CCNE1

Gene Summary

Gene:CCNE1; cyclin E1
Aliases: CCNE, pCCNE1
Location:19q12
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:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:G1/S-specific cyclin-E1
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 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.

  • Polymorphism
  • Cell Proliferation
  • Cancer Gene Expression Regulation
  • Liver Cancer
  • Oncogene Proteins
  • Gene Amplification
  • Up-Regulation
  • Messenger RNA
  • Cyclin D1
  • Gene Expression Profiling
  • Cell Cycle Proteins
  • Signal Transduction
  • Reproducibility of Results
  • siRNA
  • Ploidies
  • Biomarkers, Tumor
  • Mutation
  • Chromosome 19
  • Molecular Sequence Data
  • Apoptosis
  • Immunohistochemistry
  • Trastuzumab
  • Gene Dosage
  • Oligonucleotide Array Sequence Analysis
  • Transfection
  • Genetic Predisposition
  • Regression Analysis
  • DNA Copy Number Variations
  • Transforming Growth Factor beta
  • Phenotype
  • Osteosarcoma
  • Breast Cancer
  • RTPCR
  • Cell Cycle
  • Tumor Suppressor Proteins
  • Protein Structure, Tertiary
  • Staging
  • Cyclin-Dependent Kinase 2
  • Cyclin E
  • cdc25 Phosphatases
  • CCNE1
Tag cloud generated 11 March, 2017 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)

Lei ST, Shen F, Chen JW, et al.
MiR-639 promoted cell proliferation and cell cycle in human thyroid cancer by suppressing CDKN1A expression.
Biomed Pharmacother. 2016; 84:1834-1840 [PubMed] Related Publications
Accumulating evidence has indicated that aberrantly expressed microRNAs (miRs) are extensively involved in cancer development and progression. MiR-639 has been reported to act as tumor promoter in various types of cancer. However, the biological function and underlying molecular mechanism of miR-639 in thyroid carcinoma (TC) have not been intensively investigated. Herein the present study aimed to investigate the functional role of miR-639 in TC. We found that miR-639 expression was upregulated in TC cells and clinical tissues. Overexpression of miR-639 promoted TC cell proliferation and cell cycle, with increased expression of CyclinE and c-myc, whereas miR-639-in reverses the function. Using prediction software and luciferase reporter assay, we found that CDKN1A was a target of miR-639. CDKN1A small interfering RNA (siRNA) abrogated the role of miR-639-in on cell proliferation of TC. In summary, our data demonstrated that miR-639 upregulation was associated with development of TC, miR-639 promoted cell proliferation and cell cycle by targeting CDKN1A in TC.

Hayashi T, Kawano M, Ichimura T, et al.
Molecular Pathology and Novel Clinical Therapy for Uterine Leiomyosarcoma.
Anticancer Res. 2016; 36(10):4997-5007 [PubMed] Related Publications
Patients with uterine leiomyosarcoma (LMS) typically present with vaginal bleeding, pain, and a pelvic mass, with atypical presentations of hypercalcemia and eosinophilia also being reported. Radiographic evaluation with combined positron-emission tomography/computed tomography may assist in diagnosis and surveillance in women with uterine LMS; these are commonly used with stage and tumour grade as prognostic indicators and a recently developed risk-assessment index to predict disease-specific survival. Recent studies have shown that the addition of adjuvant therapy after surgical management does not seem to improve survival, and ovarian preservation does not appear to negatively impact outcome. Experimentally, it is noteworthy that proteasome subunit beta 9 (PSMB9)/β1i-deficient mice exhibit spontaneous development of uterine LMS, with a disease prevalence of ~37% by 12 months of age. Furthermore, a recent report showed the loss of ability to induce PSMB9/β1i expression, that is up-regulated by interferon-γ (IFNγ), in human uterine LMS tissues. Here, we reviewed human uterine LMS for genetic mutations in the IFNγ signal cascade, and found serious mutations in three genes, Janus activated kinase 1 (JAK1), signal transducer and activator of transcription 1 (STAT1) and PSMB9/β1i promoter regions. Moreover, molecular experiments demonstrated differential expression of cyclin E and P27/KIP1, that regulate cell-cycle G1 arrest via PSMB9/β1i expression. The discovery of this mutational activation of a key cell-signalling pathway may provide new targets for diagnostic approaches and therapeutic intervention.

Kitade S, Onoyama I, Kobayashi H, et al.
FBXW7 is involved in the acquisition of the malignant phenotype in epithelial ovarian tumors.
Cancer Sci. 2016; 107(10):1399-1405 [PubMed] Free Access to Full Article Related Publications
FBXW7 is a ubiquitin ligase that mediates ubiquitylation of oncoproteins, such as c-Myc, cyclin E, Notch and c-Jun. FBXW7 is a known tumor-suppressor gene, and mutations in FBXW7 have been reported in various human malignancies. In this study, we examined the sequences of the FBXW7 and p53 genes in 57 ovarian cancer clinical samples. Interestingly, we found no FBXW7 mutations associated with amino acid changes. We also investigated FBXW7 expression levels in 126 epithelial ovarian tumors. FBXW7 expression was negatively correlated with the malignant potential of ovarian tumors. That is to say, FBXW7 expression levels in ovarian cancer samples were significantly lower than those in borderline and benign tumors (P < 0.01). FBXW7 expression levels in serous carcinoma samples were the lowest among four major histological subtypes. In addition, p53-mutated ovarian cancer samples showed significantly lower levels of FBXW7 expression compared with p53 wild-type cancer samples (P < 0.001). DNA methylation arrays and bisulfite PCR sequencing experiments revealed that 5'-upstream regions of FBXW7 gene in p53-mutated samples were significantly higher methylated compared with those in p53 wild-type samples (P < 0.01). This data indicates that p53 mutations might suppress FBXW7 expression through DNA hypermethylation of FBXW7 5'-upstream regions. Thus, FBXW7 expression was downregulated in ovarian cancers, and was associated with p53 mutations and the DNA methylation status of the 5'-upstream regions of FBXW7.

