CCNG2

Gene Summary

Gene:CCNG2; cyclin G2
Location:4q21.1
Summary:The eukaryotic cell cycle is governed by cyclin-dependent protein kinases (CDKs) whose activities are regulated by cyclins and CDK inhibitors. The 8 species of cyclins reported in mammals, cyclins A through H, share a conserved amino acid sequence of about 90 residues called the cyclin box. The amino acid sequence of cyclin G is well conserved among mammals. The nucleotide sequence of cyclin G1 and cyclin G2 are 53% identical. Unlike cyclin G1, cyclin G2 contains a C-terminal PEST protein destabilization motif, suggesting that cyclin G2 expression is tightly regulated through the cell cycle. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cyclin-G2
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: CCNG2 (cancer-related)

Salem M, Shan Y, Bernaudo S, Peng C
miR-590-3p Targets Cyclin G2 and FOXO3 to Promote Ovarian Cancer Cell Proliferation, Invasion, and Spheroid Formation.
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications
Ovarian cancer is the leading cause of death from gynecological cancers. MicroRNAs (miRNAs) are small, non-coding RNAs that interact with the 3' untranslated region (3' UTR) of target genes to repress their expression. We have previously reported that miR-590-3p promoted ovarian cancer growth and metastasis, in part by targeting Forkhead box A (FOXA2). In this study, we further investigated the mechanisms by which miR-590-3p promotes ovarian cancer development. Using luciferase reporter assays, real-time PCR, and Western blot analyses, we demonstrated that miR-590-3p targets cyclin G2 (CCNG2) and Forkhead box class O3 (FOXO3) at their 3' UTRs. Silencing of CCNG2 or FOXO3 mimicked, while the overexpression of CCNG2 or FOXO3 reversed, the stimulatory effect of miR-590-3p on cell proliferation and invasion. In hanging drop cultures, the overexpression of mir-590 or the transient transfection of miR-590-3p mimics induced the formation of compact spheroids. Transfection of the CCNG2 or FOXO3 plasmid into the mir-590 cells resulted in the partial disruption of the compact spheroid formation. Since we have shown that CCNG2 suppressed β-catenin signaling, we investigated if miR-590-3p regulated β-catenin activity. In the TOPFlash luciferase reporter assays, mir-590 increased β-catenin/TCF transcriptional activity and the nuclear accumulation of β-catenin. Silencing of β-catenin attenuated the effect of mir-590 on the compact spheroid formation. Taken together, these results suggest that miR-590-3p promotes ovarian cancer development, in part by directly targeting CCNG2 and FOXO3.

Bashanfer SAA, Saleem M, Heidenreich O, et al.
Disruption of MAPK1 expression in the ERK signalling pathway and the RUNX1‑RUNX1T1 fusion gene attenuate the differentiation and proliferation and induces the growth arrest in t(8;21) leukaemia cells.
Oncol Rep. 2019; 41(3):2027-2040 [PubMed] Related Publications
The t(8;21) translocation is one of the most frequent chromosome abnormalities associated with acute myeloid leukaemia (AML). This abberation deregulates numerous molecular pathways including the ERK signalling pathway among others. Therefore, the aim of the present study was to investigate the gene expression patterns following siRNA‑mediated suppression of RUNX1‑RUNX1T1 and MAPK1 in Kasumi‑1 and SKNO‑1 cells and to determine the differentially expressed genes in enriched biological pathways. BeadChip microarray and gene ontology analysis revealed that RUNX1‑RUNX1T1 and MAPK1 suppression reduced the proliferation rate of the t(8;21) cells with deregulated expression of several classical positive regulator genes that are otherwise known to enhance cell proliferation. RUNX1‑RUNX1T1 suppression exerted an anti‑apoptotic effect through the overexpression of BCL2, BIRC3 and CFLAR genes, while MAPK1 suppression induced apopotosis in t(8;21) cells by the apoptotic mitochondrial changes stimulated by the activity of upregulated TP53 and TNFSF10, and downregulated JUN gene. RUNX1‑RUNX1T1 suppression supported myeloid differentiation by the differential expression of CEBPA, CEBPE, ID2, JMJD6, IKZF1, CBFB, KIT and CDK6, while MAPK1 depletion inhibited the differentiation of t(8;21) cells by elevated expression of ADA and downregulation of JUN. RUNX1‑RUNX1T1 and MAPK1 depletion induced cell cycle arrest at the G0/G1 phase. Accumulation of cells in the G1 phase was largely the result of downregulated expression of TBRG4, CCNE2, FOXO4, CDK6, ING4, IL8, MAD2L1 and CCNG2 in the case of RUNX1‑RUNX1T1 depletion and increased expression of RASSF1, FBXO6, DADD45A and P53 in the case of MAPK1 depletion. Taken together, the current results demonstrate that MAPK1 promotes myeloid cell proliferation and differentiation simultaneously by cell cycle progression while suppresing apoptosis.

Gao J, Zhao C, Liu Q, et al.
Cyclin G2 suppresses Wnt/β-catenin signaling and inhibits gastric cancer cell growth and migration through Dapper1.
J Exp Clin Cancer Res. 2018; 37(1):317 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gastric cancer is one of the most common malignant tumors. Cyclin G2 has been shown to be associated with the development of multiple types of tumors, but its underlying mechanisms in gastric tumors is not well-understood. The aim of this study is to investigate the role and the underlying mechanisms of cyclin G2 on Wnt/β-catenin signaling in gastric cancer.
METHODS: Real-time PCR, immunohistochemistry and in silico assay were used to determine the expression of cyclin G2 in gastric cancer. TCGA datasets were used to evaluate the association between cyclin G2 expression and the prognostic landscape of gastric cancers. The effects of ectopic and endogenous cyclin G2 on the proliferation and migration of gastric cancer cells were assessed using the MTS assay, colony formation assay, cell cycle assay, wound healing assay and transwell assay. Moreover, a xenograft model and a metastasis model of nude mice was used to determine the influence of cyclin G2 on gastric tumor growth and migration in vivo. The effects of cyclin G2 expression on Wnt/β-catenin signaling were explored using a TOPFlash luciferase reporter assay, and the molecular mechanisms involved were investigated using immunoblots assay, yeast two-hybrid screening, immunoprecipitation and Duolink in situ PLA. Ccng2
RESULTS: We found that cyclin G2 levels were decreased in gastric cancer tissues and were associated with tumor size, migration and poor differentiation status. Moreover, overexpression of cyclin G2 attenuated tumor growth and metastasis both in vitro and in vivo. Dpr1 was identified as a cyclin G2-interacting protein which was required for the cyclin G2-mediated inhibition of β-catenin expression. Mechanically, cyclin G2 impacted the activity of CKI to phosphorylate Dpr1, which has been proved to be a protein that acts as a suppressor of Wnt/β-catenin signaling when unphosphorylated. Furthermore, GSK-3β inhibitors abolished the cyclin G2-induced suppression of cell proliferation and migration.
CONCLUSIONS: This study demonstrates that cyclin G2 suppresses Wnt/β-catenin signaling and inhibits gastric cancer cell growth and migration through Dapper1.

