CCND3

Gene Summary

Gene:CCND3; cyclin D3
Location:6p21.1
Summary:The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a regulatory subunit of CDK4 or CDK6, whose activtiy is required for cell cycle G1/S transition. This protein has been shown to interact with and be involved in the phosphorylation of tumor suppressor protein Rb. The CDK4 activity associated with this cyclin was reported to be necessary for cell cycle progression through G2 phase into mitosis after UV radiation. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:G1/S-specific cyclin-D3
Source:NCBIAccessed: 16 March, 2017

Ontology:

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

Research Indicators

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

Literature Analysis

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

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

Specific Cancers (7)

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: CCND3 (cancer-related)

Hua Y, Ma X, Liu X, et al.
Identification of the potential biomarkers for the metastasis of rectal adenocarcinoma.
APMIS. 2017; 125(2):93-100 [PubMed] Related Publications
Rectal cancer is a common malignant tumor of the digestive tract, with a high incidence and high mortality. This study aimed to identify the potential biomarkers and therapeutic targets for rectal adenocarcinoma (RAC) metastasis. The expression profiling of RAC patients with metastasis and RAC patients without metastasis was downloaded from The Cancer Genome Atlas (TCGA) database. The datasets were used to identify the genes associated with RAC metastasis. Fifty up-regulated genes and seventeen down-regulated genes were identified in the primary tumor loci of RAC metastasis compared with non-metastasis. Sixty-seven dysregulated gens were conducted to construct the protein-protein network, and CCND3 was the hub protein. The dysregulated genes were significantly enriched in pancreatic secretion, cell adhesion molecules pathways, response to vitamin D of biological process, and retinoid binding of molecular function. Quantitative real-time polymerase chain reaction results demonstrated that CCND3, AQP3, PEG10, and RAB27B had the up-regulated tendency in RAC metastasis; ADCY1 had the down-regulated tendency in RAC metastasis. CCND3, AQP3, PEG10, RAB27B, and ADCY1 might play essential roles in the metastasis process of RAC through pancreatic secretion and cell adhesion molecules pathways. The five genes could be potential diagnosis biomarkers or therapeutic targets for RAC metastasis.

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

Curigliano G, Gómez Pardo P, Meric-Bernstam F, et al.
Ribociclib plus letrozole in early breast cancer: A presurgical, window-of-opportunity study.
Breast. 2016; 28:191-8 [PubMed] Related Publications
OBJECTIVES: Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). This study assessed the biological activity of ribociclib (LEE011; CDK4/6 inhibitor) plus letrozole compared with single-agent letrozole in the presurgical setting.
MATERIALS AND METHODS: Postmenopausal women (N = 14) with resectable, HR+, human epidermal growth factor receptor 2-negative (HER2-) early BC were randomized 1:1:1 to receive 2.5 mg/day letrozole alone (Arm 1), or with 400 or 600 mg/day ribociclib (Arm 2 or 3). Circulating tumor DNA and tumor biopsies were collected at baseline and, following 14 days of treatment, prior to or during surgery. The primary objective was to assess antiproliferative response per Ki67 levels in Arms 2 and 3 compared with Arm 1. Additional assessments included safety, pharmacokinetics, and genetic profiling.
RESULTS: Mean decreases in the Ki67-positive cell fraction from baseline were: Arm 1 69% (range 38-100%; n = 2), Arm 2 96% (range 78-100%; n = 6), Arm 3 92% (range 75-100%; n = 3). Decreased phosphorylated Rb levels and CDK4, CDK6, CCND2, CCND3, and CCNE1 gene expression were observed following ribociclib treatment. Ribociclib and letrozole pharmacokinetic parameters were consistent with single-agent data. The ribociclib plus letrozole combination was well tolerated, with no Grade 3/4 adverse events over the treatment.
CONCLUSION: The results suggest absence of a drug-drug interaction between ribociclib and letrozole and indicate ribociclib plus letrozole may reduce Ki67 expression in HR+, HER2- BC (NCT01919229).

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.

Čokić VP, Mitrović-Ajtić O, Beleslin-Čokić BB, et al.
Proinflammatory Cytokine IL-6 and JAK-STAT Signaling Pathway in Myeloproliferative Neoplasms.
Mediators Inflamm. 2015; 2015:453020 [PubMed] Free Access to Full Article Related Publications
The recent JAK1/2 inhibitor trial in myeloproliferative neoplasms (MPNs) showed that reducing inflammation can be more beneficial than targeting gene mutants. We evaluated the proinflammatory IL-6 cytokine and JAK-STAT signaling pathway related genes in circulating CD34(+) cells of MPNs. Regarding laboratory data, leukocytosis has been observed in polycythemia vera (PV) and JAK2V617F mutation positive versus negative primary myelofibrosis (PMF) patients. Moreover, thrombocytosis was reduced by JAK2V617F allele burden in essential thrombocythemia (ET) and PMF. 261 significantly changed genes have been detected in PV, 82 in ET, and 94 genes in PMF. The following JAK-STAT signaling pathway related genes had augmented expression in CD34(+) cells of MPNs: CCND3 and IL23A regardless of JAK2V617F allele burden; CSF3R, IL6ST, and STAT1/2 in ET and PV with JAK2V617F mutation; and AKT2, IFNGR2, PIM1, PTPN11, and STAT3 only in PV. STAT5A gene expression was generally reduced in MPNs. IL-6 cytokine levels were increased in plasma, as well as IL-6 protein levels in bone marrow stroma of MPNs, dependent on JAK2V617F mutation presence in ET and PMF patients. Therefore, the JAK2V617F mutant allele burden participated in inflammation biomarkers induction and related signaling pathways activation in MPNs.

