Study on the expression and function of chordin-like 1 in oral squamous cell carcinoma.

OBJECTIVE: The aim of this study was to investigate the role and related mechanism of chordin-like 1 (CHRDL1) in oral squamous cell carcinoma (OSCC). METHODS: The expressions of CHRDL1 were analyzed in both mRNA and protein levels by bioinformatics analysis, immunohistochemistry, and fluorescence in situ hybridization in OSCC. Survival analysis was used to determine the relationship between CHRDL1 and prognosis. In addition, enrichment analysis was used to suggest signal pathways involved in CHRDL1. Besides, the relationships between CHRDL1 and miRNAs, hypoxia, and immune infiltration were explored. RESULTS: The mRNA level of CHRDL1 in OSCC was significantly lower than that in normal tissues, while the protein level was significantly higher than that in normal tissues. The high mRNA levels of CHRDL1 suggested a poor prognosis in patients with OSCC. The enrichment results showed that CHRDL1 might be involved in the Calcium signaling pathway, dilated cardiomyopathy, and focal adhesion. 7 immune cells were positively correlated with CHRDL1, while Tgd was negatively correlated with CHRDL1. In addition, we also found that hsa-miR-455-3p directly targeted CHRDL1 and reduced the mRNA levels of CHRDL1. CONCLUSION: CHRDL1 plays a vital role in promoting cancer in OSCC and is down-regulated at the mRNA levels by hsa-miR-455-3p.

Overexpression of BMP4 protects retinal ganglion cells in a mouse model of experimental glaucoma.

PURPOSE: Activation of bone morphogenetic protein (BMP) 4 signaling promotes the survival of retinal ganglion cell (RGC) after acute injury. Chordin-like 1 (CHRDL1) is an endogenous BMP antagonist. In this study, we researched whether CHRDL1 was involved in BMP4 signaling and regulation of RGC degeneration in a mouse model of glaucoma. METHODS: Magnetic microbeads were intracameral injected to induce experimental glaucoma in a mouse model. A recombinant adeno-associated virus (rAAV) system was designed for overexpression of BMP4 or CHRDL1 in mouse retina. Immunohistochemistry and hematoxylin-eosin (HE) stains were performed to identify changes in retinal morphology. Electroretinogram (ERG) recordings were used to assess changes in visual function. RESULTS: The mRNA expression levels of Bmp4 and its downstream BMPRIa, small mothers against decapentaplegic 1 (Smad1), were significantly upregulated in retinas with glaucoma. RGC survival was significantly enhanced in the beads + AAV-BMP4 group and significantly reduced in the beads + AAV-CHRDL1 group, compared with the beads + AAV-EGFP group. Similar results were observed in retinal explant culture in vitro. Consistent with these findings, the photopic negative response (PhNR)responses in ERG, which indicate RGC function, were restored in mice overexpressing BMP4, whereas a-wave and b-wave responses were not. Activation of CHRLD1 inhibited Smad1/5/8 phosphorylation and exacerbated RGC damage. The expression of Glial fibrillary acidic protein (GFAP) was decreased significantly in beads + AAV-BMP4 group. CONCLUSIONS: BMP4 promoted RGC survival and visual function in an experimental glaucoma model. Activation of CHRDL1 exaggerated RGC degeneration by inhibiting the BMP4/Smad1/5/8 pathway. The mechanism of BMP4/Smad1/5/8 pathway may be related to the inhibition of glial cell activation. Our studies suggested that BMP4 and CHRLD1 might serve as therapeutic targets in glaucoma.

The miR-532-3p/Chrdl1 axis regulates the proliferation and migration of amniotic fluid-derived mesenchymal stromal cells.

BACKGROUND: Amniotic fluid-derived mesenchymal stromal cells (AFMSCs) are promising stem cells for regeneration medicine. However, AFMSCs isolated at different stages of pregnancy have different biological characteristics, and the therapeutic effects can differ in vivo and in vitro. The mechanisms underlying these differences have not been defined. METHODS: Bioinformatics analysis of the AFMSC transcriptome identified Chrdl1 as one of the differentially expressed genes. We evaluated the effects of Chrdl1 overexpression or knockdown on the proliferation and migration of AFMSCs. Target prediction was performed using miRanda software to identify the upstream microRNA of Chrdl1. The interaction between Chrdl1 mRNA and its upstream microRNA was evaluated using a dual-luciferase reporter gene assay. RESULTS: Chrdl1 was expressed at lower levels in AFMSCs derived from the early stages of pregnancy. It could suppress AFMSC proliferation and migration. miR-532-3p promoted AFMSC proliferation and migration by targeting the 3' UTR of Chrdl1 and downregulating its expression.

