Coiled-coil Domain-containing Research Articles

CCDC113 stabilizes sperm axoneme and head-tail coupling apparatus to ensure male fertility.

The structural integrity of the sperm is crucial for male fertility, defects in sperm head-tail linkage and flagellar axoneme are associated with acephalic spermatozoa syndrome (ASS) and the multiple morphological abnormalities of the sperm flagella (MMAF). Notably, impaired head-tail coupling apparatus (HTCA) often accompanies defects in the flagellum structure, however, the molecular mechanisms underlying this phenomenon remain elusive. Here, we identified an evolutionarily conserved coiled-coil domain-containing (CCDC) protein, CCDC113, and found the disruption of CCDC113 produced spermatozoa with disorganized sperm flagella and HTCA, which caused male infertility. Further analysis revealed that CCDC113 could bind to CFAP57 and CFAP91, and function as an adaptor protein for the connection of radial spokes, nexin-dynein regulatory complex (N-DRC), and doublet microtubules (DMTs) in the sperm axoneme. Moreover, CCDC113 was identified as a structural component of HTCA, collaborating with SUN5 and CENTLEIN to connect sperm head to tail during spermiogenesis. Together, our studies reveal that CCDC113 serve as a critical hub for sperm axoneme and HTCA stabilization in mice, providing insights into the potential pathogenesis of infertility associated with human CCDC113 mutations.

Ablation of CCDC8 provides cardioprotection against cardiomyocyte apoptosis via TNF signaling pathway in myocardial ischemia reperfusion injury

Myocardial ischemia-reperfusion (I/R) injury induces significant apoptosis and reactive oxygen species (ROS) accumulation in cardiomyocytes. Coiled-coil domain-containing 8 (CCDC8), recently identified as an interacting protein of p53, acts as a cofactor in p53-mediated apoptosis. However, its role in myocardial I/R injury remains unclear. We first assessed CCDC8 levels in patients with left ventricular failure (LVF) and in both in vivo and in vitro models of myocardial I/R injury. Next, we used adenovirus 9 (AAV9) to overexpress CCDC8 and small interfering RNA (siRNA) to investigate the role of CCDC8 in myocardial I/R injury. mRNA sequencing and KEGG pathway analysis were performed to identify CCDC8-regulated genes. In vitro experiments were conducted to examine the effects of CCDC8 silencing on TNF-α-induced apoptosis. CCDC8 expression was elevated in the left ventricle of LVF patients and in the cardiomyocytes of mice subjected to myocardial I/R injury. Overexpression of CCDC8 in cardiomyocytes via AAV9 exacerbated cardiac dysfunction caused by myocardial I/R injury, while silencing CCDC8 suppressed apoptosis and ROS production in H9c2 cells under hypoxia-reoxygenation (H/R) conditions. mRNA sequencing and KEGG analysis indicated that CCDC8 regulates genes related to cardiac contractility and the TNF signaling pathway. Additionally, CCDC8 silencing reversed TNF-α-induced cardiomyocyte apoptosis in vitro. This study identifies CCDC8 as a key mediator of cardiomyocyte apoptosis via the TNF signaling pathway in myocardial I/R injury. These findings suggest that targeting CCDC8 could be a potential therapeutic strategy for mitigating cardiac dysfunction in myocardial I/R injury.

Structural organization of the retriever-CCC endosomal recycling complex.

The recycling of membrane proteins from endosomes to the cell surface is vital for cell signaling and survival. Retriever, a trimeric complex of vacuolar protein-sorting-associated protein (VPS)35L, VPS26C and VPS29, together with the CCC complex comprising coiled-coil domain-containing (CCDC)22, CCDC93 and copper metabolism domain-containing (COMMD) proteins, plays a crucial role in this process. The precise mechanisms underlying retriever assembly and its interaction with CCC have remained elusive. Here, we present a high-resolution structure of retriever in humans determined using cryogenic electron microscopy. The structure reveals a unique assembly mechanism, distinguishing it from its remotely related paralog retromer. By combining AlphaFold predictions and biochemical, cellular and proteomic analyses, we further elucidate the structural organization of the entire retriever-CCC complex across evolution and uncover how cancer-associated mutations in humans disrupt complex formation and impair membrane protein homeostasis. These findings provide a fundamental framework for understanding the biological and pathological implications associated with retriever-CCC-mediated endosomal recycling.