Choi YC, Yoon S, Byun Y, et al.
MicroRNA library screening identifies growth-suppressive microRNAs that regulate genes involved in cell cycle progression and apoptosis.
Exp Cell Res. 2015; 339(2):320-32 [PubMed] Related Publications
Micro(mi)RNAs play important and varied roles in tumorigenesis; however, the full repertoire of miRNAs that affect cancer cell growth is not known. In this study, an miRNA library was screened to identify those that affect the growth of A549 tumor cells. Among 300 miRNAs, miR-28-5p, -323-5p, -510-5p, -552-3p, and -608 were the most effective in inhibiting cell growth. More specifically, overexpressing miR-28-5p, -323-5p, and -510-5p induced G1 arrest, as determined by flow cytometry, whereas that of miR-608 induced cell death in a caspase-dependent manner. Moreover, several genes involved in apoptosis and cell cycle progression were downregulated upon overexpression of each of the five miRNAs, with the functional targets of miR-552-3p and miR-608 confirmed by microarray, quantitative real-time PCR, and luciferase reporter assay. In miR-608-transfected cells, B cell lymphoma 2-like 1 (BCL2L1), D-type cyclin 1 (CCND1), CCND3, cytochrome b5 reductase 3 (CYB5R3), phosphoinositide 3-kinase regulatory subunit 2 (PIK3R2), specificity protein 1 (SP1), and phosphorylated Akt were all downregulated, while Bcl-2-interacting killer (BIK) was upregulated. Moreover, miR-608 was determined to have a suppressive function on tumor growth in an NCI-H460 xenograft model. These findings provide insights into the roles of five miRNAs in growth inhibition and their potential function as cancer therapeutics.

Misiewicz-Krzeminska I, Sarasquete ME, Vicente-Dueñas C, et al.
Post-transcriptional Modifications Contribute to the Upregulation of Cyclin D2 in Multiple Myeloma.
Clin Cancer Res. 2016; 22(1):207-17 [PubMed] Related Publications
PURPOSE: Dysregulation of one of the three D-cyclin genes has been observed in virtually all multiple myeloma tumors. The mechanisms by which CCND2 is upregulated in a set of multiple myeloma are not completely deciphered. We investigated the role of post-transcriptional regulation through the interaction between miRNAs and their binding sites at 3'UTR in CCND2 overexpression in multiple myeloma.
EXPERIMENTAL DESIGN: Eleven myeloma cell lines and 45 primary myeloma samples were included in the study. Interactions between miRNAs deregulated in multiple myeloma and mRNA targets were analyzed by 3'UTR-luciferase plasmid assay. The presence of CCND2 mRNA isoforms different in length was explored using qRT-PCR, Northern blot, mRNA FISH, and 3' rapid amplification of cDNA ends (RACE)-PCR.
RESULTS: We detected the presence of short CCND2 mRNA, both in the multiple myeloma cell lines and primary cells. The results obtained by 3'RACE experiments revealed that changes in CCND2 3'UTR length are explained by alternative polyadenylation. The luciferase assays using plasmids harboring the truncated CCND2 mRNA strongly confirmed the loss of miRNA sites in the shorter CCND2 mRNA isoform. Those multiple myelomas with greater abundance of the shorter 3'UTR isoform were associated with significant higher level of total CCND2 mRNA expression. Furthermore, functional analysis showed significant CCND2 mRNA shortening after CCND1 silencing and an increased relative expression of longer isoform after CCND1 and CCND3 overexpression, suggesting that cyclin D1 and D3 could regulate CCND2 levels through modifications in polyadenylation-cleavage reaction.
CONCLUSIONS: Overall, these results highlight the impact of CCND2 3'UTR shortening on miRNA-dependent regulation of CCND2 in multiple myeloma.

Han LP, Fu T, Lin Y, et al.
MicroRNA-138 negatively regulates non-small cell lung cancer cells through the interaction with cyclin D3.
Tumour Biol. 2016; 37(1):291-8 [PubMed] Related Publications
Previous studies demonstrate that microRNA-138 (miR-138) is critical in non-small cell lung cancer (NSCLC) regulation. We further explored the molecular mechanism of miR-138 in NSCLC. Lentivirus was used to upregulate miR-138 in NSCLC cell lines H460 and SPC-A1 cells. Previously known effects of miR-138 upregulation on NSCLC, proliferation, cell cycle division, and cisplatin sensitivity were examined in H460 and SPC-A1 cells. Moreover, previously unknown effect of miR-138 upregulation on NSCLC migration was also examined in H460 and SPC-A1 cells. A new miR-138 downstream target, cyclin D3 (CCND3), was assessed by dual-luciferase reporter assay and quantitative real-time PCR (qRT-PCR). CCND3 was then ectopically overexpressed in H460 and SPC-A1 cells. The effects of forced overexpression of CCND3 on miR-138-induced NSCLC regulations were further examined by proliferation, cell cycle, cisplatin sensitivity, and migration assays, respectively. Lentivirus-induced miR-138 upregulation inhibited NSCLC proliferation and cell cycle division, in line with previous findings. Moreover, we found that miR-138 upregulation had other anti-tumor effects, such as increasing cisplatin sensitivity and reducing cancer migration, in H460 and SPC-A1 cells. Luciferase assay and qRT-PCR showed that CCND3 was directly targeted by miR-138. Forced overexpression of CCND3 in H460 and SPC-A1 cells reversed the anti-tumor effects of miR-138 upregulation on cancer cell growth, cell cycle, cisplatin sensitivity, and migration. Our study revealed novel anti-cancer effects of miR-138 upregulation in NSCLC, as well as its new molecular target of CCND3.

