Gene Summary

Gene:CCNE2; cyclin E2
Aliases: CYCE2
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. This cyclin has been shown to specifically interact with CIP/KIP family of CDK inhibitors, and plays a role in cell cycle G1/S transition. The expression of this gene peaks at the G1-S phase and exhibits a pattern of tissue specificity distinct from that of cyclin E1. A significantly increased expression level of this gene was observed in tumor-derived cells. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:G1/S-specific cyclin-E2
Source:NCBIAccessed: 15 March, 2017


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 15 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Latest Publications: CCNE2 (cancer-related)

Gorjala P, Cairncross JG, Gary RK
p53-dependent up-regulation of CDKN1A and down-regulation of CCNE2 in response to beryllium.
Cell Prolif. 2016; 49(6):698-709 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
OBJECTIVES: Beryllium salts (here, beryllium sulphate) can produce a cytostatic effect in some cell types. The basis for this effect may include increased expression of proliferation inhibitors, reduced expression of proliferation promoters, or both. This study sought to determine the role of p53, the tumour-suppressing transcription factor, in mediating beryllium-induced cytostasis.
MATERIALS AND METHODS: Human A172 glioma cells express wild-type TP53 gene. Activity of p53 was experimentally manipulated using siRNA and related approaches. Key elements of the beryllium-response were compared in normal and p53-knockdown A172 cells using RT-PCR and Western blotting.
RESULTS: In A172 cells, 10 μm BeSO4 caused 300% increase in CDKN1A (cyclin-dependent kinase inhibitor p21) mRNA and 90% reduction of CCNE2 (cyclin E2) mRNA. The increased p21 mRNA and reduced cyclin E2 mRNA were each dependent on presence of functional p53. For p21, increased mRNA led to commensurately increased protein levels. In contrast, reduction in cyclin E2 mRNA levels did not lead to corresponding reductions in cyclin E2 protein. The proteasomal inhibitor MG-132 caused p53 protein to increase, but it had no effect on cyclin E2 protein levels. Cycloheximide time course studies indicated that the cyclin E2 protein half-life was more than 12 hours in these cells.
CONCLUSIONS: Beryllium elicited p53-dependent changes in mRNA levels of key determinants of cell proliferation such as p21 and cyclin E2. However, cyclin E2 protein appeared to be aberrantly regulated in this cell type, as its turnover was unexpectedly slow.

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.

Patel AV, Chaney KE, Choi K, et al.
An ShRNA Screen Identifies MEIS1 as a Driver of Malignant Peripheral Nerve Sheath Tumors.
EBioMedicine. 2016; 9:110-9 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
Malignant peripheral nerve sheath tumors (MPNST) are rare soft tissue sarcomas that are a major source of mortality in neurofibromatosis type 1 (NF1) patients. To identify MPNST driver genes, we performed a lentiviral short hairpin (sh) RNA screen, targeting all 130 genes up-regulated in neurofibroma and MPNSTs versus normal human nerve Schwann cells. NF1 mutant cells show activation of RAS/MAPK signaling, so a counter-screen in RAS mutant carcinoma cells was performed to exclude common RAS-pathway driven genes. We identified 7 genes specific for survival of MPSNT cells, including MEIS1. MEIS1 was frequently amplified or hypomethylated in human MPSNTs, correlating with elevated MEIS1 gene expression. In MPNST cells and in a genetically engineered mouse model, MEIS1 expression in developing nerve glial cells was necessary for MPNST growth. Mechanistically, MEIS1 drives MPNST cell growth via the transcription factor ID1, thereby suppressing expression of the cell cycle inhibitor p27(Kip) and maintaining cell survival.

Kumari S, Puneet, Prasad SB, et al.
Cyclin D1 and cyclin E2 are differentially expressed in gastric cancer.
Med Oncol. 2016; 33(5):40 [PubMed] Related Publications
Cell cycle regulators cyclin D1 and cyclin E2 function in G1/S transition by activating downstream cyclin-dependent kinases. Deregulated expression of these cyclins has been reported in various cancers. However, little is known about their clinical significance in gastric carcinoma. We aimed to explore that whether there is differential expression of these cyclins in clinically distinct gastric cancer patients. In this study we recruited a total of 92 subjects including 20 controls and 72 cases of histopathologically proven gastric carcinoma. Expression profiling at transcript level was done by semiquantitative RT-PCR and of protein by immunohistochemistry. Receiver operator characteristics analysis was done for determining diagnostic utility of cyclin D1 and cyclin E2. We demonstrate that cyclins D1 and E2 are frequently overexpressed in early stages of gastric carcinoma. Interestingly, expression of cyclins D1 and E2 significantly correlates with different clinical parameters such as gender, histological type (intestinal and diffuse), tumor location (proximal, middle, and distal), tumor differentiation (differentiated and undifferentiated), tumor invasion (serosal, lymphatic, and venous) and tumor metastasis (lymph node, peritoneal, ascites, and liver). Cyclin D1 has significantly higher sensitivity and specificity as diagnostic biomarker than cyclin E2. Our results suggest that overexpression of cyclin D1 and cyclin E2 is an early event in gastric carcinogenesis. The differential expression of these cyclins may be useful as diagnostic biomarkers for early detection of gastric carcinoma.

Makhlouf MM
Survivin and cyclin E2 genes expression in a cohort of Egyptian acute leukemia patients: Clinical importance and future prospects.
Cancer Biomark. 2016; 16(1):181-9 [PubMed] Related Publications
BACKGROUND: Abnormalities in the control of apoptosis play an important role in leukemogenesis. Survivin is a member of inhibitor of apoptosis proteins family, it prevents apoptosis by blocking caspase activity and play a role in cell proliferation. While, cyclin E2 is one of the cyclins proteins family that controls progression of cell cycle by activation of cyclin dependant-kinase.
OBJECTIVE: Was to assess survivin and cyclin E2 genes expression in acute leukemia (AL) patients, and to define their role in the susceptibility of AL, and their correlation with the clinical presentation, laboratory findings, as well as treatment outcome.
PATIENTS AND METHODS: This study included 60 de novo AL patients and 40 control subjects to study the expression of survivin and cyclin E2 genes using RT-PCR.
RESULTS: Survivin and cyclin E2 genes expression was significantly higher in leukemic patients compared with control subjects (P< 0.001), both genes separately were associated with increased risk of leukemia development and treatment failure (P< 0.01). Moreover, when combining the 2 genes expression, a significant elevation of the risk of leukemia and treatment failure was found (P < 0.01).
CONCLUSIONS: Survivin and cyclin E2 genes expression may have clinical relevance and can be considered as molecular risk factors for AL. Also they may be useful as predictive markers for treatment outcome in leukemic patients.