Identification of potential prognostic biomarkers among gene models for coiled-coil domain-containing family members in hepatocellular carcinoma elucidates their influence on the hypoxia pathway and immune microenvironment.

The family of coiled-coil domain-containing (CCDC) proteins participates in a wide range of physiological functions and plays a pivotal role in governing the invasion and metastasis of malignant tumor cells. Nonetheless, the precise mechanism governing the interaction among the immune microenvironment, hypoxia pathway, and proliferation in hepatocellular carcinoma (HCC) remains elusive. In this study, our objective was to identify the prognostic significance of CCDC family genes in HCC. We conducted an analysis of RNA-seq data from HCC patients sourced from The Cancer Genome Atlas (TCGA) database. Our analysis involved comparing the expression profiles of 168 CCDC family genes between tumor and normal tissues to identify differentially expressed genes (DEGs). The prognostic value of these genes was verified using overall survival (OS) data from TCGA-LIHC patients, employing Univariate and multivariate Cox proportional hazards regression models and Kaplan-Meier plots. Subsequently, we constructed a prognostic signature known as the CCDC score and validated it using additional datasets (ICGC-LIRI-JP and GSE14520). Additionally, we performed functional enrichment analysis and conducted an assessment of the tumor immune microenvironment (TIME). We identified 34 DEGs of the CCDC family. Among them, six DEGs (CCDC6/22/51/59/132/134) were upregulated and associated with poor prognosis. Higher CCDC score was an independent predictor of poor OS in TCGA-HCC patients (P<0.001, HR =2.37), which was validated in the ICGC-LIRI-JP (P=0.021, HR =2.15) and GSE14520 (P=0.002, HR =2.23) datasets. Functional enrichment analysis showed that hypoxia pathway genes were enriched in the high CCDC score group. Furthermore, immune microenvironment analysis demonstrated that high CCDC score was associated with a suppressed TIME caused by the extrinsic immune escape. The CCDC score, derived from six CCDC genes, exhibits remarkable expression levels in liver cancer and holds promise as an independent prognostic indicator. Our bioinformatics analysis revealed a high CCDC score is strongly associated with activation of the hypoxia pathway and an immunosuppressive tumor microenvironment in HCC. This profound finding may serve as a cornerstone for innovative targeted drug therapies and pave the way for further investigations into the underlying mechanisms of CCDC-related carcinogenesis in liver cancer.

CCDC167 promotes hepatocellular carcinoma cell proliferation and is associated with the immune microenvironment of hepatocellular carcinoma

CCDC167 promotes hepatocellular carcinoma cell proliferation and is associated with the immune microenvironment of hepatocellular carcinoma

Coiled-coil domain-containing 154 promotes colorectal cancer proliferation and metastasis via interacting with minichromosome maintenance complex component 2

Coiled-Coil Domain-Containing (CCDC) is a large class of structural proteins containing left-handed supercoiled structure. The clinical value and the functional implication of CCDC in colorectal cancer (CRC) remain unknown. Based on the genetic, transcriptional, and clinical data from The Cancer Genome Atlas, five of thirty-six CCDC proteins were differentially expressed in the CRC and associated with the survival of patients with CRC. A CCDC-score model was established to evaluate the prognosis of patients. The potential function of Coiled-Coil Domain-Containing 154 (CCDC154) was investigated using bioinformatical methods, which unveiled that high expression of CCDC154 indicates poor survival for patients with CRC and correlates with low infiltration of CD8+ T cells and high infiltration of neutrophils, indicating that CCDC154 enhances tumor growth and metastasis. CCDC154 interacts with Minichromosome Maintenance Complex Component 2 (MCM2) protein and promotes malignant phenotype via MCM2. We validated the expression level and survival prediction value of CCDC154 in clinical samples, and analyzed its co-expression of MCM2, Ki-67 and p53. This work discloses the role of CCDC in clinical setting and CCDC154 functions in CRC.