Wagener R, Aukema SM, Schlesner M, et al.
The PCBP1 gene encoding poly(rC) binding protein I is recurrently mutated in Burkitt lymphoma.
Genes Chromosomes Cancer. 2015; 54(9):555-64 [PubMed] Related Publications
The genetic hallmark of Burkitt lymphoma is the translocation t(8;14)(q24;q32), or one of its light chain variants, resulting in IG-MYC juxtaposition. However, these translocations alone are insufficient to drive lymphomagenesis, which requires additional genetic changes for malignant transformation. Recent studies of Burkitt lymphoma using next generation sequencing approaches have identified various recurrently mutated genes including ID3, TCF3, CCND3, and TP53. Here, by using similar approaches, we show that PCBP1 is a recurrently mutated gene in Burkitt lymphoma. By whole-genome sequencing, we identified somatic mutations in PCBP1 in 3/17 (18%) Burkitt lymphomas. We confirmed the recurrence of PCBP1 mutations by Sanger sequencing in an independent validation cohort, finding mutations in 3/28 (11%) Burkitt lymphomas and in 6/16 (38%) Burkitt lymphoma cell lines. PCBP1 is an intron-less gene encoding the 356 amino acid poly(rC) binding protein 1, which contains three K-Homology (KH) domains and two nuclear localization signals. The mutations predominantly (10/12, 83%) affect the KH III domain, either by complete domain loss or amino acid changes. Thus, these changes are predicted to alter the various functions of PCBP1, including nuclear trafficking and pre-mRNA splicing. Remarkably, all six primary Burkitt lymphomas with a PCBP1 mutation expressed MUM1/IRF4, which is otherwise detected in around 20-40% of Burkitt lymphomas. We conclude that PCBP1 mutations are recurrent in Burkitt lymphomas and might contribute, in cooperation with other mutations, to its pathogenesis.

Eroğlu C, Seçme M, Bağcı G, Dodurga Y
Assessment of the anticancer mechanism of ferulic acid via cell cycle and apoptotic pathways in human prostate cancer cell lines.
Tumour Biol. 2015; 36(12):9437-46 [PubMed] Related Publications
Studies on genetic changes underlying prostate cancer and the possible signaling pathways are getting increased day by day, and new treatment methods are being searched for. The aim of the present study is to investigate the effects of ferulic acid (FA), a phenolic compound, on cell cycle, apoptosis, invasion, and colony formation in the PC-3 and LNCaP prostate cancer cells. The effect of FA on cell viability was determined via a 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) method. Total RNA was isolated with Tri Reagent. Expression of 84 genes for both cell cycle and apoptosis separately was evaluated by reverse transcriptase PCR (RT-PCR). Protein expressions were evaluated by Western blot analysis. Furthermore, apoptotic effects of FA were observed with terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) assay. Effects of FA on cell invasion and colony formation were determined using Matrigel chamber and colony assay, respectively. The half maximal inhibitory concentration (IC50) dose of FA was found to be 300 μM in PC-3 cells and 500 μM in LNCaP cells. According to RT-PCR results, it was observed that FA inhibited cell proliferation by increasing the gene expressions of ATR, ATM, CDKN1A, CDKN1B, E2F4, RB1, and TP53 and decreasing the gene expressions of CCND1, CCND2, CCND3, CDK2, CDK4, and CDK6 in PC-3 cells. On the other hand, it was seen that FA suppressed cell proliferation by increasing in the gene expressions of CASP1, CASP2, CASP8, CYCS, FAS, FASLG, and TRADD and decreasing in the gene expressions of BCL2 and XIAP in LNCaP cells. In this study, protein expression of CDK4 and BCL2 genes significantly decreased in these cells. It could induce apoptosis in PC-3 and LNCaP cells. Also, it was observed that FA suppressed the invasion in PC-3 and LNCaP cells. Moreover, it suppressed the colony formation. In conclusion, it has been observed that FA may lead to cell cycle arrest in PC-3 cells while it may cause apoptosis in LNCaP cells.

Goda AE, Erikson RL, Ahn JS, Kim BY
Induction of G1 Arrest by SB265610 Involves Cyclin D3 Down-regulation and Suppression of CDK2 (Thr160) Phosphorylation.
Anticancer Res. 2015; 35(6):3235-43 [PubMed] Related Publications
BACKGROUND/AIM: The current study investigated the mechanisms underlying the antitumor activity of SB265610, a cysteine-amino acid-cysteine (CXC) chemokines receptor 2 (CXCR2) antagonist.
MATERIALS AND METHODS: Cell-cycle progression and regulatory molecules were assessed by flow cytometry, immunoblotting, real-time PCR and immunoprecipitation. Target validation was achieved via RNA interference.
RESULTS: G1 arrest induced by SB265610 occurred at concentrations lacking CXCR2 selectivity, persisted upon interleukin 8 (IL8) challenge, and did not affect IL8 downstream target expression. Profiling of G1 regulators revealed cyclin-dependent kinase 2 (CDK2) (Thr160) hypophosphorylation, cyclin D3 gene down-regulation, and p21 post-translational induction. However, only cyclin D3 and CDK2 contributed towards G1 arrest. Furthermore, SB265610 induced a sustained phosphorylation of the p38MAPK. Pharmacological interference with p38MAPK significantly abrogated SB265610-induced G1 arrest and normalized the expression of cyclin D3, with restoration of its exclusive binding to CDK6, but with weak recovery of CDK2 (Thr160) hypo-phosphorylation.
CONCLUSION: The present study described the mechanisms for the anti-proliferative activity of SB265610 which may be of value in IL8-rich tumor microenvironments.