Yu CC, Yang MD, Lin HY, et al.
Bisdemethoxycurcumin (BDMC) Alters Gene Expression-associated Cell Cycle, Cell Migration and Invasion and Tumor Progression in Human Lung Cancer NCI-H460 Cells.
In Vivo. 2015 Nov-Dec; 29(6):711-28 [PubMed] Related Publications
BACKGROUND/AIM: Lung cancer is one of the most common malignancies and a predominant cause of cancer-related death. It can metastasize in almost all organs, and currently, while new cases are increasing, treatment is still insufficient. Bisdemethoxycurcumin (BDMC), one of the components of turmeric, has been known to possess biological activities. However, the effects of BDMC on the genetic level remain unclear.
MATERIALS AND METHODS: Human lung cancer NCI-H460 cells were treated with 35 μM BDMC for 24 h and cells were harvested for total RNA extraction. The purified RNA was used for cDNA synthesis, labeling, microarray hybridization, and flour-labeled cDNA on-chip hybridization. The expression Console software (Affymetrix) with default RNA parameters was used to detect and quantitate concentrations of fluorescent molecules. The key genes involved and their possible interaction pathways were analyzed by the GeneGo software.
RESULTS: Seven genes, such as CCNE2 (cyclin E), associated with cell cycle, were over 4-fold overexpressed, 22 genes, such as ERCC6L (excision repair cross-complementing rodent repair deficiency, complementation group 6-like) associated with DNA damage and repair, were from 3- to 4-fold overexpressed and 266, such as cell division cycle, S-phase associated kinase and associated with cell death, genes were from 2- to 3-fold overexpressed.
CONCLUSION: BDMC induced changes in gene expression that may reveal cytotoxic information on the genetic level while presenting novel biomarkers or targets for treatment of human lung cancer in the future.

Liang W, Guan H, He X, et al.
Down-regulation of SOSTDC1 promotes thyroid cancer cell proliferation via regulating cyclin A2 and cyclin E2.
Oncotarget. 2015; 6(31):31780-91 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
Sclerostin domain containing protein 1 (SOSTDC1) is down-regulated and acts as a tumor suppressor in some kinds of cancers. However, the expression pattern and biological significance of SOSTDC1 in thyroid cancer are largely unknown. We demonstrated that SOSTDC1 was significantly down-regulated in thyroid cancer. Ectopic over-expression of SOSTDC1 inhibited proliferation and induced G1/S arrest in thyroid cancer cells. Moreover, SOSTDC1 over-expression suppressed the growth of tumor xenografts in nude mice. We also found that elevated SOSTDC1 led to inhibition of cyclin A2 and cyclin E2. Together,our results demonstrate that SOSTDC1 is down-regulated in thyroid cancer and might be a potential therapeutic target in the treatment of thyroid cancer.

Yang XR, Xiong Y, Duan H, Gong RR
Identification of genes associated with methotrexate resistance in methotrexate-resistant osteosarcoma cell lines.
J Orthop Surg Res. 2015; 10:136 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
BACKGROUND: This study aimed to better understand the mechanisms underlying methotrexate (MTX)-resistance in osteosarcoma.
METHODS: The raw transcription microarray data GSE16089 collected from three MTX-sensitive osteosarcoma (Saos-2) cell samples and three MTX-resistant osteosarcoma (Saos-2) cell samples were downloaded from Gene Expression Omnibus. After data processing, the differentially expressed genes (DEGs) were identified. Next, DEGs were submitted to DAVID for functional annotation based on the GO (Gene Ontology) database, as well as pathway enrichment analysis based on the KEGG (Kyoto Encyclopedia of Genes and Genomes) database. Transcription factors (TFs) and tumor-associated genes (TAGs) were identified with reference to TRANSFAC and TAG, and TSGene databases, respectively. The protein-protein interaction (PPI) network of the gene-encoded products was constructed, and the subnetwork with the highest score was also detected using Search Tool for the Retrieval of Interacting Genes and BioNet package.
RESULTS: A total of 690 up-regulated genes and down-regulated 626 genes were identified. Up-regulated DEGs (including AARS and PARS2) were associated to transfer RNA (tRNA) aminoacylation while down-regulated DEGs (including AURKA, CCNB1, CCNE2, CDK1, and CENPA) were correlated with mitotic cell cycle. Totally, 13 TFs (including HMGB2), 13 oncogenes (including CCNA2 and AURKA), and 19 tumor suppressor genes (TSGs) (including CDKN2C) were identified from the down-regulated DEGs. Ten DEGs, including nine down-regulated genes (such as AURKA, CDK1, CCNE2, and CENPA) and one up-regulated gene (GADD45A), were involved in the highest score subnetwork.
CONCLUSION: AARS, AURKA, AURKB, CENPA, CCNB1, CCNE2, and CDK may contribute to MTX resistance via aminoacyl-tRNA biosynthesis pathway, cell cycle pathway, or p53 signaling pathway.