Autopodial development is selectively impaired by misexpression of chordin-like 1 in the chick limb.

Chordin-like 1 (CHRDL1) is a secreted bone morphogenetic protein (BMP) antagonist expressed in mesenchymal tissues whose function in development of the skeleton has not been examined in detail. Here we show Chrdl1 is dynamically expressed in the early distal limb bud mesenchyme, with expression becoming downregulated as development proceeds. Chrdl1 expression is largely excluded from the critical signaling center of the posterior limb bud, the Zone of Polarizing Activity (ZPA), as has been described for the BMP antagonist Gremlin (GREM1) (Scherz et al., 2004, Science, 305, 396-399). Unlike Grem1, Chrdl1 is expressed in the hindlimb by a small subset of ZPA cells and their descendants suggesting divergent regulation and function between the various BMP antagonists. Ectopic expression of Chrdl1 throughout the avian limb bud using viral misexpression resulted in an oligodactyly phenotype with loss of digits from the anterior limb, although the development of more proximal elements of the zeugopod and stylopod were unaffected. Overgrowths of soft tissue and syndactyly were also observed, resulting from impaired apoptosis and failure of the anterior mesenchyme to undergo SOX9-dependent chondrogenesis, instead persisting as an interdigital-like soft tissue phenotype. Sonic hedgehog (SHH) and fibroblast growth factor (FGF) signaling were upregulated and persisted later in development, however these changes were only detected late in limb development at timepoints when endogenous Grem1 would normally be downregulated and increasing BMP signaling would cause termination of Shh and Fgf expression. Our results suggest that the early stages of the GREM1-SHH-FGF signaling network are resistant to Chrdl1-overexpression, leading to normal formation of proximal limb structures, but that later Bmp expression, impaired by ectopic CHRDL1, is essential for formation of the correct complement of digits.

Identification of an Exosome-relevant SNHG6-hsa-miR-429- CHRDL1/CCNA2 Axis for Lung Adenocarcinoma Prognosis Evaluation.

AIM: To explore an exosome-relevant molecular classification in lung adenocarcinoma (LUAD). BACKGROUND: Exosome genes or relevant non-coding RNAs are regulators of cancer treatment and prognosis, but their function in LUAD has not yet been determined. OBJECTIVE: Unraveling a molecular classification applying exosome-related RNA networks for LUAD prognosis evaluation. METHODS: MicroRNA sequencing data (miRNAs-seq) and RNA sequencing data (RNA- seq) were derived from The Cancer Genome Atlas (TCGA). The ConsensusCluster- Plus package was used for molecular typing in LUAD based on 121 Exosome-related genes. Then, a limma package was conducted to explore differentially expressed mRNAs (DEmRNAs), differentially expressed miRNAs (DEmiRNAs) and differentially expressed lncRNAs (DElncRNAs) in molecular typing for constructing an Exosome-driven competing endogenous RNA network (ceRNA). Dominant miRNAs, as well as target mRNAs, were identified by COX modeling and Kaplan-Meier survival analysis. RESULTS: Two Exosome-associated molecular clusters classified in LUAD. The C2 cluster favored high clinicopathology and showed a trend toward poor prognosis. 29 lncRNA- miRNA and 12 miRNA-mRNA interaction pairs were identified. The hsa-miR-429 was the pivotal miRNA in the network that affected the prognosis of LUAD. According to the interaction relationship and LUAD prognostic role, SNHG6-hsa- miR-429-CHRDL1/CCNA2 was identified. SNHG6-hsa-miR-429-CHRDL1 exerts oncogenic effects, and SNHG6-hsa-miR-429- CCNA2 exerts pro-oncogenic effects. CONCLUSION: Overall, our study identified an Exosome-driven ceRNA network in LUAD, and the SNHG6-hsa-miR-429-CHRDL1/CCNA2 axis could be a new therapeutic target for LUAD and our study provides new insights into the molecular mechanisms of LUAD.