Ross JS, Badve S, Wang K, et al.
Genomic profiling of advanced-stage, metaplastic breast carcinoma by next-generation sequencing reveals frequent, targetable genomic abnormalities and potential new treatment options.
Arch Pathol Lab Med. 2015; 139(5):642-9 [PubMed] Related Publications
CONTEXT: Metastatic metaplastic breast carcinoma (MPBC) is an uncommon, but aggressive, tumor resistant to conventional chemotherapy.
OBJECTIVE: To learn whether next-generation sequencing could identify potential targets of therapy for patients with relapsed and metastatic MPBC.
DESIGN: Hybridization capture of 3769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to a minimum of 50 ng of DNA extracted from 20 MPBC formalin-fixed, paraffin-embedded specimens and sequenced to high uniform coverage.
RESULTS: The 20 patients with MPBC had a median age of 62 years (range, 42-86 years). There were 9 squamous (45%), 9 chondroid (45%), and 2 spindle cell (10%) MPBCs, all of which were high grade. Ninety-three genomic alterations were identified, (range, 1-11) with 19 of the 20 cases (95%) harboring an alteration that could potentially lead to a targeted treatment option. The most-common alterations were in TP53 (n = 69; 75%), PIK3CA (n = 37; 40%), MYC (n = 28; 30%), MLL2 (n = 28; 30%), PTEN (n = 23; 25%), CDKN2A/B (n = 19; 20%), CCND3 (n = 14; 15%), CCNE1 (n = 9; 10%), EGFR (n = 9; 10%), and KDM6A (n = 9; 10%); AKT3, CCND1, CCND2, CDK4, FBXW7, FGFR1, HRAS, NF1, PIK3R1, and SRC were each altered in a single case. All 16 MPBCs (100%) that were negative for ERBB2 (HER2) overexpression by immunohistochemistry and/or ERBB2 (HER2) amplification by fluorescence in situ hybridization were also uniformly (100%) negative for ERBB2 amplification by next-generation sequencing-based copy-number assessment.
CONCLUSIONS: Our results indicate that genomic profiling using next-generation sequencing can identify clinically meaningful alterations that have the potential to guide targeted treatment decisions in most patients with metastatic MPBC.

Bovy N, Blomme B, Frères P, et al.
Endothelial exosomes contribute to the antitumor response during breast cancer neoadjuvant chemotherapy via microRNA transfer.
Oncotarget. 2015; 6(12):10253-66 [PubMed] Free Access to Full Article Related Publications
The interaction between tumor cells and their microenvironment is an essential aspect of tumor development. Therefore, understanding how this microenvironment communicates with tumor cells is crucial for the development of new anti-cancer therapies. MicroRNAs (miRNAs) are small non-coding RNAs that inhibit gene expression. They are secreted into the extracellular medium in vesicles called exosomes, which allow communication between cells via the transfer of their cargo. Consequently, we hypothesized that circulating endothelial miRNAs could be transferred to tumor cells and modify their phenotype. Using exogenous miRNA, we demonstrated that endothelial cells can transfer miRNA to tumor cells via exosomes. Using miRNA profiling, we identified miR-503, which exhibited downregulated levels in exosomes released from endothelial cells cultured under tumoral conditions. The modulation of miR-503 in breast cancer cells altered their proliferative and invasive capacities. We then identified two targets of miR-503, CCND2 and CCND3. Moreover, we measured increased plasmatic miR-503 in breast cancer patients after neoadjuvant chemotherapy, which could be partly due to increased miRNA secretion by endothelial cells. Taken together, our data are the first to reveal the involvement of the endothelium in the modulation of tumor development via the secretion of circulating miR-503 in response to chemotherapy treatment.

Demosthenous C, Han JJ, Stenson MJ, et al.
Translation initiation complex eIF4F is a therapeutic target for dual mTOR kinase inhibitors in non-Hodgkin lymphoma.
Oncotarget. 2015; 6(11):9488-501 [PubMed] Free Access to Full Article Related Publications
Deregulated mRNA translation has been implicated in disease development and in part is controlled by a eukaryotic initiation complex eIF4F (composed of eIF4E, eIF4G and eIF4A). We demonstrate here that the cap bound fraction from lymphoma cells was enriched with eIF4G and eIF4E indicating that lymphoma cells exist in an activated translational state. Moreover, 77% (110/142) of diffuse large B cell lymphoma tumors expressed eIF4E and this was associated with an inferior event free survival. Over-expression of wild-type eIF4E (eIF4E(WT)) but not cap-mutant eIF4E (eIF4E(cap mutant)) increased the activation of the eIF4F complex. Treatment with the active-site dual mTOR inhibitor CC214-1 reduced the level of the eIF4F complex by decreasing the cap bound fraction of eIF4G and increasing the levels of 4E-BP1. CC214-1 inhibited both the cap dependent and global protein translation. CC214-1 inhibited c-Myc, and cyclin D3 translation by decreasing polysomal fractions from lymphoma cells. Inhibition of eIF4E with shRNA further decreased the CC214-1 induced inhibition of the eIF4F complex, c-Myc, cyclin D3 translation, and colony formation. These studies demonstrate that the eIF4F complex is deregulated in aggressive lymphoma and that dual mTOR therapy has therapeutic potential in these patients.

Zhang C, Zhang M, Wu Q, et al.
Hepsin inhibits CDK11p58 IRES activity by suppressing unr expression and eIF-2α phosphorylation in prostate cancer.
Cell Signal. 2015; 27(4):789-97 [PubMed] Related Publications
Hepsin is a type II transmembrane serine protease frequently overexpressed in prostate cancer (PCa). However, the role of hepsin in PCa remains unclear. In this study, we found that hepsin inhibited the internal ribosome entry site (IRES) activity and expression of CDK11p58, which is associated with cell cycle progression and pro-apoptotic signaling in PCa. Hepsin suppressed CDK11p58 IRES activity in PCa by modulating unr expression and eIF-2α phosphorylation. Further studies revealed that hepsin inhibited the expression of unr by directly binding to unr IRES element and suppressing its activity, and also repressed eIF-2α phosphorylation through down-regulating the expression and phosphorylation of general control non-derepressible-2 (GCN2). Taken together, our data suggest a novel role of hepsin in regulating CDK11p58 IRES activity, and imply that hepsin may act on the machinery of translation to modulate cell cycle progression and survival in PCa cells.

