Gene Summary

Gene:CCNE1; cyclin E1
Aliases: CCNE, pCCNE1
Summary:The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a regulatory subunit of CDK2, whose activity is required for cell cycle G1/S transition. This protein accumulates at the G1-S phase boundary and is degraded as cells progress through S phase. Overexpression of this gene has been observed in many tumors, which results in chromosome instability, and thus may contribute to tumorigenesis. This protein was found to associate with, and be involved in, the phosphorylation of NPAT protein (nuclear protein mapped to the ATM locus), which participates in cell-cycle regulated histone gene expression and plays a critical role in promoting cell-cycle progression in the absence of pRB. [provided by RefSeq, Apr 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:G1/S-specific cyclin-E1
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
Show (37)
Pathways:What pathways are this gene/protein implicaed in?
Show (9)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Transforming Growth Factor beta
  • Gene Expression Profiling
  • DNA Copy Number Variations
  • Oncogene Proteins
  • Polymorphism
  • Cyclin-Dependent Kinase 2
  • Trastuzumab
  • Reproducibility of Results
  • Protein Structure, Tertiary
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Apoptosis
  • PCNA
  • Vorinostat
  • Oligonucleotide Array Sequence Analysis
  • Breast Cancer
  • Phenotype
  • Regression Analysis
  • Chromosome 19
  • Ploidies
  • Biomarkers, Tumor
  • Messenger RNA
  • Up-Regulation
  • Staging
  • Cell Cycle
  • Cyclin D1
  • CCNE1
  • Roscovitine
  • Cancer Gene Expression Regulation
  • Cyclin E
  • Cell Proliferation
  • Gene Amplification
  • Transfection
  • Signal Transduction
  • Liver Cancer
  • Gene Dosage
  • Osteosarcoma
  • Cell Cycle Proteins
  • Tumor Suppressor Proteins
  • Mutation
  • cdc25 Phosphatases
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CCNE1 (cancer-related)

Zhang X, Jin K, Luo JD, et al.
MicroRNA-107 inhibits proliferation of prostate cancer cells by targeting cyclin E1.
Neoplasma. 2019; 2019 [PubMed] Related Publications
Previous studies have reported that miR-107 could be utilized as a potential peripheral biomarker in prostate cancer (PCa). However, the specific functions of miR-107 in prostate cancer and its relevant mechanisms are still unknown. The aim of this research was to investigate the cellular functions of miR-107 in PCa and reveal the relevant mechanisms. MicroRNA tailing quantitative real-time PCR (qRT-PCR) was adopted to measure the expression of miR-107 in PCa cell line DU145 and PC3, as well as in normal prostate cell line RWPE-1. The miR-107 expression pattern in PCa tissues and paired peritumoral tissues were determined by Chromogenic In Situ Hybridization (CISH). Cell viability, colony formation, flow cytometry cell cycle and apoptosis, wound healing, and Transwell migration assays were performed to study the functions of miR-107 in PCa cells. Further, qRT-PCR, western blot analysis, and dual-luciferase reporter assays were conducted to verify the target of miR-107 in PCa. The results demonstrated that, miR-107 was down-regulated in PCa cells and tissues compared with normal prostate cells and peritumoral tissues, and over-expression of miR-107 suppressed the proliferation and induced G1/S arrest of PCa cells but had no effects on apoptosis or cell motility of PCa cells. MiR-107 was found to target cyclin E1 (CCNE1) in PCa cells by directly binding to its 3'-UTR. In conclusion, miR-107 could be a potential tumor suppressor in PCa, and the restoration of miR-107 might provide a new therapeutic option for PCa.

Grodzik M, Szczepaniak J, Strojny-Cieslak B, et al.
Diamond Nanoparticles Downregulate Expression of
Molecules. 2019; 24(8) [PubMed] Free Access to Full Article Related Publications
Our previous studies have shown that diamond nanoparticles (NDs) exhibited antiangiogenic and proapoptotic properties in vitro in glioblastoma multiforme (GBM) cells and in tumors in vivo. Moreover, NDs inhibited adhesion, leading to the suppression of migration and invasion of GBM. In the present study, we hypothesized that the NDs might also inhibit proliferation and cell cycle in glioma cells. Experiments were performed in vitro with the U87 and U118 lines of GBM cells, and for comparison, the Hs5 line of stromal cells (normal cells) after 24 h and 72 h of treatment. The analyses included cell morphology, cell death, viability, and cell cycle analysis, double timing assay, and gene expression (

Tak J, Sabarwal A, Shyanti RK, Singh RP
Berberine enhances posttranslational protein stability of p21/cip1 in breast cancer cells via down-regulation of Akt.
Mol Cell Biochem. 2019; 458(1-2):49-59 [PubMed] Related Publications
Berberine has shown anticancer properties and has potential for a chemopreventive and/or chemotherapeutic agent for breast cancer. Berberine showed cytotoxicity to breast cancer cells, with an increase in the levels of p21/cip1 and p27/kip1, cyclin-dependent kinase inhibitors (CDKI), but mechanisms involved in up-regulating these molecules are largely unknown. Herein, we studied the key regulatory mechanisms involved in berberine-mediated up-regulation of p21/cip1 and p27/kip1. Berberine treatment for 24 and 48 h decreased the number of cells by 44-84% (P < 0.0001) and 38-78% (P < 0.0001), and increased cell death by 12-17% (P < 0.005) and 38-78% (P < 0.0001) in MCF-7 and MDA-MB-231 cells, respectively. Cells were arrested in G1 phase by berberine which was accompanied with up-regulation of mRNA and protein level of both p21/cip1 and p27/kip1. Berberine decreased the expression of protein levels of cyclin D1, cyclin E, CDK2, CDK4, and CDK6 to cause G1 phase arrest. Berberine caused nuclear localization of p21/cip1 in both the cell lines. Our data for the first time showed that the post-translational stability of both the proteins was strongly increased by berberine as examined by cycloheximide chase assay. Inhibition of Akt was associated with berberine-mediated up-regulation of p21/cip1 and also led to a decrease in cell viability accompanied with significant G1 phase cell cycle arrest. Our study revealed that berberine not only up-regulates mRNA and protein levels of p21/cip1 and p27/kip1 but also increases their nuclear localization and post-translational protein stability. Further, Akt inhibition was found to mediate berberine-mediated up-regulation of p21/cip1 but not the p27/kip1.

