Gene Summary

Gene:CCNG1; cyclin G1
Aliases: CCNG
Summary:The eukaryotic cell cycle is governed by cyclin-dependent protein kinases (CDKs) whose activities are regulated by cyclins and CDK inhibitors. The protein encoded by this gene is a member of the cyclin family and contains the cyclin box. The encoded protein lacks the protein destabilizing (PEST) sequence that is present in other family members. Transcriptional activation of this gene can be induced by tumor protein p53. Two transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 16 March, 2017


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: CCNG1 (cancer-related)

Yan J, Jiang JY, Meng XN, et al.
MiR-23b targets cyclin G1 and suppresses ovarian cancer tumorigenesis and progression.
J Exp Clin Cancer Res. 2016; 35:31 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: It has been proposed that cyclin G1 (CCNG1) participates in p53-dependent G1-S and G2 checkpoints and might function as an oncogenic protein in the initiation and metastasis of ovarian carcinoma. MicroRNA 23b (miR-23b) is a critical regulatory factor in the progression of many cancer cell types that targets the relevant genes.
METHODS: MiR-23b expression in ovarian tissues was quantified by quantitative reverse transcription-PCR. The ovarian cancer cell lines OVCAR3, HO8910-PM, and SKOV3/DDP were transfected with miR-23b, after we assayed the cell phenotype and expression of the relevant molecules. Dual-luciferase reporter assay and a xenograft mouse model were used to examine the expression of miR-23b and its target gene CCNG1.
RESULTS: MIR23B mRNA expression was significantly lower in epithelial ovarian carcinoma and borderline tumors than in normal ovarian tissues and benign tumors, and miR-23b expression among ages and pathological subtypes was significantly different. CCNG1 mRNA expression was significantly lower in normal ovarian tissues than in benign tumors, borderline tumors, and ovarian carcinomas, and expression among pathological subtypes was significantly different. MiR-23b overexpression inhibited ovarian cancer cell proliferation, invasion, and migration, and induced apoptosis. Dual-luciferase reporter assay showed that miR-23b bound with the 3' untranslated region of CCNG1. MiR-23b overexpression significantly downregulated CCNG1, urokinase, survivin, Bcl-xL, P70S6K, and matrix metallopeptidase-9 (MMP9) mRNA and protein expression. Furthermore, miR-23b inhibited tumor growth and suppressed CCNG1 expression in vitro.
CONCLUSIONS: Our findings show that miR-23b may inhibit ovarian cancer tumorigenesis and progression by downregulating CCNG1 and the expression of the relevant genes. MiR-23b is a potentially novel application for regulating ovarian carcinoma progression.

Kibel AS, Ahn J, Isikbay M, et al.
Genetic variants in cell cycle control pathway confer susceptibility to aggressive prostate carcinoma.
Prostate. 2016; 76(5):479-90 [PubMed] Related Publications
BACKGROUND: Because a significant number of patients with prostate cancer (PCa) are diagnosed with disease unlikely to cause harm, genetic markers associated with clinically aggressive PCa have potential clinical utility. Since cell cycle checkpoint dysregulation is crucial for the development and progression of cancer, we tested the hypothesis that common germ-line variants within cell cycle genes were associated with aggressive PCa.
METHODS: Via a two-stage design, 364 common sequence variants in 88 genes were tested. The initial stage consisted of 258 aggressive PCa patients and 442 controls, and the second stage added 384 aggressive PCa Patients and 463 controls. European-American and African-American samples were analyzed separately. In the first stage, SNPs were typed by Illumina Goldengate assay while in the second stage SNPs were typed by Pyrosequencing assays. Genotype frequencies between cases and controls were compared using logistical regression analysis with additive, dominant and recessive models.
RESULTS: Eleven variants within 10 genes (CCNC, CCND3, CCNG1, CCNT2, CDK6, MDM2, SKP2, WEE1, YWHAB, YWHAH) in the European-American population and nine variants in 7 genes (CCNG1, CDK2, CDK5, MDM2, RB1, SMAD3, TERF2) in the African-American population were found to be associated with aggressive PCa using at least one model. Of particular interest, CCNC (rs3380812) was associated with risk in European-American cohorts from both institutions. CDK2 (rs1045435) and CDK5 (rs2069459) were associated with risk in the African-American cohorts from both institutions. Lastly, variants within MDM2 and CCNG1 were protective for aggressive PCa in both ethnic groups.
CONCLUSIONS: This study confirms that polymorphisms within cell cycle genes are associated with clinically aggressive PCa. Validation of these markers in additional populations is necessary, but these markers may help identify patients at risk for potentially lethal carcinoma.

Shang Y, Feng B, Zhou L, et al.
The miR27b-CCNG1-P53-miR-508-5p axis regulates multidrug resistance of gastric cancer.
Oncotarget. 2016; 7(1):538-49 [PubMed] Free Access to Full Article Related Publications
Multidrug resistance (MDR) correlates with treatment failure and poor prognosis among gastric cancer (GC) patients. In a previous study using high-throughput functional screening, we identified 11 microRNAs (miRNAs) that regulate MDR in GC and found that miR-508-5p reversed MDR by targeting ABCB1 and ZNRD1. However, the mechanism by which miR-508-5p was decreased in chemo-resistant GC cells was unclear. In this study, we found that ectopic miR-27b is sufficient to sensitize tumors to chemotherapy in vitro and in vivo. Moreover, miR-27b directly targets the 3' untranslated regions (3'-UTRs) of CCNG1, a well-known negative regulator of P53 stability. Interestingly, miR-27b up-regulation leads to increased miR-508-5p expression, and this phenomenon is mediated by CCNG1 and P53. Further investigation indicated that miR-508-5p is directly regulated by P53. Thus, the miR-27b/CCNG1/P53/miR-508-5p axis plays important roles in GC-associated MDR. In addition, miR-27b and miR-508-5p expression was detected in GC tissues with different chemo-sensitivities, and we found that tissues in which miR-27b and miR-508-5p are up-regulated are more sensitive to chemotherapy. Together, these data suggest that the combination of miR-27b and miR-508-5p represents a potential marker of MDR. Restoring the miR-27b and miR-508-5p levels might contribute to MDR reversion in future clinical practice.

