Evolution of chromosome-arm aberrations in breast cancer through genetic network rewiring.

The basal breast cancer subtype is enriched for triple-negative breast cancer (TNBC) and displays consistent large chromosomal deletions. Here, we characterize evolution and maintenance of chromosome 4p (chr4p) loss in basal breast cancer. Analysis of The Cancer Genome Atlas data shows recurrent deletion of chr4p in basal breast cancer. Phylogenetic analysis of a panel of 23 primary tumor/patient-derived xenograft basal breast cancers reveals early evolution of chr4p deletion. Mechanistically we show that chr4p loss is associated with enhanced proliferation. Gene function studies identify an unknown gene, C4orf19, within chr4p, which suppresses proliferation when overexpressed-a member of the PDCD10-GCKIII kinase module we name PGCKA1. Genome-wide pooled overexpression screens using a barcoded library of human open reading frames identify chromosomal regions, including chr4p, that suppress proliferation when overexpressed in a context-dependent manner, implicating network interactions. Together, these results shed light on the early emergence of complex aneuploid karyotypes involving chr4p and adaptive landscapes shaping breast cancer genomes.

Comprehensive CCM3 Mutational Analysis in Two Patients with Syndromic Cerebral Cavernous Malformation.

Cerebral cavernous malformation (CCM) is a vascular disease that affects the central nervous system, which familial form is due to autosomal dominant mutations in the genes KRIT1(CCM1), MGC4607(CCM2), and PDCD10(CCM3). Patients affected by the PDCD10 mutations usually have the onset of symptoms at an early age and a more aggressive phenotype. The aim of this study is to investigate the molecular mechanism involved with CCM3 disease pathogenesis. Herein, we report two typical cases of CCM3 phenotype and compare the clinical and neuroradiological findings with five patients with a familial form of KRIT1 or CCM2 mutations and six patients with a sporadic form. In addition, we evaluated the PDCD10 gene expression by qPCR and developed a bioinformatic pipeline to understand the structural changes of mutations. The two CCM3 patients had an early onset of symptoms and a high lesion burden. Furthermore, the sequencing showed that Patient 1 had a frameshift mutation in c.222delT; p.(Asn75Thrfs*14) that leads to lacking the last 124 C-terminal amino acids on its primary structure and Patient 2 had a variant on the splicing site region c.475-2A > G. The mRNA expression was fourfold lower in both patients with PDCD10 mutation. Using in silico analysis, we identify that the frameshift mutation transcript lacks the C-terminal FAT-homology domain compared to the wild-type PDCD10 and preserves the N-terminal dimerization domain. The two patients studied here allow estimating the potential impact of mutations in clinical interpretation as well as support to better understand the mechanism and pathogenesis of CCM3.

Deficiency of Pdcd10 causes urothelium hypertrophy and vesicle trafficking defects in ureter.

The scaffolding protein programmed cell death protein 10 (Pdcd10) has been demonstrated to play a critical role in renal epithelial cell homeostasis and function by maintaining appropriate water reabsorption in collecting ducts. Both ureter and kidney collecting duct systems are derived from the ureter bud during development. Here, we report that cadherin-16 (Cdh16)-cre drives gene recombination with high specificity in the ureter, but not the bladder, urothelium. The consequences of Pdcd10 deletion on the stratified ureter urothelium were investigated using an integrated approach including messenger RNA (mRNA) expression analysis, immunocytochemistry, and high-resolution confocal and electron microscopy. Loss of Pdcd10 in the ureter urothelium resulted in increased expression of uroplakins (Upks) and keratins (Krts), as well as hypertrophy of the ureter urothelium with an associated increase in the number of proliferation marker protein Ki-67 (Ki67)-expressing cells specifically within the basal urothelium layer. Ultrastructural analysis documented significant modification of the intracellular membrane system, including intracellular vesicle genesis and transport along the basal- to umbrella-cell-layer axis. Additionally, Pdcd10 loss resulted in swelling of Golgi compartments, disruption of mitochondrial cristae structure, and increased lysosomal fusion. Lack of Pdcd10 also resulted in decreased fusiform vesicle formation in umbrella cells, increased secretion of exosome vesicles, and alteration in microvillar structure on apical membranes. Our findings indicate that Pdcd10 expression and its influence on homeostasis is associated with modulation of endomembrane trafficking and organelle biogenesis in the ureter urothelium.