CircRNA Coiled-Coil Domain Containing 66 Up-Regulates LIM-Homeodomain Gene 2 to Promote Gastric Cancer Progression via Sponing miR-129-5p

The death rate from gastric cancer (GC) is increasing while the methods of early diagnosis and treatment of GC are still limited. CircRNAs have ability to bind with miRNA to exert therapeutic action on kinds of cancers. The purpose of this study was to explore the action mechanism of circ-CCDC66 in GC. CCDC66, miR-129-5p and LHX2 mRNA and protein expression were examine by qRT-PCR and Western blot. Flow cytometry and Western blot were used to identify cells apoptosis. Dual-luciferase reporter assay was applied to verified the binding site that miR-129-5p and CCDC66 or LHX2. Transwell assay and cell account kit 8 (CCK-8) were used to examined cells proliferation ability, migration or invasion ability. Compared with normal tissues, CCDC66 expression was obviously higher and miR-129-5p expression was significantly lower in GC tissues. Knockdown circ-CCDC66 changed malignant behavior of GC cells. MiR-129-5p inhibitor changed the effect of down-regulated circ-CCDC66 on malignant behavior of gastric cancer cells. LHX2 was bond with miR-129-5p, and circ-CCDC66 regulated LHX2 expression to participated in GC progression via miR-129-5p. All the findings suggested that CCDC66 could adjust LHX2 expression to promote GC progression through restraining miR-129-5p, which may provide a key strategy for GC therapy.

Analysis on EZH2: mechanism identification of related CeRNA and its immunoassay in hepatocellular carcinoma

ObjectiveTo screen the possible potential signaling pathways related to enhancer of zeste homolog 2 (EZH2) based on ceRNA mechanism, and to analyze the correlation between E2H2 and depths of various immune cell infiltration depths. The relationship between different immune checkpoints were also analyzed.MethodsFirst, the expression of EZH2 in pan-cancer (18 malignancies) was analyzed with the TCGA database. Hepatocellular carcinoma (HCC) tissues of 374 cases and normal tissues of 50 cases were analyzed in terms of the differential expression, overall survival (OS) and progression-free-survival (PFS). Then, we conducted GO and KEGG enrichment analysis on target gene. We also analyzed mRNA-miRNA and MicroRNA (miRNA)- long non-coding RNA (lncRNA) correlation with starbase databse, so as to determine the potential ceRNA mechanism associated with EZH2. Finally, immunoassay and drug-sensitivity analysis of EZH2 was performed.ResultsSeven potential EZH2-related ceRNA pathways were screened out, namely lncRNA: Small Nucleolar RNA Host Gene 1 (SNHG1), SNHG 3, and SNHG 6-miR-101-3p-EZH2; and lncRNA: Long Intergenic Non-Protein Coding RNA 1978 (LINC01978), SNHG12, Ring Finger Protein 216 Pseudogene 1 (RNF216P1), and Coiled-coil Domain Containing 18 Antisense RNA 1 (CCDC18-AS1)-let-7c-5p—EZH2. Finally, 4 potential EZH2-related ceRNA pathways were identified through qPCR.According to immune correlation analysis, EZH2 may be positively correlated with T cells follicular helper, T cells Cluster of differentiation (CD)4 memory activated, Macrophages M0, and B cells memory (P < 0.05, cof > 0.2); while be negatively correlated with T cells CD4 + memory resting (P < 0.05, cof < -0.2). And EZH2 is positively correlated with Programmed Cell Death 1 (PDCD1) (R = 0.22), CD274 (R = 0.3) and Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4) (R = 0.23). According to drug sensitivity analysis, patients in the high expression group were more susceptible to the effects of various drugs including Sorafenib, 5-Fluorouracil, Doxorubicin, Etoposide, Paclitaxel, and Vinorelbine than those with low expression.ConclusionThis study revealed seven potential pathways of Enhancer of Zeste Homolog 2 (EZH2)-related ceRNA mechanisms: lncRNA (SNHG3, 6) -Mir-101-3P-ezh2; lncRNA (SNHG12, RNF216P1)-let-7c-5p—EZH2. We also analyzed the immunity and drug sensitivity of EZH2. Our study proves that EZH2 still has great research prospects in HCC.