Chen N, Yin D, Lun B, Guo X
LncRNA GAS8-AS1 suppresses papillary thyroid carcinoma cell growth through the miR-135b-5p/CCND2 axis.
Biosci Rep. 2019; 39(1) [PubMed] Free Access to Full Article Related Publications
The aim of the present study was to investigate the potential role of GAS8 antisense RNA 1 (GAS8-AS1) in papillary thyroid carcinoma (PTC). PcDNA3.1-GAS8-AS1 and si-GAS8-AS1, miR-135b-5p mimic and si-CCND2 were transfected into PTC cells. Cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8). QRT-PCR was used to determine expressions of GAS8-AS1, miR-135b-5p, and CCND2, and Western blot were detected protein level of CCND2. The miRNA target gene prediction site TargetScan was used to predict potential targets of GAS8-AS1 and miR-135b-5p. Cell cycle progression was analyzed by flow cytometry. We found that GAS8-AS1 was down-regulated in PTC cell lines and inhibited proliferation and cycle of PTC cell. GAS8-AS1 directly targets miR-135b-5p, and GAS8-AS1 could regulate a downstream target of miR-135b-5p, Cyclin G2 (CCNG2), in an miR-135b-5p-mediated manner. In addition, we also proved that overexpressed GAS8-AS1 inhibited tumor formation

Zhao J, Shi L, Zeng S, et al.
Importin-11 overexpression promotes the migration, invasion, and progression of bladder cancer associated with the deregulation of CDKN1A and THBS1.
Urol Oncol. 2018; 36(6):311.e1-311.e13 [PubMed] Related Publications
OBJECTIVES: We recently determined that a novel oncogene, IPO11 from 5q12, participates in bladder cancer (BCa) progression. However, the biological function of IPO11 and the molecular mechanisms through which it contributes to BCa progression remain unclear. The aim of this study was to investigate the role of IPO11 in BCa aggressiveness and elucidate the molecular mechanisms underlying its effects in BCa.
MATERIALS AND METHODS: The mRNA expression levels of IPO11 in BIU-87, RT4, UMUC3, EJ, 5637, T24, J82, and HT-1376 cell lines were determined using quantitative real-time polymerase chain reaction. Expression of importin-11 was detected in 134 formalin-fixed and paraffin-embedded (FFPE) BCa tissues and 10 paired nonneoplastic bladder tissue specimens by immunohistochemistry. The copy number of IPO11 was examined in 25 FFPE BCa specimens using fluorescent in situ hybridization. The effects of IPO11 on migration, invasion, and cell proliferation were investigated in EJ and 5637 cell lines using RNA interference. Potential molecular mechanisms were investigated using whole transcriptome sequencing and bioinformatic approaches in EJ cells and IPO11-silenced EJ cells and verified using quantitative real-time polymerase chain reaction.
RESULTS: Endogenous IPO11 mRNA was highly expressed in 6 invasive BCa cell lines (EJ, HT-1376, UMUC3, 5637, J82, and T24) but had a low expression in the noninvasive BCa cell line BIU-87 and the papillary BCa cell line RT4. Immunohistochemical staining revealed that 87 (64.9%) of 134 FFPE BCa tissues displayed importin-11 overexpression. Moreover, importin-11 overexpression was positively associated with increased tumor stages and tumor grades, lymphatic invasion, and lymph node metastasis. Furthermore, importin-11 overexpression was detected in 100% (14/14) of BCa tissues with IPO11 amplification, and IPO11 amplification was not observed in 2 additional BCa tissues with importin-11 overexpression. Small interfering RNA-mediated knockdown of IPO11 is sufficient to inhibit the motility and invasiveness of EJ and 5637 cells. IPO11 knockdown also inhibited cell proliferation in EJ cells, whereas this was not observed in 5637 cells or the in vivo experiments. Using whole transcriptome sequencing, we found that 22 genes (including IPO11) were differentially expressed in IPO11-silenced EJ cells compared with wild-type EJ cells, 4 of which were upregulated, and 18 of which were downregulated. KEGG pathway enrichment analysis of the significantly differentially expressed genes showed that the proteoglycans in cancer pathway (pathway Id: hsa05205) was most significantly enriched among 10 genetically altered pathways and referred to 6 significantly altered genes (CDKN1A, HBEGF, PTK2, THBS1, CCNG2, and EGR1). The next 3 most significantly enriched pathways in order were the p53, ErbB, and BCa pathways. CDKN1A and THBS1 were the most 2 frequently covered genes and were involved in 9 and 6 pathways, respectively. They were also 2 key proteins in the BCa pathway (pathway Id: hsa05219) that were downregulated in IPO11-knockdown EJ cells compared with wild-type EJ cells.
CONCLUSIONS: Importin-11 overexpression can promote BCa cell invasiveness, probably associated with the deregulation of CDKN1A and THBS1 primarily through the activation of the proteoglycans in cancer pathway and the classical BCa pathway. Importin-11 may be a useful target through which the progression of noninvasive BCa to invasive BCa can be blocked.

Li XJ, Ren ZJ, Tang JH, Yu Q
Exosomal MicroRNA MiR-1246 Promotes Cell Proliferation, Invasion and Drug Resistance by Targeting CCNG2 in Breast Cancer.
Cell Physiol Biochem. 2017; 44(5):1741-1748 [PubMed] Related Publications
BACKGROUND/AIMS: Treatment of breast cancer remains a clinical challenge. This study aims to validate exosomal microRNA-1246 (miR-1246) as a serum biomarker for breast cancer and understand the underlying mechanism in breast cancer progression.
METHODS: The expression levels of endogenous and exosomal miRNAs were examined by real time PCR, and the expression level of the target protein was detected by western blot. Scanning electron and confocal microscopy were used to characterize exosomes and to study their uptake and transfer. Luciferase reporter plasmids and its mutant were used to confirm direct targeting. Furthermore, the functional significance of exosomal miR-1246 was estimated by invasion assay and cell viability assay.
RESULTS: In this study, we demonstrate that exosomes carrying microRNA can be transferred among different cell lines through direct uptake. miR-1246 is highly expressed in metastatic breast cancer MDA-MB-231 cells compared to non-metastatic breast cancer cells or non-malignant breast cells. Moreover, miR-1246 can suppress the expression level of its target gene, Cyclin-G2 (CCNG2), indicating its functional significance. Finally, treatment with exosomes derived from MDA-MB-231 cells could enhance the viability, migration and chemotherapy resistance of non-malignant HMLE cells.
CONCLUSIONS: Together, our results support an important role of exosomes and exosomal miRNAs in regulating breast tumor progression, which highlights their potential for applications in miRNA-based therapeutics.