Mechanisms of Regulation of the CHRDL1 Gene by the TWIST2 and ADD1/SREBP1c Transcription Factors.

Setleis syndrome (SS) is a rare focal facial dermal dysplasia caused by recessive mutations in the basic helix-loop-helix (bHLH) transcription factor, TWIST2. Expression microarray analysis showed that the chordin-like 1 (CHRDL1) gene is up-regulated in dermal fibroblasts from three SS patients with the Q119X TWIST2 mutation. METHODS: Putative TWIST binding sites were found in the upstream region of the CHRDL1 gene and examined by electrophoretic mobility shift (EMSA) and reporter gene assays. RESULTS: EMSAs showed specific binding of TWIST1 and TWIST2 homodimers, as well as heterodimers with E12, to the more distal E-boxes. An adjoining E-box was bound by ADD1/SREBP1c. EMSA analysis suggested that TWIST2 and ADD1/SREBP1c could compete for binding. Luciferase (luc) reporter assays revealed that the CHRDL1 gene upstream region drives its expression and ADD1/SREBP1c increased it 2.6 times over basal levels. TWIST2, but not the TWIST2-Q119X mutant, blocked activation by ADD1/SREBP1c, but overexpression of TWIST2-Q119X increased luc gene expression. In addition, EMSA competition assays showed that TWIST2, but not TWIST1, competes with ADD1/SREBP1c for DNA binding to the same site. CONCLUSIONS: Formation of an inactive complex between the TWIST2 Q119X and Q65X mutant proteins and ADD1/SREBP1c may prevent repressor binding and allow the binding of other regulators to activate CHRDL1 gene expression.

Chordin-like 1, a Novel Adipokine, Markedly Promotes Adipogenesis and Lipid Accumulation.

White adipose tissue serves as a metabolically dynamic organ that can synthesize and secrete biologically active compounds such as adipokines as well as a caloric reservoir for maintaining energy homeostasis. Adipokines are involved in diverse biological and physiological processes and there have been extensive attempts to characterize the effects of over two dozen adipokines. However, many of these adipokines are produced by not only adipose tissue, but also other tissues. Therefore, investigations into the effects of adipokines on physiological functions have been challenged. In this regard, we aimed to identify a new secreted protein that is encoded by genes specifically expressed in white adipose tissue through analysis of multi-tissue transcriptome and protein expression. As a result, we report a novel adipokine that is encoded by the adipose-specific gene, chordin-like 1 (Chrdl1), which is specifically expressed in white adipose tissue in mice; this expression pattern was conserved in the human orthologous CHRDL1 gene. The expression of Chrdl1 was enriched in fat cells and developmentally regulated in vitro and in vivo, and moreover, its retrovirus-mediated overexpression and recombinant protein treatment led to markedly increased adipogenesis. Further pathway enrichment analysis revealed enriched pathways related to lipogenesis and adipogenic signaling. Our findings support a pro-adipogenic role of CHRDL1 as a new adipokine and pave the way toward animal studies and future research on its clinical implications and development of anti-obesity therapy.

Novel CHRDL1 mutation causing X-linked megalocornea in a family with mild anterior segment manifestations in carrier females.

