LncRNA TUG1 promotes pulmonary fibrosis progression via up-regulating CDC27 and activating PI3K/Akt/mTOR pathway.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with an unclear pathogenesis. This study aimed to elucidate the function and potential mechanisms of TUG1 in IPF progression. Cell viability and migration were detected by CCK-8 and transwell assays. Autophagy, fibrosis, or EMT-related proteins were measured by Western blotting. Pro-inflammatory cytokine levels were assessed by ELISA kits. The subcellular localization of TUG1 was observed by FISH assay. RIP assay detected the interaction between TUG1 and CDC27. TUG1 and CDC27 was up-regulated in TGF-ß1-induced RLE-6TN cells. TUG1 depletion suppressed pulmonary fibrosis via attenuating inflammation, EMT, inducing autophagy and inactivating PI3K/Akt/mTOR pathway in vitro and in vivo. TUG1 knockdown prevented CDC27 expression. TUG1 silencing ameliorated pulmonary fibrosis by reducing CDC27 expression and inhibiting PI3K/Akt/mTOR pathway.

Nuclear-localized CTEN is a novel transcriptional regulator and promotes cancer cell migration through its downstream target CDC27

C-terminal tensin-like (CTEN) is a tensin family protein typically localized to the cytoplasmic side of focal adhesions, and primarily contributes to cell adhesion and migration. Elevated expression and nuclear accumulation of CTEN have been reported in several types of cancers and found to be associated with malignant behaviors. However, the function of nuclear CTEN remains elusive. In this study, we report for the first time that nuclear CTEN associates with chromatin DNA and occupies the region proximal to the transcription start site in several genes. The mRNA expression level of CTEN positively correlates with that of one of its putative target genes, cell division cycle protein 27 (CDC27), in a clinical colorectal cancer dataset, suggesting that CTEN may play a role in the regulation of CDC27 gene expression. Furthermore, we demonstrated that CTEN is recruited to the promoter region of the CDC27 gene and that the mRNA expression and promoter activity of CDC27 are both reduced when CTEN is downregulated. In addition, we found that enhanced nuclear accumulation of CTEN in HCT116 cells by overexpression of CTEN fused with nuclear localization signals increases CDC27 transcript levels and promoter activity. The increased nuclear-localized CTEN also significantly promotes cell migration, and the migratory ability is suppressed when CDC27 is knocked down. These results demonstrate that nuclear CTEN regulates CDC27 expression transcriptionally and promotes cell migration through CDC27. Our findings provide new insights into CTEN moonlighting in the nucleus as a DNA-associated protein and transcriptional regulator involved in modulating cancer cell migration. (AU)

Nuclear-localized CTEN is a novel transcriptional regulator and promotes cancer cell migration through its downstream target CDC27.

C-terminal tensin-like (CTEN) is a tensin family protein typically localized to the cytoplasmic side of focal adhesions, and primarily contributes to cell adhesion and migration. Elevated expression and nuclear accumulation of CTEN have been reported in several types of cancers and found to be associated with malignant behaviors. However, the function of nuclear CTEN remains elusive. In this study, we report for the first time that nuclear CTEN associates with chromatin DNA and occupies the region proximal to the transcription start site in several genes. The mRNA expression level of CTEN positively correlates with that of one of its putative target genes, cell division cycle protein 27 (CDC27), in a clinical colorectal cancer dataset, suggesting that CTEN may play a role in the regulation of CDC27 gene expression. Furthermore, we demonstrated that CTEN is recruited to the promoter region of the CDC27 gene and that the mRNA expression and promoter activity of CDC27 are both reduced when CTEN is downregulated. In addition, we found that enhanced nuclear accumulation of CTEN in HCT116 cells by overexpression of CTEN fused with nuclear localization signals increases CDC27 transcript levels and promoter activity. The increased nuclear-localized CTEN also significantly promotes cell migration, and the migratory ability is suppressed when CDC27 is knocked down. These results demonstrate that nuclear CTEN regulates CDC27 expression transcriptionally and promotes cell migration through CDC27. Our findings provide new insights into CTEN moonlighting in the nucleus as a DNA-associated protein and transcriptional regulator involved in modulating cancer cell migration.