Exosomal miR-30a-5p promoted intrahepatic cholangiocarcinoma progression by increasing angiogenesis and vascular permeability in PDCD10 dependent manner.

Tumor-associated angiogenesis positively associates with malignant metastasis of intrahepatic cholangiocarcinoma (ICCA). Cancer cell-derived exosomes carrying microRNAs involves in tumor microenvironment (TME) regulation. We aimed to evaluate exosomal miR-30a-5p in ICCA development. Our data showed that increased miR-30a-5p level was correlated with higher microvascular density (MVD) and worse prognosis. Augmented miR-30a-5p expression was induced by hypoxia induced factor 1α (HIF-1α) in ICCA cell. Further exploration revealed that ICCA-derived miR-30a-5p could be transferred to endothelial and increased endothelial cells recruitment and proliferation, induced angiogenesis and vascular permeability in exosome dependent manner. In addition, circulating exosomal miR-30a-5p was higher in ICCA patients, and correlated with ICCA tissues-expressing miR-30a-5p. Hypoxic stress enhanced the effects of exosomal miR-30a-5p on endothelial-associated phenotypes. Rescued experiments showed that exosomal miR-30a-5p modulated endothelial-associated phenotypes in a way relied on programmed cell death 10 (PDCD10). Moreover, we revealed that the packing of miR-30a-5p into ICCA cells-derived exosomes was mediated by eukaryotic translation initiation factor 4B (EIF4B). More importantly, the combined application of targeting miR-30a-5p and apatinib could synergistically improve antiangiogenic efficacy in ICCA. Combined, ICCA-derived exosomal miR-30a-5p could be an excellent therapeutic and monitoring indicator for ICCA patients.

Protumorigenic role of the atypical cadherin FAT1 by the suppression of PDCD10 via RelA/miR221-3p/222-3p axis in glioblastoma.

The atypical cadherin FAT1 function either as a pro or antitumorigenic in tumors of different tissue origins. Our group previously demonstrated the protumorigenic nature of FAT1 signaling in glioblastoma (GBM). In this study, we investigated how FAT1 influences the expression of clustered oncomiRs (miR-221-3p/miR-222-3p) and their downstream effects in GBM. Through several experiments involving the measurement of specific gene/microRNA expression, gene knockdowns, protein and cellular assays, we have demonstrated a novel oncogenic signaling pathway mediated by FAT1 in glioma. These results have been verified using antimiRs and miR-mimic assays. Initially, in glioma-derived cell lines (U87MG and LN229), we observed FAT1 as a novel up-regulator of the transcription factor NFκB-RelA. RelA then promotes the expression of the clustered-oncomiRs, miR-221-3p/miR-222-3p, which in turn suppresses the expression of the tumor suppressor gene (TSG), PDCD10 (Programmed cell death protein10). The suppression of PDCD10, and other known TSG targets (PTEN/PUMA), by miR-221-3p/miR-222-3p, leads to increased clonogenicity, migration, and invasion of glioma cells. Consistent with our in-vitro findings, we observed a positive expression correlation of FAT1 and miR-221-3p, and an inverse correlation of FAT1 and the miR-targets (PDCD10/PTEN/PUMA), in GBM tissue-samples. These findings were also supported by publicly available GBM databases (The Cancer Genome Atlas [TCGA] and The Repository of Molecular Brain Neoplasia Data [Rembrandt]). Patients with tumors displaying high levels of FAT1 and miR-221-3p expression (50% and 65% respectively) experienced shorter overall survival. Similar results were observed in the TCGA-GBM database. Thus, our findings show a novel FAT1/RelA/miR-221/miR-222 oncogenic-effector pathway that downregulates the TSG, PDCD10, in GBM, which could be targeted therapeutically in a specific manner.