Yao D, Cui H, Zhou S, Guo L
Morin inhibited lung cancer cells viability, growth, and migration by suppressing miR-135b and inducing its target CCNG2.
Tumour Biol. 2017; 39(10):1010428317712443 [PubMed] Related Publications
Lung cancer is one of the most severe threats with the highest mortality rate to humans in the world. Recently, morin has been reported to have anti-tumor properties observed in several types of cancers. However, its mechanism is still unclear. We assessed the influences of morin on cell viability, colony formation, and migration ability of A549 and employed microRNA array to identify the microRNAs affected by morin. We found that morin-treated A549 cells showed statistically decreased cell viability, colony formation, and migration rate when comparing with the dimethyl sulfoxide-treated cells. Microarray results showed that with the treatment of morin, the expression level of miR-135b significantly reduced compared the control group, suggesting that morin may exert its anti-cancer property by suppressing the expression of miR-135b. In addition, we found a potential binding site of miR-135b within 3' untranslated region of CCNG2-encoding cyclin homolog cyclin-G2. We evidenced that miR-135b directly targets CCNG2, which could be a potential biomarker of lung cancer prognosis. Morin exerts its anti-tumor function via downregulating the expression of miR-135b that directly targets and represses CCNG2.

Zimmermann M, Arachchige-Don AP, Donaldson MS, et al.
Cyclin G2 promotes cell cycle arrest in breast cancer cells responding to fulvestrant and metformin and correlates with patient survival.
Cell Cycle. 2016; 15(23):3278-3295 [PubMed] Free Access to Full Article Related Publications
Definition of cell cycle control proteins that modify tumor cell resistance to estrogen (E2) signaling antagonists could inform clinical choice for estrogen receptor positive (ER+) breast cancer (BC) therapy. Cyclin G2 (CycG2) is upregulated during cell cycle arrest responses to cellular stresses and growth inhibitory signals and its gene, CCNG2, is directly repressed by E2-bound ER complexes. Our previous studies showed that blockade of HER2, PI3K and mTOR signaling upregulates CycG2 expression in HER2+ BC cells, and that CycG2 overexpression induces cell cycle arrest. Moreover, insulin and insulin-like growth factor-1 (IGF-1) receptor signaling strongly represses CycG2. Here we show that blockade of ER-signaling in MCF7 and T47D BC cell lines enhances the expression and nuclear localization of CycG2. Knockdown of CycG2 attenuated the cell cycle arrest response of E2-depleted and fulvestrant treated MCF7 cells. These muted responses were accompanied by sustained inhibitory phosphorylation of retinoblastoma (RB) protein, expression of cyclin D1, phospho-activation of ERK1/2 and MEK1/2 and expression of cRaf. Our work indicates that CycG2 can form complexes with CDK10, a CDK linked to modulation of RAF/MEK/MAPK signaling and tamoxifen resistance. We determined that metformin upregulates CycG2 and potentiates fulvestrant-induced CycG2 expression and cell cycle arrest. CycG2 knockdown blunts the enhanced anti-proliferative effect of metformin on fulvestrant treated cells. Meta-analysis of BC tumor microarrays indicates that CCNG2 expression is low in aggressive, poor-prognosis BC and that high CCNG2 expression correlates with longer periods of patient survival. Together these findings indicate that CycG2 contributes to signaling networks that limit BC.

Yin G, Zhou H, Xue Y, et al.
MicroRNA-340 promotes the tumor growth of human gastric cancer by inhibiting cyclin G2.
Oncol Rep. 2016; 36(2):1111-8 [PubMed] Related Publications
Aberrant expression and function of microRNAs (miRNAs) play a critical role in the development and progression of various human cancers including gastric cancer. However, the clinical significance and underlying mechanisms of miR-340 remain largely unknown in gastric cancer. In the present study, we demonstrated that the expression of miR-340 was aberrantly elevated in both gastric cancer tissues and cells. Moreover clinical association analyses disclosed that the elevated level of miR-340 was significantly associated with unfavorable clinicopathological characteristics of the gastric cancer patients, such as poor differentiation, large tumor size and advanced tumor-node-metastasis (TNM) stage. Gastric cancer patients with high expression of miR-340 had prominently shorter overall survival and disease-free survival. Functionally, forced expression of miR-340 promoted cell viability, proliferation, colony formation and cell cycle progression in the SGC-7901 cells, while miR-340 silencing reduced cell viability, proliferation, colony formation and cell cycle progression in MGC-803 cells. Furthermore, in vivo experiments indicated that miR-340 knockdown suppressed the tumor growth of MGC-803 cells. Notably, alteration of miR-340 expression affected the luciferase activity of wild-type 3'-UTR of cyclin G2 (CCNG2) and regulated CCNG2 abundance in gastric cancer cells, indicating that CCNG2 is a direct target of miR-340. Moreover, CCNG2 knockdown eradicated the effects of miR-340 silencing on gastric cancer cells. In conclusion, our data suggest that miR-340 may potentially serve as a novel prognostic biomarker and therapeutic target for gastric cancer.

Bernaudo S, Salem M, Qi X, et al.
Cyclin G2 inhibits epithelial-to-mesenchymal transition by disrupting Wnt/β-catenin signaling.
Oncogene. 2016; 35(36):4816-27 [PubMed] Free Access to Full Article Related Publications
Epithelial ovarian cancer (EOC) has the highest mortality rate among gynecological malignancies owing to poor screening methods, non-specific symptoms and limited knowledge of the cellular targets that contribute to the disease. Cyclin G2 is an unconventional cyclin that acts to oppose cell cycle progression. Dysregulation of the cyclin G2 gene (CCNG2) in a variety of human cancers has been reported; however, the role of cyclin G2 in tumorigenesis remains unclear. In this study, we investigated the function of cyclin G2 in EOC. In vitro and in vivo studies using several EOC-derived tumor cell lines revealed that cyclin G2 inhibited cell proliferation, migration, invasion and spheroid formation, as well as tumor formation and invasion. By interrogating cDNA microarray data sets, we found that CCGN2 mRNA is reduced in several large cohorts of human ovarian carcinoma when compared with normal ovarian surface epithelium or borderline tumors of the ovary. Mechanistically, cyclin G2 was found to suppress epithelial-to-mesenchymal transition (EMT), as demonstrated by the differential regulation of various EMT genes, such as Snail, Slug, vimentin and E-cadherin. Moreover, cyclin G2 potently suppressed the Wnt/β-catenin signaling pathway by downregulating key Wnt components, namely LRP6, DVL2 and β-catenin, which could be linked to inhibition of EMT. Taken together, our novel findings demonstrate that cyclin G2 has potent tumor-suppressive effects in EOCs by inhibiting EMT through attenuating Wnt/β-catenin signaling.