A novel coiled-coil domain containing-related gene signature for predicting prognosis and treatment effect of breast cancer.

Breast cancer (BRCA) is a prevalent tumor worldwide. The association between the coiled-coil domain-containing (CCDC) protein family and different tumors has been established. However, the prognostic significance of this protein family in breast cancer remains uncertain. Gene expression and clinical data were obtained from the TCGA, METABRIC, and GEO databases. Prognosis genes were identified using univariate Cox and LASSO Cox regression, leading to the establishment of a prognostic signature. Subsequently, the risk model was conducted based on survival and clinical feature analyses, and a nomogram for prognosis prediction was developed. Furthermore, analyses of biological function, immune characteristics, and drug sensitivity were performed. Finally, single-cell sequencing data were utilized to uncover the expression patterns of genes in the risk model. Five genes were identified and utilized for risk modeling. The model demonstrated excellent prognostic value as indicated by ROC and Kaplan-Meier analysis. The high-risk group exhibited shorter survival time and higher likelihood of recurrence. Functional annotation indicated a correlation between the risk score and immune pathways. Conversely, the low-risk group displayed a greater enrichment in immune pathways and exhibited more active immune microenvironment characteristics. Additionally, drug sensitivity analysis using both public and our sequencing data revealed that the risk model possessed a broad range of predictive values. We have developed a gene signature and have verified that patients with low-risk are more likely to have better prognosis and respond positively to therapy. This finding offers a valuable point of reference for BRCA individualized treatment.

Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome

The Commander complex is required for endosomal recycling of diverse transmembrane cargos and is mutated in Ritscher-Schinzel syndrome. It comprises two sub-assemblies: Retriever composed of VPS35L, VPS26C, and VPS29; and the CCC complex which contains twelve subunits: COMMD1-COMMD10 and the coiled-coil domain-containing (CCDC) proteins CCDC22 and CCDC93. Combining X-ray crystallography, electron cryomicroscopy, and in silico predictions, we have assembled a complete structural model of Commander. Retriever is distantly related to the endosomal Retromer complex but has unique features preventing the shared VPS29 subunit from interacting with Retromer-associated factors. The COMMD proteins form a distinctive hetero-decameric ring stabilized by extensive interactions with CCDC22 and CCDC93. These adopt a coiled-coil structure that connects the CCC and Retriever assemblies and recruits a 16th subunit, DENND10, to form the complete Commander complex. The structure allows mapping of disease-causing mutations and reveals the molecular features required for the function of this evolutionarily conserved trafficking machinery.

Control of Mycobacterium avium subsp. paratuberculosis load within infected bovine monocyte-derived macrophages is associated with host genetics.