The First Potentially Causal Genetic Variant Documented in a Polish Woman with Multiple Cavernous Malformations of the Brain.

Cerebral cavernous malformations (CCMs) are relatively common in the central nervous system. They occur in two forms, sporadic and familial (FCCMs). Three genes are recognized to be associated with FCCM, including CCM1, CCM2, and CCM3, the latter also called PDCD10. In this article, we describe a single-nucleotide variant in the PDCD10 gene in a 23-year-old Polish female with CCM. The NM_007217.4 (PDCD10): c.395+1G>A variant destroys the canonical splice donor site following exon 6. This is the first reported genetically characterized case of CCM (FCCM) in Poland.

Programmed cell death 10 increased blood-brain barrier permeability through HMGB1/TLR4 mediated downregulation of endothelial ZO-1 in glioblastoma.

Dysfunction of blood brain barrier (BBB) contributes to the development of peritumoral edema (PTE) and GBM progression. Programmed cell death 10 (PDCD10) exerts various influence on cancers, especially in glioblastoma (GBM). We previously found that PDCD10 expression was positively correlated with PTE extent in GBM. Thus, the present study aims to investigate the emerging role of PDCD10 in regulating BBB permeability in GBM. Here we found that in vitro indirect co-culture of endothelial cells (ECs) with Pdcd10-overexpressed GL261 cells resulted in a significant increase of FITC-Dextran (MW, 4000) leakage by reducing endothelial zonula occluden-1 (ZO-1) and Claudin-5 expression in ECs respectively. Overexpression of Pdcd10 in GBM cells (GL261) triggered an increase of soluble high mobility group box 1 (HMGB1) release, which in turn activated endothelial toll like receptor 4 (TLR4) and downstream NF-κB, Erk1/2 and Akt signaling in ECs through a paracrine manner. Moreover, Pdcd10-overexpressed GL261 cells facilitated a formation of abnormal vasculature and increased the BBB permeability in vivo. Our present study demonstrates that upregulation of PDCD10 in GBM triggered HMGB1/TLR4 signaling in ECs and significantly decreased endothelial ZO-1 expression, which in turn dominantly increased BBB permeability and contributed to tumor progression in GBM.

PDCD10 promotes proliferation, migration, and invasion of osteosarcoma by inhibiting apoptosis and activating EMT pathway.

BACKGROUND: Osteosarcoma, a common primary malignant tumor, occurs in children and adolescents with a poor prognosis. The current treatment methods are various, while the five-year survival rate of patients has not been significantly improved. As a member of the programmed death factor (PDCD) family, programmed death factor 10 (PDCD10) plays a role in regulating cell apoptosis. Several studies of PDCD10 in CCM and cancers have been reported before. However, there are no relevant research reports on the effects of PDCD10 on osteosarcoma. METHODS: We used bioinformatics analysis, IHC, and clinical data to confirm the expression of PDCD10 and its correlation with prognosis in osteosarcoma. Then, we used shRNAs and cDNA to knock down or overexpress PDCD10 in U2OS and MG63 cell lines. A series of function assays such as CCK8, Wound healing test, Plate cloning formation assay, and Transwell were done to confirm how PDCD10 affects osteosarcoma. Animal assays were done to confirm the conclusions in cell lines. At last, WB was used to measure the protein expression levels of apoptosis and the EMT pathway. RESULTS: PDCD10 was highly expressed in patients with osteosarcoma and correlated with prognosis; PDCD10 knockdown inhibited osteosarcoma growth, proliferation, migration, and invasion; PDCD10 overexpression promoted osteosarcoma growth, proliferation, migration, and invasion. In vivo experiments confirmed the conclusions in cell lines; PDCD10 inhibited apoptosis and activated the EMT pathway. CONCLUSIONS: In this study, it was found that PDCD10 was highly expressed in patients with osteosarcoma, and it was closely related to patient prognosis. PDCD10 inhibited tumor cell apoptosis and promoted tumor progression by activating the EMT pathway. These findings may provide a potential target for gene therapy of osteosarcoma.