Sathe A, Koshy N, Schmid SC, et al.
CDK4/6 Inhibition Controls Proliferation of Bladder Cancer and Transcription of RB1.
J Urol. 2016; 195(3):771-9 [PubMed] Related Publications
PURPOSE: The retinoblastoma signaling network is frequently altered in advanced bladder cancer. We investigated the potential of CDK4/6 as a therapeutic target and determined biomarkers for patient stratification.
MATERIALS AND METHODS: Genetic alterations were analyzed using public databases, including TCGA (The Cancer Genome Atlas), COSMIC (Catalogue of Somatic Mutations in Cancer) and CCLE (Cancer Cell Line Encyclopedia). Effects of the CDK4/6-inhibitor PD-0332991 or LY2835219 were examined in 10 bladder cancer cell lines by immunoblot, cell viability, apoptosis and cell cycle progression. Efficacy of the PD-0332991 and cisplatin combination was analyzed using the combination index. Gene expression level was determined by quantitative polymerase chain reaction. Cytomegalovirus promoter regulated recombinant retinoblastoma was used for reconstitution. Three-dimensional xenografts were grown on chicken chorioallantoic membrane and analyzed by measuring tumor weight and immunohistochemical expression of total retinoblastoma and Ki-67.
RESULTS: PD-0332991 treatment decreased the proliferation of retinoblastoma positive bladder cancer cell lines and was synergistic in combination with cisplatin. PD-0332991 or LY2835219 treatment decreased the phosphorylation, total protein and transcript level of retinoblastoma. Treatment resulted in a decrease in E2F target gene expression (CCNA2 and CCNE2) and cell cycle progression from G0/G1 to the S-phase but did not affect apoptosis. In retinoblastoma negative cells reconstituted with recombinant retinoblastoma PD-0332991 affected only phosphorylation and not the total retinoblastoma level. These cells remained resistant to treatment. In 3-dimensional retinoblastoma xenografts, treatment resulted in reduced tumor weight and decreased expression of total retinoblastoma and Ki-67.
CONCLUSIONS: We provide preclinical evidence that CDK4/6 inhibition is a potential therapeutic strategy for retinoblastoma positive bladder cancer that probably acts by negatively regulating retinoblastoma transcription.

Gupta ED, Pachauri M, Ghosh PC, Rajam MV
Targeting polyamine biosynthetic pathway through RNAi causes the abrogation of MCF 7 breast cancer cell line.
Tumour Biol. 2016; 37(1):1159-71 [PubMed] Related Publications
The diamine putrescine and polyamines, spermidine (triamine) and spermine (tetraamine) are small organic polycations that play an indispensable role in key cellular processes such as the regulation of growth, differentiation, and macromolecular functions. Elevated levels of polyamines (PAs) have been shown to be one of the major factors involved in carcinogenesis. In this study, specific silencing of the expression of three genes of PA biosynthesis pathway, ornithine decarboxylase (ODC), S-adenosylmethionine decarboxylase (SAMDC), and spermidine synthase (SPDSYN) was achieved using RNA interference in MCF 7 breast cancer cell line. For optimizing the effective small interfering nucleic acid (siNA), three variants of ODC siNA [siRNA, locked nucleic acid (LNA)-modified siRNA, and siHybrid (RNA and DNA hybrid)] were used and a dose- and time-dependent study was conducted. The PA biosynthetic genes were targeted individually and in combination. RNAi-mediated reduction in the expression of PA biosynthesis genes resulted in distorted cell morphology, reduced cancer cell viability, and migration characteristic. The most promising results were observed with the combined treatment of siSPDSYN and siODC with 83 % cell growth inhibition. On analyzing the messenger RNA (mRNA) expression profile of the cell cycle and apoptosis-related genes, it was observed that RNAi against PA biosynthetic genes downregulated the expression of CDK8, CCNE2, CCNH, CCNT1, CCNT2, CCNF, PCNA, CCND1, and CDK2, and upregulated the expression of E2F4, BAX, FAS, TP53, CDKN1A, BAK1, CDKN1B, ATM, GRANB, and ATR genes when compared with control-transfected cells. These results suggest that the targeting polyamine biosynthesis through RNAi approach could be a promising strategy for breast cancer therapy and might be extended for therapy of other cancers.

Chiang IT, Wang WS, Liu HC, et al.
Curcumin alters gene expression-associated DNA damage, cell cycle, cell survival and cell migration and invasion in NCI-H460 human lung cancer cells in vitro.
Oncol Rep. 2015; 34(4):1853-74 [PubMed] Related Publications
Lung cancer is the most common cause of cancer mortality and new cases are on the increase worldwide. However, the treatment of lung cancer remains unsatisfactory. Curcumin has been shown to induce cell death in many human cancer cells, including human lung cancer cells. However, the effects of curcumin on genetic mechanisms associated with these actions remain unclear. Curcumin (2 µM) was added to NCI-H460 human lung cancer cells and the cells were incubated for 24 h. Total RNA was extracted from isolated cells for cDNA synthesis, labeling, microarray hybridization and flour‑labeled cDNA hybridized on chip. Localized concentrations of fluorescent molecules were detected and quantified using Expression Console software (Affymetrix) with default RMA parameters. GeneGo software was used for the key genes involved and their possible interaction pathways. The results showed that ~170 genes were significantly upregulated and 577 genes were significantly downregulated in curcumin‑treated cells. Specifically, the up‑ and downregulated genes included CCNE2, associated with DNA damage; ID3, associated with cell survival and 146 genes with a >2- to 3-fold change including the TP53INP1 gene, associated with DNA damage; CDC6, CDCA5, TAKMIP2, CDK14, CDK5, CDCA76, CDC25A, CDC5L and SKP2, associated with cell cycle; the CARD6, ID1 and ID2 genes, associated with cell survival and the BRMS1L, associated with cell migration and invasion. Additionally, 59 downregulated genes exhibited a >4-fold change, including the DDIT3 gene, associated with DNA damage; while 97 genes had a >3- to 4-fold change including the DDIT4 gene, associated with DNA damage; the CCPG1 gene, associated with cell cycle and 321 genes with a >2- to 3-fold including the GADD45A and CGREF1 genes, associated with DNA damage; the CCPG1 gene, associated with cell cycle, the TNFRSF10B, GAS5, TSSC1 and TNFRSF11B gene, associated with cell survival and the ARHAP29 and CADM2 genes, associated with cell migration and invasion. In conclusion, gene alterations provide information regarding the cytotoxic mechanism of curcumin at the genetic level and provide additional biomarkers or targets for the treatment of human lung cancer.