Liu X, Ma L, Rao Q, et al.
MiR-1271 Inhibits Ovarian Cancer Growth by Targeting Cyclin G1.
Med Sci Monit. 2015; 21:3152-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ovarian cancer is the most lethal gynecological malignant cancer in the female genital system. The dysfunction of miRNA contributes to ovarian cancer development.
MATERIAL AND METHODS: The miR-1271 level in ovarian cancer tissues and cells was assayed by qRT-PCR. The miR-1271 expression in cells was overexpressed by miRNA-mimic transfection and reduced by miRNA-antisense-oligonucleotide (ASO) transfection. Cell proliferation was analyzed by an MTT assay. The targeted genes were predicted by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. The protein level was assayed by Western blotting.
RESULTS: The ovarian cancer tissue and cell lines showed low levels of miR-1271. Low levels of miR-1271 in ovarian cancer tissues were correlated with a low rate of patient survival, and the overexpression of miR-1271 inhibited the proliferation of ovarian cancer cells. The 3' UTR of cyclin G1 (CCNG1) was targeted by miR-1271.
CONCLUSIONS: Low levels of miR-1271 in ovarian cancer tissues promoted cancer cell growth. MiR-1271 may be a new predictor of prognosis in ovarian cancer. MiR-1271 exerted its role by targeting CCNG1.

Hamza AH, Abdulfattah HM, Mahmoud RH, et al.
Current concepts in pathophysiology and management of hepatocellular carcinoma.
Acta Biochim Pol. 2015; 62(3):573-80 [PubMed] Related Publications
Additional approaches to control malignancies are needed due to the emerging trends in the incidence of cancer of different organ sites. Due to the high frequency of hepatocellular carcinoma (HCC) and its poor prognosis, preventing HCC is an urgent priority. To explore the antioxidant and apoptotic pathways of grape seed extract (GSE) we induce HCC experimentally by diethylnitrosoamine (DEN) and treated the animals with low and high doses of GSE. The results indicate good therapeutic possibilities for GSE use in treatment of HCC., This was evidenced via regression of liver enzymes' function (ALT&AST), the HCC markers; α-fucosidase, α-fetoprotein and carcinoembrionic antigen (CEA) in HCC groups treated with the grape seed extract. Also, tumor necrosis factor (TNF-α) showed a significant decrease using GSE in HCC bearing animals. Regarding the apoptotic pathways of GSE, we found a significant down regulation of apoptosis enhancing nuclease (Aen), Bcl2-associated X protein (Bax), B-cell translocation gene 2(Btg2), Cyclin G1 (Ccng1) and Cyclin-dependent kinase inhibitor 1A (Cdkn1a) gene expression in HCC+GSE groups as compared to HCC bearing group. In the same trend, the necrotic/apoptotic rates were significantly higher in the HCC groups treated with GSE vs. the HCC bearing group. Finally, the 8-OHdG/2-dG generation decreased by 73.8% and 52.9% in HCC+GSE at low and high doses, respectively. Based on these encouraging observations, grape seed extract could be a promising natural remedy for attenuating hepatocellular carcinoma that has a great future in approaches directed towards control of HCC.

Li X, Pan Q, Wan X, et al.
Methylation-associated Has-miR-9 deregulation in paclitaxel- resistant epithelial ovarian carcinoma.
BMC Cancer. 2015; 15:509 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Drug resistance is still one of the key causes of death in epithelial ovarian carcinoma (EOC) patients, however there are very few strategies to reverse chemoresistance. Here we try to clarify whether and how miR-9 takes part in the regulation of paclitaxel sensitivity.
METHODS: miR-9 expressions in EOC cells and tissues were detected by Realtime PCR. The target of miR-9 was validated through dual luciferase reporter assay and Western Blot. Methylation study, RNAi technique and cytotoxicity assay were used to determine the intrinsic mechanism of miR-9 in paclitaxel sensitivity regulation.
RESULTS: miR-9 is down-regulated in paclitaxel resistant EOC. The patients with lower miR-9, Grade 3, Stage III -IV and suboptimal surgery present shorter survival time. miR-9 and suboptimal surgery are independent prognostic factors of EOC. Modulating miR-9 expression could change paclitaxel sensitivity of EOC cells. CCNG1, validated as a direct target of miR-9, mediates paclitaxel resistance. miR-9-1 and 3 gene hypermethylation would decrease miR-9 expression, while demethylation of miR-9 gene could restore miR-9 expression and improve paclitaxel sensitivity in chemoresistance EOC cells. Furthermore, methylation-associated miR-9 deregulation in EOC cells could be induced by paclitaxel exposure.
CONCLUSIONS: Methylation-associated miR-9 down-regulation is probably one of the key mechanisms for paclitaxel resistance in EOC cells, via targeting CCNG1. Our findings may also provide a new potential therapeutic target to reverse paclitaxel resistance in EOC patients.