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

Geyer JT, Subramaniyam S, Jiang Y, et al.
Lymphoblastic transformation of follicular lymphoma: a clinicopathologic and molecular analysis of 7 patients.
Hum Pathol. 2015; 46(2):260-71 [PubMed] Related Publications
Approximately 30% of patients with follicular lymphoma (FL) transform to a more aggressive malignancy, most commonly diffuse large B cell lymphoma. Rarely, FL transformation results in clinical findings, histology, and immunophenotype reminiscent of B-lymphoblastic leukemia/lymphoma. We report the largest series to date with detailed analysis of 7 such patients. Lymphoblastic transformation occurred on average 2 years after initial diagnosis of FL. Five patients had prior intensive chemotherapy. Two patients developed mature high-grade lymphoma, followed by the lymphoblastic transformation. FL had BCL2 gene rearrangement in 4 of 5 cases. High-grade transformation was accompanied by MYC gene rearrangement (5 of 5). Transformation was characterized by expression of TdT, loss of Bcl6, variable loss of immunoglobulin light chain, and persistence of Pax-5, Bcl2, and CD10. Whole-exome sequencing in 1 case revealed presence of several actionable mutations (CD79B, CCND3, CDK12). FL, aggressive mature B cell lymphoma, and lymphoblastic transformation were clonally related in 6 evaluable cases. After transformation, survival ranged from 1 to 14 months. Four patients died of disease, 2 were in remission after stem cell transplant, and 1 was alive with disease.

Zhuang Y, Lu Y, Li D, et al.
Upregulation of AIOLOS induces apoptosis and enhances etoposide chemosensitivity in Jurkat leukemia cells.
Oncol Rep. 2015; 33(3):1319-25 [PubMed] Related Publications
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder of immature hematopoietic precursors committed to T-cell lineage. T-ALL accounts for ~15% of pediatric ALL cases and is prone to early relapse. With new and improved treatment protocols, the prognosis of T-ALL has improved particularly in children; however, the outcome of relapsed T-ALL cases remains poor. The AIOLOS gene is necessary to control lymphocyte differentiation and may be a potential target of T-ALL therapy. In the present study, Jurkat cells were divided into three groups: untransfected (UT) control, lentiviral vector control (Lenti-Mock) and AIOLOS-overexpressing (Lenti-AIOLOS) groups. Lenti-AIOLOS Jurkat cells were constructed by lentiviral transduction; cell cycle analysis, apoptosis and cytotoxicity assays were then performed to evaluate the effects of AIOLOS on cell cycle distribution, apoptosis and cell chemosensitivity to etoposide of Jurkat cells in vitro. Moreover, the expression levels of genes associated with apoptosis and cell cycle were investigated by quantitative reverse transcription-polymerase chain reaction. Results showed that the percentage of Jurkat cells in the G0/G1 phase increased from 71.5 (UT) to 85.4% (Lenti-AIOLOS; P<0.05), yet the percentage of cells in the S-phase decreased from 15.1 (UT) to 11.6% (Lenti‑AIOLOS; P<0.05). The percentage of total apoptotic cells was significantly increased in the AIOLOS-transfected Jurkat cells (21.93%) compared with this percentage in the Lenti-Mock (13.35%) or the UT group (13.30%; P<0.05). Consistent with these results, AIOLOS overexpression induced P21 and P27 upregulation and CCND3 and SKP2 downregulation. Furthermore, AIOLOS overexpression synergistically increased the cytotoxic effects of etoposide and downregulated NF-κB expression. Our findings revealed that lentivirus-mediated AIOLOS overexpression in Jurkat cells induced cell apoptosis, arrested the cell cycle at the G0/G1 phase, and synergistically increased the sensitivity of Jurkat cells to etoposide by inhibiting NF-κB activity.

Huang C, Sheng Y, Jia J, Chen L
Identification of melanoma biomarkers based on network modules by integrating the human signaling network with microarrays.
J Cancer Res Ther. 2014; 10 Suppl:C114-24 [PubMed] Related Publications
BACKGROUND: Melanoma is a leading cause of cancer death. Thus, accurate prognostic biomarkers that will assist rational treatment planning need to be identified.
METHODS: Microarray analysis of melanoma and normal tissue samples was performed to identify differentially expressed modules (DEMs) from the signaling network and ultimately detect molecular markers to support histological examination. Network motifs were extracted from the human signaling network. Then, significant expression-correlation differential modules were identified by comparing the network module expression-correlation differential scores under normal and disease conditions using the gene expression datasets. Finally, we obtained DEMs by the Wilcoxon rank test and considered the average gene expression level in these modules as the classification features for diagnosing melanoma.
RESULTS: In total, 99 functional DEMs were identified from the signaling network and gene expression profiles. The area under the curve scores for cancer module genes, melanoma module genes, and whole network modules are 92.4%, 90.44%, and 88.45%, respectively. The classification efficiency rates for nonmodule features are 71.04% and 79.38%, which correspond to the features of cancer genes and melanoma cancer genes, respectively. Finally, we acquired six significant molecular biomarkers, namely, module 10 (CALM3, Ca 2+ , PKC, PDGFRA, phospholipase-g, PIB5PA, and phosphatidylinositol-3-kinase), module 14 (SRC, Src homology 2 domain-containing [SHC], SAM68, GIT1, transcription factor-4, CBLB, GRB2, VAV2, LCK, YES, PTCH2, downstream of tyrosine kinase [DOK], and KIT), module 16 (ELK3, p85beta, SHC, ZFYVE9, TGFBR1, TGFBR2, CITED1, SH3KBP1, HCK, DOK, and KIT), module 45 (RB, CCND3, CCNA2, CDK4, and CDK6), module 75 (PCNA, CDK4, and CCND1), and module 114 (PSD93, NMDAR, and FYN).
CONCLUSION: We explored the gene expression profile and signaling network in a global view and identified DEMs that can be used as diagnostic or prognostic markers for melanoma.