Erdmann K, Kaulke K, Rieger C, et al.
MiR-26a and miR-138 block the G1/S transition by targeting the cell cycle regulating network in prostate cancer cells.
J Cancer Res Clin Oncol. 2016; 142(11):2249-61 [PubMed] Related Publications
PURPOSE: The tumor-suppressive microRNAs miR-26a and miR-138 are significantly down-regulated in prostate cancer (PCa) and have been identified as direct regulators of enhancer of zeste homolog 2 (EZH2), which is a known oncogene in PCa. In the present study, the influence of miR-26a and miR-138 on EZH2 and cellular function including the impact on the cell cycle regulating network was evaluated in PCa cells.
METHODS: PC-3 and DU-145 PCa cells were transfected with 100 nM of miRNA mimics, siRNA against EZH2 (siR-EZH2) or control constructs for 4 h. Analyses of gene expression and cellular function were conducted 48 h after transfection.
RESULTS: Both miRNAs influenced the EZH2 expression and activity only marginally, whereas siR-EZH2 led to a notable decrease of the EZH2 expression and activity. Both miRNAs inhibited short- and/or long-term proliferation of PCa cells but showed no effect on viability and apoptosis. In PC-3 cells, miR-26a and miR-138 caused a significant surplus of cells in the G0/G1 phase of 6 and 12 %, respectively, thus blocking the G1/S-phase transition. Treatment with siR-EZH2 was without substantial influence on cellular function and cell cycle. Therefore, alternative target genes involved in cell cycle regulation were identified in silico. MiR-26a significantly diminished the expression of its targets CCNE1, CCNE2 and CDK6, whereas CCND1, CCND3 and CDK6 were suppressed by their regulator miR-138.
CONCLUSIONS: The present findings suggest an anti-proliferative role for miR-26a and miR-138 in PCa by blocking the G1/S-phase transition independent of EZH2 but via a concerted inhibition of crucial cell cycle regulators.

Yu L, Li X, Li H, et al.
Rab11a sustains GSK3β/Wnt/β-catenin signaling to enhance cancer progression in pancreatic cancer.
Tumour Biol. 2016; 37(10):13821-13829 [PubMed] Related Publications
The Rab family GTPases regulate many major biological processes during tumor progression such as cell proliferation, cytoskeleton organization, cell movement, and invasion. The present study aims to examine the clinical significance, biological roles, and molecular mechanism of Rab11a in pancreatic cancer progression. We examined expression pattern of Rab11a in 96 cases of pancreatic cancer specimens using immunohistochemistry and found Rab11a overexpression correlated with tumor-node-metastasis (TNM) stage (p = 0.0111). We depleted Rab11a in Bxpc3 cells using small interfering RNA (siRNA) and overexpressed Rab11a in Capan2 cells. Knockdown of Rab11a inhibited cell growth, invasion, and cell cycle progression while its overexpression facilitated cell growth, invasion, and cell cycle progression. In addition, Rab11a overexpression increased gemcitabine resistance and inhibited gemcitabine-induced apoptosis in Capan2 cells while its depletion reduced drug resistance. We investigated the role of Rab11a in the regulation of Wnt/β-catenin signaling and we demonstrated that Rab11a overexpression upregulated GSK3β phosphorylation and nuclear β-catenin accumulation. Rab11a depletion inhibited while its overexpression enhanced β-catenin/T-cell factor (TCF) transcriptional activity with corresponding change of Wnt target genes including cyclin D1, cyclin E, MMP7, and c-myc. Wnt inhibitor (FH535) partly attenuated the effects of Rab11a on cell proliferation and Wnt target genes. In conclusion, the present study demonstrated that Rab11a promotes aggressiveness of pancreatic cancer through GSK3β/Wnt/β-catenin signaling pathway.

Yang D, Zhou J, Wang H, et al.
High expression of BAG3 predicts a poor prognosis in human medulloblastoma.
Tumour Biol. 2016; 37(10):13215-13224 [PubMed] Related Publications
Bcl2-associated athanogene 3 (BAG3), a co-chaperone of the heat shock protein (Hsp) 70, regulates various physiological and pathological processes. However, its role in human medulloblastoma has not been clarified. First of all, the expression of BAG3 was examined in formalin-fixed, paraffin-embedded specimens by immunohistochemical staining. And then, the prognostic role of BAG3 was analyzed in 51 medulloblastoma samples. Finally, the roles of BAG3 in the proliferation, migration, and invasion of Daoy medulloblastoma cell were investigated using a specific short hairpin RNA (shRNA). The expression of BAG3 in medulloblastoma tissues was higher than nontumorous samples. Furthermore, BAG3 overexpression significantly correlated with poor prognosis of patients with medulloblastoma. The overall survival and tumor-free survival in patients with BAG3 low expression were higher than high expression. Univariate and multivariate analysis showed that BAG3 overexpression was an independent prognostic marker for medulloblastoma. After the BAG3 knockdown, the Daoy cells exhibited decreased the ability to proliferate and form neurosphere. The preliminary mechanism study showed that overexpression of BAG3 might facilitate the cell cycle transition from G1 to S phase by modulating the cyclin-dependent kinase 2 (CDK2) and cyclin E expression. Additionally, we found that BAG3 might enhance the medulloblastoma cell migratory and invasive ability. In summary, BAG3 overexpression may regulate the survival and invasive properties of medulloblastoma and may serve as a potential therapy target for medulloblastoma.

Jagadish N, Gupta N, Agarwal S, et al.
Sperm-associated antigen 9 (SPAG9) promotes the survival and tumor growth of triple-negative breast cancer cells.
Tumour Biol. 2016; 37(10):13101-13110 [PubMed] Related Publications
Recently, we demonstrated the association of sperm-associated antigen 9 (SPAG9) expression with breast cancer. Among breast cancer, 15 % of the cancers are diagnosed as triple-negative breast cancers (TNBC) based on hormone receptor status and represent an important clinical challenge because of lack of effective available targeted therapy. Therefore, in the present investigation, plasmid-based small hairpin (small hairpin RNA (shRNA)) approach was used to ablate SPAG9 in aggressive breast cancer cell line model (MDA-MB-231) in order to understand the role of SPAG9 at molecular level in apoptosis, cell cycle, and epithelial-to-mesenchymal transition (EMT) signaling. Our data in MDA-MB-231 cells showed that ablation of SPAG9 resulted in membrane blebbing, increased mitochondrial membrane potential, DNA fragmentation, phosphatidyl serine surface expression, and caspase activation. SPAG9 depletion also resulted in cell cycle arrest in G0-G1 phase and induced cellular senescence. In addition, in in vitro and in vivo xenograft studies, ablation of SPAG9 resulted in upregulation of p21 along with pro-apoptotic molecules such as BAK, BAX, BIM, BID, NOXA, AIF, Cyto-C, PARP1, APAF1, Caspase 3, and Caspase 9 and epithelial marker, E-cadherin. Also, SPAG9-depleted cells showed downregulation of cyclin B1, cyclin D1, cyclin E, CDK1, CDK4, CDK6, BCL2, Bcl-xL, XIAP, cIAP2, MCL1, GRP78, SLUG, SNAIL, TWIST, vimentin, N-cadherin, MMP2, MMP3, MMP9, SMA, and β-catenin. Collectively, our data suggests that SPAG9 promotes tumor growth by inhibiting apoptosis, altering cell cycle, and enhancing EMT signaling in in vitro cells and in vivo mouse model. Hence, SPAG9 may be a potential novel target for therapeutic use in TNBC treatment.

