asthma in AR patients. Biomarkers were screened by identifying key genes common between AR and asthma through WGCNA and differential gene analysis. GO and KEGG analyses were performed using DAVID. Immuno-infiltration analysis was performed by CIBERSORTx. The predictive value of CST1 to distinguish Th2-high asthma was determined by ROC curves. GSEA was used to analyze the signaling pathways involved in CST1. TargetScan and miRNet were combined with GSE142237 to construct ceRNA network. CMap was used to explore potential therapeutic drugs. Validation of datasets showed that CST1 was the only gene that was up-regulated in both upper and lower airways in patients with AR and asthma, and correlation heatmaps showed that CST1 was the gene with the highest sum of correlation coefficients. GO and KEGG analysis demonstrated that the lower airways of AR patients were mainly involved in inflammatory and immune responses, similar to asthma. Immune infiltration showed that CST1 was mainly positively correlated with activated CD4 memory T cells. According to the ROC curve, CST1 showed excellent diagnostic efficiency for Th2-high asthma. GSEA indicated that CST1 was involved in the FcϵRI signaling pathway and O-glycan biosynthesis. A ceRNA network including the lncRNAs KCNQ1OT1 and NEAT1 was constructed. Four drugs, including verrucarin-A, had the potential to prevent the development of asthma in AR patients. In addition, corticosteroids were found to downregulate CST1 expression. CST1 plays a key role in the development of AR comorbid asthma and may be a biomarker for airway allergic diseases. Targeted treatment of CST1 has the potential to prevent the development of asthma in AR patients and deserves further study.

Cystatin SN (CST1) belongs to the type 2 cystatin (CST) superfamily, which restricts the proteolytic activities of cysteine proteases. CST1 has been recently considered to be involved in the development of several human cancers. However, the prognostic significance and function of CST1 in breast cancer remains unknown. In the current study, we found that CST1 was generally upregulated in breast cancer at both mRNA and protein level. Furthermore, overall survival (OS) and disease-free survival (DFS) in the low CST1 expression subgroup were significantly superior to the high CST1 expression subgroup (OS, p  < 0.001; DFS, p  < 0.001), which indicated that CST1 expression level was closely correlated to the survival risk of these patients. Univariate and multivariate analyses demonstrated that CST1 expression was an independent prognostic factor, the same as ER status and nodal status. Next, CST1 overexpression promoted breast cancer cell proliferation, clonogenicity, migration, and invasion abilities. By contrast, knockdown of CST1 attenuated these malignant characteristics in breast cancer cells. Collectively, our study indicates that CST1 cannot only serve as a significant prognostic indicator but also as a potential therapeutic target for breast cancer. Key messages High CST1 expression is negatively correlated with survival of breast cancer patients. CST1 promotes cell proliferation, clone formation, and metastasis in breast cancer cells. CST1 is a novel potential prognostic biomarker and therapeutic target for breast cancer.