PURPOSE: X-linked megalocornea (XMC) is a rare anterior segment malformation characterized by a nonprogressive enlargement of the cornea to 13 mm or greater in the setting of normal intraocular pressure. XMC is caused by mutations in the CHRDL1 gene and it is inherited as an X-linked recessive trait affecting only males. Here, we describe the results of phenotypic and genetic assessment in a novel XMC pedigree. METHODS: Three subjects (a father and his two daughters) underwent a complete clinical and imaging ocular examination including biomicroscopy, fundoscopy, tonometry, visual acuity, Pentacam Scheimpflug imaging, anterior segment Swept Source OCT, and ultrabiomicroscopy. Genetic analysis was performed through whole exome sequencing in 3 family members. Candidate variants were validated by sanger sequencing. RESULTS: The affected father exhibited megalocornea, very deep anterior chambers, retrocorneal pigmentation, iris atrophy, queer iris configuration, extremely open iridocorneal angles, and cataracts. Notably, both daughters showed queer iris configuration and abnormally widely open iridocorneal angles in both eyes. Genetic analysis identified a novel hemizygous c.207+1G>A splicing variant in CHRDL1 in the affected father. Both mildly affected daughters were heterozygous for the pathogenic variant. CONCLUSIONS: Here, we report an additional XMC family due to a novel mutation in the CHRDL1 gene. Mild anterior segment anomalies were observed in two heterozygous carriers demonstrating for the first time a CHRDL1-linked phenotype in females. A detailed comparison of the clinical and genetic features of this pedigree with those observed in previously published XMC cases is also presented.

Chordin-like 1 is a novel prognostic biomarker and correlative with immune cell infiltration in lung adenocarcinoma.

Chordin-like 1 (CHRDL1), an inhibitor of bone morphogenetic proteins(BMPs), has been recently reported to participate in the progression of numerous tumors, however, its role in lung adenocarcinoma (LUAD) remains unclear. Our study aimed to demonstrate relationship between CHRDL1 and LUAD based on data from The Cancer Genome Atlas (TCGA). Among them, CHRDL1 expression revealed promising power for distinguishing LUAD tissues form normal sample. Low CHRDL1 was correlated with poor clinicopathologic features, including high T stage (OR=0.45, P<0.001), high N stage (OR=0.57, P<0.003), bad treatment effect (OR=0.64, P=0.047), positive tumor status (OR=0.63, P=0.018), and TP53 mutation (OR=0.49, P<0.001). The survival curve illustrated that low CHRDL1 was significantly correlative with a poor overall survival (HR=0.60, P<0.001). At multivariate Cox regression analysis, CHRDL1 remained independently correlative with overall survival. GSEA identified that the CHRDL1 expression was related to cell cycle and immunoregulation. Immune infiltration analysis suggested that CHRDL1 was significantly correlative with 7 kinds of immune cells. Immunohistochemical validation showed that CHRDL1 was abnormally elevated and negatively correlated with Th2 cells in LUAD tissues. In conclusion, CHRDL1 might become a novel prognostic biomarker and therapy target in LUAD. Moreover, CHRDL1 may improve the effectiveness of immunotherapy by regulating immune infiltration.

CHRDL1 Regulates Stemness in Glioma Stem-like Cells.

Glioblastoma (GBM) still presents as one of the most aggressive tumours in the brain, which despite enormous research efforts, remains incurable today. As many theories evolve around the persistent recurrence of this malignancy, the assumption of a small population of cells with a stem-like phenotype remains a key driver of its infiltrative nature. In this article, we research Chordin-like 1 (CHRDL1), a secreted protein, as a potential key regulator of the glioma stem-like cell (GSC) phenotype. It has been shown that CHRDL1 antagonizes the function of bone morphogenic protein 4 (BMP4), which induces GSC differentiation and, hence, reduces tumorigenicity. We, therefore, employed two previously described GSCs spheroid cultures and depleted them of CHRDL1 using the stable transduction of a CHRDL1-targeting shRNA. We show with in vitro cell-based assays (MTT, limiting dilution, and sphere formation assays), Western blots, irradiation procedures, and quantitative real-time PCR that the depletion of the secreted BMP4 antagonist CHRDL1 prominently decreases functional and molecular stemness traits resulting in enhanced radiation sensitivity. As a result, we postulate CHRDL1 as an enforcer of stemness in GSCs and find additional evidence that high CHRDL1 expression might also serve as a marker protein to determine BMP4 susceptibility.

Novel disease-causing variants and phenotypic features of X-linked megalocornea.