Jiang L, Liu R, Wang Y, et al.
The role of Cyclin G1 in cellular proliferation and apoptosis of human epithelial ovarian cancer.
J Mol Histol. 2015; 46(3):291-302 [PubMed] Related Publications
Cyclin G1 plays an essential role in the development of human carcinoma. Here, we characterized the clinical significance of Cyclin G1 and investigated its role in cellular proliferation and apoptosis of epithelial ovarian cancer (EOC). Western blot was used to evaluate the expression of Cyclin G1 in nine fresh EOC tissues and three fresh normal ovarian tissues. Immunohistochemistry analysis was performed on formalin-fixed paraffin-embedded section of 119 cases of EOCs. Using cell counting kit (CCK)-8 and colony formation assays, we analyzed the effect of Cyclin G1 in cellular proliferation of EOC. Besides, the immunofluorescence and flow cytometry analysis was performed to study the role of Cyclin G1 in cellular apoptosis of EOC. We found Cyclin G1 was up-regulated in EOC tissues compared with the normal ovary tissues. Cyclin G1 expression in EOC was closely correlated with differentiation grade (P = 0.009) and malignant tumor cells in ascites (P = 0.009). The Kaplan-Meier curve showed that higher expression of Cyclin G1 was associated with significantly shorter survival in EOC patients. Multivariate analysis suggested Cyclin G1 expression was an independent prognostic factor for overall survival. CCK-8 and colony formation assays revealed that depletion of Cyclin G1 inhibited the proliferation and clone formation. Combined immunofluorescence and flow cytometry analysis showed that silencing of Cyclin G1 with shRNA could promote apoptosis of ovarian cancer cells. Additionally, the result of immunoprecipitation test showed Cyclin G1 interacted with CDK2 in EOC cells. In summary, our findings suggest that Cyclin G1 may be involved in the prognosis of EOC patients and be a useful therapeutic target for EOC.

Ohno S, Naito Y, Mukai S, et al.
ELAS1-mediated inhibition of the cyclin G1-B'γ interaction promotes cancer cell apoptosis via stabilization and activation of p53.
Oncogene. 2015; 34(49):5983-96 [PubMed] Related Publications
Radiation therapy (RT) is useful for selectively killing cancer cells. However, because high levels of ionizing radiation (IR) are toxic to normal cells, RT cannot be applied repeatedly to cancer patients. Therefore, novel chemicals that enhance the efficacy of chemoradiotherapy (CRT) would be valuable. Here, we report that ELAS1, a peptide corresponding to the protein phosphatase 2A (PP2A) association domain of cyclin G1 (CycG1), can enhance the efficacy of CRT. ELAS1 interacts with the PP2A B'γ-subunit and competitively inhibits association with CycG1, thereby preventing the PP2A holoenzyme from dephosphorylating target proteins, Mdm2 (pT218) and p53 (pS46), following DNA double-strand break (DSB) insults. Doxycycline (Dox)-induced overexpression of Myc-ELAS1 caused γ-irradiation to induce apoptosis in human osteosarcoma (U2OS) cells, at 1/10th the effective dosage of γ-irradiation required for apoptosis in Myc-vector-expressing cells; ELAS1 peptide incorporation into U2OS cells also showed similar apoptotic effects. Moreover, administration of DSB-inducing chemicals, camptothecin (CPT) or irinotecan, to Myc-ELAS1-expressing U2OS cells also induced efficient apoptosis with only 1/100th (CPT) or 1/5th (irinotecan) of the amounts of drugs required for this effect in Myc-vector-expressing cells. Taken together, ELAS1 may be important for the design of ELAS1-mimetic compounds to improve CRT efficacy.

Zhao X, Liu M, Li D
Oleanolic acid suppresses the proliferation of lung carcinoma cells by miR-122/Cyclin G1/MEF2D axis.
Mol Cell Biochem. 2015; 400(1-2):1-7 [PubMed] Related Publications
Oleanolic acid (OA) is a natural compound from plants with anti-tumor activities. However, the mechanism of the inhibitory effect of OA on cell cycle progression has not been completely explored. We employed several lung carcinoma cell lines to investigate the cell cycle-related molecular pathway affected by OA. The data revealed that OA suppressed the proliferation of lung cancer cells in both dose- and time-dependent manners, along with an increase in miR-122 abundance. The suppression of miR-122 abolished the effect of OA on lung cancer cells. CCNG1 and MEF2D, two putative miR-122 targets, were found to be downregulated by OA treatment. Restoring their expression counteracted the effect of OA on lung carcinoma cells. OA was further shown to induce the expression of miR-122-regulating transcriptional factors in lung cancer cells. Collectively, OA induced cell cycle arrest in lung cancer cells through miR-122/Cyclin G1/MEF2D pathway. This finding may contribute to the understanding of the molecular mechanism of OA's anti-tumor activity.

Giovannini C, Minguzzi M, Baglioni M, et al.
Suppression of p53 by Notch3 is mediated by Cyclin G1 and sustained by MDM2 and miR-221 axis in hepatocellular carcinoma.
Oncotarget. 2014; 5(21):10607-20 [PubMed] Free Access to Full Article Related Publications
To successfully target Notch receptors as part of a multidrug anticancer strategy, it will be essential to fully characterize the factors that are modulated by Notch signaling. We recently reported that Notch3 silencing in HCC results in p53 up-regulation in vitro and, therefore, we focused on the mechanisms that associate Notch3 to p53 protein expression. We explored the regulation of p53 by Notch3 signalling in three HCC cell lines HepG2, SNU398 and Hep3B.We found that Notch3 regulates p53 at post-transcriptional level controlling both Cyclin G1 expression and the feed-forward circuit involving p53, miR-221 and MDM2. Moreover, our results were validated in human HCCs and in a rat model of HCC treated with Notch3 siRNAs. Our findings are becoming an exciting area for further in-depth research toward targeted inactivation of Notch3 receptor as a novel therapeutic approach for increasing the drug-sensitivity, and thereby improving the treatment outcome of patients affected by HCC. Indeed, we proved that Notch3 silencing strongly increases the effects of Nutilin-3.With regard to therapeutic implications, Notch3-specific drugs could represent a valuable strategy to limit Notch signaling in the context of hepatocellular carcinoma over-expressing this receptor.