Matsushita R, Seki N, Chiyomaru T, et al.
Tumour-suppressive microRNA-144-5p directly targets CCNE1/2 as potential prognostic markers in bladder cancer.
Br J Cancer. 2015; 113(2):282-9 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
BACKGROUND: Analysis of a microRNA (miRNA) expression signature of bladder cancer (BC) by deep-sequencing revealed that clustered miRNAs microRNA (miR)-451a, miR-144-3p, and miR-144-5p were significantly downregulated in BC tissues. We hypothesised that these miRNAs function as tumour suppressors in BC. The aim of this study was to investigate the functional roles of these miRNAs and their modulation of cancer networks in BC cells.
METHODS: The functional studies of BC cells were performed using transfection of mature miRNAs. Genome-wide gene expression analysis, in silico analysis, and dual-luciferase reporter assays were applied to identify miRNA targets. The association between miR-144-5p levels and expression of the target genes was determined, and overall patient survival as a function of target gene expression was estimated by the Kaplan-Meier method.
RESULTS: Gain-of-function studies showed that miR-144-5p significantly inhibited cell proliferation by BC cells. Four cell cycle-related genes (CCNE1, CCNE2, CDC25A, and PKMYT1) were identified as direct targets of miR-144-5p. The patients with high CCNE1 or CCNE2 expression had lower overall survival probabilities than those with low expression (P=0.025 and P=0.032).
CONCLUSION: miR-144-5p functions as tumour suppressor in BC cells. CCNE1 and CCNE2 were directly regulated by miR-144-5p and might be good prognostic markers for survival of BC patients.

Chen J, Yang R, Zhang W, Wang Y
Candidate pathways and genes for nasopharyngeal carcinoma based on bioinformatics study.
Int J Clin Exp Pathol. 2015; 8(2):2026-32 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
PURPOSE: To reveal the potential microRNAs (miRNAs), genes, pathways and regulatory network involved in the process of nasopharyngeal carcinoma (NPC) by using the method of bioinformatics.
METHODS: Gene expression profiles GSE12452 (31 NPC and 10 normal samples) and GSE53819 (18 NPC and 18 normal samples), as well as miRNA expression profiles GSE32960 (312 NPC and 18 normal samples) and GSE36682 (62 NPC and 6 normal samples) were obtained from Gene Expression Omnibus database. The differentially expressed genes (DEGs) and miRNAs (DEmiRNAs) between NPC and normal samples were identified by using t-test based on MATLAB software (FDR < 0.01), followed by pathway enrichment analysis based on DAVID software (P-value < 0.1). Then, DEmiRNA-DEG regulatory network was constructed.
RESULTS: A total of 1254 DEGs and 107 DEmiRNAs were identified, respectively. Then, 16 pathways (including cell cycle) and 32 pathways (including pathways in cancer) were enriched by DEGs and target genes of DEmiRNAs, respectively. Furthermore, DEmiRNA-DEG regulatory network was constructed, containing 12 DEmiRNAs (including has-miR-615-3P) and 180 DEGs (including MCM4 and CCNE2).
CONCLUSION: has-miR-615-3p might take part in the pathogenetic process of NPC through regulating MCM4 which is enriched in cell cycle. The DEmiRNAs identified in the present study might serve as new biomarkers for NPC.

Chen D, Guo W, Qiu Z, et al.
MicroRNA-30d-5p inhibits tumour cell proliferation and motility by directly targeting CCNE2 in non-small cell lung cancer.
Cancer Lett. 2015; 362(2):208-17 [PubMed] Related Publications
MicroRNAs (miRNAs) are small, single-stranded, non-coding RNA molecules that are dysregulated in many types of human cancers, although their precise functions in driving non-small cell lung cancer (NSCLC) are incompletely understood. In the present study, we found that miR-30d-5p, often downregulated in NSCLC tissues, significantly inhibited the growth, cell cycle distribution, and motility of NSCLC cells. Furthermore, we demonstrated that cyclin E2 (CCNE2), which was often upregulated in NSCLC tissues, was a direct target of miR-30d-5p. CCNE2 expression promoted the proliferation, invasion, and migration of NSCLC cells. In addition, the re-introduction of CCNE2 expression antagonised the inhibitory effects of miR-30d-5p on the capacity of NSCLC cells for proliferation and motility. Together, these results suggest that the miR-30d-5p/CCNE2 axis may contribute to NSCLC cell proliferation and motility, indicating miR-30d-5p as a potential therapeutic target for the treatment of NSCLC.

Zhao Z, Ma X, Sung D, et al.
microRNA-449a functions as a tumor suppressor in neuroblastoma through inducing cell differentiation and cell cycle arrest.
RNA Biol. 2015; 12(5):538-54 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
microRNA-449a (miR-449a) has been identified to function as a tumor suppressor in several types of cancers. However, the role of miR-449a in neuroblastoma has not been intensively investigated. We recently found that the overexpression of miR-449a significantly induces neuroblastoma cell differentiation, suggesting its potential tumor suppressor function in neuroblastoma. In this study, we further investigated the mechanisms underlying the tumor suppressive function of miR-449a in neuroblastoma. We observed that miR-449a inhibits neuroblastoma cell survival and growth through 2 mechanisms--inducing cell differentiation and cell cycle arrest. Our comprehensive investigations on the dissection of the target genes of miR-449a revealed that 3 novel targets- MFAP4, PKP4 and TSEN15 -play important roles in mediating its differentiation-inducing function. In addition, we further found that its function in inducing cell cycle arrest involves down-regulating its direct targets CDK6 and LEF1. To determine the clinical significance of the miR-449a-mediated tumor suppressive mechanism, we examined the correlation between the expression of these 5 target genes in neuroblastoma tumor specimens and the survival of neuroblastoma patients. Remarkably, we noted that high tumor expression levels of all the 3 miR-449a target genes involved in regulating cell differentiation, but not the target genes involved in regulating cell cycle, are significantly correlated with poor survival of neuroblastoma patients. These results suggest the critical role of the differentiation-inducing function of miR-449a in determining neuroblastoma progression. Overall, our study provides the first comprehensive characterization of the tumor-suppressive function of miR-449a in neuroblastoma, and reveals the potential clinical significance of the miR-449a-mediated tumor suppressive pathway in neuroblastoma prognosis.