The Dual Role of PDCD10 in Cancers: A Promising Therapeutic Target.

Programmed cell death 10 (PDCD10) was initially considered as a protein associated with apoptosis. However, recent studies showed that PDCD10 is actually an adaptor protein. By interacting with multiple molecules, PDCD10 participates in various physiological processes, such as cell survival, migration, cell differentiation, vesicle trafficking, cellular senescence, neurovascular development, and gonadogenesis. Moreover, over the past few decades, accumulating evidence has demonstrated that the aberrant expression or mutation of PDCD10 is extremely common in various pathological processes, especially in cancers. The dysfunction of PDCD10 has been strongly implicated in oncogenesis and tumor progression. However, the updated data seem to indicate that PDCD10 has a dual role (either pro- or anti-tumor effects) in various cancer types, depending on cell/tissue specificity with different cellular interactors. In this review, we aimed to summarize the knowledge of the dual role of PDCD10 in cancers with a special focus on its cellular function and potential molecular mechanism. With these efforts, we hoped to provide new insight into the future development and application of PDCD10 as a clinical therapeutic target in cancers.

PDCD10 promotes the aggressive behaviors of pituitary adenomas by up-regulating CXCR2 and activating downstream AKT/ERK signaling.

As the second most common primary intracranial neoplasms, about 40% of pituitary adenomas (PAs) exhibit aggressive behaviors and resulting in poor patient prognosis. The molecular mechanisms underlying the aggressive behaviors of PAs are not yet fully understood. Biochemical studies have reported that programmed cell death 10 (PDCD10) is a component of the striatin-interacting phosphatase and kinase (STRIPAK) complex and plays a dual role in cancers in a tissue- or disease-specific manner. In the present study, we report for the first time that the role of PDCD10 in PAs. Cell proliferation, migration and invasion were either enhanced by overexpressing or inhibited by silencing PDCD10 in PA cells. Moreover, PDCD10 significantly promoted epithelial-mesenchymal transition (EMT) of pituitary adenoma cells. Mechanistically, we showed that the expression of CXCR2, together with phosphorylation levels of AKT and ERK1/2 were regulated by PDCD10. Activation of CXCR2 inversed inactivation of AKT/ERK signal pathways and the tumor-suppressive effects induced by PDCD10 silencing. Finally, the pro-oncogenic effect of PDCD10 was confirmed by in vivo tumor grafting. Taken together, we demonstrate for the first time that PDCD10 can induce aggressive behaviors of PAs by promoting cellular proliferation, migration, invasion and EMT through CXCR2-AKT/ERK signaling axis.

Beware of missed diagnosis in patients with multiple genetic diseases: a case report.

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked recessive inherited disorder caused by the absence of the Dystrophin protein. Cerebral cavernous malformations (CCMs) are the most common vascular abnormalities in the central nervous system caused by the absence of the products of the CCM genes. Most CCMs cases reported occurring in a sporadic form are often asymptomatic. CASE PRESENTATION: We report a rare case of a 7-year-old Chinese boy with a co-existing DMD and sporadic CCMs. We found classic clinical features of DMD and non-specific pathological changes in his brain. We made the definitive diagnosis based on the results of whole-exome sequencing (WES), a repeat from exon 3 to exon 9 of the DMD inherited from his mother, and a de novo heterozygote nonsense mutation C.418G > T of the PDCD10 exon 6. CONCLUSION: We should take care to avoid missed diagnoses in patients with multiple genetic disorders.

Transcriptome Analysis Reveals Altered Expression of Genes Involved in Hypoxia, Inflammation and Immune Regulation in Pdcd10-Depleted Mouse Endothelial Cells.