Wang S, Zeng Y, Zhou JM, et al.
MicroRNA-1246 promotes growth and metastasis of colorectal cancer cells involving CCNG2 reduction.
Mol Med Rep. 2016; 13(1):273-80 [PubMed] Related Publications
Colorectal cancer (CRC) is the third most common cancer type and the fourth leading cause of cancer‑associated mortality worldwide. MicroRNA (miR)‑1246 is involved in differentiation, invasion, metastasis and chemoresistance of certain types of tumor cells. CCNG2 encodes an unconventional cyclin homolog, cyclin G2 (CycG2), associated with growth inhibition, which correlated significantly with lymph node metastasis, clinical stage, histological grade and poor overall survival in numerous cancer types. To investigate the regulation of miR‑1246 on CycG2 expression, and their effects on proliferation and metastasis of CRC, HCT‑116 and LOVO cells were transfected with pre‑miR‑1246 anti‑miR‑1246 and their negative controls. It was demonstrated that the expression of miR‑1246 was significantly increased in CRC tissues and cell lines, which was the opposite of CycG2. miR‑1246 negatively regulated the expression of CycG2 in HCT‑116 and LOVO CRC cells. CCNG2 is a direct target of miR‑1246 in CRC cells. Overexpression of miR‑1246 induced cell proliferation, migration and invasion, while knockdown of miR‑1246 inhibited proliferation, migration and invasion in the CRC cells. Upregulation of miR‑1246 mediated the malignant progression of CRC and is partly attributed to the downregulation of the expression of CycG2. Consequently, these findings provided a molecular basis for the role of miR‑1246/CCNG2 in the progression of human CRC and suggested a novel target for the treatment of CRC.

Diniz MG, Silva Jde F, de Souza FT, et al.
Association between cell cycle gene transcription and tumor size in oral squamous cell carcinoma.
Tumour Biol. 2015; 36(12):9717-22 [PubMed] Related Publications
Higher tumor size correlates with poor prognosis and is an independent predictive survival factor in oral squamous cell carcinoma (OSCC) patients. However, the molecular events underlining OSCC tumor evolution are poorly understood. We aimed to investigate if large OSCC tumors show different cell cycle gene transcriptional signature compared to small tumors. Seventeen fresh OSCC tumor samples with different tumor sizes (T) were included in the study. Tumors were from the tongue or from the floor of the mouth, and only three patients were nonsmokers. Samples were categorized according to clinical tumor size in tumors ≤2 cm (T1, n = 5) or tumors >2 cm (T2, n = 9; T3, n = 2; T4, n = 1). The group of tumors ≤2 cm was considered the reference group, while the larger tumors were considered the test group. We assessed the expression of 84 cell cycle genes by qRT-PCR array and normalized it to the expression of two housekeeping genes. Results were analyzed according to the formula 2(^-DeltaCt). A five-fold change cutoff was used, and p values <0.05 were considered statistically significant. Ki-67 immunohistochemistry was performed to estimate cell proliferation index. Twenty-nine genes were downregulated in the test group (larger tumors) compared to the reference group (smaller tumors). Among these genes, 13 reached statistical significance: ANAPC4, CUL1, SUMO1, KPNA2, MAD2L2, CCNG2, E2F4, NBN, CUL2, PCNA, TFDP1, KNTC1, and ATR. Ki-67 labeling index was similar in both tumor groups. Our findings suggest that the transcriptional activity of specific cell cycle genes varies according to the size of OSCC tumor, which probably reflects tumor molecular evolution and adaptation to the microenvironment.

Maniwa Y, Kasukabe T, Kumakura S
Vitamin K2 and cotylenin A synergistically induce monocytic differentiation and growth arrest along with the suppression of c-MYC expression and induction of cyclin G2 expression in human leukemia HL-60 cells.
Int J Oncol. 2015; 47(2):473-80 [PubMed] Free Access to Full Article Related Publications
Although all-trans retinoic acid (ATRA) is a standard and effective drug used for differentiation therapy in acute promyelocytic leukemia, ATRA-resistant leukemia cells ultimately emerge during this treatment. Therefore, the development of new drugs or effective combination therapy is urgently needed. We demonstrate that the combined treatment of vitamin K2 and cotylenin A synergistically induced monocytic differentiation in HL-60 cells. This combined treatment also synergistically induced NBT-reducing activity and non-specific esterase-positive cells as well as morphological changes to monocyte/macrophage-like cells. Vitamin K2 and cotylenin A cooperatively inhibited the proliferation of HL-60 cells in short-term and long-term cultures. This treatment also induced growth arrest at the G1 phase. Although 5 µg/ml cotylenin A or 5 µM vitamin K2 alone reduced c-MYC gene expression in HL-60 cells to approximately 45% or 80% that of control cells, respectively, the combined treatment almost completely suppressed c-MYC gene expression. We also demonstrated that the combined treatment of vitamin K2 and cotylenin A synergistically induced the expression of cyclin G2, which had a positive effect on the promotion and maintenance of cell cycle arrest. These results suggest that the combination of vitamin K2 and cotylenin A has therapeutic value in the treatment of acute myeloid leukemia.

Mourgues L, Imbert V, Nebout M, et al.
The BMI1 polycomb protein represses cyclin G2-induced autophagy to support proliferation in chronic myeloid leukemia cells.
Leukemia. 2015; 29(10):1993-2002 [PubMed] Related Publications
The BMI1 polycomb protein regulates self-renewal, proliferation and survival of cancer-initiating cells essentially through epigenetic repression of the CDKN2A tumor suppressor locus. We demonstrate here for the first time that BMI1 also prevents autophagy in chronic myeloid leukemia (CML) cell lines, to support their proliferation and clonogenic activity. Using chromatin immunoprecipitation, we identified CCNG2/cyclin G2 (CCNG2) as a direct BMI1 target. BMI1 downregulation in CD34+ CML cells by PTC-209 pharmacological treatment or shBMI1 transduction triggered CCNG2 expression and decreased clonogenic activity. Also, ectopic expression of CCNG2 in CD34+ CML cells strongly decreased their clonogenicity. CCNG2 was shown to act by disrupting the phosphatase 2A complex, which activates a PKCζ-AMPK-JNK-ERK pathway that engages autophagy. We observed that BMI1 and CCNG2 levels evolved inversely during the progression of CML towards an acute deadly phase, and therefore hypothesized that BMI1 could support acute transformation of CML through the silencing of a CCNG2-mediated tumor-suppressive autophagy response.