Wang X, Liu Y, Shao D, et al.
Recurrent amplification of MYC and TNFRSF11B in 8q24 is associated with poor survival in patients with gastric cancer.
Gastric Cancer. 2016; 19(1):116-27 [PubMed] Related Publications
BACKGROUND: Gastric cancer (GC) is an aggressive malignancy whose mechanisms of development and progression are poorly understood. The identification of prognosis-related genomic loci and genes may suffer from the relatively small case numbers and a lack of systematic validation in previous studies.
METHODS: Array-based comparative genomic hybridization (aCGH) coupled with patient clinical information was applied to identify prognosis-related loci and genes with high-frequency recurrent gains in 129 GC patients. The candidate loci and genes were then validated using an independent cohort of 384 patients through branched DNA signal amplification analysis (QuantiGene assays).
RESULTS: In the 129 patients, a copy number gain of three chromosome regions-namely, 8q22 (including ESRP1 and CCNE2), 8q24 (including MYC and TNFRSF11B), and 20q11-q13 (including SRC, MMP9, and CSE1L)--conferred poor survival for patients. In addition, the correlation between the branched DNA signal amplification analysis results and the aCGH results was analyzed in 73 of these 129 patients, and MYC, TNFRSF11B, ESRP1, CSE1L, and MMP9 were found to be well correlated. Further validation using an independent cohort (n = 384) verified that only MYC and TNFRSF11B within 8q24 are related to survival. Patients with gains in both MYC and TNFRSF11B had poorer survival than those with no gains, particularly those with noncardia GC. Gains in both of these genes were also a significant independent prognostic indicator.
CONCLUSIONS: Our results revealed that copy number gains in MYC and TNFRSF11B located at 8q24 are associated with survival in GC, particularly noncardia GC.

Perez-Neut M, Shum A, Cuevas BD, et al.
Stimulation of hERG1 channel activity promotes a calcium-dependent degradation of cyclin E2, but not cyclin E1, in breast cancer cells.
Oncotarget. 2015; 6(3):1631-9 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
Cyclin E2 gene amplification, but not cyclin E1, has been recently defined as marker for poor prognosis in breast cancer, and appears to play a major role in proliferation and therapeutic resistance in several breast cancer cells. Our laboratory has previously reported that stimulation of the hERG1 potassium channel with selective activators led to down-regulation of cyclin E2 in breast cancer cells. In this work, we demonstrate that stimulation of hERG1 promotes an ubiquitin-proteasome-dependent degradation of cyclin E2 in multiple breast cancer cell lines representing Luminal A, HER2+ and Trastuzumab-resistant breast cancer cells. In addition we have also reveal that hERG1 stimulation induces an increase in intracellular calcium that is required for cyclin E2 degradation. This novel function for hERG1 activity was specific for cyclin E2, as cyclins A, B, D E1 were unaltered by the treatment. Our results reveal a novel mechanism by which hERG1 activation impacts the tumor marker cyclin E2 that is independent of cyclin E1, and suggest a potential therapeutic use for hERG1 channel activators.

Zhang F, Mijiti M, Ding W, et al.
(+)‑Terrein inhibits human hepatoma Bel‑7402 proliferation through cell cycle arrest.
Oncol Rep. 2015; 33(3):1191-200 [PubMed] Related Publications
Hepatoma is a common malignant tumor. Thus, the development of a high‑efficacy therapeutic drug for hepatoma is required. In this study, (+)‑terrein isolated from the marine sponge‑derived Aspergillus terreus PF‑26 against cell growth, apoptosis and cell cycle were assessed by MTT and flow cytometry. mRNA array containing 73 cell cycle‑related genes and three cell morphology‑related genes was generated and its performance evaluated. The cell cycle pathway map was created using the pathview package. The results showed that (+)‑terrein inhibited the growth of Bel‑7402 cells with alterations in cell morphology and a reduced transcript expression of cell morphology genes (fibronectin, N‑cadherin, and vimentin). In addition, flow cytometric analysis revealed that (+)‑terrein arrested the Bel‑7402 cell cycle without inducing apoptosis. Based on multiple mRNA analysis, the downregulated expression of the CCND2, CCNE2, CDKN1C, CDKN2B, ANAPC, PKMYT1, CHEK2 and PCNA genes was observed in 10 µM (+)‑terrein‑treated Bel‑7402 cells (>2‑fold and P≤0.05), compared with the controls. Thus, the antiprolife-rative mechanism of (+)‑terrein against Bel‑7402 cells may be due to the cell cycle arrest by blocking cell cycle gene expression and changing cell morphology.

Zhou X, Xia Y, Li L, Zhang G
MiR-101 inhibits cell growth and tumorigenesis of Helicobacter pylori related gastric cancer by repression of SOCS2.
Cancer Biol Ther. 2015; 16(1):160-9 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
Several microRNAs (miRNA) have been implicated in H. pylori related gastric cancer (GC). However, the molecular mechanism of miRNAs in gastric cancer has not been fully understood. In this study, we reported that miR-101 is significantly down-regulated in H. pylori positive tissues and cells and in tumor tissues with important functional consequences. Ectopic expression of miR-101 dramatically suppressed cell proliferation and colony formation by inducing G1-phase cell-cycle arrest. We found that miR-101 strongly reduced the expression of SOCS2 oncogene in GC cells. Similar to the restoring miR-26 expression, SOCS2 down-regulation inhibited cell growth and cell-cycle progression, whereas SOCS2 over-expression rescued the suppressive effect of miR-101. Mechanistic investigations revealed that miR-101 suppressed the expression of c-myc, CDK2, CDK4, CDK6, CCND2, CCND3, and CCNE2, while promoted tumor suppressor p14, p16, p21 and p27 expression. In clinical specimens, SOCS2 was over-expressed in tumors and H. pylori positive tissues and its mRNA levels were inversely correlated with miR-101 expression. Taken together, our results indicated that miR-101 functions as a growth-suppressive miRNA in H. pylori related GC, and that its suppressive effects are mediated mainly by repressing SOCS2 expression.