Cerebral cavernous malformations (CCM) are capillary malformations affecting the central nervous system and commonly present with headaches, epilepsy and stroke. Treatment of CCM is symptomatic, and its prevention is limited. CCM are often sporadic but sometimes may be multifocal and/or affect multiple family members. Heterozygous pathogenic variants in PDCD10 cause the rarest and apparently most severe genetic variant of familial CCM. We carried out an RNA-Seq and a Q-PCR validation analysis in Pdcd10-silenced and wild-type mouse endothelial cells in order to better elucidate CCM molecular pathogenesis. Ninety-four differentially expressed genes presented an FDR-corrected p-value < 0.05. A functionally clustered dendrogram showed that differentially expressed genes cluster in cell proliferation, oxidative stress, vascular processes and immune response gene-ontology functions. Among differentially expressed genes, the major cluster fell in signaling related to inflammation and pathogen recognition, including HIF1α and Nos2 signaling and immune regulation. Validation analysis performed on wild-type, Pdcd10-null and Pdcd10-null reconstituted cell lines was consistent with RNA-Seq data. This work confirmed previous mouse transcriptomic data in endothelial cells, which are recognized as a critical tissue for CCM formation and expands the potential molecular signatures of PDCD10-related familial CCM to alterations in inflammation and pathogen recognition pathways.

Cerebral Cavernous Malformation Pathogenesis: Investigating Lesion Formation and Progression with Animal Models.

Cerebral cavernous malformation (CCM) is a cerebromicrovascular disease that affects up to 0.5% of the population. Vessel dilation, decreased endothelial cell-cell contact, and loss of junctional complexes lead to loss of brain endothelial barrier integrity and hemorrhagic lesion formation. Leakage of hemorrhagic lesions results in patient symptoms and complications, including seizures, epilepsy, focal headaches, and hemorrhagic stroke. CCMs are classified as sporadic (sCCM) or familial (fCCM), associated with loss-of-function mutations in KRIT1/CCM1, CCM2, and PDCD10/CCM3. Identifying the CCM proteins has thrust the field forward by (1) revealing cellular processes and signaling pathways underlying fCCM pathogenesis, and (2) facilitating the development of animal models to study CCM protein function. CCM animal models range from various murine models to zebrafish models, with each model providing unique insights into CCM lesion development and progression. Additionally, these animal models serve as preclinical models to study therapeutic options for CCM treatment. This review briefly summarizes CCM disease pathology and the molecular functions of the CCM proteins, followed by an in-depth discussion of animal models used to study CCM pathogenesis and developing therapeutics.

Description of Two Families with New Mutations in Familial Cerebral Cavernous Malformations Genes.

Cerebral cavernous malformations (CCMs) are dilated aberrant leaky capillaries located in the Central Nervous System. Familial CCM is an autosomal dominant inherited disorder related to mutations in KRIT1, Malcavernin or PDCD10. We show two unrelated families presenting familial CCM due to two new mutations in KRIT1 and PDCD10, producing truncated proteins. Clinical phenotype was highly variable among patients from asymptomatic individuals to diplopia, seizures or severe intracranial hemorrhage. PDCD10 patients usually show a more aggressive course and they frequently showed multiple meningiomas. This work provides evidence for the pathogenicity of two new mutations in CCM genes and supports previous findings regarding familial CCM and multiple meningiomas.

The multifaceted PDCD10/CCM3 gene.

The programmed cell death 10 (PDCD10) gene was originally identified as an apoptosis-related gene, although it is now usually known as CCM3, as the third causative gene of cerebral cavernous malformation (CCM). CCM is a neurovascular disease that is characterized by vascular malformations and is associated with headaches, seizures, focal neurological deficits, and cerebral hemorrhage. The PDCD10/CCM3 protein has multiple subcellular localizations and interacts with several multi-protein complexes and signaling pathways. Thus PDCD10/CCM3 governs many cellular functions, which include cell-to-cell junctions and cytoskeleton organization, cell proliferation and apoptosis, and exocytosis and angiogenesis. Given its central role in the maintenance of homeostasis of the cell, dysregulation of PDCD10/CCM3 can result in a wide range of altered cell functions. This can lead to severe diseases, including CCM, cognitive disability, and several types of cancers. Here, we review the multifaceted roles of PDCD10/CCM3 in physiology and pathology, with a focus on its functions beyond CCM.