Effect of the At-CDC27a gene on Nicotiana benthamiana phenotype and accumulation of recombinant proteins.

In this study the anaphase promoting complex subunit CDC27a from Arabidopsis thaliana was introduced in the genome of Nicotiana benthamiana by Agrobacterium tumefaciens. The presence of the At-CDC27a gene facilitates plant biomass production. Compared to wild type N. benthamiana the leaf mass fraction of the best performing transgenic line At-CDC27a-29 was increased up to 154%. The positive effect of the At-CDC27a expression on leaf biomass accumulation was accompanied by an enlarged total leaf area. Furthermore, the ectopic expression of the At-CDC27a also affected cellular conditions for the production of foreign proteins delivered by the TRBO vector. In comparison to the non-transgenic control, the protein accumulation in the At-CDC27a-29 plant host increased up to 146% for GFP and up to 181% for scFv-TM43-E10. Collectively, the modified N. benthamiana plants developed in this study might be useful to improve the yield of recombinant proteins per biomass unit in closed facilities.

Prognostic and clinical significance of subcellular CDC27 for patients with rectal adenocarcinoma treated with adjuvant chemotherapy.

Rectal adenocarcinoma (READ) constitutes one-third of newly diagnosed colorectal cancer cases. Surgery, chemotherapy and concurrent chemoradiotherapy are the main treatments to improve patient outcomes for READ. However, patients with READ receiving these treatments eventually relapse, leading to a poor survival outcome. The present study collected surgical specimens from patients with READ and determined that cytoplasmic cell division cycle 27 (CDC27) expression was associated with the risk of lymph node metastasis and distant metastasis. Nuclear CDC27 expression was negatively associated with 5-year disease-free survival (DFS) and 5-year overall survival (OS) rates. Multivariate Cox proportional regression analysis showed that nuclear CDC27 was an independent prognostic factor in the patients with READ, especially in those treated with adjuvant chemotherapy. High nuclear CDC27 expression was significantly associated with poorer 5-year DFS (HR, 2.106; 95% CI, 1.275-3.570; P=0.003) and 5-year OS (HR, 2.369; 95% CI, 1.270-4.6810; P=0.005) rates. The data indicated that cytoplasmic CDC27 expression could affect tumor progression and that it plays an important role in metastasis. Nuclear CDC27 expression was markedly associated with poorer survival outcomes and was an independent prognostic factor in patients with postoperative adjuvant chemotherapy-treated READ. Thus, CDC27 expression serves as a potential prognostic marker for rectal tumor progression and chemotherapy treatment.

Circ_0000775 promotes the migration, invasion and EMT of hepatic carcinoma cells by recruiting IGF2BP2 to stabilize CDC27.

BACKGROUND: Hepatic carcinoma (HC) is one of the leading causes of cancer-related death, and the incidence keeps high in the world. The vital role of circular RNAs (circRNAs) in HC development has been revealed to some extent. Circ_0000775, a novel circRNA, has never been thoroughly studied regarding HC. METHODS: Online datasets were utilized to obtain expression pattern of genes in tumor tissues. RT-qPCR and western blot examined the RNA and protein levels of indicated genes. ChIP, DNA pull down, RNA pull down, RIP and luciferase reporter assays were carried out to verify correlation between different factors. Supported by RT-qPCR and western blot analyses, transwell and wound healing assay were implemented for detecting cell migration and invasion and EMT. Additionally, cell EMT was also evaluated via cell morphology observation for calculation of spindle cell number. RESULTS: High expression of circ_0000775 in HC cells was induced by transcriptionally stimulation by TCF7L2. Circ_0000775 in cytoplasm recruited IGF2BP2 to enhance the mRNA stability of CDC27, thus positively modulating CDC27 expression. Circ_0000775 exacerbated HC cell migration, invasion and EMT through CDC27. CONCLUSION: TCF7L2 promoted the transcription of circ_0000775, and circ_0000775 recruited IGF2BP2 to maintain CDC27 mRNA stability, thereby facilitating HC cell migration, invasion and EMT.