Toxoplasma gondii is a highly prevalent parasite worldwide that presents life-threatening risks to immunocompromised and pregnant individuals. Whereas the life stage responsible for acute infection can be treated, the life stage responsible for chronic infection is refractory to currently available therapeutics. Little is known about the protein composition of the cyst wall, an amorphous structure formed by parasites that is suspected to facilitate persistence within muscle and nervous tissue during chronic (latent) infection. By implementing a refined approach to selectively purify cyst wall fragments, we identified several known and novel cyst wall proteins from our sample preparations. We confirmed the localizations of several proteins from this data set and identified one that is involved in parasite virulence. These data will propel further studies on cyst wall structure and function, leading to therapeutic strategies that can eliminate the chronic infection stage. The tissue cyst of Toxoplasma gondii , found in latent infection, serves a critical role in both transmission and reactivation of this organism. Within infected cells, slowly replicating parasites (bradyzoites) are surrounded by a cyst matrix, cyst wall, and cyst membrane. The cyst wall is clearly delineated by ultrastructural analysis; however, the composition and function of this layer in host-parasite interactions are not fully understood. In order to understand the composition of the cyst wall, a proteomic analysis of purified cyst wall fragments, that were enriched with Percoll gradients and subsequently immunoprecipitated with CST1 antibody, was performed. Known cyst wall proteins, such as CST1, BPK1, MCP4, MAG1, GRA2, GRA3, and GRA5, were identified in this preparation by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In addition, dense granule proteins (GRAs) not previously shown to associate with the cyst wall, as well as uncharacterized hypothetical proteins, were identified in this cyst wall preparation. Several of these hypothetical cyst wall (CST) proteins were epitope tagged, and immunofluorescence assays confirmed their localization as novel cyst matrix and cyst wall proteins. Expression of two of these newly identified cyst wall proteins was eliminated by gene knockout (CST2-KO and CST3-KO). CST2-KO parasites were highly attenuated in virulence and did not establish detectable cyst burdens. This targeted proteomic approach allowed the identification of new components of the cyst wall that probably have roles in the parasite/host interface. IMPORTANCE Toxoplasma gondii is a highly prevalent parasite worldwide that presents life-threatening risks to immunocompromised and pregnant individuals. Whereas the life stage responsible for acute infection can be treated, the life stage responsible for chronic infection is refractory to currently available therapeutics. Little is known about the protein composition of the cyst wall, an amorphous structure formed by parasites that is suspected to facilitate persistence within muscle and nervous tissue during chronic (latent) infection. By implementing a refined approach to selectively purify cyst wall fragments, we identified several known and novel cyst wall proteins from our sample preparations. We confirmed the localizations of several proteins from this data set and identified one that is involved in parasite virulence. These data will propel further studies on cyst wall structure and function, leading to therapeutic strategies that can eliminate the chronic infection stage.

In this study, we found Cystatin SN (CST1), a type 2 cystatin subfamily member, to be highly expressed in nasal polyps from patients with intractable chronic rhinosinusitis (CRS) with nasal polyps, using a whole-transcript analysis with next-generation sequencing. Eosinophilic CRS (ECRS) involves nasal polyps that are refractory and recur immediately after endoscopic sinus surgery. We hypothesized that CST1 may contribute to the pathogenesis of ECRS. We examined the expression of CST1 in nasal polyps from patients with ECRS by assessing mRNA expression levels using real-time PCR and immunohistochemistry. CST1 showed significantly greater expression in the epithelial cells of nasal polyps from patients with ECRS than in those from patients who did not have ECRS (non-ECRS). In particular, CST1 showed very strong expression in patients with severe ECRS. The expression of CST1 may be correlated with the recurrent and refractory nature of ECRS. We examined the function of CST1 using nasal epithelial cells and nasal fibroblasts. Stimulation by a combination of IL-4 plus double-stranded RNA plus CST1 significantly elevated mRNA expression levels and protein levels of TSLP in nasal epithelial cells. Stimulation by TSLP or IL-33 significantly elevated mRNA expression levels of CST1 in nasal epithelial cells. Stimulation of CST1 significantly elevated mRNA expression levels of CCL11 and POSTN in nasal fibroblasts. CST1 could amplify eosinophilic infiltration and T-helper cell type 2 inflammation by interacting with epithelial-derived cytokines and fibroblasts on nasal polyps. CST1 may be involved in the pathogenesis of ECRS, and may contribute to the severity and recurrence of CRS with nasal polyps after endoscopic sinus surgery.