Chang YY, Kuo WH, Hung JH, et al.
Deregulated microRNAs in triple-negative breast cancer revealed by deep sequencing.
Mol Cancer. 2015; 14:36 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: MicroRNAs (miRNAs) are short, non-coding RNA molecules that play critical roles in human malignancy. However, the regulatory characteristics of miRNAs in triple-negative breast cancer, a phenotype of breast cancer that does not express the genes for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, are still poorly understood.
METHODS: In this study, miRNA expression profiles of 24 triple-negative breast cancers and 14 adjacent normal tissues were analyzed using deep sequencing technology. Expression levels of miRNA reads were normalized with the quantile-quantile scaling method. Deregulated miRNAs in triple-negative breast cancer were identified from the sequencing data using the Student's t-test. Quantitative reverse transcription PCR validations were carried out to examine miRNA expression levels. Potential target candidates of a miRNA were predicted using published target prediction algorithms. Luciferase reporter assay experiments were performed to verify a putative miRNA-target relationship. Validated molecular targets of the deregulated miRNAs were retrieved from curated databases and their associations with cancer progression were discussed.
RESULTS: A novel 25-miRNA expression signature was found to effectively distinguish triple-negative breast cancers from surrounding normal tissues in a hierarchical clustering analysis. We documented the evidence of seven polycistronic miRNA clusters preferentially harboring deregulated miRNAs in triple-negative breast cancer. Two of these miRNA clusters (miR-143-145 at 5q32 and miR-497-195 at 17p13.1) were markedly down-regulated in triple-negative breast cancer, while the other five miRNA clusters (miR-17-92 at 13q31.3, miR-183-182 at 7q32.2, miR-200-429 at 1p36.33, miR-301b-130b at 22q11.21, and miR-532-502 at Xp11.23) were up-regulated in triple-negative breast cancer. Moreover, miR-130b-5p from the miR-301b-130b cluster was shown to directly repress the cyclin G2 (CCNG2) gene, a crucial cell cycle regulator, in triple-negative breast cancer cells. Luciferase reporter assays showed that miR-130b-5p-mediated repression of CCNG2 was dependent on the sequence of the 3'-untranslated region. The findings described in this study implicate a miR-130b-5p-CCNG2 axis that may be involved in the malignant progression of triple-negative breast cancer.
CONCLUSIONS: Our work delivers a clear picture of the global miRNA regulatory characteristics in triple-negative breast cancer and extends the current knowledge of microRNA regulatory network.

Wu H, Wang W, Xu H
Depletion of C3orf1/TIMMDC1 inhibits migration and proliferation in 95D lung carcinoma cells.
Int J Mol Sci. 2014; 15(11):20555-71 [PubMed] Free Access to Full Article Related Publications
In our previous study, we identified an association of high expression of c3orf1, also known as TIMMDC1 (translocase of inner mitochondrial membrane domain-containing protein 1), with metastatic characteristics in lung carcinoma cells. To investigate the preliminary function and mechanism of this mitochondrial protein, we depleted C3orf1 expression by introducing siRNA into 95D lung carcinoma cells. We demonstrated that C3orf1 depletion significantly suppressed 95D cell growth and migration. We confirmed C3orf1 localization in the inner mitochondrial membrane and showed that mitochondrial viability, membrane potential, and ATPase activity were remarkably reduced upon depletion of C3orf1. Microarray data indicated that genes involved in regulation of cell death, migration, and cell-cycle arrest were significantly altered after C3orf1 depletion for 48 h. The expression of genes involved in focal adhesion, ECM-receptor interaction, and p53-signaling pathways were notably altered. Furthermore, cell-cycle arrest genes such as CCNG2 and PTEN as well as genes involved in cell migration inhibition, such as TIMP3 and COL3A1, were upregulated after C3orf1 depletion in 95D cells. Concurrently, expression of the migration-promoting gene NUPR1 was markedly reduced, as confirmed by real-time PCR. We conclude that C3orf1 is critical for mitochondrial function, migration, and proliferation in 95D lung carcinoma cells. Depletion of C3orf1 inhibited cell migration and cell proliferation in association with upregulation of genes involved in cell-cycle arrest and cell migration inhibition. These results suggest that C3orf1 (TIMMDC1) may be a viable treatment target for lung carcinoma, and that further study of the role of this protein in lung carcinoma pathogenesis is justified.

Xiao X, Zhou L, Cao P, et al.
MicroRNA-93 regulates cyclin G2 expression and plays an oncogenic role in laryngeal squamous cell carcinoma.
Int J Oncol. 2015; 46(1):161-74 [PubMed] Related Publications
microRNA93 (miR-93) is expressed in the miR‑106b-25 cluster, located in intron 13 of the MCM7 gene. Our previous study found that miR-93 was significantly upregulated in laryngeal squamous cell carcinoma (LSCC), and cyclin G2 (CCNG2) was a potential target of miR-93 in LSCC. However, the possible functions and molecular mechanisms of miR-93 in LSCC remain unknown. In the present study, we show that the level of CCNG2 protein expression was significantly lower in LSCC cancer tissue than normal tissues. The level of CCNG2 was correlated with clinical stages, lymph node metastasis and histological grade. We further show that the expression level of miR-93 was inversely correlated with CCNG2 expression in clinical specimens. Furthermore, gain-of-function assays revealed that miR-93 promoted cell proliferation, decreased apoptosis rates, induced cell cycle arrest and promoted cell migration and invasion, whereas silencing of miR-93 attenuated these carcinogenic processes. In addition, overexpression of miR-93 in Hep-2 cells could reduce the mRNA and protein levels of CCNG2, whereas silencing of miR-93 in Hep-2 cells significantly increased CCNG2 expression. A luciferase assay verified that miR-93 could bind to the 3' untranslated region of CCNG2. Importantly, ectopic expression of CCNG2 in miR-93 cells rescued the effect of miR-93 on LSCC proliferation. Knockdown of CCNG2 promoted cell proliferation resembling that of miR-93 overexpression. These findings demonstrated that miR-93 promotes tumor growth by directly suppressing CCNG2. Taken together, these results suggested that this newly identified miR-93-CCNG2 axis may be involved in LSCC proliferation and progression. Our findings provide novel potential targets for LSCC therapy and prognosis.

Han B, Li W, Sun Y, et al.
A prolyl-hydroxylase inhibitor, ethyl-3,4-dihydroxybenzoate, induces cell autophagy and apoptosis in esophageal squamous cell carcinoma cells via up-regulation of BNIP3 and N-myc downstream-regulated gene-1.
PLoS One. 2014; 9(9):e107204 [PubMed] Free Access to Full Article Related Publications
The protocatechuic acid ethyl ester ethyl-3,4-dihydroxybenzoate is an antioxidant found in the testa of peanut seeds. Previous studies have shown that ethyl-3,4-dihydroxybenzoate can effectively reduce breast cancer cell metastasis by inhibiting prolyl-hydroxylase. In this study, we investigated the cytotoxic effect of ethyl-3,4-dihydroxybenzoate on esophageal squamous cell carcinoma cells in vitro and identified key regulators of ethyl-3,4-dihydroxybenzoate-induced esophageal cancer cell death through transcription expression profiling. Using flow cytometry analysis, we found that ethyl-3,4-dihydroxybenzoate induced S phase accumulation, a loss in mitochondrial membrane permeabilization, and caspase-dependent apoptosis. Moreover, an expression profile analysis identified 46 up- and 9 down-regulated genes in esophageal cancer KYSE 170 cells treated with ethyl-3,4-dihydroxybenzoate. These differentially expressed genes are involved in several signaling pathways associated with cell cycle regulation and cellular metabolism. Consistent with the expression profile results, the transcriptional and protein expression levels of candidate genes NDRG1, BNIP3, AKR1C1, CCNG2 and VEGFA were found to be significantly increased in treated KYSE 170 cells by reverse-transcription PCR and western blot analysis. We also found that protein levels of hypoxia-inducible factor-1α, BNIP3, Beclin and NDRG1 were increased and that enriched expression of BNIP3 and Beclin caused autophagy mediated by microtubule-associated protein 1 light chain 3 in the treated cells. Autophagy and apoptosis were activated together in esophageal cancer cells after exposed to ethyl-3,4-dihydroxybenzoate. Furthermore, knock-down of NDRG1 expression by siRNA significantly attenuated apoptosis in the cancer cells, implying that NDRG1 may be required for ethyl-3,4-dihydroxybenzoate-induced apoptosis. Together, these results suggest that the cytotoxic effects of ethyl-3,4-dihydroxybenzoate were mediated by the up-regulation of NDRG1, BNIP3, Beclin and hypoxia-inducible factor-1α, initiating BNIP3 and Beclin mediated autophagy at an early stage and ultimately resulting in esophageal cancer cell apoptosis.