Ma J, Wu Q, Zhang Y, et al.
MicroRNA sponge blocks the tumor-suppressing functions of microRNA-122 in human hepatoma and osteosarcoma cells.
Oncol Rep. 2014; 32(6):2744-52 [PubMed] Related Publications
MicroRNAs (miRNAs), as gene expression regulators, have been identified to be closely associated with tumorigenesis. Thus a loss-of-function study is more likely to reveal the biological roles of endogenous miRNAs. Genetic knockout, antisense oligonucleotide inhibitors, and miRNA sponge (miR‑SP) are usually performed to inhibit the activities of miRNAs of interest. In the present study, we utilized the miR-SP method, which has long-term rather than short-term effects of antisense oligonucleotide inhibitors, to generate a microRNA-122 sponge (miR-122-SP) mediated by lentivirus, and identified its silencing role in the Huh7 hepatoma cell line and U2OS osteosarcoma cell line. The results showed that miR-122-SP effectively sequestered ectopic miR-122 and restored the expression of miR-122 which targets cyclin G1 (CCNG1), Bcl-w and disintegrin and metalloprotease 10. Moreover, miR-122-SP overexpression rescued the effects of ectopic miR-122 on suppressing proliferation, inhibiting cell migration and invasion, arresting cell cycle at G1 phase, and activating caspase-3/7, not only in Huh7 human hepatoma cells, but also in U2OS osteosarcoma cells. miR-122-SP also knocked down endogenous miR-122 expression in Huh7 and promoted tumorigenesis in vivo. miR-122-SP therefore is a useful tool that may be utilized to study the functions of miR-122 with regard to liver development and tumorigenesis in vitro and in vivo.

Wen W, Han T, Chen C, et al.
Cyclin G1 expands liver tumor-initiating cells by Sox2 induction via Akt/mTOR signaling.
Mol Cancer Ther. 2013; 12(9):1796-804 [PubMed] Related Publications
Recurrence and chemoresistance of liver cancer has been attributed to the existence of liver tumor-initiating cells (T-ICs). It is important to decipher the molecular mechanism for acquisition of drug resistance and to design combinatorial therapeutic strategies. Cyclin G1 has been shown to play a pivotal role in initiation and metastasis of hepatocellular carcinoma. In this study, we found that enhanced cyclin G1 expression was associated with drug resistance of hepatoma cells and higher recurrence rate in hepatocellular carcinoma patients. Expression of cyclin G1 was elevated in liver T-ICs and closely correlated with the expression of liver T-IC markers. Forced cyclin G1 expression remarkably enhanced self-renewal and tumorigenicity of hepatoma cells. Cyclin G1 overexpression dramatically upregulated the expression of Sox2 both in vitro and in vivo, which was impaired by chemical inhibitors of Akt/mTOR signaling. Furthermore, blockade of Akt/mTOR signaling or interference of Sox2 expression suppressed cyclin G1-enhanced self-renewal, chemoresistance, and tumorigenicity of hepatoma cells, indicating that cyclin G1 expands liver T-ICs through Sox2 induction via Akt/mTOR signaling pathway. These results suggest that cyclin G1-induced liver T-IC expansion contributes to the recurrence and chemoresistance of hepatoma, and cyclin G1 may be a promising biomarker for individualized therapy of hepatocellular carcinoma patients.

Munagala R, Aqil F, Vadhanam MV, Gupta RC
MicroRNA 'signature' during estrogen-mediated mammary carcinogenesis and its reversal by ellagic acid intervention.
Cancer Lett. 2013; 339(2):175-84 [PubMed] Free Access to Full Article Related Publications
Dysregulated miRNA expression has been associated with the development and progression of cancers, including breast cancer. The role of estrogen (E2) in regulation of cell proliferation and breast carcinogenesis is well-known. Recent reports have associated several miRNAs with estrogen receptors in breast cancers. Investigation of the regulatory role of miRNAs is critical for understanding the effect of E2 in human breast cancer, as well as developing strategies for cancer chemoprevention. In the present study we used the well-established ACI rat model that develops mammary tumors upon E2 exposure and identified a 'signature' of 33 significantly modulated miRNAs during the process of mammary tumorigenesis. Several of these miRNAs were altered as early as 3 weeks after initial E2 treatment and their modulation persisted throughout the mammary carcinogenesis process, suggesting that these molecular changes are early events. Furthermore, ellagic acid, which inhibited E2-induced mammary tumorigenesis in our previous study, reversed the dysregulation of miR-375, miR-206, miR-182, miR-122, miR-127 and miR-183 detected with E2 treatment and modulated their target proteins (ERα, cyclin D1, RASD1, FoxO3a, FoxO1, cyclin G1, Bcl-w and Bcl-2). This is the first systematic study examining the changes in miRNA expression associated with E2 treatment in ACI rats as early as 3 week until tumor time point. The effect of a chemopreventive agent, ellagic acid in reversing miRNAs modulated during E2-mediated mammary tumorigenesis is also established. These observations provide mechanistic insights into the new molecular events behind the chemopreventive action of ellagic acid and treatment of breast cancer.

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.

Zhao L, Li F, Taylor EW
Can tobacco use promote HCV-induced miR-122 hijacking and hepatocarcinogenesis?
Med Hypotheses. 2013; 80(2):131-3 [PubMed] Related Publications
Chronic hepatitis C virus (HCV) infection is a well-recognized risk factor for hepatocellular carcinoma (HCC). As a co-risk factor, the role of tobacco use in HCV-driven carcinogenesis and relevant underlying mechanisms remain largely unclear. The latest discoveries about HCV replication have shown that HCV RNA hijacks cellular miRNA-122 by forming an Ago2-HCV-miR-122 complex that stabilizes the HCV genome and enhances HCV replication. Our previous work has demonstrated that aqueous tobacco smoke extract (TSE) is a potent activator of HIV replication via TSE-mediated viral protection from oxidative stress and activation of a set of genes that can promote viral replication. Since HCV is, like HIV, an enveloped virus that should be equally susceptible to lipid peroxidation, and since one of the TSE-upregulated genes, the DDX3 helicase, is known to facilitate HCV replication, we hypothesize that (1) tobacco use can similarly enhance HCV viability and replication, and promote HCC progression by up-regulation of DDX3, and (2) by competing for binding with miR-122 as a competing endogenous RNA (ceRNA), HCV replication can liberate miR-122's direct target, oncogenic gene cyclin G1 (CCNG1); furthermore, simultaneous tobacco use can synergistically enhance this competing effect via HCV upregulation. Our hypotheses may lay a foundation for better understanding of carcinogenesis in HCV-driven HCC and the potential role of tobacco as a cofactor. Disrupting the HCV ceRNA effect may provide a new strategy for designing anti HCV/HCC drugs.