Zhao Z, Liu J, Wang C, et al.
MicroRNA-25 regulates small cell lung cancer cell development and cell cycle through cyclin E2.
Int J Clin Exp Pathol. 2014; 7(11):7726-34 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
PURPOSE: We intended to examine the underlying mechanism of microRNA-25 (miR-25) in regulating small cell lung cancer (SCLC).
METHODS: The miR-25 expression was measured by quantitative RT-PCR (qRT-PCR) in 5 SCLC cell lines and 9 human SCLC tissues. In SCLC cell line H510A cells, endogenous miR-25 was downregulated by stable transfection of antisense oligonucleotide of miR-25 (miR-25-as). Then the effects of miR-25 downregulation on SCLC growth, invasion and chemoresistance were assessed by MTT, migration and cisplatin assays, respectively. Furthermore, the effects of miR-25 downregulation on cancer cell cycle arrest, production of cell cycle proteins cyclin E2 and CDK2 were examined by cell cycle assay, western blot and luciferase assays, respectively. Finally, cyclin E2 was over-expressed in H510A cells to investigate its effect on miR-25 mediated SCLC regulation.
RESULTS: In both SCLC cells and human SCLC tumor tissues, miR-25 was overexpressed. Down-regulation of miR-25 in H510A cells significantly reduced cancer cell growth, invasive capability and resistance to cisplatin. Also, it induced G1 cell cycle arrest and downregulated cell cycle related proteins cyclin E2 and CDK2. Luciferase assay demonstrated cyclin E2 was directly targeted by miR-25. Overexpression of cyclin E2 in H510A cells reversed the cell cycle arrest and restored invasive capability impaired by miR-25 downregulation.
CONCLUSIONS: Our study shows miR-25 is overexpressed in SCLC and acting as oncogenic regulator by regulating cyclin E2.

Wan L, Tan HL, Thomas-Ahner JM, et al.
Dietary tomato and lycopene impact androgen signaling- and carcinogenesis-related gene expression during early TRAMP prostate carcinogenesis.
Cancer Prev Res (Phila). 2014; 7(12):1228-39 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
Consumption of tomato products containing the carotenoid lycopene is associated with a reduced risk of prostate cancer. To identify gene expression patterns associated with early testosterone-driven prostate carcinogenesis, which are impacted by dietary tomato and lycopene, wild-type (WT) and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed control or tomato- or lycopene-containing diets from 4 to 10 weeks of age. Eight-week-old mice underwent sham surgery, castration, or castration followed by testosterone repletion (2.5 mg/kg/d initiated 1 week after castration). Ten-week-old intact TRAMP mice exhibit early multifocal prostatic intraepithelial neoplasia. Of the 200 prostate cancer-related genes measured by quantitative NanoString, 189 are detectable, 164 significantly differ by genotype, 179 by testosterone status, and 30 by diet type (P < 0.05). In TRAMP, expression of Birc5, Mki67, Aurkb, Ccnb2, Foxm1, and Ccne2 is greater compared with WT and is decreased by castration. In parallel, castration reduces Ki67-positive staining (P < 0.0001) compared with intact and testosterone-repleted TRAMP mice. Expression of genes involved in androgen metabolism/signaling pathways is reduced by lycopene feeding (Srd5a1) and by tomato feeding (Srd5a2, Pxn, and Srebf1). In addition, tomato feeding significantly reduced expression of genes associated with stem cell features, Aldh1a and Ly6a, whereas lycopene feeding significantly reduced expression of neuroendocrine differentiation-related genes, Ngfr and Syp. Collectively, these studies demonstrate a profile of testosterone-regulated genes associated with early prostate carcinogenesis that are potential mechanistic targets of dietary tomato components. Future studies on androgen signaling/metabolism, stem cell features, and neuroendocrine differentiation pathways may elucidate the mechanisms by which dietary tomato and lycopene impact prostate cancer risk.

Chuang TD, Ho M, Khorram O
The regulatory function of miR-200c on inflammatory and cell-cycle associated genes in SK-LMS-1, a leiomyosarcoma cell line.
Reprod Sci. 2015; 22(5):563-71 [PubMed] Related Publications
Uterine leiomyosarcoma is a relatively rare malignancy with high mortality due to metastasis and chemoresistance. Leiomyosarcomas share similar morphological characteristics with leiomyomas which are considered to have the potential of transformation into leiomyosarcoma. Accumulated evidence suggests that microRNAs acting as regulators of gene expression at the posttranscriptional level play key roles in diverse biological processes including cellular transformation and tumorigenesis. We hypothesized that miR-200c, whose expression is altered in leiomyomas, equally plays a key role in pathogenesis of leiomyosarcoma. Using SK-LMS-1 leiomyosarcoma cell line as an in vitro model here, we found that the level of expression of miR-200c was significantly lower as compared to isolated leiomyoma smooth muscle cells. Overexpression (gain-of-function) of miR-200c in SK-LMS-1 through direct interaction with 3'-untranslated region of IKBKB, IL8, CDK2, and CCNE2, respectively, resulted in suppression of their expression as determined by quantitative polymerase chain reaction and Western blot analysis. Additionally, gain-of-function of miR-200c through inhibition of IKBKB expression resulted in decreased p65 transcriptional activity in IL8 promoter. Gain-of-function of miR-200c also increased SK-LMS-1 caspase 3/7 activity and inhibited their proliferation and migration. In summary, the results suggest that a progressive decline in miR-200c expression which alters transcriptional regulation of specific target genes that control nuclear factor-κB signaling pathway, inflammation, cell cycle, and migration, in part may promote development and progression of leiomyosarcomas, including their transformation from leiomyomas.

Ye P, Shen L, Jiang W, et al.
Zn-driven discovery of a hydrothermal vent fungal metabolite clavatustide C, and an experimental study of the anti-cancer mechanism of clavatustide B.
Mar Drugs. 2014; 12(6):3203-17 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
A naturally new cyclopeptide, clavatustide C, was produced as a stress metabolite in response to abiotic stress elicitation by one of the hydrothermal vent fluid components Zn in the cultured mycelia of Aspergillus clavatus C2WU, which were isolated from Xenograpsus testudinatus. X. testudinatus lives at extreme, toxic habitat around the sulphur-rich hydrothermal vents in Taiwan Kueishantao. The known compound clavatustide B was also isolated and purified. This is the first example of a new hydrothermal vent microbial secondary metabolite produced in response to abiotic Zn treatment. The structures were established by spectroscopic means. The regulation of G1-S transition in hepatocellular carcinoma cell lines by clavatustide B was observed in our previous study. The purpose of the present study was to verify these results in other types of cancer cell lines and elucidate the possible molecular mechanism for the anti-cancer activities of clavatustide B. In different human cancer cell lines, including pancreatic cancer (Panc-1), gastric cancer (MGC-803), colorectal cancer (SW-480), retinoblastoma (WERI-Rb-1) and prostate cancer (PC3), clavatustide B efficiently suppressed cell proliferations in a dose-dependent manner. Although different cancer cell lines presented variety in Max effect dose and IC50 dose, all cancer cell lines showed a lower Max effect dose and IC50 dose compared with human fibroblasts (hFB) (p < 0.05). Moreover, significant accumulations in G1 phases and a reduction in S phases (p < 0.05) were observed under clavatustide B treatment. The expression levels of 2622 genes including 39 cell cycle-associated genes in HepG2 cells were significantly altered by the treatment with 15 μg/mL clavatustide B after 48 h. CCNE2 (cyclin E2) was proved to be the key regulator of clavatustide B-induced G1-S transition blocking in several cancer cell lines by using real-time PCR.