A Novel Gene CDC27 Causes SLE and Is Associated With the Disease Activity.

Background: As genetic genetic factors are important in SLE, so screening causative genes is of great significance for the prediction and early prevention in people who may develop SLE. At present, it is very difficult to screen causative genes through pedigrees. The analytical method described herein can be used to screen causative genes for SLE and other complex diseases through pedigrees. Methods: For the first time, 24 lupus pedigrees were analyzed by combining whole exon sequencing and a variety of biological information tools including common-specific analysis, pVAAST (pedigree variant annotation, analysis and search tool), Exomiser (Combining phenotype and PPI associated analysis), and FARVAT (family based gene burden), and the causative genes of these families with lupus identified. Selected causative genes in peripheral-blood mononuclear cells (PBMCs) were evaluated by quantitative polymerase chain reaction (qPCR). Results: Cell division cycle 27 (CDC27) was screened out by common-specific analysis and Exomiser causative gene screening. FARVAT analysis on these families detected only CDC27 at the extremely significant level (false discovery rate <0.05) by three family-based burden analyses (BURDEN, CALPHA, and SKATO). QPCR was performed to detect for CDC27 in the PBMCs of the SLE family patients, sporadic lupus patients, and healthy people. Compared with the healthy control group, CDC27 expression was low in lupus patients (familial and sporadic patients) (P<0.05) and correlated with lupus activity indicators: negatively with C-reactive protein (CRP) (P<0.05) and erythrocyte sedimentation rate (P<0.05) and positively with complement C3 and C4 (P<0.05). The CDC27 expression was upregulated in PBMCs from SLE patients with reduced lupus activity after immunotherapy (P<0.05). Based on Receiver operating characteristic (ROC) curve analysis, the sensitivity and specificity of CDC27 in diagnosing SLE were 82.30% and 94.40%. Conclusion: The CDC27 gene, as found through WES combined with multiple analytical method may be a causative gene of lupus. CDC27 may serve as a marker for the diagnosis of SLE and is closely related to the lupus activity. We hope that the analytical method in this study will be used to screen causative genes for other diseases through small pedigrees, especially among non-close relatives.

CDC27-ODC1 Axis Promotes Metastasis, Accelerates Ferroptosis and Predicts Poor Prognosis in Neuroblastoma.

Neuroblastoma (NB) is a devastating malignancy threatening children's health, and amplification of MYCN is associated with treatment failure and a poor outcome. Here, we aimed to demonstrate the role of cell division cycle 27 (CDC27), an important core subunit of the anaphase-promoting complex, and its clinical significance in NB patients. In functional assays, we illustrated that CDC27 promoted the cell growth, metastasis and sphere-formation ability of NB cells both in vitro and in vivo. To further understand the potential mechanism, SK-N-SH cells were transfected with CDC27 siRNA, and RNA-sequencing was performed. The results revealed that downregulation of CDC27 led to markedly reduced expression of ODC1, which is a well-established direct target of MYCN. Subsequently, we further illustrated that suppression of ODC1 significantly attenuated the promotion effect of CDC27 on the proliferation, metastasis, and sphere-formation ability of NB cells, hinting that CDC27 exerted its biological behavior in NB at least partly in an ODC1-dependent manner. In addition, CDC27 rendered cells more vulnerable to ferroptosis, while knockdown of ODC1 markedly reversed the pro-ferroptotic effect of CDC27. Collectively, our data is the first to report that the CDC27/ODC1 axis promotes tumorigenesis and acts as a positive regulator of ferroptosis in NB, highlighting that CDC27 may represent a novel therapeutic strategy and prognostic biomarker in neuroblastoma.

Circular RNA circSLC8A1 inhibits the proliferation and invasion of glioma cells through targeting the miR-214-5p/CDC27 axis.