Programmed Cell Death 10 Mediated CXCL2-CXCR2 Signaling in Regulating Tumor-Associated Microglia/Macrophages Recruitment in Glioblastoma.

Background: Programmed cell death 10 (PDCD10) plays a crucial role in regulating tumor phenotyping, especially in glioblastoma (GBM). Glioma-associated microglia/macrophages (GAMs) in tumor pathological microenvironment contribute to GBM progression. We previously found that the infiltration of GAMs was associated with PDCD10 expression in GBM patients. The present study aims to further explore the regulation of PDCD10 on GAMs in GBM. Methods: Overexpression of PDCD10 in human- and murine-GBM cells was established by lentiviral transduction. Cell behaviors and polarization of primary microglia, microglia- and macrophage-like cells were investigated through indirect co-culture with GBM cells in vitro respectively. The PDCD10-induced release of chemokines was identified by a chemokine protein array. The cross-talk between GBM and microglia as well as macrophages was further studied using selective antagonist SB225002. Finally, an orthotopic homograft mouse model was employed to verify the results of in vitro experiments. Results: Indirect co-culture with PDCD10-overexpressed GBM cells promoted proliferation and migration of microglia- and macrophage-like cells, and stimulated pro-tumorigenic polarization of primary microglia, microglia- and macrophage-like cells. Pdcd10-upregulated GBM cells triggered a nearly 6-fold increase of CXC motif chemokine ligand 2 (CXCL2) release, which in turn activated CXC chemokine receptor 2 (CXCR2) and downstream Erk1/2 and Akt signaling in primary microglia, microglia- and macrophage-like cells. The blockage of CXCR2 signaling with specific inhibitor (SB225002) abolished microglia- and macrophage-like cell migration induced by PDCD10-upregulated GBM cells. Moreover, Pdcd10-upregulated GL261 cells promoted GAMs recruitment and tumor growth in vivo. Conclusion: Our study demonstrates that overexpression of PDCD10 in GBM recruits and activates microglia/macrophages, which in turn promotes tumor progression. CXCL2-CXCR2 signaling mediated by PDCD10 is potentially involved in the crosstalk between GBM cells and GAMs.

Molecular Genetic Features of Cerebral Cavernous Malformations (CCM) Patients: An Overall View from Genes to Endothelial Cells.

Cerebral cavernous malformations (CCMs) are vascular lesions that affect predominantly microvasculature in the brain and spinal cord. CCM can occur either in sporadic or familial form, characterized by autosomal dominant inheritance and development of multiple lesions throughout the patient's life. Three genes associated with CCM are known: CCM1/KRIT1 (krev interaction trapped 1), CCM2/MGC4607 (encoding a protein named malcavernin), and CCM3/PDCD10 (programmed cell death 10). All the mutations identified in these genes cause a loss of function and compromise the protein functions needed for maintaining the vascular barrier integrity. Loss of function of CCM proteins causes molecular disorganization and dysfunction of endothelial adherens junctions. In this review, we provide an overall vision of the CCM pathology, starting with the genetic bases of the disease, describing the role of the proteins, until we reach the cellular level. Thus, we summarize the genetics of CCM, providing a description of CCM genes and mutation features, provided an updated knowledge of the CCM protein structure and function, and discuss the molecular mechanisms through which CCM proteins may act within endothelial cells, particularly in endothelial barrier maintenance/regulation and in cellular signaling.

Improving clinical interpretation of five KRIT1 and PDCD10 intronic variants.