Wang W, Gao W, Zhang L, et al.
Deoxypodophyllotoxin inhibits cell viability and invasion by blocking the PI3K/Akt signaling pathway in human glioblastoma cells.
Oncol Rep. 2019; 41(4):2453-2463 [PubMed] Related Publications
Deoxypodophyllotoxin (DPT) is a natural chemical that has been demonstrated to inhibit cellular viability and motility in various cancer cell types. Although previous studies have indicated that programmed cell death and cell cycle arrest are involved in the suppression of glioma development by DPT, the underlying mechanism has not been fully explored. Different methods were used to the elucidate the mechanisms of DPT that inhibit the malignant behavior of glioma cells. Cellular viability was assessed by MTT assay. Relative protein and mRNA expression levels were detected by western blot analysis and reverse transcription‑quantitative polymerase chain reaction analyses, respectively. Cell cycle distribution and the apoptosis rate were detected by flow cytometry. Hochest 33258 staining was also performed to detect apoptosis. Transwell assays without and with Matrigel were used to assess migration and invasion abilities, respectively. It was determined that DPT suppressed cellular viability by inducing cell cycle arrest at the G1/S phase by targeting the phosphatidylinositol 4,5‑bisphosphate 3‑kinase (PI3K)/RAC‑α serine/threonine‑protein kinase (Akt)‑cyclin‑dependent kinase inhibitor 1‑cyclin‑dependent kinase 2/cyclin E signaling cascades. Additionally, DPT significantly enhanced apoptosis by attenuating the PI3K/Akt‑mediated suppression of Bcl‑2‑associated agonist of cell death expression, which was accompanied by an increased apoptosis regulator BAX/apoptosis regulator Bcl‑2 ratio. Furthermore, DPT downregulated the invasiveness of glioma cells by hindering PI3K/Akt‑matrix metalloproteinase (MMP)9/MMP2 signaling pathways. In conclusion, DPT effectively inhibited the expression of PI3K and downregulated PI3K/Akt‑mediated signaling pathways to prevent glioblastoma progression.

Zhang J, Cai M, Jiang D, Xu L
Upregulated LncRNA-CCAT1 promotes hepatocellular carcinoma progression by functioning as miR-30c-2-3p sponge.
Cell Biochem Funct. 2019; 37(2):84-92 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death over the world. It is well studied that long noncoding RNA colon cancer-associated transcript-1 (CCAT1) played important roles in variety of cancers promoting cell proliferation and metastasis by acting as a competing endogenous RNA (ceRNA) of microRNAs. However, whether CCAT1 could regulate HCC by serving as a ceRNA of microRNA remains to be revealed. In this study, we demonstrated that CCAT1 was highly expressed in HCC tissues and remarkably associated with metastasis. With a bioinformatics prediction and functional assay validation, we found a binding site of miR-30c-2-3p on CCAT1, which was important for CCAT1 to promote cell proliferation. Interestingly, we further revealed a novel recognition site for miR-30c-2-3p on the 3'UTR of CCNE1 by mutative method, luciferase assay, and cell viability confirmation. In general, CCAT1 regulate the expression of CCNE1 by acting as a ceRNA to sponge miR-30c-2-3p in regulating the cell proliferation of HCC. These results suggest that CCAT1 may be a new therapy target for HCC in the future. SIGNIFICANCE OF THE STUDY: Our findings may broaden the understanding of the role of CCAT1 in tumorigenesis and may provide a new therapy target for HCC.

Viswanathan A, Kute D, Musa A, et al.
2-(2-(2,4-dioxopentan-3-ylidene)hydrazineyl)benzonitrile as novel inhibitor of receptor tyrosine kinase and PI3K/AKT/mTOR signaling pathway in glioblastoma.
Eur J Med Chem. 2019; 166:291-303 [PubMed] Related Publications
Nerve growth factor receptor (NGFR), a member of kinase protein, is emerging as an important target for Glioblastoma (GBM) treatment. Overexpression of NGFR is observed in many metastatic cancers including GBM, promoting tumor migration and invasion. Hydrazones have been reported to effectively interact with receptor tyrosine kinases (RTKs). We report herein the synthesis of 23 arylhydrazones of active methylene compounds (AHAMCs) compounds and their anti-proliferative activity against GBM cell lines, LN229 and U87. Compound R234, 2-(2-(2,4-dioxopentan-3-ylidene)hydrazineyl)benzonitrile, was identified as the most active anti-neoplastic compound, with the IC

Zhao ZM, Yost SE, Hutchinson KE, et al.
CCNE1 amplification is associated with poor prognosis in patients with triple negative breast cancer.
BMC Cancer. 2019; 19(1):96 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Triple negative breast cancer (TNBC) is aggressive with limited treatment options upon recurrence. Molecular discordance between primary and metastatic TNBC has been observed, but the degree of biological heterogeneity has not been fully explored. Furthermore, genomic evolution through treatment is poorly understood. In this study, we aim to characterize the genomic changes between paired primary and metastatic TNBCs through transcriptomic and genomic profiling, and to identify genomic alterations which may contribute to chemotherapy resistance.
METHODS: Genomic alterations and mRNA expression of 10 paired primary and metastatic TNBCs were determined through targeted sequencing, microarray analysis, and RNA sequencing. Commonly mutated genes, as well as differentially expressed and co-expressed genes were identified. We further explored the clinical relevance of differentially expressed genes between primary and metastatic tumors to patient survival using large public datasets.
RESULTS: Through gene expression profiling, we observed a shift in TNBC subtype classifications between primary and metastatic TNBCs. A panel of eight cancer driver genes (CCNE1, TPX2, ELF3, FANCL, JAK2, GSK3B, CEP76, and SYK) were differentially expressed in recurrent TNBCs, and were also overexpressed in TCGA and METABRIC. CCNE1 and TPX2 were co-overexpressed in TNBCs. DNA mutation profiling showed that multiple mutations occurred in genes comprising a number of potentially targetable pathways including PI3K/AKT/mTOR, RAS/MAPK, cell cycle, and growth factor receptor signaling, reaffirming the wide heterogeneity of mechanisms driving TNBC. CCNE1 amplification was associated with poor overall survival in patients with metastatic TNBC.
CONCLUSIONS: CCNE1 amplification may confer resistance to chemotherapy and is associated with poor overall survival in TNBC.