Nadeem U, Ye G, Salem M, Peng C
MicroRNA-378a-5p targets cyclin G2 to inhibit fusion and differentiation in BeWo cells.
Biol Reprod. 2014; 91(3):76 [PubMed] Related Publications
MicroRNAs are expressed abundantly in the placenta throughout pregnancy. We have previously reported that microRNA (miR)-378a-5p promoted trophoblast migration and invasion. To further understand the role of miR-378a-5p during placental development, we investigated whether it may regulate the differentiation of syncytiotrophoblast (STB). Using a choriocarcinoma cell line, BeWo, we found that miR-378a-5p was down-regulated during forskolin-induced STB differentiation. Transfection of a miR-378a-5p mimic into BeWo cells decreased the formation of multinucleated STB, increased E-cadherin, and decreased the expression level of STB marker genes. On the other hand, transfection of anti-miR-378a-5p resulted in an increase in formation of multinucleated STB and expression of STB marker genes, as well as the loss of E-cadherin. Bioinformatic analysis revealed that miR-378a-5p has four potential binding sites at the 3' untranslated region (UTR) of cyclin G2 (CCNG2). Using luciferase reporter assays, we showed that miR-378a-5p decreased the luciferase activity of reporter constructs that contain CCNG2 3' UTR. In addition, miR-378a-5p decreased, whereas anti-miR-378a-5p increased, CCNG2 mRNA levels. Overexpression of CCNG2 increased the expression of syncytin-1 and fusion index and reversed the inhibitory effects of miR-378a-5p. In contrast, silencing of CCNG2 using siRNA increased E-cadherin and decreased syncytin-1 levels. These findings provide initial evidence that CCNG2 promotes STB differentiation and suggest that miR-378a-5p exerts an inhibitory role in STB differentiation, in part, by down-regulating CCNG2 expression, in the BeWo cell model.

Pereira-Caro G, Mateos R, Traka MH, et al.
Hydroxytyrosyl ethyl ether exhibits stronger intestinal anticarcinogenic potency and effects on transcript profiles compared to hydroxytyrosol.
Food Chem. 2013; 138(2-3):1172-82 [PubMed] Related Publications
The anticarcinogenic activity of hydroxytyrosyl ethyl ether (HTy-Et) compared to its precursor hydroxytyrosol (HTy) has been studied in human Caco-2 colon adenocarcinoma cells. 451 and 977 genes were differentially expressed in Caco-2 cells exposed to HTy or HTy-Et for 24h, respectively, compared with untreated cells (P<0.005; FDR=0), using Affymetrix microarrays. Results showed that both HTy and HTy-Et inhibited cell proliferation and arrested the cell cycle by up-regulating p21 and CCNG2 and down-regulating CCNB1 protein expression. HTy and HTy-Et also altered the transcription of specific genes involved in apoptosis, as suggested by the up-regulation of BNIP3, BNIP3L, PDCD4 and ATF3 and the activation of caspase-3. Moreover, these polyphenols up-regulated xenobiotic metabolizing enzymes UGT1A10 and CYP1A1, enhancing carcinogen detoxification. In conclusion, these results highlight that HTy and its derivative HTy-Et modulate molecular mechanisms involved in colon cancer, with HTy-Et being more effective than HTy.

Dodurga Y, Oymak Y, Gündüz C, et al.
Leukemogenesis as a new approach to investigate the correlation between up regulated gene 4/upregulator of cell proliferation (URG4/URGCP) and signal transduction genes in leukemia.
Mol Biol Rep. 2013; 40(4):3043-8 [PubMed] Related Publications
The aim of the study is to the determine the profiles of cell cycle genes and a new candidate oncogene of URG4/URGCP which play role in leukemia, establishing the association between the early prognosis of cancer and the quantitation of genetic changes, and bringing a molecular approach to definite diagnosis. In this study, 36 newly diagnosed patients' with ALL-AML in the range of 0-18 years and six control group patients' bone marrow samples were included. Total RNA was isolated from samples and then complementary DNA synthesis was performed. The obtained cDNAs have been installed 96 well plates after prepared appropriate mixtures and assessed with LightCycler(®) 480 Real-Time PCR quantitatively. CHEK1, URG4/URGCP, CCNG1, CCNC, CDC16, KRAS, CDKN2D genes in the T-ALL group; CCND2, ATM, CDK8, CHEK1, TP53, CHEK2, CCNG2, CDK4, CDKN2A, E2F4, CCNC, KRAS genes in the precursor B-ALL group and CCND2, CDK6 genes in the AML group have shown significant increase in mRNA expression level. In the featured role of acute leukemia the regulating signaling pathways of leukemogenesis partially defined, although identification of new genetic markers in acute leukemia subgroups, will allow the development of early diagnostic and new treatment protocols.

Montagner M, Enzo E, Forcato M, et al.
SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors.
Nature. 2012; 487(7407):380-4 [PubMed] Related Publications
The molecular determinants of malignant cell behaviours in breast cancer remain only partially understood. Here we show that SHARP1 (also known as BHLHE41 or DEC2) is a crucial regulator of the invasive and metastatic phenotype in triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer. SHARP1 is regulated by the p63 metastasis suppressor and inhibits TNBC aggressiveness through inhibition of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α (HIFs). SHARP1 opposes HIF-dependent TNBC cell migration in vitro, and invasive or metastatic behaviours in vivo. SHARP1 is required, and sufficient, to limit expression of HIF-target genes. In primary TNBC, endogenous SHARP1 levels are inversely correlated with those of HIF targets. Mechanistically, SHARP1 binds to HIFs and promotes HIF proteasomal degradation by serving as the HIF-presenting factor to the proteasome. This process is independent of pVHL (von Hippel-Lindau tumour suppressor), hypoxia and the ubiquitination machinery. SHARP1 therefore determines the intrinsic instability of HIF proteins to act in parallel to, and cooperate with, oxygen levels. This work sheds light on the mechanisms and pathways by which TNBC acquires invasiveness and metastatic propensity.