Circular RNA circSLC8A1 is one of the cancer-related circRNAs that is implicated in various cancers. However, studies focusing on the role of circSLC8A1 in glioma is rare. Here we attempted to evaluate the biological function of circSLC8A1 in glioma and explore the potential mechanism. The relative expression of circSLC8A1, miR-214-5p and CDC27 in tissues and cell lines was determined by qRT-PCR. Cell proliferation and invasion were respectively measured by CCK-8 and transwell assays. Protein level of CDC27 was analyzed by western blot. Luciferase reporter assay was performed to confirm the regulatory interaction of cirRNA-miRNA-mRNA. Lowly expressed circSLC8A1 was observed in both glioma tissues and cell lines. Further biological analyses showed that circSLC8A1 inhibits the cell proliferation and invasion of glioma cells. CircSLC8A1 directly sponged miR-214-5p and inhibited miR-214-5p expression in glioma cells. CDC27 was a direct target of miR-214-5p and could be regulated by miR-214-5p. Moreover, miR-214-5p mimics and CDC27 knockdown reversed the inhibitory effects of circSLC8A1 on cell proliferation and invasion. Taken together, our results demonstrated a tumor suppressive role of circSLC8A1 in glioma through regulation of glioma cells proliferation and invasion. The effects of circSLC8A1 were mediated by miR-214-5p/CDC27 axis. Our study provided a new understanding of the occurrence and development of glioma.

The importance of CDC27 in cancer: molecular pathology and clinical aspects.

BACKGROUND: CDC27 is one of the core components of Anaphase Promoting complex/cyclosome. The main role of this protein is defined at cellular division to control cell cycle transitions. Here we review the molecular aspects that may affect CDC27 regulation from cell cycle and mitosis to cancer pathogenesis and prognosis. MAIN TEXT: It has been suggested that CDC27 may play either like a tumor suppressor gene or oncogene in different neoplasms. Divergent variations in CDC27 DNA sequence and alterations in transcription of CDC27 have been detected in different solid tumors and hematological malignancies. Elevated CDC27 expression level may increase cell proliferation, invasiveness and metastasis in some malignancies. It has been proposed that CDC27 upregulation may increase stemness in cancer stem cells. On the other hand, downregulation of CDC27 may increase the cancer cell survival, decrease radiosensitivity and increase chemoresistancy. In addition, CDC27 downregulation may stimulate efferocytosis and improve tumor microenvironment. CONCLUSION: CDC27 dysregulation, either increased or decreased activity, may aggravate neoplasms. CDC27 may be suggested as a prognostic biomarker in different malignancies.

A novel long non-coding RNA RP11-286H15.1 represses hepatocellular carcinoma progression by promoting ubiquitination of PABPC4.

Hepatocellular carcinoma (HCC) is a malignancy found at high frequency around the world. Unfortunately, the scarcity of effective early diagnostic methods invariably results in poor outcomes. Long noncoding RNAs (lncRNAs) are known to regulate the progression of hepatocellular carcinoma (HCC). A novel lncRNA RP11-286H15.1(OTTHUMG00000186042) has been identified and associated with HCC; however, the potential role of RP11-286H15.1 in HCC remains undefined. The transcript abundance of RP11-286H15.1 in 80 pairs of HCC samples and cell lines was evaluated by qRT-PCR analysis. The functional role of RP11-286H15.1 in HCC was tested in vivo and in vitro. The mechanisms underlying the role of RP11-286H15.1 in HCC were explored by RNA pulldown, transcriptome sequencing, and RNA immunoprecipitation (RIP), ubiquitination and fluorescence in situ hybridization (FISH) assays as well as Western blot analysis. The qRT-PCR and FISH assays revealed that RP11-286H15.1 was significantly decreased in HCC, and implied a shorter survival time. RP11-286H15.1 overexpression inhibited HCC cell proliferation and metastasis in vitro and in vivo, whereas RP11-286H15.1 knockdown produced the opposite results. Furthermore, we confirmed that RP11-286H15.1 (620-750 nucleotides) binds to poly(A) binding protein 4 (PABPC4) and promotes its ubiquitination, thus, reducing the stability of TRIM37 and CDC27 mRNAs. Our study demonstrates that a novel lncRNA, RP11-286H15.1, represses HCC progression by promoting PABPC4 ubiquitination. These findings highlight potential therapeutic targets for HCC.