Cysteine protease inhibitor 1 (CST1) is a cystatin superfamily protein that inhibits cysteine protease activity and is reported to be involved in the development of many malignancies. Mitochondrial oxidative phosphorylation (OXPHOS) also plays an important role in cancer cell growth regulation. However, the relationship and roles of CST1 and OXPHOS in esophageal squamous cell carcinoma (ESCC) remains unclear. In our pilot study, CST1 was shown the potential of promoting ESCC migration and invasion by the activation of MEK/ERK pathway. Transcriptome sequencing analysis revealed that CST1 is closely associated with OXPHOS. Based on a real-time ATP rate assay, mitochondrial complex I enzyme activity assay, immunofluorescence, co-immunoprecipitation, and addition of the OXPHOS inhibitor Rotenone and MEK/ERK inhibitor PD98059, we determined that CST1 affects mitochondrial complex I enzyme activity by interacting with the GRIM19 protein to elevate OXPHOS levels, and a reciprocal regulatory relationship exists between OXPHOS and the MEK/ERK pathway in ESCC cells. Finally, an in vivo study demonstrated the potential of CST1 in ESCC metastasis through regulation of the OXPHOS and MEK/ERK pathways. This study is the first to reveal the oncogenic role of CST1 in ESCC development by enhancing mitochondrial respiratory chain complex I activity to activate the OXPHOS/MEK/ERK axis, and then promote ESCC metastasis, suggesting that CST1/OXPHOS is a promising target for ESCC treatment.

Homeodomain-containing gene 10 (HOXC10) is a member of the homeobox transcription factors that plays an important role in the development of multicellular organisms. HOXC10 is overexpressed in a variety of human cancers, and recent studies have revealed that HOXC10 is upregulated in gastric cancer as well. However, its mechanism of action is not fully understood, thus, the role of HOXC10 was investigated in the present study in human gastric cancer. First, HOXC10 expression was revealed to be significantly increased in gastric cancer tissues compared to normal tissues (TCGA dataset), and HOXC10 upregulation was associated with decreased recurrence-free survival in gastric cancer patients in a public gene expression dataset. HOXC10 promoted cell proliferation and metastasis in two gastric cancer cell lines (AGS and MKN74). Analyzing TCGA 450K DNA methylation dataset, it was revealed that HOXC10 CpG sites were hypomethylated in gastric cancer tissues. Bisulfite sequencing revealed that CpG sites in the HOXC10 first intronic region were hypomethylated in three gastric cancer tissues, and HOXC10 expression was increased in gastric cancer cell lines (AGS and SNU620) in response to 5-azacytidine treatment. By RNA-sequencing of AGS cells with ectopic HOXC10 expression, it was revealed that many genes were upregulated by HOXC10 overexpression. Among them, CST1 was predicted to be a HOXC10 direct target gene via prediction of HOXC10 binding sites from the JASPAR database. A chromatin immunoprecipitation assay revealed that HOXC10 directly bound to CST1 promoter regions. The present study proposes HOXC10 is a potential prognostic marker or therapeutic target in human gastric cancer.

Background Cystatins are a class of proteins that can inhibit cysteine protease and are widely distributed in human bodily fluids and secretions. Cystatin SN (CST1), a member of the CST superfamily, is abnormally expressed in a variety of tumors. However, its effect on the occurrence and development of lung adenocarcinoma (LUAD) remains unclear. Methods We obtained transcriptome analysis data of CST1 from The Cancer Genome Atlas (TCGA) and GSE31210 databases. The association of CST1 expression with prognosis, gene mutations and tumor immune microenvironment was analyzed using public databases. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were performed to investigate the potential mechanisms of CST1. Results In this study, we found that CST1 was highly expressed in lung adenocarcinoma and was associated with prognosis and tumor immune microenvironment. Genetic mutations of CST1 were shown to be related to disease-free survival (DFS) by using the c-BioPortal tool. Potential proteins binding to CST1 were identified by constructing a protein-protein interaction (PPI) network. Gene set enrichment analysis (GSEA) of CST1 revealed that CST1 was notably enriched in epithelial-mesenchymal transition (EMT). Cell experiments confirmed that overexpression of CST1 promoted lung adenocarcinoma cells migration and invasion, while knockdown of CST1 significantly inhibited lung adenocarcinoma cells migration and invasion. Conclusions Our comprehensive bioinformatics analyses revealed that CST1 may be a novel prognostic biomarker in LUAD. Experiments confirmed that CST1 promotes epithelial-mesenchymal transition in LUAD cells. These findings will help to better understand the distinct role of CST1 in LUAD.