Ahmed S, Al-Saigh S, Matthews J
FOXA1 is essential for aryl hydrocarbon receptor-dependent regulation of cyclin G2.
Mol Cancer Res. 2012; 10(5):636-48 [PubMed] Related Publications
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the effects of the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Recently, AHR has emerged as a potential therapeutic target for breast cancer by virtue of its ability to modulate estrogen receptor-α (ERα) signalling and/or its ability to block cell proliferation. Our previous studies identified cyclin G2 (CCNG2), an inhibitor of cell-cycle progression, as an AHR target gene; however, the mechanism of this regulation is unknown. Chromatin immunoprecipitation assays in T-47D human breast cancer cells revealed a TCDD-dependent recruitment of AHR, nuclear co-activator 3 (NCoA3) and the transcription factor forkhead box A1 (FOXA1), a key regulator of breast cancer cell signaling, to CCNG2 resulting in increases in CCNG2 mRNA and protein levels. Mutation of the AHR response element (AHRE) and forkhead-binding sites abolished TCDD-induced CCNG2-regulated reporter gene activity. RNA interference-mediated knockdown of FOXA1 prevented the TCDD-dependent recruitment of AHR and NCoA3 to CCNG2 and reduced CCNG2 mRNA levels. Interestingly, knockdown of FOXA1 also caused a marked decrease in ERα, but not AHR protein levels. However, RNA interference-mediated knockdown of ERα, a negative regulator of CCNG2, had no effect on TCDD-dependent AHR or NCoA3 recruitment to or expression of CCNG2. These findings show that FOXA1, but not ERα, is essential for AHR-dependent regulation of CCNG2, assigning a role for FOXA1 in AHR action.

Zimmermann M, Arachchige-Don AS, Donaldson MS, et al.
Elevated cyclin G2 expression intersects with DNA damage checkpoint signaling and is required for a potent G2/M checkpoint arrest response to doxorubicin.
J Biol Chem. 2012; 287(27):22838-53 [PubMed] Free Access to Full Article Related Publications
To maintain genomic integrity DNA damage response (DDR), signaling pathways have evolved that restrict cellular replication and allow time for DNA repair. CCNG2 encodes an unconventional cyclin homolog, cyclin G2 (CycG2), linked to growth inhibition. Its expression is repressed by mitogens but up-regulated during cell cycle arrest responses to anti-proliferative signals. Here we investigate the potential link between elevated CycG2 expression and DDR signaling pathways. Expanding our previous finding that CycG2 overexpression induces a p53-dependent G(1)/S phase cell cycle arrest in HCT116 cells, we now demonstrate that this arrest response also requires the DDR checkpoint protein kinase Chk2. In accord with this finding we establish that ectopic CycG2 expression increases phosphorylation of Chk2 on threonine 68. We show that DNA double strand break-inducing chemotherapeutics stimulate CycG2 expression and correlate its up-regulation with checkpoint-induced cell cycle arrest and phospho-modification of proteins in the ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR) signaling pathways. Using pharmacological inhibitors and ATM-deficient cell lines, we delineate the DDR kinase pathway promoting CycG2 up-regulation in response to doxorubicin. Importantly, RNAi-mediated blunting of CycG2 attenuates doxorubicin-induced cell cycle checkpoint responses in multiple cell lines. Employing stable clones, we test the effect that CycG2 depletion has on DDR proteins and signals that enforce cell cycle checkpoint arrest. Our results suggest that CycG2 contributes to DNA damage-induced G(2)/M checkpoint by enforcing checkpoint inhibition of CycB1-Cdc2 complexes.

Elangovan S, Ramachandran S, Venkatesan N, et al.
SIRT1 is essential for oncogenic signaling by estrogen/estrogen receptor α in breast cancer.
Cancer Res. 2011; 71(21):6654-64 [PubMed] Free Access to Full Article Related Publications
The NAD-dependent histone deacetylase silent information regulator 1 (SIRT1) is overexpressed and catalytically activated in a number of human cancers, but recent studies have actually suggested that it may function as a tumor suppressor and metastasis inhibitor in vivo. In breast cancer, SIRT1 stabilization has been suggested to contribute to the oncogenic potential of the estrogen receptor α (ERα), but SIRT1 activity has also been associated with ERα deacetylation and inactivation. In this study, we show that SIRT1 is critical for estrogen to promote breast cancer. ERα physically interacted and functionally cooperated with SIRT1 in breast cancer cells. ERα also bound to the promoter for SIRT1 and increased its transcription. SIRT1 expression induced by ERα was sufficient to activate antioxidant and prosurvival genes in breast cancer cells, such as catalase and glutathione peroxidase, and to inactivate tumor suppressor genes such as cyclin G2 (CCNG2) and p53. Moreover, SIRT1 inactivation eliminated estrogen/ERα-induced cell growth and tumor development, triggering apoptosis. Taken together, these results indicated that SIRT1 is required for estrogen-induced breast cancer growth. Our findings imply that the combination of SIRT1 inhibitors and antiestrogen compounds may offer more effective treatment strategies for breast cancer.

Zhao Z, Liu Y, He H, et al.
Candidate genes influencing sensitivity and resistance of human glioblastoma to Semustine.
Brain Res Bull. 2011; 86(3-4):189-94 [PubMed] Related Publications
OBJECTIVE: The prognosis of glioblastoma (GBM) is poor. The therapeutic outcome of conventional surgical and adjuvant treatments remains unsatisfactory, and therefore individualized adjuvant chemotherapy has aroused more attention. Microarrays have been applied to study mechanism of GBM development and progression but it has difficulty in determining responsible genes from the plethora of genes on microarrays unrelated to outcome. The present study was attempted to use bioinformatics method to investigate candidate genes that may influence chemosensitivity of GBM to Semustine (Me-CCNU).
METHODS: Clinical data of 4 GBM patients in Affymetrix microarray were perfected through long-term follow-up study. Differential expression genes between the long- and short-survival groups were picked out, GO-analysis and pathway-analysis of the differential expression genes were performed. Me-CCNU-related signal transduction networks were constructed. The methods combined three steps before were used to screen core genes that influenced Me-CCNU chemosensitivity in GBM.
RESULTS: In Affymetrix microarray there were altogether 2018 differential expression genes that influenced survival duration of GBM. Of them, 934 genes were up-regulated and 1084 down-regulated. They mainly participated in 94 pathways. Me-CCNU-related signal transduction networks were constructed. The total number of genes in the networks was 466, of which 66 were also found in survival duration-related differential expression genes. Studied key genes through GO-analysis, pathway-analysis and in the Me-CCNU-related signal transduction networks, 25 core genes that influenced chemosensitivity of GBM to Me-CCNU were obtained, including TP53, MAP2K2, EP300, PRKCA, TNF, CCND1, AKT2, RBL1, CDC2, ID2, RAF1, CDKN2C, FGFR1, SP1, CDK6, IGFBP3, MDM4, PDGFD, SOCS2, CCNG2, CDK2, SDC2, STMN1, TCF7L1, TUBB.
CONCLUSION: Bioinformatics may help excavate and analyze large amounts of data in microarrays by means of rigorous experimental planning, scientific statistical analysis and collection of complete data about survival of GBM patients. In the present study, a novel differential gene expression pattern was constructed and advanced study will provide new targets for chemosensitivity of GBM.