Nowakowska M, Matysiak-Burzyńska Z, Kowalska K, et al.
Angiotensin II promotes endometrial cancer cell survival.
Oncol Rep. 2016; 36(2):1101-10 [PubMed] Related Publications
Endometrial cancer (EC) is one of the most common female cancers. One of the key processes involved in EC development is uncontrolled proliferation stimulated by local factors such as angiotensin. The aim of the present study was to evaluate the influence of angiotensin II (Ang II) on human EC cells. Biological assays and gene expression analysis were performed on three cell lines: ISH, MFE-296 and MFE-280. Our results indicated that at the beginning of cancerogenesis Ang II induced abnormal proliferation at lower doses. We also showed that dose-dependent induction of proliferation was connected with changes in the expression of MKI67, CCND1 and CCNE1 genes in well- and poorly differentiated cancer cells. After Ang II treatment, poorly differentiated endometrial cancer cell line acquired a mesenchymal phenotype, which was characterized by induced expression of EMT-related genes (VIM, CD44, SNAI1, ZEB1 and ZEB2). Our study revealed that Ang II influences EC cells in terms of cancer-related processes, and is responsible for increased proliferation, reduction in apoptosis, increased mobility and modulation of adhesion potential. Its effect and effectiveness appear to be highly connected with the differentiation status of the cancerous cells, as Ang II appears to play a crucial role in the early and late stages of malignant transformation.

Muralidharan R, Babu A, Amreddy N, et al.
Folate receptor-targeted nanoparticle delivery of HuR-RNAi suppresses lung cancer cell proliferation and migration.
J Nanobiotechnology. 2016; 14(1):47 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Human antigen R (HuR) is an RNA binding protein that is overexpressed in many human cancers, including lung cancer, and has been shown to regulate the expression of several oncoproteins. Further, HuR overexpression in cancer cells has been associated with poor-prognosis and therapy resistance. Therefore, we hypothesized that targeted inhibition of HuR in cancer cells should suppress several HuR-regulated oncoproteins resulting in an effective anticancer efficacy. To test our hypothesis, in the present study we investigated the efficacy of folate receptor-α (FRA)-targeted DOTAP:Cholesterol lipid nanoparticles carrying HuR siRNA (HuR-FNP) against human lung cancer cells.
RESULTS: The therapeutic efficacy of HuR-FNP was tested in FRA overexpressing human H1299 lung cancer cell line and compared to normal lung fibroblast (CCD16) cells that had low to no FRA expression. Physico-chemical characterization studies showed HuR-FNP particle size was 303.3 nm in diameter and had a positive surface charge (+4.3 mV). Gel retardation and serum stability assays showed that the FNPs were efficiently protected siRNA from rapid degradation. FNP uptake was significantly higher in H1299 cells compared to CCD16 cells indicating a receptor-dose effect. The results of competitive inhibition studies in H1299 cells demonstrated that HuR-FNPs were efficiently internalized via FRA-mediated endocytosis. Biologic studies demonstrated HuR-FNP but not C-FNP (control siRNA) induced G1 phase cell-cycle arrest and apoptosis in H1299 cells resulting in significant growth inhibition. Further, HuR-FNP exhibited significantly higher cytotoxicity against H1299 cells than it did against CCD16 cells. The reduction in H1299 cell viability was correlated with a marked decrease in HuR mRNA and protein expression. Further, reduced expression of HuR-regulated oncoproteins (cyclin D1, cyclin E, and Bcl-2) and increased p27 tumor suppressor protein were observed in HuR-FNP-treated H1299 cells but not in C-FNP-treated cells. Finally, cell migration was significantly inhibited in HuR-FNP-treated H1299 cells compared to C-FNP.
CONCLUSIONS: Our results demonstrate that HuR is a molecular target for lung cancer therapy and its suppression using HuR-FNP produced significant therapeutic efficacy in vitro.

Lee HM, Kim CW, Hwang KA, et al.
Three components of cigarette smoke altered the growth and apoptosis of metastatic colon cancer cells via inducing the synthesis of reactive oxygen species and endoplasmic reticulum stress.
Environ Toxicol Pharmacol. 2016; 45:80-9 [PubMed] Related Publications
Cigarette smoke (CS) is a well-known risk factor for carcinogenesis and has been found to be related to the occurrence and development of colon cancer. In this study, the effect of formaldehyde (FA), benzene (Bz), and isoprene (IP), which are included in main components of CS, on cell viability and apoptosis of SW620 colorectal cancer cells was examined to identify the connection between CS components and colon cancer. In cell viability assay, FA, Bz, and IP decreased cell viability of SW620 cells in a dose dependent manner. In Western blot assay, the protein expression of cell cycle related genes, cyclin D1 & E1, was decreased by FA, Bz, and IP, which corresponded to their inhibitory effect on cell viability. In addition, FA, Bz, and IP increased the protein expression of pro-apoptotic genes, C/EBP homologous protein (CHOP) and Bax, and reduced the protein expression of anti-apoptotic gene, Bcl-2. In reactive oxygen species (ROS) assay using dichlorofluorescin diacetate (DCFH-DA), FA, Bz, and IP increased the ROS production in SW620 cells. In the measurement of apoptotic cells, the numbers of apoptotic cells were increased by the treatment of FA, Bz, and IP. As CHOP is an endoplasmic reticulum (ER)-stress related apoptosis marker of which production is induced by ROS, it was considered that these CS components induce apoptosis of SW620 cells by increasing ROS synthesis and ER-stress. Taken together, these results showed that CS components, i.e., FA, Bz, and IP, inhibited the cell viability of SW620 cells by down-regulating the protein expression of cyclin D1 & E1 and induced apoptosis of SW620 cells by increasing ROS production and simultaneously activating ER-stress.

Zhang D, Li Y, Wang R, et al.
Inhibition of REST Suppresses Proliferation and Migration in Glioblastoma Cells.
Int J Mol Sci. 2016; 17(5) [PubMed] Free Access to Full Article Related Publications
Glioblastoma (GBM) is the most common primary brain tumor, with poor prognosis and a lack of effective therapeutic options. The aberrant expression of transcription factor REST (repressor element 1-silencing transcription factor) had been reported in different kinds of tumors. However, the function of REST and its mechanisms in GBM remain elusive. Here, REST expression was inhibited by siRNA silencing in U-87 and U-251 GBM cells. Then CCK-8 assay showed significantly decreased cell proliferation, and the inhibition of migration was verified by scratch wound healing assay and transwell assay. Using cell cycle analysis and Annexin V/PI straining assay, G1 phase cell cycle arrest was found to be a reason for the suppression of cell proliferation and migration upon REST silencing, while apoptosis was not affected by REST silencing. Further, the detection of REST-downstream genes involved in cytostasis and migration inhibition demonstrated that CCND1 and CCNE1 were reduced; CDK5R1, BBC3, EGR1, SLC25A4, PDCD7, MAPK11, MAPK12, FADD and DAXX were enhanced, among which BBC3 and DAXX were direct targets of REST, as verified by ChIP (chromatin immunoprecipitation) and Western blotting. These data suggested that REST is a master regulator that maintains GBM cells proliferation and migration, partly through regulating cell cycle by repressing downstream genes, which might represent a potential target for GBM therapy.