Deng Z, Chai J, Zeng Q, et al.
The anticancer properties and mechanism of action of tablysin-15, the RGD-containing disintegrin, in breast cancer cells.
Int J Biol Macromol. 2019; 129:1155-1167 [PubMed] Related Publications

Yang R, Xing L, Zheng X, et al.
The circRNA circAGFG1 acts as a sponge of miR-195-5p to promote triple-negative breast cancer progression through regulating CCNE1 expression.
Mol Cancer. 2019; 18(1):4 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In recent years, circular RNAs (circRNAs), a new star of non-coding RNA, have been emerged as vital regulators and gained much attention for involvement of initiation and progression of diverse kinds of human diseases, especially cancer. However, regulatory role, clinical significance and underlying mechanisms of circRNAs in triple-negative breast cancer (TNBC) still remain largely unknown.
METHODS: Here, the expression profile of circRNAs in 4 pairs of TNBC tissues and adjacent non-tumor tissues was analyzed by RNA-sequencing. Quantitative real-time PCR and in situ hybridization were used to determine the level and prognostic values of circAGFG1 in two TNBC cohorts. Then, functional experiments in vitro and in vivo were performed to investigate the effects of circAGFG1 on tumor growth and metastasis in TNBC. Mechanistically, fluorescent in situ hybridization, dual luciferase reporter assay, RNA pull-down and RNA immunoprecipitation experiments were performed to confirm the interaction between circAGFG1 and miR-195-5p in TNBC.
RESULTS: We found that circAGFG1 was evidently up-regulated in TNBC, and its level was correlated with clinical stage, pathological grade and poor prognosis of patients with TNBC. The results indicated that circAGFG1 could promote TNBC cell proliferation, mobility and invasion as well as tumorigenesis and metastasis in vivo. Mechanistic analysis showed that circAGFG1 may act as a ceRNA (competing endogenous RNA) of miR-195-5p to relieve the repressive effect of miR-195-5p on its target cyclin E1 (CCNE1).
CONCLUSIONS: Our findings suggest that circAGFG1 promotes TNBC progression through circAGFG1/miR-195-5p/CCNE1 axis and it may serve as a new diagnostic marker or target for treatment of TNBC patients.

Zhang S, Pei Y, Lang F, et al.
EBNA3C facilitates RASSF1A downregulation through ubiquitin-mediated degradation and promoter hypermethylation to drive B-cell proliferation.
PLoS Pathog. 2019; 15(1):e1007514 [PubMed] Free Access to Full Article Related Publications
EBV latent antigen 3C (EBNA3C) is essential for EBV-induced primary B-cell transformation. Infection by EBV induces hypermethylation of a number of tumor suppressor genes, which contributes to the development of human cancers. The Ras association domain family isoform 1A (RASSF1A) is a cellular tumor suppressor, which regulates a broad range of cellular functions, including apoptosis, cell-cycle arrest, mitotic arrest, and migration. However, the expression of RASSF1A is lost in many human cancers by epigenetic silencing. In the present study, we showed that EBNA3C promoted B-cell transformation by specifically suppressing the expression of RASSF1A. EBNA3C directly interacted with RASSF1A and induced RASSF1A degradation via the ubiquitin-proteasome-dependent pathway. SCFSkp2, an E3-ubiquitin ligase, was recruited by EBNA3C to enhance RASSF1A degradation. Moreover, EBNA3C decreased the transcriptional activity of RASSF1A promoter by enhancing its methylation through EBNA3C-mediated modulation of DNMTs expression. EBNA3C also inhibited RASSF1A-mediated cell apoptosis, disrupted RASSF1A-mediated microtubule and chromosomal stability, and promoted cell proliferation by upregulating Cyclin D1 and Cyclin E expression. Our data provides new details, which sheds light on additional mechanisms by which EBNA3C can induce B-cell transformation. This will also facilitate the development of novel therapeutic approaches through targeting of the RASSF1A pathway.

Joseph C, Arshad M, Kurozomi S, et al.
Overexpression of the cancer stem cell marker CD133 confers a poor prognosis in invasive breast cancer.
Breast Cancer Res Treat. 2019; 174(2):387-399 [PubMed] Related Publications
PURPOSE: CD133/ prominin 1 is a cancer stem cell marker associated with cancer progression and patient outcome in a variety of solid tumours, but its role in invasive breast cancer (BC) remains obscure. The current study aims to assess the prognostic value of CD133 expression in early invasive BC.
METHODS: CD133 mRNA was assessed in the METABRIC cohort and at the proteomic level using immunohistochemistry utilising a large well-characterised BC cohort. Association with clinicopathological characteristics, expression of other stem cell markers and patient outcome were evaluated.
RESULTS: High expression of CD133 either in mRNA or protein levels was associated with characteristics of poor prognosis including high tumour grade, larger tumour size, high Nottingham Prognostic Index, HER2 positivity and hormonal receptor negativity (all; p < 0.001). High CD133 expression was positively associated with proliferation biomarkers including p16, Cyclin E and Ki67 (p < 0.01). Tumours expressing CD133 showed higher expression of other stem cell markers including CD24, CD44, SOX10, ALDHA3 and ITGA6. High expression of CD133 protein was associated with shorter BC-specific survival (p = 0.026). Multivariate analysis revealed that CD133 protein expression was an independent risk factor for shorter BC-specific survival (p = 0.038).
CONCLUSION: This study provides evidence for the prognostic value of CD133 in invasive BC. A strong positive association of BC stem cell markers is observed at the protein level. Further studies to assess the value of stem cell markers individually or in combination in BC is warranted.