Hou W, Bukong TN, Kodys K, Szabo G
Alcohol facilitates HCV RNA replication via up-regulation of miR-122 expression and inhibition of cyclin G1 in human hepatoma cells.
Alcohol Clin Exp Res. 2013; 37(4):599-608 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Clinical studies demonstrate synergistic liver damage by alcohol and hepatitis C virus (HCV); however, the mechanisms by which alcohol promotes HCV infection remain obscure. The liver-specific microRNA-122 (miR-122) regulates HCV replication and expression of host genes, including Cyclin G1. Here, we hypothesized that alcohol regulates miR-122 expression and thereby modulates HCV RNA replication.
METHODS: The J6/JFH/Huh-7.5 model of HCV infection was used in this study. Real-time quantitative polymerase chain reaction, Western blotting, electrophoretic mobility shift assay, and confocal microscopy were used for experimental analysis.
RESULTS: We found that acute alcohol exposure (25 mM) significantly increased intracellular HCV RNA as well as miR-122 levels in Huh-7.5 and Huh-7.5/CYP2E1 expressing cells in the presence and absence of J6/JFH-HCV infection. Expression of the miR-122 target, Cyclin G1, was inhibited by alcohol both in J6/JFH-infected and uninfected Huh-7.5 cells. The use of a miR-122 inhibitor increased Cyclin G1 expression and prevented the alcohol-induced increase in HCV RNA and protein levels, suggesting a mechanistic role for alcohol-induced miR122 in HCV replication. We discovered that siRNA-mediated silencing of Cyclin G1 significantly increased intracellular HCV RNA levels compared with controls, suggesting a mechanistic role for Cyclin G1 in HCV replication. Alcohol-induced increase in miR-122 was associated with increased nuclear translocation and DNA binding of the nuclear regulatory factor-κB and could be prevented by NF-κB inhibition.
CONCLUSIONS: Our novel data indicate a miR-122-mediated mechanism for alcohol increasing HCV RNA replication. We show for the first time that Cyclin G1, a miR-122 target gene, has regulatory effects on HCV replication and that alcohol increases HCV replication by regulating miR-122 and Cyclin G1.

Jamshidi M, Schmidt MK, Dörk T, et al.
Germline variation in TP53 regulatory network genes associates with breast cancer survival and treatment outcome.
Int J Cancer. 2013; 132(9):2044-55 [PubMed] Free Access to Full Article Related Publications
Germline variation in the TP53 network genes PRKAG2, PPP2R2B, CCNG1, PIAS1 and YWHAQ was previously suggested to have an impact on drug response in vitro. Here, we investigated the effect on breast cancer survival of germline variation in these genes in 925 Finnish breast cancer patients and further analyzed five single nucleotide polymorphisms (SNPs) in PRKAG2 (rs1029946, rs4726050, rs6464153, rs7789699) and PPP2R2B (rs10477313) for 10-year survival in breast cancer patients, interaction with TP53 R72P and MDM2-SNP309, outcome after specific adjuvant therapy and correlation to tumor characteristics in 4,701 invasive cases from four data sets. We found evidence for carriers of PRKAG2-rs1029946 and PRKAG2-rs4726050 having improved survival in the pooled data (HR 0.53, 95% CI 0.3-0.9; p = 0.023 for homozygous carriers of the rare G-allele and HR 0.85, 95% CI 0.7-0.9; p = 0.049 for carriers of the rare G allele, respectively). PRKAG2-rs4726050 showed a significant interaction with MDM2-SNP309, with PRKAG2-rs4726050 rare G-allele having a dose-dependent effect for better breast cancer survival confined only to MDM2 SNP309 rare G-allele carriers (HR 0.45, 95% CI 0.2-0.7; p = 0.001). This interaction also emerged as an independent predictor of better survival (p = 0.047). PPP2R2B-rs10477313 rare A-allele was found to predict better survival (HR 0.82, 95% CI 0.6-0.9; p = 0.018), especially after hormonal therapy (HR 0.66, 95% CI 0.5-0.9; p = 0.048). These findings warrant further studies and suggest that genetic markers in TP53 network genes such as PRKAG2 and PPP2R2B might affect prognosis and treatment outcome in breast cancer patients.

Kang D, Cho HS, Toyokawa G, et al.
The histone methyltransferase Wolf-Hirschhorn syndrome candidate 1-like 1 (WHSC1L1) is involved in human carcinogenesis.
Genes Chromosomes Cancer. 2013; 52(2):126-39 [PubMed] Related Publications
Histone lysine methylation plays a fundamental role in chromatin organization. Although a set of histone methyltransferases have been identified and biochemically characterized, the pathological roles of their dysfunction in human cancers are still not well understood. In this study, we demonstrate important roles of WHSC1L1 in human carcinogenesis. Expression levels of WHSC1L1 transcript were significantly elevated in various human cancers including bladder carcinoma. Immunohistochemical analysis of bladder, lung, and liver cancers confirmed overexpression of WHSC1L1. WHSC1L1-specific small interfering RNAs significantly knocked down its expression and resulted in suppression of proliferation of bladder and lung cancer cell lines. WHSC1L1 knockdown induced cell cycle arrest at the G(2)/M phase followed by multinucleation of cancer cells. Expression profile analysis using Affymetrix GeneChip(®) showed that WHSC1L1 affected the expression of a number of genes including CCNG1 and NEK7, which are known to play crucial roles in the cell cycle progression at mitosis. As WHSC1L1 expression is significantly low in various normal tissues including vital organs, WHSC1L1 could be a good candidate molecule for development of novel treatment for various types of cancer.