Zhang Y, Peng Z, Zhao Y, Chen L
microRNA-25 Inhibits Cell Apoptosis of Human Gastric Adenocarcinoma Cell Line AGS via Regulating CCNE1 and MYC.
Med Sci Monit. 2016; 22:1415-20 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Gastric carcinoma is the second leading cause of cancer death. microRNAs play vital roles in regulating expression of related oncogenes. microRNA-25 (miR-25) has been found to be up-regulated in gastric carcinoma. However, its roles in affecting cell apoptosis of gastric carcinoma and the related mechanism remain elusive. This study aimed to uncover the influences of miR-25 on gastric carcinoma cell apoptosis and the possible functional mechanisms involved. MATERIAL AND METHODS Human gastric adenocarcinoma cell line AGS was used and transfected with lentivirus containing miR-25-specifc inhibitor sponge or expression vector to analyze the effects of miR-25. RESULTS miR-25 had higher expression in AGS than in human gastric epithelial cell line GES-1 (P<0.01). Inhibition of miR-25 by its sponge in AGS cells resulted in suppressed cell viability (P<0.01) and promoted cell apoptosis (P<0.01), while overexpression of miR-25 abrogated these effects (P<0.01 and P<0.05), indicating that miR-25 can promote cell viability and inhibit cell apoptosis in AGS cells. Expression analysis of related factors by Western blot showed that inhibiting miR-25 led to the up-regulation of F-box and WD repeat domain-containing 7 (FBXW7, P<0.01) and the down-regulation of FBXW7 substrates, cyclin E1 (CCNE1, P<0.01), and v-myc avian myelocytomatosis viral oncogene homolog (MYC, P<0.001). CONCLUSIONS These results indicate that miR-25 has anti-apoptosis roles in AGS cells, possibly via inhibiting FBXW7 and thus promoting oncogenes, such as CCNE1 and MYC. This study provides basic evidence for using miR-25 as a possible therapeutic target in treating gastric carcinoma.

Zhang Y, Xue C, Zhu X, et al.
Suppression of microRNA-125a-5p upregulates the TAZ-EGFR signaling pathway and promotes retinoblastoma proliferation.
Cell Signal. 2016; 28(8):850-60 [PubMed] Related Publications
Retinoblastoma is the most common intraocular malignancy that occurs during childhood; however, the mechanism underlying retinoblastoma proliferation and progression remains unclear. MicroRNAs (miRNAs) play an important role in the regulation of a myriad of biological processes in various types of cancer. In this study, we performed microarray analysis followed by qRT-PCR using four classes of retinoblastoma tissues with increasing cTNM classification stages to identify crucial miRNAs whose expression was correlated with retinoblastoma progression. miR-125a-5p was downregulated, and its expression levels were inversely correlated with cell proliferation in retinoblastoma compared with adjacent non-tumor retinal tissues. The overexpression of miR-125a-5p significantly suppressed cell proliferation and tumor formation in retinoblastoma. We further identified the transcriptional co-activator with PDZ binding motif (TAZ) as a direct target of miR-125a-5p. Importantly, TAZ levels were inversely correlated with miRNA-125a-5p expression, and TAZ promoted retinoblastoma cell proliferation. Moreover, the overexpression of miR-125a-5p led to a decrease in TAZ expression and downstream EGFR signaling pathway activation both in vitro and vivo. Finally, TAZ overexpression in retinoblastoma cells overexpressing miR-125a-5p restored retinoblastoma cell proliferation and EGFR pathway activation. Taken together, our data demonstrated that miR-125a-5p functions as an important tumor suppressor that suppresses the EGFR pathway by targeting TAZ to inhibit tumor progression in retinoblastoma. Thus, the miR-125a-5p/TAZ/EGFR axis may be a potential therapeutic target for retinoblastoma.

Ren C, Ren T, Yang K, et al.
Inhibition of SOX2 induces cell apoptosis and G1/S arrest in Ewing's sarcoma through the PI3K/Akt pathway.
J Exp Clin Cancer Res. 2016; 35:44 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ewing's sarcoma is an aggressive bone and soft tissue tumor with a high incidence in children and adolescents. Due to its high malignancy and poor prognosis, identification of novel biomarkers for intervention therapies is necessary to improve outcome. The EWS/FLI1 fusion gene is a characteristic of Ewing's sarcoma in most cases. Sex determining region Y-box 2 (SOX2) is a primary target of EWS/FLI1. It has been identified as an oncogene and linked to apoptotic resistance in several types of cancer. However, its role and regulatory mechanisms in Ewing's sarcoma are largely unknown.
METHODS: We systematically investigated the role of SOX2 in Ewing's sarcoma cell lines, human tissue samples and xenograft models. The expression of SOX2 was detected in Ewing's sarcoma samples by WB and IHC. siRNAs were used to knockdown EWS/FLI1 and SOX2 in A673 and RD-ES cell lines with the efficiencies tested by qRT-PCR and WB. The effect of SOX2 on cell cycle and apoptosis was determined by Flow cytometric and TUNEL assays. Akt overexpression was performed with plasmid. The protein expression of the corresponding factors was examined by WB analysis. Inhibition of SOX2 in vivo was performed by siRNA against SOX2 in xenograft models, and the protein expression of the regulators testified in vitro was examined in xenograft tumors by IHC and WB.
RESULTS: The results confirmed that SOX2 was highly expressed in Ewing's sarcoma and was the target of EWS/FLI1. SOX2 advanced Ewing's sarcoma cell survival and proliferation by regulating p21, p27 and cyclin-E to facilitate G1/S phase transition and mediating caspase-3, PARP via both extrinsic (Fas and caspase-8) and intrinsic (caspase-9, Bad, Bcl-2 and XIAP) apoptotic pathways to restrain cell apoptosis. Additionally, SOX2 regulated the cell-cycle progression and apoptosis via activation of the PI3K/Akt signaling pathway. The mechanisms were proved both in vitro and in vivo.
CONCLUSIONS: The results demonstrate that SOX2 played a central role in promoting Ewing's sarcoma cell proliferation in vitro and in vivo with the underlying mechanisms expounded. These findings suggest that SOX2 may serve as a potential biomarker for targeted intervention in Ewing's sarcoma.