Matsuda T, Takeuchi H, Matsuda S, et al.
EpCAM, a potential therapeutic target for esophageal squamous cell carcinoma.
Ann Surg Oncol. 2014; 21 Suppl 3:S356-64 [PubMed] Related Publications
BACKGROUND: Molecular-targeted drugs are not available for esophageal squamous cell carcinoma (ESCC), which has a poor prognosis. We investigated the clinicopathological significance of epithelial cell adhesion molecule (EpCAM) expression and the utility of EpCAM as a potential therapeutic target.
METHODS: The relationship between EpCAM expression and clinicopathological factors was examined by immunohistochemistry in 74 patients with resectable ESCC. A total of ten ESCC cell lines were analyzed for EpCAM expression. The effects of EpCAM knockdown in TE4, TE10, and TE14 cells were examined with regard to cell proliferation and gene expression in vitro and tumor growth in vivo. The antitumor effect of catumaxomab in ESCC cell lines was examined.
RESULTS: EpCAM overexpression was associated with poor survival in ESCC patients (P = 0.026). Multivariate Cox regression analysis showed that EpCAM overexpression was a significant and independent prognostic factor for surgically treated ESCC (P = 0.004). TE4 and TE10 cells showed high EpCAM expression, in contrast to TE14. EpCAM siRNA knockdown in TE4 and TE10 cells downregulated CCND1 and CCNE2 and suppressed cell proliferation. Low EpCAM expression reduced tumorigenesis; TE4 cells initiated tumorigenesis in seven of the ten mice injected, whereas shRNA knockdown resulted in smaller tumors in two of ten mice at 6 weeks after transplantation. Concentration- and time-dependent antitumor effects of catumaxomab were observed in TE4 and TE10 cells.
CONCLUSIONS: EpCAM overexpression is an independent prognostic factor for surgically treated ESCC. EpCAM contributes to cell proliferation and tumorigenesis and may be a useful therapeutic target for ESCC.

Pils D, Bachmayr-Heyda A, Auer K, et al.
Cyclin E1 (CCNE1) as independent positive prognostic factor in advanced stage serous ovarian cancer patients - a study of the OVCAD consortium.
Eur J Cancer. 2014; 50(1):99-110 [PubMed] Related Publications
Cyclin E, coded by the genes CCNE1 and CCNE2, is the main regulator for transition from G1 to S phase determining cell division. CCNE1 and CCNE2 are known oncogenes in many cancer entities. Especially CCNE1 has frequently been associated with gene amplifications in various malignancies, emphasising its role as a putative oncogene. We determined gene expression and copy number of CCNE1 and CCNE2 by quantitative polymerase chain reaction (PCR) from 172 International Federation of Obstetrics and Gynecology (FIGO) II/III/IV stage serous epithelial ovarian cancer (EOC) tissues and analysed its impact on outcome. Furthermore, whole transcriptome gene expression changes correlating with CCNE1 expression were determined by microarray technology, interpreted by Signalling Pathway Impact Analysis (SPIA), Tool for Inferring Network of Genes (TINGe), and illustrated by hive plots. Protein-protein interaction (PPI) networks were also used for the interpretation. Interestingly, and contradictory to most reports and intuitive expectations, high CCNE1 expression correlated with better overall survival (p=0.005) if corrected for usual clinicopathologic parameters and a molecular subclassification. Using different grading systems or only high graded tumours had no impact on this correlation. Copy number of CCNE1 was increased in 25% of cases which correlated highly significantly with expression but showed no impact on outcome. CCNE2 had no impact on outcomes at all. Whole genome transcriptome analysis revealed 1872 differentially expressed genes correlated to CCNE1 expression, which were significantly enriched with genes from five pathways (e.g. cell cycle and viral carcinogenesis pathway were up-regulated and the Fanconi anaemia pathway was down-regulated). High CCNE1 gene expression is a significant and independent predictor for prolonged overall survival in FIGO III/IV EOC patients. This upside down impact of CCNE1 on survival probably reflects the special characteristic of EOC with tumour dissemination in the near anaerobic peritoneal cavity as the predominant cause of death, compared to other cancer entities where distant metastasis are predominantly lethal.

Deng J, He M, Chen L, et al.
The loss of miR-26a-mediated post-transcriptional regulation of cyclin E2 in pancreatic cancer cell proliferation and decreased patient survival.
PLoS One. 2013; 8(10):e76450 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
BACKGROUND: miR-26a plays a critical role in tumorigenesis, either as a tumor suppressor or as an oncogenic miRNA, depending on different tumor types. However, the function of miR-26a in pancreatic cancer has not been clearly elucidated. The present study was designed to determine the roles of miR-26a in pancreatic cancer and its association with the survival of patients with pancreatic cancer.
METHODS: The expression of miR-26a was examined in 15 pairs of pancreatic duct adenocarcinoma (PDAC) and their adjacent benign pancreatic tissues (ABPT), by qRT-PCR. The results were confirmed by in situ hybridization using two panels of 106 PDACs and their ABPT microarray. The association of miR-26a expression with overall survival was determined. The proliferation and cell cycle distribution of Capan-2, SW-1990, and Panc-1 cells, transfected with miR-26a mimics or a miR-26a inhibitor, were assessed using the Cell Counting Kit-8 assay and flow cytometry, respectively. The cell tumorigenicity was evaluated via murine xenograft experiments. Cyclin D2, E2, EZH2, and PCNA levels were analyzed by Western blot and immunohistochemistry.
RESULTS: miR-26a was expressed in the cytoplasm of pancreatic ductal epithelial cells, whereas its expression was significantly downregulated in PDAC tissues compared with that of ABPT. Patients with low miR-26a expression had a significantly shorter survival than those with high miR-26a expression. The in vitro and in vivo assays showed that overexpression of miR-26a resulted in cell cycle arrest, inhibited cell proliferation, and decreased tumor growth, which was associated with cyclin E2 downregulation.
CONCLUSIONS: miR-26a is an important suppressor of pancreatic ductal carcinoma, and can prove to be a novel prognostic factor and therapeutic target for pancreatic cancer treatment.