Cui X, Yu L, Wang Y, et al.
The relationship between Cyclin G1 and survival in patients treated surgically for HCC.
Hepatogastroenterology. 2013 Jan-Feb; 60(121):153-9 [PubMed] Related Publications
BACKGROUND/AIM: Cyclin G1 is a cell-cycle-regulatory protein that is frequently seen in elevated amounts in malignant tissue, including astrocytomas; melanoma; carcinoma of the esophagus, lung, and breast; as well as cancer of the cervix, uterus, and ovary. By contrast, it has demonstrated inhibitory activity in human hepatocellular carcinoma (HCC).
METHODOLOGY: We investigated the role of cyclin G1 in HCC tissue obtained from 76 donors using immunohistochemistry and Western blot analysis to explore its relationship with HCC pathology and univariate and multivariate analyses to explore its relationship with surgical prognosis and patient survival.
RESULTS: We found that cyclin G1 levels were increased in normal tissue compared with HCC tissue and vary over the course of the cell cycle, with equal distribution between the nucleus and cytoplasm observed during normal serum support and accelerated release from the nucleus into the cytoplasm observed during serum starvation.
CONCLUSION: Our findings suggest a role for cyclin G1 in anti-HCC gene therapy.

Selcuklu SD, Donoghue MT, Rehmet K, et al.
MicroRNA-9 inhibition of cell proliferation and identification of novel miR-9 targets by transcriptome profiling in breast cancer cells.
J Biol Chem. 2012; 287(35):29516-28 [PubMed] Free Access to Full Article Related Publications
Although underexpression of miR-9 in cancer cells is reported in many cancer types, it is currently difficult to classify miR-9 as a tumor suppressor or an oncomir. We demonstrate that miR-9 expression is down-regulated in MCF-7 and MDA-MB-231 breast cancer cells compared with MCF-10-2A normal breast cell line. Increasing miR-9 expression levels in breast cancer cells induced anti-proliferative, anti-invasive, and pro-apoptotic activity. In addition, microarray profiling of the transcriptome of MCF-7 cells overexpressing miR-9 identified six novel direct miR-9 targets (AP3B1, CCNG1, LARP1, MTHFD1L, MTHFD2, and SRPK1). Among these, MTHFD2 was identified as a miR-9 target gene that affects cell proliferation. Knockdown of MTHFD2 mimicked the effect observed when miR-9 was overexpressed by decreasing cell viability and increasing apoptotic activity. Despite variable effects on different cell lines, proliferative and anti-apoptotic activity of MTHFD2 was demonstrated whereby it could escape from miR-9-directed suppression (by overexpression of MTHFD2 with mutated miR-9 binding sites). Furthermore, endogenous expression levels of miR-9 and MTHFD2 displayed inverse expression profiles in primary breast tumor samples compared with normal breast samples; miR-9 was down-regulated, and MTHFD2 was up-regulated. These results indicate anti-proliferative and pro-apoptotic activity of miR-9 and that direct targeting of MTHFD2 can contribute to tumor suppressor-like activity of miR-9 in breast cancer cells.

Wang S, Qiu L, Yan X, et al.
Loss of microRNA 122 expression in patients with hepatitis B enhances hepatitis B virus replication through cyclin G(1) -modulated P53 activity.
Hepatology. 2012; 55(3):730-41 [PubMed] Related Publications
UNLABELLED: Hepatitis B virus (HBV) causes chronic infection in about 350 million people worldwide. Given the important role of the most abundant liver-specific microRNA, miR-122, in hepatic function and liver pathology, here we investigated the potential role and mechanism of miR-122 in regulating HBV replication. We found that miR-122 expression in liver was significantly down-regulated in patients with HBV infection compared with healthy controls, and the miR-122 levels were negatively correlated with intrahepatic viral load and hepatic necroinflammation. The depletion of endogenous miR-122 by its antisense inhibitor led to enhanced HBV replication, whereas overexpression of miR-122 by transfection of mimic or its expression vector inhibited viral production. We next identified cyclin G(1) as an miR-122 target from multiple candidate target genes that are involved in the regulation of HBV replication. Overexpression and knockdown studies both showed that cyclin G(1) regulated viral replication in HBV transfected cells. We also observed that cyclin G(1) expression was up-regulated in HBV-infected patients, and cyclin G(1) levels were inversely associated with miR-122 expression in liver tissues. Using coimmunoprecipitation, a luciferase reporter system, and electrophoretic mobility shift assay, we further demonstrated that cyclin G(1) specifically interacted with p53, and this interaction blocked the specific binding of p53 to HBV enhancer elements and simultaneously abrogated p53-mediated inhibition of HBV transcription. Finally, we show that miR-122 suppressed HBV replication in p53 wildtype cells but not in null isogenic cells.
CONCLUSION: miR-122 down-regulates its target cyclin G(1) , and thus interrupts the interaction between cyclin G(1) and p53 and abrogates p53-mediated inhibition of HBV replication. Our work shows that miR-122 down-regulation induced by HBV infection can impact HBV replication and possibly contribute to viral persistence and carcinogenesis.