Kim SH, Ho JN, Jin H, et al.
Upregulated expression of BCL2, MCM7, and CCNE1 indicate cisplatin-resistance in the set of two human bladder cancer cell lines: T24 cisplatin sensitive and T24R2 cisplatin resistant bladder cancer cell lines.
Investig Clin Urol. 2016; 57(1):63-72 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The mechanism of resistance to cisplatin during treatment of bladder cancer (BC) has been a subject of intense investigation in clinical research. This study aims to identify candidate genes associated with resistance to cisplatin, in order to understand the resistance mechanism of BC cells to the drug, by combining the use of microarray profiling, quantitative reverse transcription-polymerase chain reaction (RT-PCR), and Western blot analyses.
MATERIALS AND METHODS: The cisplatin sensitive human BC cell line (T24) and the cisplatin resistant BC cell line, T24R2, were used for microarray analysis to determine the differential expression of genes that are significant in cisplatin resistance. Candidate upregulated genes belonging to three well-known cancer-related KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways (p53 tumor suppressor, apoptosis, and cell cycle) were selected from the microarray data. These candidate genes, differentially expressed in T24 and T24R2, were then confirmed by quantitative RT-PCR and western blot. A fold change ≥2 with a p-value <0.05 was considered significant.
RESULTS: A total of 18 significantly upregulated genes were detected in the three selected cancer-related pathways in both microarray and RT-PCR analyses. These genes were PRKAR2A, PRKAR2B, CYCS, BCL2, BIRC3, DFFB, CASP6, CDK6, CCNE1, STEAP3, MCM7, ORC2, ORC5, ANAPC1, and ANAPC7, CDC7, CDC27, and SKP1. Western blot analyses also confirmed the upregulation of BCL2, MCM7, and CCNE1 at the protein level, indicating their crucial association with cisplatin resistance.
CONCLUSIONS: The BCL2, MCM7, and CCNE1 genes might play distinctive roles in cisplatin resistance in BC.

Green AR, Aleskandarany MA, Agarwal D, et al.
MYC functions are specific in biological subtypes of breast cancer and confers resistance to endocrine therapy in luminal tumours.
Br J Cancer. 2016; 114(8):917-28 [PubMed] Article available free on PMC after 12/04/2017 Related Publications
BACKGROUND: MYC is amplified in approximately 15% of breast cancers (BCs) and is associated with poor outcome. c-MYC protein is multi-faceted and participates in many aspects of cellular function and is linked with therapeutic response in BCs. We hypothesised that the functional role of c-MYC differs between molecular subtypes of BCs.
METHODS: We therefore investigated the correlation between c-MYC protein expression and other proteins involved in different cellular functions together with clinicopathological parameters, patients' outcome and treatments in a large early-stage molecularly characterised series of primary invasive BCs (n=1106) using immunohistochemistry. The METABRIC BC cohort (n=1980) was evaluated for MYC mRNA expression and a systems biology approach utilised to identify genes associated with MYC in the different BC molecular subtypes.
RESULTS: High MYC and c-MYC expression was significantly associated with poor prognostic factors, including grade and basal-like BCs. In luminal A tumours, c-MYC was associated with ATM (P=0.005), Cyclin B1 (P=0.002), PIK3CA (P=0.009) and Ki67 (P<0.001). In contrast, in basal-like tumours, c-MYC showed positive association with Cyclin E (P=0.003) and p16 (P=0.042) expression only. c-MYC was an independent predictor of a shorter distant metastases-free survival in luminal A LN+ tumours treated with endocrine therapy (ET; P=0.013). In luminal tumours treated with ET, MYC mRNA expression was associated with BC-specific survival (P=0.001). In ER-positive tumours, MYC was associated with expression of translational genes while in ER-negative tumours it was associated with upregulation of glucose metabolism genes.
CONCLUSIONS: c-MYC function is associated with specific molecular subtypes of BCs and its overexpression confers resistance to ET. The diverse mechanisms of c-MYC function in the different molecular classes of BCs warrants further investigation particularly as potential therapeutic targets.

Qu H, Yin H, Yan S, et al.
Inhibitor of growth 4 suppresses colorectal cancer growth and invasion by inducing G1 arrest, inhibiting tumor angiogenesis and reversing epithelial-mesenchymal transition.
Oncol Rep. 2016; 35(5):2927-35 [PubMed] Related Publications
Previous studies have found that inhibitor of growth 4 (ING4), a tumor suppressor, is reduced in human colorectal cancer (CRC), and is inversely correlated with clinical Dukes' stage, histological grade, lymph node metastasis and microvessel density (MVD). However, its underlying mechanism remains undetermined. In the present study, we analyzed ING4 expression in a panel of human CRC cells using low (LS174T and SW480) and high (LoVo and SW620) metastatic cell lines. We demonstrated that both the low and high metastatic CRC cells exhibited a lower level of ING4 compared to the level in normal human colorectal mucous epithelial FHC cells. Furthermore, ING4 expression in high metastatic CRC cells was less than that in low metastatic CRC cells. We then generated a lentivirus construct expressing ING4 and green fluorescent protein (GFP), established a ING4-stably transgenic LoVo CRC cell line, and investigated the effect of lentiviral-mediated ING4 expression on high metastatic LoVo CRC cells. Gain-of-function studies revealed that ING4 significantly inhibited LoVo CRC cell growth and invasion in vitro and induced cell cycle G1 phase arrest. Moreover, ING4 obviously suppressed LoVo CRC subcutaneously xenografted tumor growth and reduced tumor MVD in vivo in athymic BALB/c nude mice. Mechanistically, ING4 markedly upregulated P21 and E-cadherin but downregulated cyclin E, interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF), Snail1, N-cadherin and vimentin in the LoVo CRC cells. Our data provide compelling evidence that i) ING4 suppresses CRC growth possibly via induction of G1 phase arrest through upregulation of P21 cyclin-dependent kinase (CDK) inhibitor and downregulation of cyclin E as well as inhibition of tumor angiogenesis through reduction of IL-6, IL-8 and VEGF proangiogenic factors; ii) ING4 inhibits CRC invasion and metastasis probably via a switch from mesenchymal marker N-cadherin to epithelial marker E-cadherin through downregulation of Snail1 epithelial-mesenchymal transition (EMT)-inducing transcription factor (EMT-TF).

Conconi D, Sala E, Bovo G, et al.
Using Copy Number Alterations to Identify New Therapeutic Targets for Bladder Carcinoma.
Int J Mol Sci. 2016; 17(3):271 [PubMed] Article available free on PMC after 12/04/2017 Related Publications
Bladder cancer represents the ninth most widespread malignancy throughout the world. It is characterized by the presence of two different clinical and prognostic subtypes: non-muscle-invasive bladder cancers (NMIBCs) and muscle-invasive bladder cancers (MIBCs). MIBCs have a poor outcome with a common progression to metastasis. Despite improvements in knowledge, treatment has not advanced significantly in recent years, with the absence of new therapeutic targets. Because of the limitations of current therapeutic options, the greater challenge will be to identify biomarkers for clinical application. For this reason, we compared our array comparative genomic hybridization (array-CGH) results with those reported in literature for invasive bladder tumors and, in particular, we focused on the evaluation of copy number alterations (CNAs) present in biopsies and retained in the corresponding cancer stem cell (CSC) subpopulations that should be the main target of therapy. According to our data, CCNE1, MYC, MDM2 and PPARG genes could be interesting therapeutic targets for bladder CSC subpopulations. Surprisingly, HER2 copy number gains are not retained in bladder CSCs, making the gene-targeted therapy less interesting than the others. These results provide precious advice for further study on bladder therapy; however, the clinical importance of these results should be explored.