The genetic loci influencing individual resistance to Mycobacterium avium subsp. paratuberculosis (MAP) infection are still largely unknown. In the current study, we searched for genetic loci associated with resistance to MAP infection by evaluating the performance of monocyte-derived macrophages (MDMs) isolated from the peripheral blood of 75 healthy Holsteins cows and infected ex vivo with MAP. Bacterial load (log colony-forming units, log CFUs) within MDMs was quantified at 2h and 7 days p. i. using a BACTEC MGIT 960 instrument. In addition, the expression levels of some genes with important roles in the innate immune response including epiregulin (EREG), complement component C3 (C3), galectin-9 (Gal9), and nitric oxide (NO-) were measured in the supernatant of the infected cells. DNA from peripheral blood samples of the animals included in the study was isolated and genotyped with the EuroG MD bead Chip (44,779 single nucleotide-polymorphisms, SNPs). Linear mixed models were used to calculate the heritability (h2 ) estimates for each indicator of MDM performance, MAP load within MDMs and EREG, C3, Gal9, and NO-expression. After performing a genome-wide association study, the only phenotypes that showed SNPs with a significant association were the bacterial load within MDMs at 2h (h2 = 0. 87) and 7 days (h2 = 0.83) p.i. A total of 6 SNPs, 5 candidate genes, and one microRNA on the Bos taurus chromosomes BTA2, BTA17, BTA18, and BTA21 were associated with MAP load at 2h p.i. Overlap was seen in two SNPs associated with the log CFUs at 2h and 7d p.i. The identified SNPs had negative regression coefficients, and were, therefore, associated with a low bacterial load within MDMs. Some of the identified SNPs were located within QTLs previously associated with longevity, reproductive, and udder health traits. Some of the identified candidate genes; Oxysterol Binding Protein Like 6, Cysteine and Serine Rich Nuclear Protein 3, and the Coiled-Coil Domain Containing 92 regulate cellular cholesterol trafficking and efflux, apoptosis, and interferon production, respectively. Taken together, our results define a heritable and distinct immunogenetic profile in MAP-infected macrophages designed to limit bacterial load early after infection.

High Level of Serum Coiled-coil Domain Containing 25 (CCDC25) as a Diagnostic Marker for Cholangiocarcinoma But Not for Other Cancers.

Recently, we reported that coiled-coil domain containing 25 (CCDC25) protein is elevated in the sera of patients with cholangiocarcinoma (CCA) and is suggested to be a diagnostic biomarker for CCA. This study aimed to examine whether serum CCDC25 level can be a unique biomarker for CCA. Bioinformatic analyses using Human Protein Atlas (HPA) database and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) indicated that CCDC25 protein and mRNA are expressed not only in CCA but also in other cancers, such as colorectal cancer (CRC), breast cancer (BC), and hepatocellular carcinoma (HCC), all of which are the top 5 cancers highly prevalent in Thailand. Using a quantitative dot blot assay, serum CCDC25 levels were measured for 30 healthy controls (HC), 34 CRC, 42 BC, 43 HCC, and 83 CCA. The serum CCDC25 levels of CCA patients (0.193±0.039 ng/μl) were significantly higher than those of CRC (0.019±0.006 ng/μl), BC (0.036±0.015 ng/μl), HCC (0.035±0.016 ng/μl), and higher than those of HC (0.012±0.003 ng/μl). The serum CCDC25 level can discriminate CCA from the HC, CRC, BC, and HCC with a sensitivity of 100, 99, 94, and 94%, respectively, and specificity of 100, 100, 98, and 95%, respectively. CCDC25 is a candidate diagnostic biomarker for CCA.

Prognostic Significance of CCDC137 Expression and Its Association with Immune Infiltration in Hepatocellular Carcinoma.

Globally, hepatocellular carcinoma (HCC) is one of the most common causes of cancer-associated mortalities. The clinical outcome of HCC patients remains poor due to distant metastasis and recurrence. In recent years, growing evidences have confirmed that the coiled-coil domain-containing (CCDC) family proteins are involved in the progression of several diseases. However, the expression and clinical significance of the coiled-coil domain-containing 137 (CCDC137) in hepatocellular carcinoma (HCC) have not been investigated. Level 3 mRNA expression profiles and clinicopathological data were obtained in TCGA-LIHC. Differentially expressed genes (DEGs) were screened between 371 HCC and 50 nontumor specimens. The prognostic value of CCDC137 was analyzed in HCC patients. The correlations between CCDC137 and cancer immune infiltrates were investigated. In this study, a total of 2897 DEGs were obtained: 2451 genes were significantly upregulated and 446 genes were significantly downregulated. KEGG assays revealed that these DEGs were involved in tumor progression. Among 2897 DEGs, we found that CCDC137 expression was distinctly increased in HCC specimens compared with nontumor specimens. A high level of CCDC137 expression was related to an advanced tumor stage and grade. Moreover, patients with higher levels of CCDC137 expression had a shorter overall survival and disease-free survival than patients with lower CCDC137 levels. CCDC137 expression was positively correlated with infiltrating levels of several immune cells, such as CD8 T cells and Th2 cells. Finally, in vitro experiments confirmed that CCDC137 expression was highly expressed in HCC cells, and its knockdown suppressed the proliferation of HCC cells. Taken together, our findings revealed that CCDC137 might be used as a biomarker for immune infiltration and poor prognosis in HCC, which offered fresh insight on potential therapies for HCC.