Cerebral cavernous malformation (CCM) is a vascular malformation of the central nervous system which may occur sporadically or segregate within families due to heterozygous variants in KRIT1/CCM1, MGC4607/CCM2 or PDCD10/CCM3. Intronic variants are not uncommon in familial CCM, but their clinical interpretation is often hampered by insufficient data supporting in silico predictions. Here, the mRNA analysis for two intronic unpublished variants (KRIT1 c.1147-7 T > G and PDCD10 c.395 + 2 T > G) and three previously published variants in KRIT1 but without data supporting their effects was carried out. This study demonstrated that all variants can induce a frameshift with the lack of residues located in the C-terminal regions and involved in protein-protein complex formation, which is essential for vascular homeostasis. These results support the introduction of mRNA analysis in the diagnostic pathway of familial CCM and expand the knowledge of abnormal splicing patterning in this disorder.

Genome-wide analysis of copy number alterations led to the characterisation of PDCD10 as oncogene in ovarian cancer.

Copy Number Alterations (CNAs) represent the most common genetic alterations identified in ovarian cancer cells, being responsible for the extensive genomic instability observed in this cancer. Here we report the identification of CNAs in a cohort of Italian patients affected by ovarian cancer performed by SNP-based array. Our analysis allowed the identification of 201 significantly altered chromosomal bands (70 copy number gains; 131 copy number losses). The 3300 genes subjected to CNA identified here were compared to those present in the TCGA dataset. The analysis allowed the identification of 11 genes with increased CN and mRNA expression (PDCD10, EBAG9, NUDCD1, ENY2, CSNK2A1, TBC1D20, ZCCHC3, STARD3, C19orf12, POP4, UQCRFS1). PDCD10 was selected for further studies because of the highest frequency of CNA. PDCD10 was found, by immunostaining of three different Tissue Micro Arrays, to be over-expressed in the majority of ovarian primary cancer samples and in metastatic lesions. Moreover, significant correlations were found in specific subsets of patients, between increased PDCD10 expression and grade (p < 0.005), nodal involvement (p < 0.05) or advanced FIGO stage (p < 0.01). Finally, manipulation of PDCD10 expression by shRNA in ovarian cancer cells (OVCAR-5 and OVCA429) demonstrated a positive role for PDCD10 in the control of cell growth and motility in vitro and tumorigenicity in vivo. In conclusion, this study allowed the identification of novel genes subjected to copy number alterations in ovarian cancer. In particular, the results reported here point to a prominent role of PDCD10 as a bona fide oncogene.

CircSMARCA5 Facilitates the Progression of Prostate Cancer Through miR-432/PDCD10 Axis.

Background: Circular RNAs (circRNAs) have been reported to be implicated in the pathogenesis of prostate cancer (PCa). Herein, the authors explore the role and molecular mechanism of circRNA SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 5 (circSMARCA5) in PCa. Materials and Methods: The levels of circSMARCA5, SMARCA5, miR-432, and programmed cell death 10 (PDCD10) were determined by quantitative real-time polymerase chain reaction (qRT-PCR). The circular structure and stability of circSMARCA5 were validated by qRT-PCR using Oligo dT primer, transcriptional inhibitor actinomycin D, or RNase R treatment, respectively. Cell proliferation, migration, invasion, epithelial/mesenchymal transition (EMT), and glycolysis were detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), transwell migration and invasion assays, Western blot assay, and Glucose or Lactate Detection Kit, respectively. The target relationship between miR-432 and circSMARCA5 or PDCD10 was validated by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Western blot was performed to detect the protein expression of PDCD10 in PCa cells. Results: CircSMARCA5 was aberrantly upregulated, and was a circular and stable RNA in PCa cells. CircSMARCA5 accelerated the proliferation, metastasis, and glycolysis of PCa cells. MiR-432 was a direct target of circSMARCA5, and circSMARCA5 accelerated the development of PCa through miR-432 in PCa cells. PDCD10 was a direct target of miR-432, and PDCD10 addition reversed the inhibitory effects of miR-432 accumulation on the proliferation, metastasis, and glycolysis of PCa cells. CircSMARCA5 upregulated the expression of PDCD10 through sponging miR-432 in PCa cells. Conclusion: CircSMARCA5 deteriorated PCa through the miR-432/PDCD10 axis. CircSMARCA5/miR-432/PDCD10 axis might be an underlying therapeutic target for PCa treatment.