Tang YL, Huang LB, Lin WH, et al.
Butein inhibits cell proliferation and induces cell cycle arrest in acute lymphoblastic leukemia via FOXO3a/p27kip1 pathway.
Oncotarget. 2016; 7(14):18651-64 [PubMed] Article available free on PMC after 12/04/2017 Related Publications
Acute lymphoblastic leukemia (ALL) is a common hematological malignancy characterized by the uncontrolled proliferation of leukemia cells in children. Discovering and developing effective chemotherapeutic drugs are needed for ALL. In this study, we investigated the anti-leukemic activity of butein and its action mechanisms in ALL. Butein was found to significantly suppress the cellular proliferation of ALL cell lines and primary ALL blasts in a dose-dependent manner. It also induced cell cycle arrest by decreasing the expression of cyclin E and CDK2. We also found that butein promoted nuclear Forkhead Class box O3a (FOXO3a) localization, enhanced the binding of FOXO3a on the p27kip1 gene promoter and then increased the expression of p27kip1. Moreover, we showed that FOXO3a knockdown significantly decreased the proliferation inhibition by butein, whereas overexpression of FOXO3a enhanced the butein-mediated proliferation inhibition. However, overexpression of FOXO3a mutation (C-terminally truncated FOXO3a DNA-binding domain) decreased the proliferation inhibition by butein through decreasing the expression of p27kip1. Our results therefore demonstrate the therapeutic potential of butein for ALL via FOXO3a/p27kip1 pathway.

Zhang Q, Chen X, Zhang X, et al.
Knockdown of TMEM14A expression by RNAi inhibits the proliferation and invasion of human ovarian cancer cells.
Biosci Rep. 2016; 36(1):e00298 [PubMed] Article available free on PMC after 12/04/2017 Related Publications
Transmembrane protein 14A (TMEM14A) is a member of TMEMs. Alterations in TMEMs expression have been identified in several types of cancer, but the expression and function of TMEM14A in ovarian cancer is still unclear. Here, analysis on the expression data of the Cancer Genome Atlas (TCGA) ovarian serous cystadenocarcinoma (OV) dataset demonstrated the overexpression of TMEM14A in ovarian cancer tissues compared with normal tissues, which was consistent with our real-time PCR analysis on ovarian cancer and normal tissues collected from 30 patients. In addition, TMEM14A knockdown in two ovarian cancer cell lines, A2780 and HO-8910, reduced cell proliferation, causes cell cycle arrest and suppressed cell invasion. Moreover, silencing of TMEM14A notably repressed G1/S cell cycle transition and cell invasion via down-regulating the expression of cell cycle related proteins (Cyclin D1, Cyclin E and PCNA) and metastasis-related proteins (MMP-2 and MMP-9), respectively. TMEM14A knockdown significantly reduced the phosphorylation status of Smad2 and Smad3, downstream effectors of TGF-β signalling. In summary, these results indicate that TMEM14A has a pro-tumorigenic effect in ovarian cancer cells, suggesting an important role of this protein in ovarian cancer oncogenesis and metastasis.

Kim SH, Hwang KA, Choi KC
Treatment with kaempferol suppresses breast cancer cell growth caused by estrogen and triclosan in cellular and xenograft breast cancer models.
J Nutr Biochem. 2016; 28:70-82 [PubMed] Related Publications
As a phytoestrogen, kaempferol (Kaem) is one of bioflavonoids, which are found in a variety of vegetables including broccoli, tea and tomato. In this study, the antiproliferative effects of Kaem in triclosn (TCS)-induced cell growth were examined in MCF-7 breast cancer cells. TCS promoted the cell viability of MCF-7 cells via estrogen receptor α (ERα) as did 17β-estradiol (E2), a positive control. On the other hand, Kaem significantly suppressed E2 or TCS-induced cell growth. To elucidate the molecular mechanisms of TCS and Kaem, alterations in the expressions of cell cycle, apoptosis and metastasis-related genes were identified using western blot assay. The treatment of the cells with TCS up-regulated the protein expressions of cyclin D1, cyclin E and cathepsin D, while down-regulated p21 and bax expressions. Kaem reversed TCS-induced gene expressions in an opposite manner. The phosphorylation of IRS-1, AKT, MEK1/2 and ERK was increased by TCS, indicating that TCS induced MCF-7 cell proliferation via nongenomic ER signaling pathway associated with IGF-1R. Kaem presented an antagonistic activity on this signaling by down-regulating the protein expression of pIRS-1, pAkt and pMEK1/2 promoted by E2 or TCS. In an in vivo xenografted mouse model, tumor growth was induced by treatment with E2 or TCS, which was identified in the measurement of tumor volume, hematoxylin and eosin staining, bromodeoxyuridine and immunohistochemistry assay. On the contrary, E2 or TCS-induced breast tumor growth was inhibited by co-treatment with Kaem, which is consistent with in vitro results. Taken together, these results revealed that Kaem has an anticancer effect against procancer activity of E2 or TCS, a xenoestrogen, in breast cancer and may be suggested as a prominent agent to neutralize breast cancer risk caused by TCS.

Turunen A, Hukkanen V, Kulmala J, Syrjanen S
HSV-1 Infection Modulates the Radioresponse of a HPV16-positive Head and Neck Cancer Cell Line.
Anticancer Res. 2016; 36(2):565-74 [PubMed] Related Publications
BACKGROUND: The combined effects of Human papillomavirus (HPV) and Herpes simplex type 1 (HSV-1) infections and their effects on cancer cell radioresistance are unexplored.
MATERIALS AND METHODS: An HPV16-positive hypopharyngeal carcinoma cell line (UD-SCC-2) was infected with wt-HSV-1 at low multiplicity of infection (MOI) and irradiated with 2 Gy at 24 h postinfection. Viability assays and quantitative reverse-transcriptase PCR for HPV16 E6, E7, nuclear factor kappa B1, B-cell CLL/lymphoma 2 (BCL2), and caspases 3, 8 and 9 at 24, and 72 h, as well as immunocytochemistry for BCL2, caspase 3, cyclin E, mouse double minute 2 homolog (MDM2), HSV-1 and Ki-67 were performed at 144 h postirradiation.
RESULTS: At 144 h, cell viability was significantly lowered by irradiation only in uninfected cells. Infection combined with irradiation resulted in increased expression of E6, E7, BCL2 and NF-κB1 at 144 h. Simultaneously, E6 and E7 were down-regulated in non-irradiated infected cells. Irradiation and infection with 0.00001 MOI separately up-regulated caspase 3 but infection with 0.0001 MOI halved its expression in irradiated cells.
CONCLUSION: HSV-1 infection modulates radioresistance of HPV16-positive hypopharyngeal carcinoma cells.