CCDC38 is required for sperm flagellum biogenesis and male fertility in mice.

The sperm flagellum is essential for male fertility, and defects in flagellum biogenesis are associated with male infertility. Deficiency of coiled-coil domain-containing (CCDC) 42 (CCDC42) is specifically associated with malformation of mouse sperm flagella. Here, we find that the testis-specific protein CCDC38 interacts with CCDC42, localizing on the manchette and sperm tail during spermiogenesis. Inactivation of CCDC38 in male mice results in a distorted manchette, multiple morphological abnormalities of the flagella of spermatozoa and eventually male sterility. Furthermore, we find that CCDC38 interacts with intraflagellar transport protein 88 (IFT88), as well as outer dense fibrous 2 (ODF2), and the knockout of Ccdc38 reduces transport of ODF2 to the flagellum. Altogether, our results uncover the essential role of CCDC38 in sperm flagellum biogenesis, and suggest that some mutations of these genes might be associated with male infertility in humans.

Association of a Novel DOCK2 Mutation-Related Gene Signature With Immune in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a malignant tumor with high morbidity and mortality worldwide. Many studies have shown that dedicator of cytokinesis 2 (DOCK2) has a crucial role as a prognostic factor in various cancers. However, the potentiality of DOCK2 in the diagnosis of HCC has not been fully elucidated. In this work, we aimed to investigate the prognostic role of DOCK2 mutation in HCC. The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) cohorts were utilized to identify the mutation frequency of DOCK2. Then, univariate Cox proportional hazard regression analysis, random forest (RF), and multivariate Cox regression analysis were performed to develop the risk score that was significantly related to DOCK2 mutation. Moreover, Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA), and immune correlation analysis were conducted for an in-depth study of the biological process of DOCK2 mutation involved in HCC. The results revealed that the mutation frequency of DOCK2 was relatively higher than that in non-cancer control subjects, and patients with DOCK2 mutations had a low survival rate and a poor prognosis compared with the DOCK2-wild group. In addition, the secretin receptor (SCTR), tetratricopeptide repeat, ankyrin repeat and coiled-coil domain-containing 1 (TANC1), Alkb homolog 7 (ALKBH7), FRAS1-related extracellular matrix 2 (FREM2), and G protein subunit gamma 4 (GNG4) were found to be the most relevant prognostic genes of DOCK2 mutation, and the risk score based on the five genes played an excellent role in predicting the status of survival, tumor mutation burden (TMB), and microsatellite instability (MSI) in DOCK2 mutant patients. In addition, DOCK2 mutation and the risk score were closely related to immune responses. In conclusion, the present study identifies a novel prognostic signature in light of DOCK2 mutation-related genes that shows great prognostic value in HCC patients; and this gene mutation might promote tumor progression by influencing immune responses. These data may provide valuable insights for future investigations into personalized forecasting methods and also shed light on stratified precision oncology treatment.

A Nonsense Variant in CCDC65 Gene Causes Respiratory Failure Associated with Increased Lamb Mortality in French Lacaune Dairy Sheep.