PURPOSE: The aim of the study was to describe the phenotype and molecular genetic causes of X-linked megalocornea (MGC1). We recruited four British, one New Zealand, one Vietnamese and four Czech families. METHODS: All probands and three female carriers underwent ocular examination and Sanger sequencing of the CHRDL1 gene. Two of the probands also had magnetic resonance imaging (MRI) of the brain. RESULTS: We identified nine pathogenic or likely pathogenic and one variant of uncertain significance in CHRDL1, of which eight are novel. Three probands had ocular findings that have not previously been associated with MGC1, namely pigmentary glaucoma, unilateral posterior corneal vesicles, unilateral keratoconus and unilateral Fuchs heterochromic iridocyclitis. The corneal diameters of the three heterozygous carriers were normal, but two had abnormally thin corneas, and one of these was also diagnosed with unilateral keratoconus. Brain MRI identified arachnoid cysts in both probands, one also had a neuroepithelial cyst, while the second had a midsagittal neurodevelopmental abnormality (cavum septum pellucidum et vergae). CONCLUSION: The study expands the spectrum of pathogenic variants and the ocular and brain abnormalities that have been identified in individuals with MGC1. Reduced corneal thickness may represent a mild phenotypic feature in some heterozygous female carriers of CHRDL1 pathogenic variants.

RUNX2 Regulates Osteoblast Differentiation via the BMP4 Signaling Pathway.

RUNX2 is a master osteogenic transcription factor, and mutations in RUNX2 cause the inherited skeletal disorder cleidocranial dysplasia (CCD). Studies have revealed that RUNX2 is not only a downstream target of the bone morphogenetic protein (BMP) pathway but can also regulate the expression of BMPs. However, the underlying mechanism of the regulation of BMPs by RUNX2 remains unknown. In this project, we diagnosed a CCD patient with a 7.86-Mb heterozygous deletion on chromosome 6 containing all exons of RUNX2 by multiplex ligation-dependent probe amplification (MLPA) and whole-genome sequencing (WGS). Bone marrow mesenchymal stem cells (BMSCs) were further extracted from patient alveolar bone fragments (CCD-BMSCs), an excellent natural model to explore the possible mechanism. The osteogenic differentiation ability of CCD-BMSCs was severely affected by RUNX2 heterozygous deletion. Also, BMP4 decreased most in BMP ligands, and CHRDL1, a BMP antagonist, was abnormally elevated in CCD-BMSCs. Furthermore, BMP4 treatment essentially rescued the osteogenic capacity of CCD-BMSCs, and RUNX2 overexpression reversed the abnormal expression of BMP4 and CHRDL1. Notably, we constructed CRISPR/Cas9 Runx2+/m MC3T3-E1 cells, which simulated a variant in CCD-BMSCs, to exclude the interference of other gene deletions and the heterogeneity of the genetic background of primary cells, and verified all findings from the CCD-BMSCs. Moreover, the luciferase reporter experiment showed that RUNX2 could inhibit the transcription of CHRDL1. Through immunofluorescence, the inhibitory effect of CHRDL1 on BMP4/Smad signaling was confirmed in MC3T3-E1 cells. These results revealed that RUNX2 regulated the BMP4 pathway by inhibiting CHRDL1 transcription. We collectively identified a novel RUNX2/CHRDL1/BMP4 axis to regulate osteogenic differentiation and noted that BMP4 might be a valuable therapeutic option for treating bone diseases.

Bioinformatics analysis of the molecular mechanism of obesity in polycystic ovary syndrome.

BACKGROUND: Obesity is an important part of polycystic ovary syndrome (PCOS) pathologies. The present study utilized the bioinformatics method to identify the molecular mechanism of obesity status in PCOS. METHODS: Six transcriptome profiles of adipose tissue were obtained from online databases. The background correction and normalization were performed, and the DEGs were detected with the settings p < 0.05. The GO, KEGG pathway enrichment, and PPI network analysis were performed with the detected DEGs. RESULTS: A total of 37 DGEs were found between obesity PCOS and healthy controls, and 8 of them were tested significant in the third database. The expression patterns of the 8 detected DGEs were then measured in another two datasets based on lean/obesity PCOS patients and healthy controls. The gene CHRDL1 was found to be in linear regression with the BMI index in PCOS patients (p = 0.0358), but such a difference was not found in healthy controls (p = 0.2487). The expression of CHRDL1 was significantly higher in obesity PCOS cases than the BMI matched healthy controls (p = 0.0415). Further enrichment research demonstrated the CHRDL1 might function as an inhibitor of the BMP4 or IGF1 signalling. CONCLUSION: In summary, the present study identified CHRDL1 as a candidate gene responsible for the obesity of PCOS patients.