Hsa_circ_0044226 knockdown attenuates progression of pulmonary fibrosis by inhibiting CDC27.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disorder. Here, we performed a bioinformatics analysis using the GSE102660 dataset from the Gene Expression Omnibus database to identify differentially expressed circRNAs (DEcircRNAs) in tissues from IPF patients and healthy controls. The results identified 45 DEcircRNAs, among which expression of hsa_circ_0044226 was markedly higher in lung tissues from IPF patients than from healthy controls. Knocking down hsa_circ_0044226 expression using a targeted shRNA inhibited TGF-ß1-induced fibrosis in RLE-6TN cells and in a bleomycin-induced mouse model of IPA. The diminished TGF-ß1-induced fibrosis was associated with upregulated expression of E-cadherin and downregulated expression of α-SMA, collagen III and fibronectin 1, as well as with reduced expression of CDC27, suggesting inhibition of epithelial-to-mesenchymal transition (EMT). All of those effects were reversed by overexpression of CDC27. This suggests CDC27 overexpression abolishes the antifibrotic effect of hsa_circ_0044226 knockdown through activation of EMT. Furthermore, hsa_circ_0044226 knockdown decreased the expression of CDC27 in BLM-induced pulmonary fibrosis mouse model. Collectively then, these findings indicate that downregulation of hsa_circ_0044226 attenuates pulmonary fibrosis in vitro and in vivo by inhibiting CDC27, which in turn suppresses EMT. This suggests hsa_circ_0044226 may be a useful therapeutic target for the treatment of IPF.

Comprehensive Analysis of CDC27 Related to Peritoneal Metastasis by Whole Exome Sequencing in Gastric Cancer.

INTRODUCTION: The peritoneum is the most common metastatic site of gastric cancer and is associated with a dismal prognosis. However, there is no reliable biomarker for predicting peritoneal metastasis (PM). MATERIALS AND METHODS: Whole-exome sequencing (WES) was performed on formalin-fixed, paraffin-embedded (FFPE) samples from 63 patients with stage I-III gastric cancer and circulating tumor DNA (ctDNA) samples from 10 patients with stage IV gastric cancer. Differentially expressed genes (DEGs) were identified between the PM and non-PM groups and analyzed by multiple bioinformatics analyses. Univariate and multivariate Cox regression analyses were used to identify the risk factors for PM and a risk score model was developed. RESULTS: The number of mutant genes and the tumor mutation burden (TMB) in the PM group were higher than those in the non-PM group (p < 0.05). There was a significant positive correlation between the number of mutant genes and the TMB (R2 = 0.9997). The risk of PM was significantly higher in the high TMB group than in the low TMB group (p = 0.045). Forty-nine DEGs were identified as associated with PM in gastric cancer. CDC27 mutations were associated with a higher risk for PM and poor survival. The CDC27 mutations were located in the Apc3 region, the TPR region, and the phosphorylation region, and new mutation sites were not included in the TCGA database. Multivariable Cox regression analysis demonstrated that pathological T stage, poor tumor differentiation, Borrmann type, and CDC27 mutations were independent predictive factors of PM. A risk score model was constructed that demonstrated good performance. CONCLUSION: Through WES, we identified 49 DEGs relevant to PM in gastric cancer. CDC27 mutations were independently associated with PM by statistical and bioinformatics analyses. A risk score model was built and was demonstrated to effectively discriminate gastric cancer patients with and without PM.

CDC27 Promotes Tumor Progression and Affects PD-L1 Expression in T-Cell Lymphoblastic Lymphoma.

T-lymphoblastic lymphoma (T-LBL) is a rare hematological malignancy with highly aggressive, unique clinical manifestations, and poor prognosis. Cell division cycle 27 (CDC27) was previously reported to be a significant subunit of the anaphase-promoting complex/cyclosome. However, the specific functions and relevant mechanisms of CDC27 in T-LBL remain unknown. Through immunohistochemistry staining, we identified that CDC27 was overexpressed in T-LBL tissues and related to tumor progression and poor survival. Functional experiments demonstrated that CDC27 promoted proliferation in vivo and in vitro. Further experiment suggested the role of CDC27 in facilitating G1/S transition and promoting the expression of Cyclin D1 and CDK4. Then the effect of CDC27 in inhibiting apoptosis was also identified. Furthermore, we found a positive correlation between the expression of CDC27 and Programmed death ligand-1 (PD-L1) by immunohistochemistry staining. The interaction between CDC27 and PD-L1 was also proved by western blot, luciferase gene reporter assay and immunofluorescence. Taken together, our results showed that CDC27 contributes to T-LBL progression and there is a positive correlation between PD-L1 and CDC27, which offers novel perspectives for future studies on targeting CDC27 in T-LBL.