Guo T, Gu C, Chen X, et al.
Inhibition of succinate dehydrogenase sensitizes cyclin E-driven ovarian cancer to CDK inhibition.
Biofactors. 2016 Mar-Apr; 42(2):171-8 [PubMed] Related Publications
AIM: High-grade serous ovarian cancer (HGS-OvCa) is characterized by widespread CCNE1 amplification. Current treatments lack specificity to target Cyclin E-driven OvCa.
METHODS: By in silico analysis of the TCGA OvCa dataset we searched association between genes involved in glucose metabolism and cell cycle control. Metabolic shift was studied in Cyclin E-driven OvCa cells treated with CDK inhibition (CDKi). Genetic and pharmaceutical inhibition of succinate dehydrogenase (SDH) was tested in combination with CDKi.
RESULTS: OvCa patients with CCNE1 amplification could be divided by concomitant SDHA amplification. A2780 OvCa cells were similar to the Cyclin E-driven and SDHA neutral genotype. CDKi in A2780 cells using Dinaciclib resulted in compensatory enhancement of tricarboxylicacid cycle (TCA) cycle activity. Combined blockade of CDK and SDH, both genetically and pharmaceutically, showed synergy and resulted in inhibited proliferation, migration, invasion and migration in A2780 cells. The combined inhibition did not further alter cell cycle population, but induced apoptosis of A2780 cells.
CONCLUSION: Cyclin E-driven OvCa cells appeared addicted to glucose metabolism via TCA. Combined CDKi with modalities targeting TCA, like SDHA inhibition showed promising effects for this genotype.

Mitra P, Yang RM, Sutton J, et al.
CDK9 inhibitors selectively target estrogen receptor-positive breast cancer cells through combined inhibition of MYB and MCL-1 expression.
Oncotarget. 2016; 7(8):9069-83 [PubMed] Article available free on PMC after 12/04/2017 Related Publications
Our previous studies showed that MYB is required for proliferation of, and confers protection against apoptosis on, estrogen receptor-positive (ER(+ve)) breast cancer cells, which are almost invariably also MYB(+ve). We have also shown that MYB expression in ER(+ve) breast cancer cells is regulated at the level of transcriptional elongation and as such, is suppressed by CDK9i. Here we examined the effects of CDK9i on breast cancer cells and the involvement of MYB in these effects. ER(+ve) breast cancer cell lines including MCF-7 were much more sensitive (> 10 times) to killing by CDK9i than ER(-ve)/MYB(-ve) cells. Moreover, surviving cells showed a block at the G2/M phase of the cell cycle. Importantly, ectopic MYB expression conferred resistance to apoptosis induction, cell killing and G2/M accumulation. Expression of relevant MYB target genes including BCL2 and CCNB1 was suppressed by CDK9 inhibition, and this too was reversed by ectopic MYB expression. Nevertheless, inhibition of BCL2 alone either by MYB knockdown or by ABT-199 treatment was insufficient for significant induction of apoptosis. Further studies implied that suppression of MCL-1, a well-documented target of CDK9 inhibition, was additionally required for apoptosis induction, while maximal levels of apoptosis induced by CDK9i are likely to also involve inhibition of BCL2L1 expression. Taken together these data suggest that MYB regulation of BCL2 underlies the heightened sensitivity of ER(+ve) compared to ER(-ve) breast cancer cells to CDK9 inhibition, and that these compounds represent a potential therapeutic for ER(+ve) breast cancers and possibly other MYB-dependent cancers.

Luhtala S, Staff S, Tanner M, Isola J
Cyclin E amplification, over-expression, and relapse-free survival in HER-2-positive primary breast cancer.
Tumour Biol. 2016; 37(7):9813-23 [PubMed] Related Publications
Cyclin E is a well-characterized cell cycle regulator and an amplified oncogene in breast cancer. Over-expression of cyclin E has generally been associated with poor survival. Recent studies have shown an interaction between HER-2 (ERBB2) and cyclin E, but the exact mechanism is unknown. Interestingly, cyclin E over-expression has been associated with trastuzumab resistance. We studied cyclin E over-expression, CCNE1 amplification, and relapse-free survival in HER-2-positive primary breast cancers treated with and without trastuzumab therapy. Formalin-fixed paraffin-embedded tissue samples from 202 HER-2-positive breast carcinomas were studied. Expression levels of cyclin E and proliferation marker Ki-67 were determined using immunohistochemistry. Chromogenic in situ hybridization (CISH) with a gene-specific bacterial artificial chromosome (BAC) probe was used to analyze presence of CCNE1 amplification. Majority of HER-2-positive breast carcinomas exhibited nuclear staining for cyclin E protein. Cyclin E was highly expressed (≥50 % cells) in 37 % of cases. Incidence of CCNE1 amplification (≥6 gene copies/cell or clusters) was 8 %. Cyclin E amplification and over-expression were strongly associated with each other, grade, hormone receptors, and Ki-67. Neither high cyclin E expression nor CCNE1 amplification was associated with relapse-free survival (RFS) irrespective of short-term (9-week regimen) adjuvant trastuzumab therapy. These results confirm cyclin E and HER-2 gene co-amplification in a fraction of HER-2-positive breast cancers. Cyclin E is frequently over-expressed but appears to have limited value as a prognostic or predictive factor in HER-2-positive breast cancer regardless of trastuzumab therapy.

Kim SH, Nam KH, Hwang KA, Choi KC
Influence of hexabromocyclododecane and 4-nonylphenol on the regulation of cell growth, apoptosis and migration in prostatic cancer cells.
Toxicol In Vitro. 2016; 32:240-7 [PubMed] Related Publications
The aim of the present study was to determine whether hexabromocyclododecane (HBCD) or 4-nonylphenol (NP) may induce prostatic cancer progression in LNCaP cells. Androgenic effects of HBCD and NP were examined in LNCaP prostate cancer cells expressing androgen receptors (ARs). HBCD and NP increased LNCaP cell viability similar to dihydrotestosterone (DHT) by MTT assay. This phenomenon was reversed by treatment with Casodex, an AR antagonist, suggesting that they act as xenoandrogens via AR signaling pathway. In cell migration assay, HBCD and NP also enhanced LNCaP cell migration similar to DHT. To elucidate underlying mechanisms of their actions on LNCaP, transcriptional levels of cell cycle- and apoptosis-related markers, including cyclin D1, cyclin E, p27, bcl-2, and bax, were determined by reverse transcription (RT)-PCR. An increase in expression cyclin D1 and cyclin E and reduction in p27 and bax mRNA levels were observed by their treatments. Western blot assay showed their alterations in translational levels of cyclin D1, cyclin E, p21, bax, and cathepsin D. Expressions of genes related to a G1/S transition of cell cycle and cathepsin D were elevated, while expression of p21 and bax was decreased. Taken together, these results indicate that HBCD and NP may enhance progression of prostate cancer by modulating growth and migration of LNCaP prostate cells by acting on cell cycle, apoptosis, and metastasis.