Lin C, Yuan G, Hu Z, et al.
Bioinformatics analysis of the interactions among lncRNA, miRNA and mRNA expression, genetic mutations and epigenetic modifications in hepatocellular carcinoma.
Mol Med Rep. 2019; 19(2):1356-1364 [PubMed] Related Publications
The present study aimed to investigate the regulatory networks involving long noncoding RNA (lncRNA), microRNA (miRNA), mRNA, genetic mutations and epigenetic modifications in hepatocellular carcinoma (HCC) by analyzing datasets from The Cancer Genome Atlas (TCGA) database. TCGA was mined, and miRNAs, lncRNAs and mRNAs that were differentially expressed in HCC were identified using R software. A gene regulatory network was constructed using Cytoscape software. Representative genes were selected for functional enrichment analysis using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. The associations among various proteins and protein networks were identified using the online software Search Tool for the Retrieval of Interacting Genes/Proteins. The cBioPortal database was used to analyze the association between genetic mutations and epigenetic modification, and the development of HCC. A total of 35 mRNAs were predicted to be targeted by 77 lncRNAs and 16 miRNAs, establishing a lncRNA‑miRNA‑mRNA regulatory network for HCC. Multivariable Cox regression analysis suggested that long intergenic non‑protein coding RNA 200, miRNA‑137, PDZ binding kinase and DNA polymerase θ were independent prognostic factors. In a regulatory network centered on miRNA‑424, six mRNA target genes were associated with HCC survival rates. Protein‑protein interaction analysis suggested that cell division cycle 25A (CDC25A) interacted with centrosomal protein 55 (CEP55), claspin, E2F transcription factor 7 and cyclin E1 (CCNE1. Mutations in CEP55 affected overall survival and disease‑free survival in HCC, whereas, mutations in CDC25A affected overall survival, and mutations in E2F7 affected disease‑free survival. Decreased methylation levels of CEP55, CDC25A and CCNE1 were associated with vascular invasion. The survival rate of patients with hypermethylation of CCNE1 and CEP55 was significantly associated with the rate of methylation of these loci. The present study provides an integrated bioinformatics analysis of gene expression, genetic mutations and epigenetic modifications that may be associated with the development of HCC.

Bayard Q, Meunier L, Peneau C, et al.
Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress.
Nat Commun. 2018; 9(1):5235 [PubMed] Free Access to Full Article Related Publications
Cyclins A2 and E1 regulate the cell cycle by promoting S phase entry and progression. Here, we identify a hepatocellular carcinoma (HCC) subgroup exhibiting cyclin activation through various mechanisms including hepatitis B virus (HBV) and adeno-associated virus type 2 (AAV2) insertions, enhancer hijacking and recurrent CCNA2 fusions. Cyclin A2 or E1 alterations define a homogenous entity of aggressive HCC, mostly developed in non-cirrhotic patients, characterized by a transcriptional activation of E2F and ATR pathways and a high frequency of RB1 and PTEN inactivation. Cyclin-driven HCC display a unique signature of structural rearrangements with hundreds of tandem duplications and templated insertions frequently activating TERT promoter. These rearrangements, strongly enriched in early-replicated active chromatin regions, are consistent with a break-induced replication mechanism. Pan-cancer analysis reveals a similar signature in BRCA1-mutated breast and ovarian cancers. Together, this analysis reveals a new poor prognosis HCC entity and a rearrangement signature related to replication stress.

Roskoski R
Cyclin-dependent protein serine/threonine kinase inhibitors as anticancer drugs.
Pharmacol Res. 2019; 139:471-488 [PubMed] Related Publications
Cyclins and cyclin-dependent protein kinases (CDKs) are important proteins that are required for the regulation and expression of the large number of components necessary for the passage through the cell cycle. The concentrations of the CDKs are generally constant, but their activities are controlled by the oscillation of the cyclin levels during each cell cycle. Additional CDK family members play significant roles in a wide range of activities including gene transcription, metabolism, and neuronal function. In response to mitogenic stimuli, cells in the G1-phase of the cell cycle produce D type cyclins that activate CDK4/6. These activated enzymes catalyze the monophosphorylation of the retinoblastoma protein. Subsequently, CDK2-cyclin E catalyzes the hyperphosphorylation of Rb that promotes the release and activation of the E2F transcription factor, which in turn lead to the biosynthesis of dozens of proteins required for cell cycle progression. Consequently, cells pass the G1-restriction point and are committed to complete cell division in the absence of mitogenic stimulation. CDK2-cyclin A, CDK1-cyclin A, and CDK1-cyclin B are required for S-, G2-, and M-phase progression. A crucial mechanism in controlling cell cycle progression is the precise timing of more than 32,000 phosphorylation and dephosphorylation reactions catalyzed by a network of protein kinases and phosphoprotein phosphatases as determined by mass spectrometry. Increased cyclin or CDK expression or decreased levels of endogenous CDK modulators/inhibitors such as INK4 or CIP/KIP have been observed in a wide variety of carcinomas, hematological malignancies, and sarcomas. The pathogenesis of neoplasms because of mutations in the CDKs are rare. Owing to their role in cell proliferation, CDKs represent natural targets for anticancer therapies. Palbociclib, ribociclib, and abemaciclib are FDA-approved CDK4/6 inhibitors used in the treatment of breast cancer. These drugs have IC