Corrigendum: CDC27 Promotes Tumor Progression and Affects PD-L1 Expression in T-Cell Lymphoblastic Lymphoma.

[This corrects the article DOI: 10.3389/fonc.2020.00488.].

CDC27 Facilitates Gastric Cancer Cell Proliferation, Invasion and Metastasis via Twist-Induced Epithelial-Mesenchymal Transition.

BACKGROUND/AIMS: Lymph node metastasis is the primary cause of cancer-related death among patients with gastric cancer (GC), and cell division cycle 27 (CDC27) promotes the metastasis and epithelial-mesenchymal transition in many cancers. Till now, the mechanisms underlying CDC27-induced the epithelial-mesenchymal transition (EMT) of GC are still unclear. METHODS: We analyzed the expression levels of CDC27 and EMT-related biomarkers using immunohistochemistry and Western blot in 60 cases of GC tissues, and then GC cells with CDC27 shRNAs or plasmids were subjected to in vitro and in vivo assays, including CCK-8, wound healing and transwell assays. RESULTS: The CDC27 expression was obviously increased in GC tissues, and significantly correlates with EMT-related biomarkers, lymph node metastasis and poor 5-year overall survival. Additionally, in vitro and in vivo assays demonstrated that silencing of CDC27 expression effectively inhibited GC cell proliferation, invasion and metastasis. Conversely, CDC27 overexpression led to the opposite results. Finally, we demonstrated that Twist shRNA inhibited CDC27-meditated invasion and EMT of GC cells. CONCLUSION: CDC27 facilitates gastric cancer cell proliferation, invasion and metastasis via Twist-induced EMT; thus, this study offered a new therapy method for GC patients.

Germline and somatic variations influence the somatic mutational signatures of esophageal squamous cell carcinomas in a Chinese population.

BACKGROUND: Esophageal squamous cell carcinomas (ESCC) is the fourth most lethal cancer in China. Previous studies reveal several highly conserved mutational processes in ESCC. However, it remains unclear what are the true regulators of the mutational processes. RESULTS: We analyzed the somatic mutational signatures in 302 paired whole-exome sequencing data of ESCC in a Chinese population for potential regulators of the mutational processes. We identified three conserved subtypes based on the mutational signatures with significantly different clinical outcomes. Our results show that patients of different subpopulations of Chinese differ significantly in the activity of the "NpCpG" signature (FDR = 0.00188). In addition, we report ZNF750 and CDC27, of which the somatic statuses and the genetic burdens consistently influence the activities of specific mutational signatures in ESCC: the somatic ZNF750 status is associated with the AID/APOBEC-related mutational process (FDR = 0.0637); the somatic CDC27 copy-number is associated with the "NpCpG" (FDR = 0.00615) and the AID/APOBEC-related mutational processes (FDR = 8.69 × 10- 4). The burdens of germline variants in the two genes also significantly influence the activities of the same somatic mutational signatures (FDR < 0.1). CONCLUSIONS: We report multiple factors that influence the mutational processes in ESCC including: the subpopulations of Chinese; the germline and somatic statuses of ZNF750 and CDC27 and exposure to alcohol and tobacco. Our findings based on the evidences from both germline and somatic levels reveal potential genetic regulators of the somatic mutational processes and provide insights into the biology of esophageal carcinogenesis.

Genetic landscape of sporadic vestibular schwannoma.