Xu Y, Xia F, Ma L, et al.
MicroRNA-122 sensitizes HCC cancer cells to adriamycin and vincristine through modulating expression of MDR and inducing cell cycle arrest.
Cancer Lett. 2011; 310(2):160-9 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a hypervascular cancer characterized by rapid progression as well as resistance to conventional chemotherapy. It has been shown that microRNAs play critical roles in pathogenesis of HCC. MicroRNA-122 (miR-122) is a liver-specific microRNA and is frequently downregulated in HCC. In the present study, we investigated whether restoration of miR-122 in HCC cells could render cells sensitive to chemotherapeutic agents adriamycin (ADM) or vincristine (VCR). Our data showed that overexpression of miR-122 in HCC cells induced by adenovirus expressing miR-122 could render cell sensitive to ADM or VCR. Analysis of cell cycle distribution showed that the anti-proliferative effect of miR-122 is associated with increase of cell number in the G2/M phase. Moreover, treatment with Ad-miR122 and ADM or VCR resulted in high accumulation of HCC cells in G2/M phase. We further demonstrated that overexpression of miR-122 could modulate the sensitivity of the HCC cells to chemotherapeutic drugs through downregulating MDR related genes MDR-1, GST-π, and MRP, antiapoptotic gene Bcl-w and cell cycle related gene cyclin B1. Taken together, our findings demonstrated that combination of Ad-miR122 with chemotherapeutic agents inhibited HCC cell growth by inducing G2/M arrest and that this arrest is associated, at least in part, with reduced expression of MDR related genes and Cyclin B1.

Tao Y, Ruan J, Yeh SH, et al.
Rapid growth of a hepatocellular carcinoma and the driving mutations revealed by cell-population genetic analysis of whole-genome data.
Proc Natl Acad Sci U S A. 2011; 108(29):12042-7 [PubMed] Free Access to Full Article Related Publications
We present the analysis of the evolution of tumors in a case of hepatocellular carcinoma. This case is particularly informative about cancer growth dynamics and the underlying driving mutations. We sampled nine different sections from three tumors and seven more sections from the adjacent nontumor tissues. Selected sections were subjected to exon as well as whole-genome sequencing. Putative somatic mutations were then individually validated across all 9 tumor and 7 nontumor sections. Among the mutations validated, 24 were amino acid changes; in addition, 22 large indels/copy number variants (>1 Mb) were detected. These somatic mutations define four evolutionary lineages among tumor cells. Separate evolution and expansion of these lineages were recent and rapid, each apparently having only one lineage-specific protein-coding mutation. Hence, by using a cell-population genetic definition, this approach identified three coding changes (CCNG1, P62, and an indel/fusion gene) as tumor driver mutations. These three mutations, affecting cell cycle control and apoptosis, are functionally distinct from mutations that accumulated earlier, many of which are involved in inflammation/immunity or cell anchoring. These distinct functions of mutations at different stages may reflect the genetic interactions underlying tumor growth.

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.

Filiano AN, Fathallah-Shaykh HM, Fiveash J, et al.
Gene expression analysis in radiotherapy patients and C57BL/6 mice as a measure of exposure to ionizing radiation.
Radiat Res. 2011; 176(1):49-61 [PubMed] Related Publications
Dose assessment after radiological disasters is imperative to decrease mortality through rationally directed medical intervention. Our goal was to identify biomarkers capable of qualitative (nonirradiated/irradiated) and/or quantitative (dose) assessment of radiation exposure. Using real-time quantitative PCR, biodosimetry genes were identified in blood samples from cancer patients undergoing total-body irradiation. Time- (5, 12, 23, 48 h) and dose- (0-8 Gy) dependent changes in gene expression were examined in C57BL/6 mice. A training set was used to derive weighted voting classification algorithms (nonirradiated/irradiated) and continuous regression (dose assessment) models that were tested in a separate validation set of mice. Of eight biodosimetry genes identified in cancer patients ( ACTA2 , BBC3 , CCNG1 , CDKN1A , GADD45A , MDK , SERPINE1 , Tnfrsf10b ), expression of BBC3 , CCNG1 , CDKN1A , SERPINE1 and Tnfrsf10b was significantly (P < 0.05) increased in irradiated mice. CCNG1 and CDKN1A expression segregated irradiated mice from controls with an accuracy, specificity and sensitivity of 96.3, 100.0 and 94.4%, respectively, at 48 h. Multiple linear regression analysis predicted doses for the 0-, 1-, 2-, 4-, 6- and 8-Gy treatment groups as 0.0 ± 0.2, 1.6 ± 1.0, 2.9 ± 1.4, 5.1 ± 2.0, 5.3 ± 0.7 and 10.5 ± 5.6 Gy, respectively. These results suggest that gene expression analysis could be incorporated into biodosimetry protocols for qualitative and quantitative assessment of radiation exposure.

Jiang J, Wojnowski R, Jedinak A, Sliva D
Suppression of proliferation and invasive behavior of human metastatic breast cancer cells by dietary supplement BreastDefend.
Integr Cancer Ther. 2011; 10(2):192-200 [PubMed] Related Publications
AIM: The study was to evaluate the effect of the dietary supplement BreastDefend (BD) on the proliferation and invasive behavior of highly metastatic human breast cancer cells in vitro.
METHODS: Cell proliferation and cytotoxicity of BD was evaluated in MDA-MB-231 cells treated with BD (0-40 μg/mL) by MTT assay and trypan blue staining, respectively. Expression of cell cycle regulatory genes were determined by DNA-microarray analysis. Effect of BD on invasiveness was assessed by cellular adhesion, migration, and invasion assays.
RESULTS: BD treatment of cells MDA-MB-231 resulted in the cytostatic inhibition of cell proliferation with IC(50) 22.2, 19.1, and 17.5 μg/mL for 24, 48, and 72 hours, respectively. The inhibition of proliferation was mediated by the upregulation expression of CCNG1, CHEK1, CDKN1C, GADD45A, and E2F2, whereas BD downregulated expression of CCNA1 and CDK6 genes. The induction of expression of GADD45A and inhibition of expression of cyclin A1 (gene CCNA1) by BD was also confirmed on the protein level. BD treatment suppressed the invasive behavior of MDA-MB-231 cells by the inhibition of cellular adhesion, migration, and invasion. This inhibition of invasiveness was mediated by the suppression of secretion of urokinase plasminogen activator (uPA), and by the downregulation of expression of CXCR4 in breast cancer cells treated with BD.
CONCLUSION: BD inhibits proliferation and invasive behavior of the highly metastatic human breast cancer cells in vitro. BD may have a therapeutic potential for prevention or treatment of highly metastatic breast cancers.