Jang YG, Hwang KA, Choi KC
Rosmarinic Acid, a Component of Rosemary Tea, Induced the Cell Cycle Arrest and Apoptosis through Modulation of HDAC2 Expression in Prostate Cancer Cell Lines.
Nutrients. 2018; 10(11) [PubMed] Free Access to Full Article Related Publications
Rosmarinic acid (RA), a main phenolic compound contained in rosemary which is used as tea, oil, medicine and so on, has been known to present anti-inflammatory, anti-oxidant and anti-cancer effects. Histone deacetylases (HDACs) are enzymes that play important roles in gene expression by removing the acetyl group from histone. The aberrant expression of HDAC in human tumors is related with the onset of human cancer. Especially, HDAC2, which belongs to HDAC class I composed of HDAC 1, 2, 3 and 8, has been reported to be highly expressed in prostate cancer (PCa) where it downregulates the expression of p53, resulting in an inhibition of apoptosis. The purpose of this study is to investigate the effect of RA in comparison with suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor used as an anti-cancer agent, on survival and apoptosis of PCa cell lines, PC-3 and DU145, and the expression of HDAC. RA decreased the cell proliferation in cell viability assay, and inhibited the colony formation and tumor spheroid formation. Additionally, RA induced early- and late-stage apoptosis of PC-3 and DU145 cells in Annexin V assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, respectively. In western blot analysis, RA inhibited the expression of HDAC2, as SAHA did. Proliferating cell nuclear antigen (PCNA), cyclin D1 and cyclin E1 were downregulated by RA, whereas p21 was upregulated. In addition, RA modulated the protein expression of intrinsic mitochondrial apoptotic pathway-related genes, such as Bax, Bcl-2, caspase-3 and poly (ADP-ribose) polymerase 1 (

Yang SYC, Lheureux S, Karakasis K, et al.
Landscape of genomic alterations in high-grade serous ovarian cancer from exceptional long- and short-term survivors.
Genome Med. 2018; 10(1):81 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Patients diagnosed with high-grade serous ovarian cancer (HGSOC) who received initial debulking surgery followed by platinum-based chemotherapy can experience highly variable clinical responses. A small percentage of women experience exceptional long-term survival (long term (LT), 10+ years), while others develop primary resistance to therapy and succumb to disease in less than 2 years (short term (ST)). To improve clinical management of HGSOC, there is a need to better characterize clinical and molecular profiles to identify factors that underpin these disparate survival responses.
METHODS: To identify clinical and tumor molecular biomarkers associated with exceptional clinical response or resistance, we conducted an integrated clinical, exome, and transcriptome analysis of 41 primary tumors from LT (n = 20) and ST (n = 21) HGSOC patients.
RESULTS: Younger age at diagnosis, no residual disease post debulking surgery and low CA125 levels following surgery and chemotherapy were clinical characteristics of LT. Tumors from LT survivors had increased somatic mutation burden (median 1.62 vs. 1.22 non-synonymous mutations/Mbp), frequent BRCA1/2 biallelic inactivation through mutation and loss of heterozygosity, and enrichment of activated CD4+, CD8+ T cells, and effector memory CD4+ T cells. Characteristics of ST survival included focal copy number gain of CCNE1, lack of BRCA mutation signature, low homologous recombination deficiency scores, and the presence of ESR1-CCDC170 gene fusion.
CONCLUSIONS: Our findings suggest that exceptional long- or short-term survival is determined by a concert of clinical, molecular, and microenvironment factors.

Wang D, Xu Y, Feng L, et al.
RGS5 decreases the proliferation of human ovarian carcinoma‑derived primary endothelial cells through the MAPK/ERK signaling pathway in hypoxia.
Oncol Rep. 2019; 41(1):165-177 [PubMed] Free Access to Full Article Related Publications
Regulator of G‑protein signaling 5 (RGS5), a tissue‑specific signal‑regulating molecule, plays a key role in the development of the vasculature. It was recently found that RGS5 is abundantly expressed in epithelial ovarian cancer (EOC) compared with the normal ovaries. However, the distribution of RGS5 in EOC and its significance require further investigation. The aim of the present study was to investigate the expression of RGS5 in EOC, as well as its association with cancer differentiation, metastasis and clinicopathological parameters. Immunohistochemistry (IHC), western blotting, RT‑PCR, wound‑healing, cell proliferation and flow cytometric assays were the methods used in the present study. RGS5 was highly expressed in the cytoplasm of ovarian carcinoma cells and in microvascular structures. The expression of RGS5 in EOC was negatively associated with peritoneal metastasis (P=0.004), but it was not found to be associated with age, tumor size, clinical stage or lymph node metastasis (P>0.05). EOC patients with high RGS5 expression had a prolonged progression‑free survival (72.34±8.41 vs. 43.56±5.41 months, P<0.001). High expression of RGS5 was correlated with significantly lower microvascular density (MVD) as indicated by the expression of CD34, whereas the opposite was observed in tissues with low RGS5 expression (P<0.05). Hypoxia increased RGS5 expression in ovarian carcinoma‑derived endothelial cells (ODMECs), whereas the proliferative capacity of ODMECs exhibited a significant increase following RNAi‑mediated reduction of RGS5 expression. These data indicated that RGS5 plays a key role in angiogenesis in ovarian carcinoma. In addition, RGS5 downregulated the expression of the downstream proteins CDC25A, CDK2 and cyclin E, which are mediated by the mitogen‑activated protein kinase/extracellular signal‑regulated kinase pathway, causing ODMEC arrest in the G1 phase of the cell cycle under hypoxic conditions. Collectively, our data indicated that RGS5 is crucial for the occurrence and development of ovarian cancer, and that RGS5 and its signaling pathway may serve as anti‑angiogenesis targets for the treatment of ovarian cancer.

Li X, Dong M, Zhou J, et al.
C6orf106 accelerates pancreatic cancer cell invasion and proliferation via activating ERK signaling pathway.
Mol Cell Biochem. 2019; 454(1-2):87-95 [PubMed] Related Publications
C6orf106 was highly expressed in lung and breast cancer, and proposed as clinicopathologic factor for the development of those types of cancer. However, its expression in pancreatic cancer and the mechanism that C6orf106 functions as an oncogene has not been confirmed. In the present study, we found that C6orf106 was also up-regulated in pancreatic cancer tissues and cell lines. Furthermore, C6orf106 expression was associated with advanced T stage (P = 0.010), positive regional lymph node metastasis (P = 0.012), and advanced TNM stage (P = 0.006). In vitro experiments also showed that C6orf106 served a tumor enhancer in pancreatic cancer, through increasing the expression of Snail, Cyclin D1 and Cyclin E1, and reducing the expression of E-cadherin via activating extracellular-signal-regulated kinase (ERK)- p90-kDa ribosomal S6 kinases (P90RSK) signaling pathway. The addition of ERK inhibitor PD98059 counteracted the upregulation of Snail, Cyclin D1 and Cyclin E1, and restored the expression of E-cadherin, which indicated that C6orf106 was an upstream factor of ERK signaling pathway. Taken together, the present study indicates that C6orf106 facilitates invasion and proliferation of pancreatic cancer cells, likely via activating ERK-P90RSK signaling pathway.