Yin A, Wang C, Sun J, et al.
Overexpression of NDRG2 Increases Iodine Uptake and Inhibits Thyroid Carcinoma Cell Growth In Situ and In Vivo.
Oncol Res. 2016; 23(1-2):43-51 [PubMed] Related Publications
Medullary thyroid carcinoma (MTC) is an uncommon and highly aggressive tumor of the neuroendocrine system, which derives from the neuroendocrine C cells of the thyroid gland. Except for surgical resection, there are not very many effective systemic treatment options for MTC. N-Myc downstream-regulated gene 2 (NDRG2) had a significantly lower expression in MTC compared with normal thyroid tissue. However, the function of NDRG2 in MTC oncogenesis is largely unknown. In this study, we found that overexpression of NDRG2 inhibited the proliferation of TT cells (human medullary thyroid carcinoma cells) in vitro and suppressed the development of MTC in a nude mouse xenograft model. Further analysis revealed that NDRG2 arrested the cell cycle G0/G1 phase progression and induced TT cell apoptosis. Moreover, NDRG2 overexpression may mediate the antiproliferative effect by reducing cyclin D1 and cyclin E protein levels. We also found aberrant NDRG2-mitigated TT cell migration and invasion in vitro. Sodium/iodide symporter (NIS) mediates active I(-) transport into the thyroid follicular cells, and radionuclide treatment is a promising therapy for MTC. Our current data revealed that NDRG2 overexpression enhanced NIS level in TT cells and increased their iodine uptake in vitro. Furthermore, (99m)TcO4(-) radionuclide imaging of the xenograft tumors indicated that NDRG2 could promote NIS-mediated radionuclide transport. In conclusion, the present study suggested that NDRG2 is a critical molecule in the regulation of MTC biological behavior and a potential promoter in radioactive iodine therapy.

Li L, Jiang X, Zhang Q, et al.
Neuropilin-1 is associated with clinicopathology of gastric cancer and contributes to cell proliferation and migration as multifunctional co-receptors.
J Exp Clin Cancer Res. 2016; 35:16 [PubMed] Article available free on PMC after 12/04/2017 Related Publications
BACKGROUND: Neuropilin-1 (NRP-1) is a transmembrane glycoprotein participating in the growth and metastasis of cancer cells as multifunctional co-receptors by interacting with the signaling pathways. However, its role in gastric cancer has not yet been clarified. This study aims to investigate whether NRP-1 expression is associated with the clinicopathology of gastric cancer, and involved in the growth and metastasis of gastric cancer cells.
METHODS: NRP-1 expression in clinical gastric cancer specimens was examined by immunohistochemistry and its association with clinicopathology analyzed. The expression of NRP-1 in a panel of human gastric cancer cells was examined by real-time RT-PCR and immunoblotting. Stable transfectants depleted of NRP-1, termed MGC-803-NRP(low), were generated from MGC-803 cells. Cell proliferation was analyzed by the Cell Counting Kit-8 and Bromodeoxyuridine incorporation assays, and migrating ability analyzed by migration assays. The xenograft model was used to assess the effects of NRP-1 depletion on tumorigenesis, growth, metastasis and therapeutic potentials. The role of NRP-1 as co-receptors in the signaling pathways stimulated by ligands was examined. The key molecules involved in cell proliferation, migration and related signaling pathways were detected by immunoblotting.
RESULTS: Gastric cancer tissues expressed higher levels of NRP-1 compared to normal gastric mucosa. Its expression correlated with clinical staging, tumor differentiation and pathological types. NRP-1 depletion inhibited cell proliferation by inducing cell cycle arrest in the G1/S phase by upregulating p27, and downregulating cyclin E and cyclin-dependent kinase 2. NRP-1 depletion reduced the ability of cells to migrate by inhibiting the phosphorylation of focal adhesion kinase. NRP-1 depletion suppressed tumorigenesis, tumor growth and lung metastasis by inhibiting cell proliferation and tumor angiogenesis in situ. Therapeutic NRP-1 shRNA inhibited the growth of established BGC823 tumors. Depletion of NRP-1 inhibited the activation of VEGF/VEGFR2, EGF/EGFR and HGF/c-Met pathways stimulated by respective recombinant human VEGF-165, EGF and HGF proteins.
CONCLUSIONS: The present results indicate that NRP-1 may be a potentially valuable biomarker and therapeutic target for gastric cancer.

Wang X, Sun Q, Chen C, et al.
ZYG11A serves as an oncogene in non-small cell lung cancer and influences CCNE1 expression.
Oncotarget. 2016; 7(7):8029-42 [PubMed] Article available free on PMC after 12/04/2017 Related Publications
By analyzing The Cancer Genome Atlas (TCGA) database, we identified ZYG11A as a potential oncogene. We determined the expression of ZYG11A in NSCLC tissues and explored its clinical significance. And also evaluated the effects of ZYG11A on NSCLC cell proliferation, migration, and invasion both in vitro and in vivo. Our results show that ZYG11A is hyper-expressed in NSCLC tissues compared to adjacent normal tissues, and increased expression of ZYG11A is associated with a poor prognosis (HR: 2.489, 95%CI: 1.248-4.963, p = 0.010). ZYG11A knockdown induces cell cycle arrest and inhibits proliferation, migration, and invasion of NSCLC cells. ZYG11A knockdown also results in decreased expression of CCNE1. Over-expression of CCNE1 in cells with ZYG11A knockdown restores their oncogenic activities. Our data suggest that ZYG11A may serve as a novel oncogene promoting tumorigenicity of NSCLC cells by inducing cell cycle alterations and increasing CCNE1 expression.

Wang Z, Chen J, Zhang W, et al.
Axon guidance molecule semaphorin3A is a novel tumor suppressor in head and neck squamous cell carcinoma.
Oncotarget. 2016; 7(5):6048-62 [PubMed] Article available free on PMC after 12/04/2017 Related Publications
Semaphorin3A (SEMA3A), an axon guidance molecule in the nervous system, plays an inhibitory role in oncogenesis. Here, we investigated the expression pattern and biological roles of SEMA3A in head and neck squamous cell carcinoma (HNSCC) by gain-of-function assays using adenovirus transfection and recombinant human SEMA3A protein. In addition, we explored the therapeutic efficacy of SEMA3A against HNSCC in vivo. We found that lower expression of SEMA3A correlated with shorter overall survival and had independent prognostic importance in patients with HNSCC. Both genetic and recombinant SEMA3A protein inhibited cell proliferation and colony formation and induced apoptosis, accompanied by decreased cyclin E, cyclin D, CDK2, CDK4 and CDK6 and increased P21, P27, activated caspase-5 and caspase-7. Moreover, over-expression of SEMA3A suppressed migration, invasion and epithelial-to-mesenchymal transition due in part to the inhibition of NF-κB and SNAI2 in HNSCC cell lines. Furthermore, intratumoral SEMA3A delivery significantly stagnated tumor growth in a xenograft model. Taken together, our results indicate that SEMA3A serves as a tumor suppressor during HNSCC tumorigenesis and a new target for the treatment of HNSCC.

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