Hall FL, Levy JP, Reed RA, et al.
Pathotropic targeting advances clinical oncology: tumor-targeted localization of therapeutic gene delivery.
Oncol Rep. 2010; 24(4):829-33 [PubMed] Related Publications
The advent of pathotropic (disease-seeking) targeting has transported genetic medicine across the threshold of history with the progressive clinical validation of Rexin-G, a tumor-targeted nanosized anti-cancer agent. Achieving noteworthy single-agent efficacy and survival benefits in otherwise intractable cancers, the molecular biotechnology platform has stimulated intense interest in the underlying mechanisms-of-action. This report exhibits the effective localization of Rexin-G nanoparticles within a metastatic liver lesion, as observed upon its surgical excision.

Gordon EM, Hall FL
Rexin-G, a targeted genetic medicine for cancer.
Expert Opin Biol Ther. 2010; 10(5):819-32 [PubMed] Related Publications
IMPORTANCE OF THE FIELD: Rexin-G, a tumor-targeted retrovector bearing a cytocidal cyclin G1 construct, is the first targeted gene therapy vector to gain fast track designation and orphan drug priorities for multiple cancer indications in the US.
AREAS COVERED IN THIS REVIEW: This review describes the major milestones in the clinical development of Rexin-G: from the molecular cloning and characterization of the human cyclin G1 proto-oncogene in 1994, to the design of the first knockout constructs and genetic engineering of the targeted delivery system from 1995 to 1997, through the initial proofs-of-concept, molecular pharmacology and toxicology studies of Rexin-G in preclinical cancer models from 1997 to 2001, to the pioneering clinical studies in humans from 2002 to 2004, which--together with the advancements in bioprocess development of high-potency clinical grade vectors circa 2005 - 2006--led to the accelerated approval of Rexin-G for all solid tumors by the Philippine FDA in 2007 and the rapid progression of clinical studies from 2007 to 2009 to the cusp of pivotal Phase III trials in the US.
WHAT THE READER WILL GAIN: In recording the development of Rexin-G as a novel form of targeted biological therapy, this review also highlights important aspects of vector design engineering which served to overcome the physiological barriers to gene delivery as it addresses the key regulatory issues involved in the development of a targeted gene therapy product.
TAKE HOME MESSAGE: Progressive clinical development of Rexin-G demonstrates the potential safety and efficacy of targeted genetic medicine, while validating the design engineering of the molecular biotechnology platform.

Ma L, Liu J, Shen J, et al.
Expression of miR-122 mediated by adenoviral vector induces apoptosis and cell cycle arrest of cancer cells.
Cancer Biol Ther. 2010; 9(7):554-61 [PubMed] Related Publications
BACKGROUND: microRNA-122 (miR-122) plays an important role in both of hepatic physiology and pathology. Downregulation of miR-122 was reported in human primary hepatocellular carcinoma (HCC) and restoration of miR-122 could suppress the growth of cancer cells. In this study, we presented a novel strategy for cancer therapy based on gene transfer of miR-122 by adenoviral vector.
METHODS: We generated a recombinant adenoviral vector expressing miR-122 (Ad-miR122). The miR-122 expression was measured by quantitative Real-Time PCR (qRT-PCR). Cell survival rate was determined by MTT assay.
RESULTS: Our data showed that Ad-miR122 could express functional miR-122 in tumor cells at a high level. Infection of tumor cells with Ad-miR122 resulted in inhibition of growth of cancer cells originating from liver (HepG2, Hep3B, Huh7 and PLC/PRF/5), lung (NCI-H460) and uterine cervix (HeLa). This antitumor activity was related to the induction of apoptosis and/or cell cycle arrest in cancer cells. Infection with Ad-miR122 resulted in decreased expression of Bcl-W and CCNG1 in cancer cells.
CONCLUSION: The antitumor activity of Ad-miR122 was probably due to the induction of apoptosis and/or cell cycle arrest in cancer cells through inhibiting Bcl-W and/or CCNG1 expression. We concluded that expression of therapeutic microRNA, such as miR-122, via adenoviral vector is a promising strategy for cancer treatment.

Zheng H, Hu W, Deavers MT, et al.
Nuclear cyclin B1 is overexpressed in low-malignant-potential ovarian tumors but not in epithelial ovarian cancer.
Am J Obstet Gynecol. 2009; 201(4):367.e1-6 [PubMed] Related Publications
OBJECTIVE: To investigate the role of cyclin G1 and cyclin B1 in ovarian tumorigenesis.
STUDY DESIGN: We examined cyclin B1 and G1 expression in 58 epithelial ovarian cancer, 18 low-malignant-potential ovarian tumors, and 6 normal ovarian epithelium samples using immunohistochemistry. We also examined cyclin G1 and p53 expression in 7 epithelial ovarian cancer cell lines using Western blot analysis.
RESULTS: Nuclear cyclin B1 expression was significantly higher in low-malignant-potential tumors than in normal ovarian epithelium. There was no difference in nuclear or cytoplasmic cyclin B1 or cyclin G1 expression between epithelial ovarian cancer and normal ovarian epithelium. Cyclin G1 and B1 expression was not associated with p53 expression or clinicopathologic features in patients with epithelial ovarian cancer or low-malignant-potential tumors.
CONCLUSION: Our data demonstrated that nuclear cyclin B1 is overexpressed in low-malignant-potential tumors, which may contribute to the development of low-malignant-potential tumors. Cyclin B1 and G1 may not be suitable targets for epithelial ovarian cancer treatment.

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