We recently demonstrated that the Lacaune deficient homozygous haplotype 6 (LDHH6) potentially hosts a recessive perinatal lethal mutation in Lacaune dairy sheep mapped on OAR3. In the present study, we have analyzed the whole-genome sequences of two Lacaune ram heterozygous carriers of LDHH6. After variant calling and filtering against the variants of 86 non-carrier rams, we have identified a single nucleotide variant (SNV) in the two LDHH6 carriers whose variant allele induced a premature stop codon (p.Glu111*) in the Coiled-Coil Domain Containing 65 (CCDC65) gene. CCDC65 is involved in the assembly of the nexin-dynein regulatory complex for the formation of microtubules in ciliated cells. In order to identify the phenotype in homozygous sheep, we generated at-risk matings (n = 17) between rams and ewes heterozygous for the candidate variant in CCDC65. A total of 16 lambs were born alive with five genotyped as homozygous carriers. The homozygous lambs suffered from respiratory problems, and four of them died within the first month of life. At necropsy, we observed a broad hepatization of lung lobes possibly induced by infectious pneumonia. The management of this lethal recessive allele (frequency of 0.06) through reasoned mating in the Lacaune sheep selection schemes could reduce lamb mortality by 2%.

Downregulation of the Coiled-Coil Domain Containing 80 and Its Perspective Mechanisms in Ovarian Carcinoma: A Comprehensive Study.

Introduction We aimed to explore the downregulation of the coiled-coil domain containing 80 (CCDC80) and its underlying molecular mechanisms in ovarian carcinoma (OVCA). Materials/Methods. Immunohistochemical staining was performed to confirm the expression status of CCDC80 protein. Combining the data from in-house tissue microarrays and high-throughput datasets, we identified the expression level of CCDC80 in OVCA. We utilized cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm and single-sample gene set enrichment analysis (ssGSEA) to explore the relationship between CCDC80 and the tumor microenvironment (TME) landscape in OVCA. Pathway enrichment, function annotation, and transcription factor (TFs) exploration were conducted to study the latent molecular mechanisms. Moreover, the cell line data in the Genomics of Drug Sensitivity in Cancer (GDSC) database was used to discover the relationship between CCDC80 and drug sensitivity. Results An integrated standard mean difference (SMD) of −0.919 (95% CI: −1.515–0.324, P = 0.002) identified the downregulation of CCDC80 in OVCA based on 1048 samples, and the sROC (AUC = 0.76) showed a moderate discriminatory ability of CCDC80 in OVCA. The fraction of infiltrating naive B cells showed significant differences between the high- and low-CCDC80 expression groups. Also, CCDC80-related genes are enriched in the Ras signaling pathway and metabolic of lipid. Nuclear receptor subfamily three group C member 1 (NR3C1) may be an upstream TF of CCDC80, and CCDC80 may be related to the sensitivity of mitocycin C and nilotinib. Conclusion CCDC80 was downregulated in OVCA and may play a role as a tumor suppressor in OVCA.

CSIG-28. REGULATION OF GEMC1 MULTICILIOGENESIS PROGRAM IN CHOROID PLEXUS CARCINOMA

Abstract Tumors of the choroid plexus (CP) are rare primary brain neoplasms mostly found in children. CP tumors exist in three forms: CP papilloma (CPP), atypical CPP, and CP carcinoma (CPC). Though CPP is more benign, CPC is a highly lethal and little understood cancer with poor survival rate and a tendency for recurrence and metastasis. CP tumors are thought to arise from CP epithelial cells that secrets cerebral spinal fluid and generate multiple cilia on their apical surface. Here we show that aberrant NOTCH and Sonic Hedgehog signaling in mice drive tumors that resemble CPC in humans. In contrast to CP epithelial cells with clusters of multiple cilia, NOTCH-driven CP tumors were monociliated, and disruption of the NOTCH complex restored multiciliation and decreased tumor growth. NOTCH suppressed multiciliation in tumor cells by inhibiting the expression of Geminin Coiled-Coil Domain Containing 1 (GEMC1), and multiciliate differentiation and DNA synthesis associated cell cycle protein (MCIDAS), early transcriptional regulators of multiciliated cell (MCC) differentiation. Consistently, Gemc1-Mcidas deficiency led to a lack of MCCs in the CP, and impaired the correction of the multiciliation defect in tumor cells by a NOTCH inhibitor. Disturbances to the GEMC1 program are commonly observed in human CPCs characterized by solitary cilia and frequent somatic TP53 mutations. Accordingly, CPC driven by deletion of tumor suppressors Trp53 and Rb1 in mice exhibits a cilia deficit consequent to loss of Gemc1-Mcidas expression. Taken together, these findings reveal that the GEMC1-MCIDAS multiciliogenesis program in the CP is critical for inhibiting tumorigenesis, whereas a defective multiciliation program promotes CPC and may represent a therapeutic avenue for this cancer.