Huang B, Li H, Huang L, et al.
Clinical significance of microRNA 138 and cyclin D3 in hepatocellular carcinoma.
J Surg Res. 2015; 193(2):718-23 [PubMed] Related Publications
BACKGROUND: MicroRNA 138 (miR-138) is recently shown to inhibit tumor growth and block cell cycle arrest of hepatocellular carcinoma (HCC) by targeting cyclin D3 (CCND3). The aim of this study was to investigate the clinical significance of miR-138 and CCND3 in human HCC, which remains unclear.
METHODS: Quantitative real-time polymerase chain reaction analysis was performed to detect the expression levels of miR-138 and CCND3 messenger RNA (mRNA) in 180 self-pairs of HCC and noncancerous liver tissues.
RESULTS: Compared with noncancerous liver tissues, the expression levels of miR-138 in HCC tissues were significantly downregulated (P < 0.001), whereas the expression levels of CCND3 mRNA in HCC tissues were significantly upregulated (P < 0.001). There was a negative correlation between miR-138 and CCND3 mRNA expression in HCC tissues (r = -0.56, P = 0.02). Additionally, statistical analysis showed that the combined miR 138 downregulation and CCND3 upregulation (miR-138-low-CCND3-high) was significantly associated with the advanced tumor-node-metastasis stage (P = 0.008) and the presence of portal vein invasion (P = 0.008) and lymph node metastasis (P = 0.01). More importantly, a significant trend was identified between the combined expression of miR-138-low-CCND3-high in HCC and worsening clinical prognosis. Multivariate survival analysis further recognized miR-138-low-CCND3-high expression as an independent prognostic factor for patients with HCC.
CONCLUSIONS: Our data suggest that the combined expression of miR-138 and its direct target CCND3 may be correlated with significant characteristics of HCC. MiR-138 downregulation and CCND3 upregulation maybe concurrently associated with prognosis in patients with HCC.

Yang JL
Investigation of osteosarcoma genomics and its impact on targeted therapy: an international collaboration to conquer human osteosarcoma.
Chin J Cancer. 2014; 33(12):575-80 [PubMed] Free Access to Full Article Related Publications
Osteosarcoma is a genetically unstable malignancy that most frequently occurs in children and young adults. The lack of progress in managing this devastating disease in the clinic has prompted international researchers to collaborate to profile key genomic alterations that define osteosarcoma. A team of researchers and clinicians from China, Finland, and the United States investigated human osteosarcoma by integrating transcriptome sequencing (RNA-seq), high-density genome-wide array comparative genomic hybridization (aCGH), fluorescence in situ hybridization (FISH), reverse transcription-polymerase chain reaction (RT-PCR), Sanger sequencing, cell culture, and molecular biological approaches. Systematic analysis of genetic/genomic alterations and further functional studies have led to several important findings, including novel rearrangement hotspots, osteosarcoma-specific LRP1-SNRNP25 and KCNMB4-CCND3 fusion genes, VEGF and Wnt signaling pathway alterations, deletion of the WWOX gene, and amplification of the APEX1 and RUNX2 genes. Importantly, these genetic events associate significantly with pathogenesis, prognosis, progression, and therapeutic activity in osteosarcoma, suggesting their potential impact on improved managements of human osteosarcoma. This international initiative provides opportunities for developing new treatment modalities to conquer osteosarcoma.

Wu J, Lv Q, He J, et al.
MicroRNA-188 suppresses G1/S transition by targeting multiple cyclin/CDK complexes.
Cell Commun Signal. 2014; 12:66 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Accelerated cell cycle progression is the common feature of most cancers. MiRNAs can act as oncogenes or tumor suppressors by directly modulating cell cycle machinery. It has been shown that miR-188 is upregulated in UVB-irradiated mouse skin and human nasopharyngeal carcinoma CNE cells under hypoxic stress. However, little is known about the function of miR-188 in cell proliferation and growth control.
RESULTS: Overexpression of miR-188 inhibits cell proliferation, tumor colony formation and G1/S cell cycle transition in human nasopharyngeal carcinoma CNE cells. Using bioinformatics approach, we identify a series of genes regulating G1/S transition as putative miR-188 targets. MiR-188 inhibits both mRNA and protein expression of CCND1, CCND3, CCNE1, CCNA2, CDK4 and CDK2, suppresses Rb phosphorylation and downregulates E2F transcriptional activity. The expression level of miR-188 also inversely correlates with the expression of miR-188 targets in human nasopharyngeal carcinoma (NPC) tissues. Moreover, studies in xenograft mouse model reveal that miR-188 is capable of inhibiting tumor initiation and progression by suppressing target genes expression and Rb phosphorylation.
CONCLUSIONS: This study demonstrates that miR-188 exerts anticancer effects, via downregulation of multiple G1/S related cyclin/CDKs and Rb/E2F signaling pathway.

Yang J, Annala M, Ji P, et al.
Recurrent LRP1-SNRNP25 and KCNMB4-CCND3 fusion genes promote tumor cell motility in human osteosarcoma.
J Hematol Oncol. 2014; 7:76 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The identification of fusion genes such as SYT-SSX1/SSX2, PAX3-FOXO1, TPM3/TPM4-ALK and EWS-FLI1 in human sarcomas has provided important insight into the diagnosis and targeted therapy of sarcomas. No recurrent fusion has been reported in human osteosarcoma.
METHODS: Transcriptome sequencing was used to characterize the gene fusions and mutations in 11 human osteosarcomas.
RESULTS: Nine of 11 samples were found to harbor genetic inactivating alterations in the TP53 pathway. Two recurrent fusion genes associated with the 12q locus, LRP1-SNRNP25 and KCNMB4-CCND3, were identified and validated by RT-PCR, Sanger sequencing and fluorescence in situ hybridization, and were found to be osteosarcoma specific in a validation cohort of 240 other sarcomas. Expression of LRP1-SNRNP25 fusion gene promoted SAOS-2 osteosarcoma cell migration and invasion. Expression of KCNMB4-CCND3 fusion gene promoted SAOS-2 cell migration.
CONCLUSIONS: Our study represents the first whole transcriptome analysis of untreated human osteosarcoma. Our discovery of two osteosarcoma specific fusion genes associated with osteosarcoma cellular motility highlights the heterogeneity of osteosarcoma and provides opportunities for new treatment modalities.