Lycium barbarum polysaccharide (LBP) inhibits palmitic acid (PA)-induced MC3T3-E1 cell apoptosis by regulating miR-200b-3p/Chrdl1/PPARγ.

BACKGROUND: Obesity is closely related to osteoporosis. Lycium barbarum polysaccharides (LBPs) have anti-osteoporosis activity. OBJECTIVE: This study aimed to explore the role of LBPs in palmitic acid (PA)-induced osteoblast apoptosis. METHODS: The microarray data set GSE37676 was downloaded from Gene Expression Ominibus (GEO) database. Top 300 differentially expressed genes (DEGs) were used to construct a protein-protein interaction (PPI) network based on STRING database, and significant modules were analyzed and their key genes were screened by using Cytoscape software. COEXPEDIA database showed that there was co-expression between Chrdl1 and peroxisome proliferator-activated receptor (PPARγ). MC3T3-E1 cells were treated with 100-500 µg/mL of PA. Reverse transcription polymerase chain reaction (RT-PCR) and western blot assays were used to detect mRNA and protein levels. Cell Counting Kit-8 (CCK-8) assay and flow cytometry were used to detect cell viability and cell apoptosis. RESULTS: Chrdl1 was the key gene from the most significant module and downregulation in MC3T3-E1 cells treated with PA. MicroRNA miR-200b-3p and PPARγ were significantly upregulated among PA-treated MC3T3-E1 cells. The results of luciferase reporter gene assay showed that miR-200b-3p targeted Chrdl1 3'-UTR. Over-expressing miR-200b-3p promoted PA-induced cell apoptosis and inhibited cell viability. After pre-treating cells with PA and LBP, MC3T3-E1 cell apoptosis rate was relatively lower than that of mimics+PA200 group. Chrdl1 inhibition partly reversed miR-200b-3p effect on inhibiting apoptosis among MC3T3-E1 cells pre-treated with LBP and PA. Decreased C CASP3, PPARγ and increased Chrdl1 by miR-200b-3p inhibition were partly reversed by Chrdl1 inhibition. CONCLUSIONS: LBPs inhibit PA-induced MC3T3-E1 cell apoptosis by mainly decreasing miR-200b-3p to upregulate Chrdl1, but miR-200b-3p/Chrdl1/PPARγ is not the only mechanism for LBPs protecting osteoblasts from PA.

Chordin-Like 1 Improves Osteogenesis of Bone Marrow Mesenchymal Stem Cells Through Enhancing BMP4-SMAD Pathway.

Chordin-like 1 (CHRDL1) is a secreted glycoprotein with repeated cysteine-rich domains, which can bind to BMPs family ligands. Although it has been reported to play important roles in several systems, the exact roles of CHRDL1 on human bone mesenchymal stem cells (hBMSCs) osteogenesis remain to be explored. The present study aimed to investigate the roles of CHRDL1 on the osteogenic differentiation of hBMSCs and the underlying molecular mechanisms. We found that CHRDL1 was upregulated during hBMSCs osteogenesis, and rhBMP-4 administration could enhance CHRDL1 mRNA expression in a dose and time dependent manner. Knockdown of CHRDL1 did not affect hBMSCs proliferation, but inhibited the BMP-4-dependent osteogenic differentiation, showing decreased mRNA expression levels of osteogenic markers and reduced mineralization. On the contrary, overexpression of CHRDL1 enhanced BMP-4 induced osteogenic differentiation of hBMSCs. Moreover, in vivo experiments by transplanting CHRDL1 gene modified hBMSCs into nude mice defective femur models displayed higher new bone formation in CHRDL1 overexpression groups, but lower new bone formation in CHRDL1 knockdown groups, compared with control groups. In consistent with the bone formation rate, there were increased CHRDL1 protein expression in new bone formation regions of defective femur in CHRDL1 overexpression groups, while reduced CHRDL1 protein expression in CHRDL1 knockdown groups compared with control groups. These indicate that CHRDL1 can promote osteoblast differentiation in vivo. Furthermore, the mechanisms study showed that CHRDL1 improved BMP-4 induced phosphorylation of SMAD1/5/9 during osteogenic differentiation of hBMSCs. Besides, promotion of osteogenic differentiation and the activation of SMAD phosphorylation by CHRDL1 can be blocked by BMP receptor type I inhibitor LDN-193189. In conclusion, our results suggested that CHRDL1 can promote hBMSCs osteogenic differentiation through enhancing the activation of BMP-4-SMAD1/5/9 pathway.