Long Q, Johnson BA, Osunkoya AO, et al.
Protein-coding and microRNA biomarkers of recurrence of prostate cancer following radical prostatectomy.
Am J Pathol. 2011; 179(1):46-54 [PubMed] Free Access to Full Article Related Publications
An important challenge in prostate cancer research is to develop effective predictors of tumor recurrence following surgery to determine whether immediate adjuvant therapy is warranted. To identify biomarkers predictive of biochemical recurrence, we isolated the RNA from 70 formalin-fixed, paraffin-embedded radical prostatectomy specimens with known long-term outcomes to perform DASL expression profiling with a custom panel that we designed of 522 prostate cancer-relevant genes. We identified a panel of 10 protein-coding genes and two miRNA genes (RAD23B, FBP1, TNFRSF1A, CCNG2, NOTCH3, ETV1, BID, SIM2, LETMD1, ANXA1, miR-519d, and miR-647) that could be used to separate patients with and without biochemical recurrence (P < 0.001), as well as for the subset of 42 Gleason score 7 patients (P < 0.001). We performed an independent validation analysis on 40 samples and found that the biomarker panel was also significant at prediction of biochemical recurrence for all cases (P = 0.013) and for a subset of 19 Gleason score 7 cases (P = 0.010), both of which were adjusted for relevant clinical information including T-stage, prostate-specific antigen, and Gleason score. Importantly, these biomarkers could significantly predict clinical recurrence for Gleason score 7 patients. These biomarkers may increase the accuracy of prognostication following radical prostatectomy using formalin-fixed specimens.

Ye XX, Liu CB, Chen JY, et al.
The expression of cyclin G in nasopharyngeal carcinoma and its significance.
Clin Exp Med. 2012; 12(1):21-4 [PubMed] Related Publications
To investigate the expression of cyclin G1, cyclin G2 in nasopharyngeal carcinoma (NPC) cell lines and its significance. The protein expression of cyclin G1, cyclin G2 in NPC cell lines of different differentiation degree (HNE2, CNE1) was detected by indirect immunofluorescence. The mRNA expression of cyclin G1, cyclin G2 in HNE2 and CNE1 was measured with RT-PCR. The cyclin G1 expression in HNE2 and CNE1 was weak, and cyclin G2 expression in the cytoplasm near cell membrane was strong, continuous, and homogeneous. The expression level of cyclin G1-mRNA in HNE2 was 2.097 ± 0.262, which was significantly higher than CNE1 (0.997 ± 0.286, P < 0.05); the expression level of cyclin G2-mRNA in HNE2 was 0.708 ± 0.107, which was significantly lower than CNE1 (1.216 ± 0.037, P < 0.05). Abnormal expression of cyclin G was closely related to tumor differentiation, the origin, and progression of NPC.

Fu G, Peng C
Nodal enhances the activity of FoxO3a and its synergistic interaction with Smads to regulate cyclin G2 transcription in ovarian cancer cells.
Oncogene. 2011; 30(37):3953-66 [PubMed] Related Publications
Nodal, a member of the transforming growth factor-β superfamily, has been recently shown to suppress cell proliferation and to stimulate the expression of cyclin G2 (CCNG2) in human epithelial ovarian cancer cells. However, the precise mechanisms underlying these events are not fully understood. In this study, we investigated the transcriptional regulation of CCNG2 by the Nodal signaling pathway. In ovarian cancer cells, overexpression of Nodal or its receptors, activin receptor-like kinase 7 (ALK7) or ALK4, resulted in an increase in the CCNG2 promoter activity. Several putative Forkhead box class O (FoxO)3a-binding sites are present in the human CCNG2 promoter and overexpression of FoxO3a enhanced the CCNG2 promoter activity. The functional FoxO3a-binding element (FBE) was mapped to a proximal region located between -398 and -380 bp (FBE1) through deletion and mutation analyses, as well as chromatin immunoprecipitation (IP) assay. Interestingly, mutation of the FBE1 not only abolished the effect of FoxO3a, but also blocked Nodal-induced CCNG2 transcription. Nodal stimulated FoxO3a mRNA and protein expression through the canonical Smad pathway and suppressed FoxO3a inactivation by inhibiting AKT activity. Silencing of FoxO3a using small interfering RNA significantly reduced the effect of Nodal on the CCNG2 promoter activity. On the other hand, overexpression of Smad2 and Smad3 enhanced the FoxO3a-induced CCNG2 promoter activity whereas knockdown of Smad4 blocked the activity of FoxO3a. Furthermore, IP assays revealed that FoxO3a formed complexes with Smad proteins and that Nodal enhanced the binding of FoxO3a to the CCNG2 promoter. Finally, silencing of FoxO3a reversed the inhibitory effect of Nodal on cell proliferation. Taken together, these findings demonstrated that Nodal signaling promotes CCNG2 transcription by upregulating FoxO3a expression, inhibiting FoxO3a phosphorylation and enhancing its synergistic interaction with Smads. These results also suggest that FoxO3a is an important mediator of Nodal signaling in ovarian cancer cells.

Bunt J, de Haas TG, Hasselt NE, et al.
Regulation of cell cycle genes and induction of senescence by overexpression of OTX2 in medulloblastoma cell lines.
Mol Cancer Res. 2010; 8(10):1344-57 [PubMed] Related Publications
The transcription factor orthodenticle homeobox 2 (OTX2) has been implicated in the pathogenesis of medulloblastoma, as it is often highly expressed and sometimes amplified in these tumors. Little is known of the downstream pathways regulated by OTX2. We therefore generated MED8A and DAOY medulloblastoma cell lines with doxycycline-inducible OTX2 expression. In both cell lines, OTX2 inhibited proliferation and induced a senescence-like phenotype with senescence-associated β-galactosidase activity. Expression profiles of time series after OTX2 induction in MED8A showed early upregulation of cell cycle genes related to the G(2)-M phase, such as AURKA, CDC25C, and CCNG2. Paradoxically, G(1)-S phase genes such as MYC, CDK4, CDK6, CCND1, and CCND2 were strongly downregulated, in line with the observed G(1) arrest. ChIP-on-chip analyses of OTX2 binding to promoter regions in MED8A and DAOY showed a strong enrichment for binding to the G(2)-M genes, suggesting a direct activation. Their mRNA expression correlated with OTX2 expression in primary tumors, underscoring the in vivo relevance of this regulation. OTX2 induction activated the P53 pathway in MED8A, but not in DAOY, which carries a mutated P53 gene. In DAOY cells, senescence-associated secretory factors, such as interleukin-6 and insulin-like growth factor binding protein 7, were strongly upregulated after OTX2 induction. We hypothesize that the imbalance in cell cycle stimulation by OTX2 leads to cellular senescence either by activating the P53 pathway or through the induction of secretory factors. Our data indicate that OTX2 directly induces a series of cell cycle genes but requires cooperating genes for an oncogenic acceleration of the cell cycle.

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