Yuan J, Hu Z, Mahal BA, et al.
Integrated Analysis of Genetic Ancestry and Genomic Alterations across Cancers.
Cancer Cell. 2018; 34(4):549-560.e9 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
Disparities in cancer care have been a long-standing challenge. We estimated the genetic ancestry of The Cancer Genome Atlas patients, and performed a pan-cancer analysis on the influence of genetic ancestry on genomic alterations. Compared with European Americans, African Americans (AA) with breast, head and neck, and endometrial cancers exhibit a higher level of chromosomal instability, while a lower level of chromosomal instability was observed in AAs with kidney cancers. The frequencies of TP53 mutations and amplification of CCNE1 were increased in AAs in the cancer types showing higher levels of chromosomal instability. We observed lower frequencies of genomic alterations affecting genes in the PI3K pathway in AA patients across cancers. Our result provides insight into genomic contribution to cancer disparities.

Li Y, Cai B, Chen S, et al.
Overexpression of Tat-interacting protein 30 inhibits the proliferation, migration, invasion and promotes apoptosis in bladder cancer cells.
J Cancer Res Ther. 2018; 14(Supplement):S713-S718 [PubMed] Related Publications
Aims: Tat-interacting protein 30 (TIP30), a transcriptional repressor, possesses antitumor effect in different cancer cells. However, little is known about the function of TIP30 in bladder cancer till now.
Materials and Methods: A TIP30-overexpressing plasmid was transfected into the bladder cancer cells (T24). The cell cycle and apoptosis were detected by flow cytometry. The cell proliferation was analyzed using the cell counting kit-8 assay. The migrative and invasive abilities of T24 cells were measured by the transwell assay. The expression of TIP30, cell cycle proteins, migration-related proteins, and cell apoptosis-related proteins was assessed by Western blotting.
Results: The cell proliferation, migration, and invasion of T24 cells were inhibited by overexpression of TIP30. Moreover, the rate of cell apoptosis was increased by the overexpression of TIP30. The expression of cell cycle proteins, phosphorylated EGFR, p-Akt, Bcl-2, cyclin D, cyclin E), migration-related proteins (matrix metalloproteinases 2 [MMP2], MMP6, MMP9), were downregulated, and cell apoptosis-related proteins (bax, cleaved caspase3) were upregulated.
Conclusions: These results suggest that TIP30, as a tumor suppressor in the bladder cancer, might be served as a target in cancer therapies in the future.

Ma B, Zhang J, Zhou W, et al.
LINC01510 suppresses cell proliferation and invasion by inhibiting Wnt/β-catenin signaling in renal cell carcinoma.
Biochem Biophys Res Commun. 2018; 505(1):7-12 [PubMed] Related Publications
The role of long non-coding RNA in Renal cell carcinoma (RCC) tumorigenesis and progression remains largely unknown. Here, we found that LINC01510 functions as a tumor suppressor in RCC tumorigenesis. We screened TCGA database and then found that LINC01510 is significantly down-regulated in malignant RCC tissues, and the lower expression of LINC01510 predicts poor prognosis. Moreover, the down-regulated LINC01510 was further confirmed in our fresh tissues and cell lines. Biological functions assays shown that Ectopic expression of LINC01510 not only inhibits RCC cell proliferation both in vitro and in vivo, but also impairs cell invasion ability. Moreover, we found overexpression of LINC01510 inhibits the expression of CCND1 and CCNE1, as well as MMPs (MMP2, MMP7 and MMP9), and thus affecting RCC cell cycle and invasion. Meanwhile, Western blot assays revealed that the expression of β-catenin is regulated by LINC01510; overexpression of β-catenin could partly rescue the cell viability and invasion ability caused by ectopic expression of LINC01510. Taken together, we found that LINC01510 regulates cell proliferation and invasion by modulating Wnt/β-catenin signaling in RCC.

Aziz D, Etemadmoghadam D, Caldon CE, et al.
19q12 amplified and non-amplified subsets of high grade serous ovarian cancer with overexpression of cyclin E1 differ in their molecular drivers and clinical outcomes.
Gynecol Oncol. 2018; 151(2):327-336 [PubMed] Related Publications
OBJECTIVES: Readily apparent cyclin E1 expression occurs in 50% of HGSOC, but only half are linked to 19q12 locus amplification. The amplified/cyclin E1
METHODS: 262 HGSOC cases were analyzed by in situ hybridization for 19q12 locus amplification and immunohistochemistry for cyclin E1, URI1 (another protein encoded by the 19q12 locus), FBXW7 and USP28 expression. Tumors were classified by 19q12 amplification status and correlated to cyclin E1 and URI1 expression, BRCA1/2 germline mutation, FBXW7 and USP28 expression, and clinical outcomes. Additionally, we assessed the relative genomic instability of amplified/cyclin E1
RESULTS: Of the 82 cyclin E1
CONCLUSIONS: Amplified/cyclin E1