Mansoor A, Akhter A, Pournazari P, et al.
Protein Expression for Novel Prognostic Markers (Cyclins D1, D2, D3, B1, B2, ITGβ7, FGFR3, PAX5) Correlate With Previously Reported Gene Expression Profile Patterns in Plasma Cell Myeloma.
Appl Immunohistochem Mol Morphol. 2015 May-Jun; 23(5):327-33 [PubMed] Related Publications
Among plasma cell myeloma (PCM) patients, gene expression profiling (GEP)-based molecular classification has proven to be an independent predictor of survival, after autologous stem cell transplantation. However, GEP has limited routine clinical applicability given its complex methodology, high cost, and limited availability in clinical laboratories. In this study, we have evaluated biomarkers identified from GEP discoveries, utilizing immunohistochemistry (IHC) platform in a cohort of PCM patients. IHC staining for cyclins B1, B2, D1, D2, D3, FGFR3, PAX5, and integrin β7 (ITGβ7) was performed on the bone marrow biopsies of 93 newly diagnosed PCM patients. Expression of FGFR3 was noted in 10 (11%) samples correlating completely with t(4;14)(p16;q32) results (P<0.001); however, the association between FGFR3 and cyclin D2 expression was not significant (P=0.14). ITGβ7 expression was present in 9/93 (9%) patients and all these samples also demonstrated upregulated expression of cyclin D2 (P=0.014). Expression of cyclins D1, D2, and D3 was variable in this cohort. Positive protein expression of cyclin D1 was noted in 30/93 (32%), D2 in 17/93 (18%), and D3 in 5/93 (5%) samples. Coexpression of cyclins D1 and D2 was observed in 13/93 (14%) samples, whereas 28 (30%) samples were negative for all the 3 cyclin D proteins. Cyclin B1 was not expressed in any sample, despite adequate staining in positive controls. Cyclin B2 was expressed in 33/93 (35%) and PAX5 protein was noted in 7/93 (8%) samples. In summary, we have demonstrated that mRNA-based prognostic markers can be detected by routine IHC in decalcified bone marrow samples. This approach may provide a useful tool for the wider adoption of prognostic makers for risk stratification of PCM patients. We anticipate that such an approach might allow patients with high-risk immunoprofiles to be considered for other potential novel therapeutic agents, potentially sparing some patients the toxicity of stem cell transplant.

Atsaves V, Lekakis L, Drakos E, et al.
The oncogenic JUNB/CD30 axis contributes to cell cycle deregulation in ALK+ anaplastic large cell lymphoma.
Br J Haematol. 2014; 167(4):514-23 [PubMed] Related Publications
Anaplastic lymphoma kinase (ALK)+ anaplastic large cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35) resulting in expression of NPM1(NPM)-ALK oncogenic kinase. The latter is capable of activating ERK kinase, which upregulates JUNB expression through ETS1. JUNB, in turn, interacts with the TNFRSF8 (CD30) gene promoter and induces CD30 (TNFRSF8) overexpression. However, the role of CD30 overexpression in ALK+ ALCL oncogenesis remains unknown. Here we show that the JUNB gene is frequently amplified in ALK+ ALCL, suggesting gene amplification as an additional underlying mechanism for JUNB overexpression. Silencing of JUNB resulted in reduced cell growth and colony formation associated with decreased activator protein-1 activity and G1/S and G2/M cell cycle arrest. These effects were linked to decreased CD30 levels, downregulation of CCNA2 (Cyclin A), CCND2 (Cyclin D2) and CCND3 (Cyclin D3) and upregulation of cyclin-dependent kinase inhibitors CDKN2A (p14) and CDKN1A (p21), but not CDKN1B (p27). Similar cell cycle changes were observed following the knock-down of TNFRSF8 gene or blockade of its function using anti-CD30 antibodies, which were associated with upregulation of CDKN2A and CDKN1A, but not CDKN1B. These findings indicate that JUNB may partly operate through CD30 signalling. Silencing of JUNB also sensitized NPM1-ALCL+ cells to standard chemotherapeutic agents. Our findings uncover the oncogenic role of the JUNB/CD30 axis and its potential as therapeutic target in ALK+ ALCL.

Chi Y, Huang S, Wang L, et al.
CDK11p58 inhibits ERα-positive breast cancer invasion by targeting integrin β3 via the repression of ERα signaling.
BMC Cancer. 2014; 14:577 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: CDK11(p58), a Ser/Thr kinase that belongs to the cell division cycle 2-like 1 (CDC2L1) subfamily, is associated with cell cycle progression, tumorigenesis and apoptotic signaling. CDK11(p58) is also involved in the regulation of steroid receptors, such as androgen and estrogen receptors. We previously found that CDK11(p58) was abnormally expressed in prostate cancer. However, its role in breast cancer remains unclear.
METHODS: CDK11(p58) expression was evaluated by immunohistochemical staining in a tissue array. A Transwell assay was used to detect invasion and metastasis in breast cancer cells. The TaqMan® Metastasis Gene Expression Assay was used to search for potential downstream factors in the CDK11(p58) signaling pathway. qRT-PCR was used to evaluate mRNA levels, and the dual luciferase array was used to analyze promoter activity. Western blotting was used to detect the protein level.
RESULTS: CDK11(p58) expression was negatively correlated with node status (P = 0.012), relapse status (P = 0.002) and metastasis status (P = 0.023). Kaplan-Meier survival curves indicated that the disease-free survival (DFS) was significantly poor in breast cancer patients with low CDK11 expression. Interestingly, using the breast cancer cell lines ZR-75-30 and MDA-MB-231, we found that CDK11(p58) was capable of repressing the migration and invasion of ERα-positive breast cancer cells, but not ERα-negative breast cancer cells, in a kinase-dependent manner. Gene expression assays demonstrated that integrin β3 mRNA was dramatically repressed by CDK11(p58), and luciferase results confirmed that the integrin β3 promoter was inhibited by CDK11(p58) through ERα repression. The expression of integrin β3 was highly related to ERα signaling; ERα overexpression stimulated integrin β3 expression, whereas siRNA-mediated knockdown of ERα attenuated integrin β3 expression.
CONCLUSIONS: These data indicate that CDK11(p58) is an anti-metastatic gene in ERα-positive breast cancer and that the regulation of integrin β3 by CDK11(p58) via the repression of ERα signaling may constitute part of a signaling pathway underlying breast cancer invasion.