Yang B, Zhang J, Yin Y, Zhang Y
Network-based inference framework for identifying cancer genes from gene expression data.
Biomed Res Int. 2013; 2013:401649 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
Great efforts have been devoted to alleviate uncertainty of detected cancer genes as accurate identification of oncogenes is of tremendous significance and helps unravel the biological behavior of tumors. In this paper, we present a differential network-based framework to detect biologically meaningful cancer-related genes. Firstly, a gene regulatory network construction algorithm is proposed, in which a boosting regression based on likelihood score and informative prior is employed for improving accuracy of identification. Secondly, with the algorithm, two gene regulatory networks are constructed from case and control samples independently. Thirdly, by subtracting the two networks, a differential-network model is obtained and then used to rank differentially expressed hub genes for identification of cancer biomarkers. Compared with two existing gene-based methods (t-test and lasso), the method has a significant improvement in accuracy both on synthetic datasets and two real breast cancer datasets. Furthermore, identified six genes (TSPYL5, CD55, CCNE2, DCK, BBC3, and MUC1) susceptible to breast cancer were verified through the literature mining, GO analysis, and pathway functional enrichment analysis. Among these oncogenes, TSPYL5 and CCNE2 have been already known as prognostic biomarkers in breast cancer, CD55 has been suspected of playing an important role in breast cancer prognosis from literature evidence, and other three genes are newly discovered breast cancer biomarkers. More generally, the differential-network schema can be extended to other complex diseases for detection of disease associated-genes.

Knoblich K, Wang HX, Sharma C, et al.
Tetraspanin TSPAN12 regulates tumor growth and metastasis and inhibits β-catenin degradation.
Cell Mol Life Sci. 2014; 71(7):1305-14 [PubMed] Related Publications
Ablation of tetraspanin protein TSPAN12 from human MDA-MB-231 cells significantly decreased primary tumor xenograft growth, while increasing tumor apoptosis. Furthermore, TSPAN12 removal markedly enhanced tumor-endothelial interactions and increased metastasis to mouse lungs. TSPAN12 removal from human MDA-MB-231 cells also caused diminished association between FZD4 (a key canonical Wnt pathway receptor) and its co-receptor LRP5. The result likely explains substantially enhanced proteosomal degradation of β-catenin, a key effecter of canonical Wnt signaling. Consistent with disrupted canonical Wnt signaling, TSPAN12 ablation altered expression of LRP5, Naked 1 and 2, DVL2, DVL3, Axin 1, and GSKβ3 proteins. TSPAN12 ablation also altered expression of several genes regulated by β-catenin (e.g. CCNA1, CCNE2, WISP1, ID4, SFN, ME1) that may help to explain altered tumor growth and metastasis. In conclusion, these results provide the first evidence for TSPAN12 playing a role in supporting primary tumor growth and suppressing metastasis. TSPAN12 appears to function by stabilizing FZD4-LRP5 association, in support of canonical Wnt-pathway signaling, leading to enhanced β-catenin expression and function.

Che CL, Zhang YM, Zhang HH, et al.
DNA microarray reveals different pathways responding to paclitaxel and docetaxel in non-small cell lung cancer cell line.
Int J Clin Exp Pathol. 2013; 6(8):1538-48 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
The wide use of paclitaxel and docetaxel in NSCLC clinical treatment makes it necessary to find biomarkers for identifying patients who can benefit from paclitaxel or docetaxel. In present study, NCI-H460, a NSCLC cell line with different sensitivity to paclitaxel and docetaxel, was applied to DNA microarray expression profiling analysis at different time points of lower dose treatment with paclitaxel or docetaxel. And the complex signaling pathways regulating the drug response were identified, and several novel sensitivity-realted markers were biocomputated.The dynamic changes of responding genes showed that paclitaxel effect is acute but that of docetaxel is durable at least for 48 hours in NCI-H460 cells. Functional annotation of the genes with altered expression showed that genes/pathways responding to these two drugs were dramatically different. Gene expression changes induced by paclitaxel treatment were mainly enriched in actin cytoskeleton (ACTC1, MYL2 and MYH2), tyrosine-protein kinases (ERRB4, KIT and TIE1) and focal adhesion pathway (MYL2, IGF1 and FLT1), while the expression alterations responding to docetaxel were highly co-related to cell surface receptor linked signal transduction (SHH, DRD5 and ADM2), cytokine-cytokine receptor interaction (IL1A and IL6) and cell cycle regulation (CCNB1, CCNE2 and PCNA). Moreover, we also confirmed some different expression patterns with real time PCR. Our study will provide the potential biomarkers for paclitaxel and docetaxel-selection therapy in clinical application.

Kitagawa M, Niisato N, Shiozaki A, et al.
A regulatory role of K(+)-Cl(-) cotransporter in the cell cycle progression of breast cancer MDA-MB-231 cells.
Arch Biochem Biophys. 2013; 539(1):92-8 [PubMed] Related Publications
K(+)-Cl(-) cotransporter (KCC) has been shown to be involved in cell proliferation as well as cell volume regulation. A regulatory role of KCC in cell cycle progression of breast cancer MDA-MB-231 cells was explored by using synchronized MDA-MB-231 cells and dihydro-indenyloxy-alkanoic acid (DIOA), a potent inhibitor of KCC. MDA-MB-231 cells cultured in the presence of DIOA exhibited an increase in cell volume, a decrease in intracellular Cl(-) concentration, and reduction in cell proliferation with the G0/G1 phase arrest, which was accompanied with down-regulation of cyclin D1 and cyclin E2, and up-regulation of p21. Among these molecules, the expression of cyclin E2, a molecule essential for the transition from G1 to S phase, was markedly suppressed by DIOA treatment. DIOA-mediated up- or down-regulation of these molecules occurred at the transcriptional level. These findings suggest that KCC plays an important role in the early phase of cell cycle progression by regulating the expression of cyclin D1, cyclin E2, and p21, the molecules essential for the cell cycle progression.

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