GCC2 as a New Early Diagnostic Biomarker for Non-Small Cell Lung Cancer.

Simple SummaryLung cancer, including non-small cell lung cancer, is the leading cause of cancer-related death worldwide. A better prognosis is associated with early diagnosis of lung cancer patients. Although annual screening guidelines for lung cancer are recommended, using various tools such as chest X-ray, low-dose computed tomography, and positron emission tomography, these screening procedures are expensive and difficult to repeat. They are also invasive and have a high risk of radiation exposure. Therefore, a low-risk, convenient diagnostic method using liquid biopsy and biomarkers is required for the early diagnosis of lung cancer. The newly proposed biomarker GCC2 was identified through proteomic analysis of exosomes secreted from lung cancer cell lines. GCC2 expression levels in peripheral blood of the patients showed high specificity and sensitivity in early lung cancer, demonstrating that our novel exosomal biomarker GCC2 can greatly contribute to improving the diagnosis of lung cancer patients, even though it has been tested in only a few pilot studies.No specific markers have been identified to detect non-small cell lung cancer (NSCLC) cell-derived exosomes circulating in the blood. Here, we report a new biomarker that distinguishes between cancer and non-cancer cell-derived exosomes. Exosomes isolated from patient plasmas at various pathological stages of NSCLC, NSCLC cell lines, and human pulmonary alveolar epithelial cells isolated using size exclusion chromatography were characterized. The GRIP and coiled-coil domain-containing 2 (GCC2) protein, involved in endosome-to-Golgi transport, was identified by proteomics analysis of NSCLC cell line-derived exosomes. GCC2 protein levels in the exosomes derived from early-stage NSCLC patients were higher than those from healthy controls. Receiver operating characteristic curve analysis revealed the diagnostic sensitivity and specificity of exosomal GCC2 to be 90% and 75%, respectively. A high area under the curve, 0.844, confirmed that GCC2 levels could effectively distinguish between the exosomes. These results demonstrate GCC2 as a promising early diagnostic biomarker for NSCLC.

Coiled-Coil Domain Containing 80 Suppresses Nonylphenol-Induced Colorectal Cancer Cell Proliferation by Inhibiting the Activation of ERK1/2.

Recently, the effect of endocrine-disrupting chemicals on the cancer procession has been a concern. Nonylphenol (NP) is a common environmental estrogen that has been shown to enhance the proliferation of colorectal cancer (CRC) cells in our previous studies; however, the underlying mechanism remains unclear. In this study, we confirmed the increased concentration of NP in the serum of patients with CRC. RNA sequencing was used to explore the differentially expressed genes after NP exposure. We found 16 upregulated genes and 12 downregulated genes in COLO205 cells after NP treatment. Among these differentially expressed genes, we found that coiled-coil domain containing 80 (CCDC80) was downregulated by NP treatment and was associated with CRC progression. Further experiments revealed that the overexpression of CCDC80 significantly suppressed NP-induced cell proliferation and recovered the reduced cell apoptosis. Meanwhile, the overexpression of CCDC80 significantly inhibited the activation of ERK1/2 induced by NP treatment. ERK1/2 inhibitor (PD98059) treatment also suppressed NP-induced CRC cell growth, but the overexpression of CCDC80 did not enhance the effect of ERK1/2 inhibitor. Taken together, NP treatment significantly inhibited the expression of CCDC80, and the overexpression of CCDC80 suppressed NP-induced CRC cell growth by inhibiting the activation of ERK1/2. These results suggest that NP could induce CRC cell growth by influencing the expression of multiple genes. CCDC80 and ERK1/2 inhibitors may be suitable therapeutic targets in NP-related CRC progression.