Zaharieva MM, Kirilov M, Chai M, et al.
Reduced expression of the retinoblastoma protein shows that the related signaling pathway is essential for mediating the antineoplastic activity of erufosine.
PLoS One. 2014; 9(7):e100950 [PubMed] Free Access to Full Article Related Publications
Erufosine is a new antineoplastic agent of the group of alkylphosphocholines, which interferes with signal transduction and induces apoptosis in various leukemic and tumor cell lines. The present study was designed to examine for the first time the mechanism of resistance to erufosine in malignant cells with permanently reduced expression of the retinoblastoma (Rb) protein. Bearing in mind the high number of malignancies with reduced level of this tumor-suppressor, this investigation was deemed important for using erufosine, alone or in combination, in patients with compromised RB1 gene expression. For this purpose, clones of the leukemic T-cell line SKW-3 were used, which had been engineered to constantly express differently low Rb levels. The alkylphosphocholine induced apoptosis, stimulated the expression of the cyclin dependent kinase inhibitor p27Kip1 and inhibited the synthesis of cyclin D3, thereby causing a G2 phase cell cycle arrest and death of cells with wild type Rb expression. In contrast, Rb-deficiency impeded the changes induced by erufosine in the expression of these proteins and abrogated the induction of G2 arrest, which was correlated with reduced antiproliferative and anticlonogenic activities of the compound. In conclusion, analysis of our results showed for the first time that the Rb signaling pathway is essential for mediating the antineoplastic activity of erufosine and its efficacy in patients with malignant diseases may be predicted by determining the Rb status.

Murali A, Nalinakumari KR, Thomas S, Kannan S
Association of single nucleotide polymorphisms in cell cycle regulatory genes with oral cancer susceptibility.
Br J Oral Maxillofac Surg. 2014; 52(7):652-8 [PubMed] Related Publications
Alterations in the regulation of the cell cycle are strongly linked to tumorigenesis, so genetic variants in genes critical to control of the cycle are good candidates to have their association with susceptibility to oral cancer assessed. In this hospital-based, case-control study of 445 patients who had been newly-diagnosed with oral cancer and 449 unaffected controls, we used a multigenic approach to examine the associations among a panel of 10 selected polymorphisms in the pathway of the cell cycle that were possibly susceptible to oral cancer. Six of 9 single nucleotide polymorphisms in the cell cycle showed significant risks for oral cancer, the highest risk being evident for p27 (rs34329; Odds ratio 3.05, 95% CI 2.12 to 4.40). A significant risk of oral cancer was also evident for individual polymorphisms of cyclin E (rs1406), cyclin H (rs3093816), cyclin D1-1 (rs647451), cyclin D2 (rs3217901) and Rb1-2 (rs3092904). The risk of oral cancer increased significantly as the number of unfavourable genotypes in the pathway increased, and so the results point to a stronger combined effect of polymorphisms in important cell cycle regulatory genes on predisposition to oral cancer.

Türkmen S, Binder A, Gerlach A, et al.
High prevalence of immunoglobulin light chain gene aberrations as revealed by FISH in multiple myeloma and MGUS.
Genes Chromosomes Cancer. 2014; 53(8):650-6 [PubMed] Related Publications
Multiple myeloma (MM) is a malignant B-cell neoplasm characterized by an uncontrolled proliferation of aberrant plasma cells in the bone marrow. Chromosome aberrations in MM are complex and represent a hallmark of the disease, involving many chromosomes that are altered both numerically and structurally. Nearly half of the cases are nonhyperdiploid and show IGH translocations with the following partner genes: CCND1, FGFR3 and MMSET, MAF, MAFB, and CCND3. The remaining 50% are grouped into a hyperdiploid group that is characterized by multiple trisomies involving chromosomes 3, 5, 7, 9, 11, 15, 19, and 21. In this study, we analyzed the immunoglobulin light chain kappa (IGK, 2p12) and lambda (IGL, 22q11) loci in 150 cases, mostly with MM but in a few cases monoclonal gammopathy of undetermined significance (MGUS), without IGH translocations. We identified aberrations in 27% (= 40 patients) including rearrangements (12%), gains (12%), and deletions (4.6%). In 6 of 18 patients with IGK or/and IGL rearrangements, we detected a MYC rearrangement which suggests that MYC is the translocation partner in the majority of these cases.

Tian E, Sawyer JR, Heuck CJ, et al.
In multiple myeloma, 14q32 translocations are nonrandom chromosomal fusions driving high expression levels of the respective partner genes.
Genes Chromosomes Cancer. 2014; 53(7):549-57 [PubMed] Free Access to Full Article Related Publications
In studies of patients with multiple myeloma (MM), gene expression profiling (GEP) of myeloma cells demonstrates substantially higher expression of MMSET, FGFR3, CCND3, CCND1, MAF, and MAFB--the partner genes of 14q32 translocations--than GEP of plasma cells from healthy individuals. Interphase fluorescent in situ hybridization (FISH) was used to discriminate between chromosomal translocations involving different regions of the immunoglobulin heavy chain (IGH) genes at 14q32. With special probes designed for the constant region (IGHC) and the variable region (IGHV), IGH translocations were shown to be definite, nonrandom chromosomal fusions of IGHC with the loci of FGFR3, CCND1, CCND3, MAF, and MAFB genes; and IGHV with the locus of MMSET gene. When correlated with GEP results, the IGH translocations were found to drive expression levels of the partner genes to significantly higher levels (spikes) than copy-number variations. Hence, 42% of IGH translocations were identified among newly diagnosed MM patients (448/1,060). As GEP has become essential for assessing cancer risk, this novel approach is highly consistent with the cytogenetic features of the chromosomal translocations to effectively stratify molecular subgroups of MM on the basis of gene expression profiles of the IGH translocation partner genes in myeloma cells. © 2014 Wiley Periodicals, Inc.

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