Zhang J, Hu H, Zhao Y, Zhao Y
CDR1as is overexpressed in laryngeal squamous cell carcinoma to promote the tumour's progression via miR-7 signals.
Cell Prolif. 2018; 51(6):e12521 [PubMed] Related Publications
OBJECTIVES: To investigate the roles played by the circular RNA (circRNA) molecule ciRS-7 (CDR1as) and tumour suppressor miRNA-7 (miR-7) in laryngeal squamous cell carcinoma (LSCC).
METHODS: Specimens of LSCC tissue (n = 30) and corresponding relative normal tissue (n = 30) were collected to determine their levels and clinical significance of CDR1as/mir-7 expression. The CDR1as and miR-7 were overexpressed in LSCC cells to investigate its function and mechanism in vitro and in vivo.
RESULTS: Patients with high TNM stages, poorly differentiated tumours, lymph node metastases and poor prognosis had high CDR1as levels but low miR-7 levels. CDR1 expression was negatively associated with miR-7 expression in LSCC. Overexpression of CDR1as in vitro enhanced cell vitality, and promoted the proliferation, migration, and invasion of two LSCC cell lines (Hep2 and AMC-HN-8.) However, these effects could be abrogated by knockdown of CDR1as or the forced expression of miR-7. Mechanistically, overexpressed CDR1 molecules functioned as miR-7 sponges and upregulated the key targets of miR-7, CCNE1, and PIK3CD in Hep2 and AMC-HN-8 cells. In vivo studies demonstrated the tumourigenic role of CDR1as. Overexpression of CDR1as alone promoted tumour growth and increased expression of the proliferation indices ki-67, CCNE1, and PIK3CD. Although the tumour suppressor miR-7 effectively inhibited the tumour growth, this effect could be counteracted by co-treatment with CDR1as in vivo.
CONCLUSION: CDR1as is an oncogene that promotes LSCC progression by regulating miR-7 signals.

Romero-Masters JC, Ohashi M, Djavadian R, et al.
An EBNA3C-deleted Epstein-Barr virus (EBV) mutant causes B-cell lymphomas with delayed onset in a cord blood-humanized mouse model.
PLoS Pathog. 2018; 14(8):e1007221 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
EBV causes human B-cell lymphomas and transforms B cells in vitro. EBNA3C, an EBV protein expressed in latently-infected cells, is required for EBV transformation of B cells in vitro. While EBNA3C undoubtedly plays a key role in allowing EBV to successfully infect B cells, many EBV+ lymphomas do not express this protein, suggesting that cellular mutations and/or signaling pathways may obviate the need for EBNA3C in vivo under certain conditions. EBNA3C collaborates with EBNA3A to repress expression of the CDKN2A-encoded tumor suppressors, p16 and p14, and EBNA3C-deleted EBV transforms B cells containing a p16 germline mutation in vitro. Here we have examined the phenotype of an EBNAC-deleted virus (Δ3C EBV) in a cord blood-humanized mouse model (CBH). We found that the Δ3C virus induced fewer lymphomas (occurring with a delayed onset) in comparison to the wild-type (WT) control virus, although a subset (10/26) of Δ3C-infected CBH mice eventually developed invasive diffuse large B cell lymphomas with type III latency. Both WT and Δ3C viruses induced B-cell lymphomas with restricted B-cell populations and heterogeneous T-cell infiltration. In comparison to WT-infected tumors, Δ3C-infected tumors had greatly increased p16 levels, and RNA-seq analysis revealed a decrease in E2F target gene expression. However, we found that Δ3C-infected tumors expressed c-Myc and cyclin E at similar levels compared to WT-infected tumors, allowing cells to at least partially bypass p16-mediated cell cycle inhibition. The anti-apoptotic proteins, BCL2 and IRF4, were expressed in Δ3C-infected tumors, likely helping cells avoid c-Myc-induced apoptosis. Unexpectedly, Δ3C-infected tumors had increased T-cell infiltration, increased expression of T-cell chemokines (CCL5, CCL20 and CCL22) and enhanced type I interferon response in comparison to WT tumors. Together, these results reveal that EBNA3C contributes to, but is not essential for, EBV-induced lymphomagenesis in CBH mice, and suggest potentially important immunologic roles of EBNA3C in vivo.

Dong X, Ni B, Fu J, et al.
Emodin induces apoptosis in human hepatocellular carcinoma HepaRG cells via the mitochondrial caspase‑dependent pathway.
Oncol Rep. 2018; 40(4):1985-1993 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
Emodin‑induced hepatotoxicity in vivo and in vitro has been gaining increasing attention. However, the exact molecular pathways underlying these effects remain poorly clarified. The aim of the present study was to evaluate the cytotoxic effect of emodin on HepaRG cells and to define the underlying mechanism. The results demonstrated that emodin evidently inhibited HepaRG cell growth in a dose‑ and time‑dependent manner by blocking cell cycle progression in the S and G2/M phase and by inducing apoptosis. Emodin treatment also resulted in generation of reactive oxygen species (ROS), which abrogated mitochondrial membrane potential (MMP). The above effects were all suppressed by antioxidants, such as N‑acetylcysteine (NAC). Further studies by western blot analysis howed that emodin upregulated p53, p21, Bax, cyclin E, cleaved caspase‑3, 8 and 9, and cleaved poly(ADP‑ribose)polymerase (PARP). However, the protein expression of Bcl‑2, cyclin A and CDK2 was downregulated. Taken together, our results suggest that emodin induces apoptosis via the mitochondrial apoptosis pathway through cell cycle arrest and ROS generation in HepaRG cells.

Meng M, Chen Y, Jia J, et al.
Knockdown of PAICS inhibits malignant proliferation of human breast cancer cell lines.
Biol Res. 2018; 51(1):24 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
BACKGROUND: Phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), an enzyme required for de novo purine biosynthesis, is associated with and involved in tumorigenesis. This study aimed to evaluate the role of PAICS in human breast cancer, which remains the most frequently diagnosed cancer and the leading cause of cancer-related death among women in less developed countries.
RESULTS: Lentivirus-based short hairpin RNA targeting PAICS specifically depleted its endogenous expression in ZR-75-30 and MDA-MB-231 breast cancer cells. Depletion of PAICS led to a significant decrease in cell viability and proliferation. To ascertain the mechanisms through which PAICS modulates cell proliferation, flow cytometry was performed, and it was confirmed that G1-S transition was blocked in ZR-75-30 cells through PAICS knockdown. This might have occurred partly through the suppression of Cyclin E and the upregulation of Cyclin D1, P21, and CDK4. Moreover, PAICS knockdown obviously promoted cell apoptosis in ZR-75-30 cells through the activation of PARP and caspase 3 and downregulation of Bcl-2 and Bcl-xl expression in ZR-75-30 cells.
CONCLUSIONS: These findings demonstrate that PAICS plays an essential role in breast cancer proliferation in vitro, which provides a new opportunity for discovering and identifying novel effective treatment strategies.