OBJECTIVE Vestibular schwannoma (VS) is a benign tumor with associated morbidities and reduced quality of life. Except for mutations in NF2, the genetic landscape of VS remains to be elucidated. Little is known about the effect of Gamma Knife radiosurgery (GKRS) on the VS genome. The aim of this study was to characterize mutations occurring in this tumor to identify new genes and signaling pathways important for the development of VS. In addition, the authors sought to evaluate whether GKRS resulted in an increase in the number of mutations. METHODS Forty-six sporadic VSs, including 8 GKRS-treated tumors and corresponding blood samples, were subjected to whole-exome sequencing and tumor-specific DNA variants were called. Pathway analysis was performed using the Ingenuity Pathway Analysis software. In addition, multiplex ligation-dependent probe amplification was performed to characterize copy number variations in the NF2 gene, and microsatellite instability testing was done to investigate for DNA replication error. RESULTS With the exception of a single sample with an aggressive phenotype that harbored a large number of mutations, most samples showed a relatively low number of mutations. A median of 14 tumor-specific mutations in each sample were identified. The GKRS-treated tumors harbored no more mutations than the rest of the group. A clustering of mutations in the cancer-related axonal guidance pathway was identified (25 patients), as well as mutations in the CDC27 (5 patients) and USP8 (3 patients) genes. Thirty-five tumors harbored mutations in NF2 and 16 tumors had 2 mutational hits. The samples without detectable NF2 mutations harbored mutations in genes that could be linked to NF2 or to NF2-related functions. None of the tumors showed microsatellite instability. CONCLUSIONS The genetic landscape of VS seems to be quite heterogeneous; however, most samples had mutations in NF2 or in genes that could be linked to NF2. The results of this study do not link GKRS to an increased number of mutations.

CDC27 Induces Metastasis and Invasion in Colorectal Cancer via the Promotion of Epithelial-To-Mesenchymal Transition.

Distant metastasis is the primary cause of cancer-related death among patients with colorectal cancer (CRC), and the discovery of novel therapeutic targets by further exploring the molecular mechanisms of CRC metastasis is therefore urgently needed. We previously illustrated that CDC27 overexpression promoted proliferation in CRC, but no studies have emphasized the role of CDC27 in cancer metastasis thus far. Our previous data indicated that the expression of CDC27 was significantly associated with distant metastasis in patient tissues, and therefore, in this study, we focused on the investigation of the potential mechanisms of CDC27 in CRC metastasis. The results revealed that CDC27 promoted the metastasis, invasion and sphere-formation capacity of DLD1 cells, but that the inhibition of CDC27 in HCT116 cells suppressed metastasis both in vitro and in vivo. Mechanistic analyses revealed that CDC27 promoted epithelial-to-mesenchymal transition (EMT), as demonstrated by the reduced expression of the epithelial markers ZO-1 and E-cadherin and the enhanced expression of the mesenchymal markers ZEB1 and Snail in HCT116 and DLD1 cells. Further mechanistic investigation indicated that CDC27 promoted metastasis and sphere-formation capacity in an ID1-dependent manner. In conclusion, we first demonstrated the role of CDC27 in cancer metastasis and showed that CDC27 may serve as a promising therapeutic target for CRC.

mir-218-2 promotes glioblastomas growth, invasion and drug resistance by targeting CDC27.

Glioma has become a significant global health problem with substantial morbidity and mortality, underscoring the importance of elucidating its underlying molecular mechanisms. Recent studies have identified mir-218 as an anti-oncogene; however, the specific functions of mir-218-1 and mir-218-2 remain unknown, especially the latter. The objective of this study was to further investigate the role of mir-218-2 in glioma. Our results indicated that mir-218-2 is highly overexpressed in glioma. Furthermore, we showed that mir-218-2 is positively correlated with the growth, invasion, migration, and drug susceptibility (to ß-lapachone) of glioma cells. In vitro, the overexpression of mir-218-2 promoted glioma cell proliferation, invasion, and migration. In addition, the overexpression of mir-218-2 in vivo was found to increase glioma tumor growth. Accordingly, the inhibition of mir-218-2 resulted in the opposite effects. Cell division cycle 27 (CDC27), the downstream target of mir-218-2, is involved in the regulation of glioma cells. Our results indicate that the overexpression of CDC27 counteracted the function of mir-218-2 in glioma cells. These novel findings provide new insight in the application of mir-218-2 as a potential glioma treatment.