Expression of microRNA-514a-5p and its biological function in experimental pulmonary thromboembolism.

It is difficult to diagnose pulmonary thromboembolism (PTE) in clinical practice. While microRNAs (miRNAs) have been widely investigated as biomarkers for various diseases, their value as biomarkers for PTE remains largely unknown. In the present study, 83 miRNAs showed altered expression in an intermediate-risk PTE group when compared with their expression in a low-risk PTE group as detected by miRNA microarray analysis. After reviewing those data, hsa-miR-514a-5p was selected as a potential biomarker for PTE progression. Disordered myocardial fibroblast arrangements, broadened intercellular spaces, diapedesis of erythrocytes, and lower numbers of nuclei in the right ventricular wall were observed in rats in a PTE model group when compared to rats in a normal saline (NS) group. Furthermore, hyperexpression of miR-514a-5p exacerbated the morphological characteristics of lung and right ventricular tissues, and caused increased RVHI and lung index values, as well as increased BNP and NT-pro-BNP levels in the PTE model rats, possibly by downregulating Chordin-like 1 (CHRDL1) expression. These results suggest that MiR-514a-5p helps to exasperate PTE development by promoting several aspects of PTE pathology, including inflammation, lung injury, and right ventricular hypertrophy by targeting CHRDL1.

Hypermethylation of the CHRDL1 promoter induces proliferation and metastasis by activating Akt and Erk in gastric cancer.

CHRDL1 (Chordin-like 1) is a secreted protein that acts as an antagonist of bone morphogenetic protein (BMP). BMP plays a role as an activator of BMP receptor II (BMPR II), which mediates extracellular to intracellular signal transmission and is involved in carcinogenesis and metastasis. Herein, we report that CHRDL1 expression was significantly down-regulated in gastric cancer tissues and associated with poor survival. Clinic-pathological parameters demonstrated a close relationship between low CHRDL1 expression and metastasis. In vitro, CHRDL1 knockdown promoted tumor cell proliferation and migration through BMPR II by activating Akt, Erk and ß-catenin. Furthermore, we observed the hypermethylation of the CHRDL1 promoter in gastric cancer, which induced low expression of CHRDL1 and decreased its secretion to the supernatant. Finally, in vivo experiments confirmed that CHRDL1 acted as a tumor suppressor gene in suppressing tumor growth and metastasis.

X-linked Megalocornea Associated with the Novel CHRDL1 Gene Mutation p.(Pro56Leu*8).

BACKGROUND: The genetic basis of X-linked megalocornea (MGC1) was reported in 2012 to be caused by mutations in the CHRDL1 gene. We sought to confirm that mutations in CHRDL1 are associated with MGC1 in a previously unreported pedigree. MATERIALS AND METHODS: Slit lamp examination, corneal pachymetry, corneal topography and DNA collection for screening of the CHRDL1 gene were performed for members of an affected family. RESULTS: Examination of a woman and her four sons, ranging in age between 3 and 15 years, demonstrated horizontal corneal diameters of 14 mm in three of the four sons and a normal corneal diameter of 12 mm in the mother and other son. Central corneal thickness in the individuals with enlarged corneal diameters averaged 474 microns, compared to 604 microns in their unaffected brother. Corneal topographic imaging demonstrated an average K value of 44.4 D in the affected individuals compared with 41.6 D in their unaffected sibling. Screening of the CHRDL1 gene demonstrated the novel hemizygous frameshift mutation c.167delC (p.(Pro56Leu*8)) in exon 3 in the affected individuals and in the heterozygous state in their mother. This mutation was not present in the unaffected brother or in unrelated controls. CONCLUSION: We provide the initial confirmation that X-linked megalocornea is associated with mutations in the CHRDL1 gene.