Yeh CH, Bellon M, Nicot C
FBXW7: a critical tumor suppressor of human cancers.
Mol Cancer. 2018; 17(1):115 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
The ubiquitin-proteasome system (UPS) is involved in multiple aspects of cellular processes, such as cell cycle progression, cellular differentiation, and survival (Davis RJ et al., Cancer Cell 26:455-64, 2014; Skaar JR et al., Nat Rev Drug Discov 13:889-903, 2014; Nakayama KI and Nakayama K, Nat Rev Cancer 6:369-81, 2006). F-box and WD repeat domain containing 7 (FBXW7), also known as Sel10, hCDC4 or hAgo, is a member of the F-box protein family, which functions as the substrate recognition component of the SCF E3 ubiquitin ligase. FBXW7 is a critical tumor suppressor and one of the most commonly deregulated ubiquitin-proteasome system proteins in human cancer. FBXW7 controls proteasome-mediated degradation of oncoproteins such as cyclin E, c-Myc, Mcl-1, mTOR, Jun, Notch and AURKA. Consistent with the tumor suppressor role of FBXW7, it is located at chromosome 4q32, a genomic region deleted in more than 30% of all human cancers (Spruck CH et al., Cancer Res 62:4535-9, 2002). Genetic profiles of human cancers based on high-throughput sequencing have revealed that FBXW7 is frequently mutated in human cancers. In addition to genetic mutations, other mechanisms involving microRNA, long non-coding RNA, and specific oncogenic signaling pathways can inactivate FBXW7 functions in cancer cells. In the following sections, we will discuss the regulation of FBXW7, its role in oncogenesis, and the clinical implications and prognostic value of loss of function of FBXW7 in human cancers.

Xia Y, Yan Z, Wan Y, et al.
Knockdown of long noncoding RNA GHET1 inhibits cell‑cycle progression and invasion of gastric cancer cells.
Mol Med Rep. 2018; 18(3):3375-3381 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
GHET1 is an oncogenic long noncoding RNA (lncRNA) that promotes the proliferation and invasion of many malignant cell types. However, the function and underlying mechanisms of lncRNA GHET1 in gastric cancer are not fully understood. In this study, the expression of GHET1 was investigated in gastric cancer and it was determined whether GHET1 may potentially be used as a biomarker for the disease. The gastric cancer cell lines MGC‑803 and AGS were transfected with GHET1‑directed small interfering RNA (siRNA) and the changes in phenotype and cell‑cycle‑related molecules were assessed. The downregulation of GHET1 induced G0/G1‑phase arrest in gastric cancer cells and inhibited their proliferation, migration, and invasion. DNA synthesis and the expression of proliferating cell nuclear antigen (PCNA) decreased, which was consistent with the results of the CCK‑8 assay. The levels of specific cell‑cycle regulators were determined and the expression and activities of positive cell‑cycle regulators (cyclin D, CDK4, CDK6, cyclin E, CDK2) were reduced, whereas those of a negative regulator (P21) were increased in GHET1‑knockdown cells. Taken together, the present findings show that the downregulation of GHET1 not only inhibits the migration and invasion of gastric cancer cells, but also inhibits their proliferation, at least in part by upregulating P21 expression and downregulating cyclin and CDK expression to inhibit the G0/G1 to S phase transition. The present findings may provide a potential therapeutic target for gastric cancer.

Shi Y, Zhao Y, Zhang Y, et al.
TNNT1 facilitates proliferation of breast cancer cells by promoting G
Life Sci. 2018; 208:161-166 [PubMed] Related Publications
AIMS: Breast cancer is the major diagnosed cancer and the leading reason of cancer related death among women, and the tumor size is one of the risk factors. Therefore, it is significant to reveal the principle of breaking the subtle homeostasis of cell cycle and sustaining chronic proliferation of cancer cells.
MAIN METHODS: The expression of TNNT1 was examined by qPCR and western blotting. The effect of TNNT1 on cell proliferation was detected by MTT, colony formation and anchorage-independent growth assay. The percent of cells in different cell phase was analyzed by Flow cytometry. The mRNA and protein expression of genes involved in G
KEY FINDINGS: The results showed that TNNT1 expression is significantly increased in breast cancer tissues and closely correlated with clinical stage, T and N classification. Further experiments demonstrate that TNNT1 contributes to proliferation of breast cells by promoting G
SIGNIFICANCE: Our results extend the mechanisms of controlling cell cycle and may provide a novel therapeutic target to therapy breast cancer.

Menghi F, Barthel FP, Yadav V, et al.
The Tandem Duplicator Phenotype Is a Prevalent Genome-Wide Cancer Configuration Driven by Distinct Gene Mutations.
Cancer Cell. 2018; 34(2):197-210.e5 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
The tandem duplicator phenotype (TDP) is a genome-wide instability configuration primarily observed in breast, ovarian, and endometrial carcinomas. Here, we stratify TDP tumors by classifying their tandem duplications (TDs) into three span intervals, with modal values of 11 kb, 231 kb, and 1.7 Mb, respectively. TDPs with ∼11 kb TDs feature loss of TP53 and BRCA1. TDPs with ∼231 kb and ∼1.7 Mb TDs associate with CCNE1 pathway activation and CDK12 disruptions, respectively. We demonstrate that p53 and BRCA1 conjoint abrogation drives TDP induction by generating short-span TDP mammary tumors in genetically modified mice lacking them. Lastly, we show how TDs in TDP tumors disrupt heterogeneous combinations of tumor suppressors and chromatin topologically associating domains while duplicating oncogenes and super-enhancers.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. CCNE1, Cancer Genetics Web: Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 30 August, 2019     Cancer Genetics Web, Established 1999