Gastric cancer is one of the main reasons of cancer-induced death, exploring the molecular mechanisms of gastric cancer progression is critical for gastric cancer therapy. Here, we studied the role of cysteine protease inhibitor CST1 in gastric cancer progression. Matrigel-coated or -uncoated transwell assay was used to determine the effect of CST1 on gastric cancer invasion and migration, luciferase reporter system was used to determine the effect of CST1 on Wnt pathway activity. CST1 had high expression levels in gastric cancer tissues and cells, patients who had high CST1 expression had poor outcome. Overexpression of CST1 increased gastric cancer migration and invasion, while knockdown of CST1 suppressed gastric cancer migration invasion. Mechanism analysis showed CST1 promoted WNT signaling pathway activity, promoted the nuclear translocation of β-catenin and the expression of Wnt signaling targets. Inhibition of Wnt pathway in CST1 overexpression cells inhibited migration and invasion, suggesting CST1 promoted gastric cancer cell migration and invasion through activating the Wnt pathway. In summary, we found CST1 promoted gastric cancer migration and invasion through activating Wnt signaling, providing a novel target for gastric cancer therapy.

Dysregulation of circRNAs is associated with human cancer progression, but its expression pattern and function in cancer are not fully understood. The aim of our study is to investigate the effects of circ_0001821 on colorectal cancer (CRC) proliferation, migration, invasion, and stemness. The expression level of circ_0001821 in CRC tissues and cells was detected by quantitative real-time PCR. The effects of circ_0001821 silencing on the proliferation, migration, invasion, and stemness of CRC cells were examined by cell counting kit-8, 5-Ethynyl-2′-deoxyuridine, transwell, sphere formation, and western blot assays. Bioinformatics and dual-luciferase reporter gene assay were used to verify the relationship between circ_0001821 and miR-339-3p, miR-339-3p and CST1 in CRC cells. Circ_0001821 was highly expressed in CRC tissues and cells. Circ_0001821 silencing inhibited the proliferation, migration, invasion, and stemness of CRC cells, and transfection of miR-339-3p inhibitor partly attenuated this effect. In addition, circ_0001821 can bind miR-339-3p to regulate CST1 expression. Circ_0001821 silencing also curbed tumor growth in vivo. Circ_0001821 promoted CRC cell proliferation, migration, invasion, and stemness by regulating the miR-339-3p/CST1 axis.

Cystatin SN (CST1) has been reported to act as an oncogene in cancers, but its underlying mechanism remains unclear. We performed Western blotting analyses to observe protein expression and conducted transwell invasion, wound healing, and colony formation assays to assess cell invasion, migration, and proliferation, respectively. We also performed cell cycle analyses by flow cytometry to determine the role of CST1 in the cell cycle. In vivo experiments used subcutaneous tumor models in BALB/c-nu athymic female mice to evaluate the effect of CST1 on tumor growth. Western blotting analyses showed that CST1 was upregulated in ER+ breast cancer cells such as MCF7, T47D, and BT474. CST1 knockdown led to slower cell growth and inhibited the G1 to S phase transition in ER+ breast cancer cells. In vivo experiments showed that CST1 deletion inhibited tumor growth, and led to decreased expression of estrogen receptor α (ERα) and p-AKT. In vitro experiments showed that the over-expression of CST1 led to the upregulation of ERα, and inhibition of CST1 inhibited the expression of ERα. Western blotting analyses showed that CST1 regulated the activity of the PI3K/AKT signaling pathway in breast cancer cells. We confirmed that CST1 acted as an oncogene in ER+ breast cancer by regulating the ERα/PI3K/AKT/ERα loopback pathway. CST1 acts as an oncogene in ER+ breast cancer, and CST1 contributes to cancer development by regulating the ERα/PI3K/AKT/ERα loopback pathway in ER+ breast cancer. Our findings indicate that CST1 could be a significant therapeutic target for ER+ breast cancer patients. Our discovery should inspire further studies on the role of CST1 in cancers.