CCND1

Gene Summary

Gene:CCND1; cyclin D1
Aliases: BCL1, PRAD1, U21B31, D11S287E
Location:11q13.3
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 throughout 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 activity is required for cell cycle G1/S transition. This protein has been shown to interact with tumor suppressor protein Rb and the expression of this gene is regulated positively by Rb. Mutations, amplification and overexpression of this gene, which alters cell cycle progression, are observed frequently in a variety of tumors and may contribute to tumorigenesis. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:G1/S-specific cyclin-D1
Source:NCBIAccessed: 09 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 09 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 09 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.

Entity Topic PubMed Papers
Lymphoma, Mantle-Cellt(11;14)(q13;q32) in Mantle Cell Lymphoma
Mantle cell lymphoma (MCL) is characterised by a t(11;14)(q13;q32) translocation. This juxtaposes the CCND1 (bcl-1) locus to the immunoglobulin (IgH) gene sequences and leads to deregulation of cyclin D1. See Espinet B, et al, 1999 and Stamatopoulos K, et al, 1999.
View Publications433
Breast CancerCCND1 and Breast Cancer View Publications268
Lymphoma, Mantle-CellCCND1 mutations in Mantle Cell Lymphoma
In a GWAS study Bea et al (2013) reported CCND1 mutations in 35% (10/29) of MTC cases.
View Publications178
Lung CancerCCND1 and Lung Cancer View Publications70
Rectal CancerCCND1 and Rectal Cancer View Publications7
RhabdomyosarcomaCCND1 and Rhabdomyosarcoma View Publications3

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CCND1 (cancer-related)

Zamani-Ahmadmahmudi M, Aghasharif S, Ilbeigi K
Prognostic efficacy of the human B-cell lymphoma prognostic genes in predicting disease-free survival (DFS) in the canine counterpart.
BMC Vet Res. 2017; 13(1):17 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Canine B-cell lymphoma is deemed an ideal model of human non-Hodgkin's lymphoma where the lymphomas of both species share similar clinical features and biological behaviors. However there are some differences between tumor features in both species. In the current study, we sought to evaluate the prognostic efficacy of human B-cell lymphoma prognostic gene signatures in canine B-cell lymphoma.
METHODS: The corresponding probe sets of 36 human B-cell lymphoma prognostic genes were retrieved from 2 canine B-cell lymphoma microarray datasets (GSE43664 and GSE39365) (76 samples), and prognostic probe sets were thereafter detected using the univariate and multivariate Cox proportional-hazard model and the Kaplan-Meier analysis. The two datasets were employed both as training sets and as external validation sets for each other. Results were confirmed using quantitative real-time PCR (qRT-PCR) analysis.
RESULTS: In the univariate analysis, CCND1, CCND2, PAX5, CR2, LMO2, HLA-DQA1, P53, CD38, MYC-N, MYBL1, and BIRCS5 were associated with longer disease-free survival (DFS), while CD44, PLAU, and FN1 were allied to shorter DFS. However, the multivariate Cox proportional-hazard analysis confirmed CCND1 and BIRCS5 as prognostic genes for canine B-cell lymphoma. qRT-PCR used for verification of results indicated that expression level of CCND1 was significantly higher in B-cell lymphoma patients with the long DFS than ones with the short DFS, while expression level of BIRCS5 wasn't significantly different between two groups.
CONCLUSION: Our results confirmed CCND1 as important gene that can be used as a potential predictor in this tumor type.

Cho BB, Kelting SM, Gru AA, et al.
Cyclin D1 expression and polysomy in lymphocyte-predominant cells of nodular lymphocyte-predominant Hodgkin lymphoma.
Ann Diagn Pathol. 2017; 26:10-15 [PubMed] Related Publications
Cyclin D1 protein expression in lymphocytes is classically associated with mantle cell lymphoma. Although increasingly recognized in other lymphoproliferative disorders, cyclin D1 expression and CCND1 gene abnormalities have not been well studied in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Using a double stain for CD20/cyclin D1, we quantified cyclin D1 expression in 10 cases of NLPHL and correlated those findings with SOX11 expression, CCND1 gene abnormalities, and clinical data. For comparison, we examined 5 cases of T cell-/histiocyte-rich large B-cell lymphoma (THRLBCL). All cases of NLPHL stained for cyclin D1 showed at least rare positivity in lymphocyte-predominant (LP) cells. In 4 cases, at least 20% of LP cells were positive for CD20/cyclin D1. Neither SOX11 expression nor CCND1 gene rearrangement was found in any of the cases, but fluorescence in situ hybridization showed a proportion of the large cells with 3 to 4 copies of nonfused IGH and CCND1 signals or 3 intact CCND1 break-apart signals. Further study with CCND1/CEP11 showed polysomy in 6 of 9 cases with cyclin D1 expression and 5 of 16 NLPHL not examined for cyclin D1. Two of 5 cases of THRLBCL showed rare positive staining for CD20/cyclin D1; 1 case showed polysomy with CCND1/CEP11. Results show that cyclin D1 may be expressed in LP cells without SOX11 expression or CCND1 translocation. Polysomy with increased copies of CCND1 may account for cyclin D1 expression in some cases. Cyclin D1 expression is not useful for distinguishing NLPHL from THRLBCL and has no apparent clinical significance in NLPHL.

Miao Y, Lin P, Wang W, et al.
CCND1-IGH Fusion-Amplification and MYC Copy Number Gain in a Case of Pleomorphic Variant Mantle Cell Lymphoma.
Am J Clin Pathol. 2016; 146(6):747-752 [PubMed] Related Publications
OBJECTIVES: Mantle cell lymphoma (MCL) may present de novo or undergo progression to a clinically aggressive variant, known as a blastoid or pleomorphic variant. We report an unusual case of classic MCL in a 78-year-old man with a typical immunophenotype, including CD5 positivity, who subsequently relapsed with CD5-negative pleomorphic variant MCL.
METHODS: Biopsy specimens were evaluated using Wright-Giemsa-stained or H&E-stained sections, flow cytometry, immunohistochemistry, conventional cytogenetic, next-generation sequencing, and fluorescence in situ hybridization.
RESULTS: The patient continued to be refractory to intensive chemotherapy and radiation therapy. Initial conventional cytogenetic analysis showed a complex karyotype with amplification of the CCND1-IGH fusion gene on the der(14): 44, Y, t(X;2)(p22.3;q21), del(2)(p21), del(6)(p23), add(7)(p22),-9, del(9)(p22), add(11)(q13),-13, add(14)(p11.2), der(14)t(11;14)(q13;q32)hsr(14)(q32), add(18)(q23), add(21)(p11.1),-22,+mar[12]. A repeat biopsy revealed MCL, pleomorphic variant, with loss of CD5 expression and extra copies of the MYC CONCLUSIONS: CCND1-IGH fusion-amplification with MYC copy number gain is extremely rare and may play a role in disease progression in a subset of MCL cases.

Pectasides D, Kotoula V, Papaxoinis G, et al.
Expression Patterns of Growth and Survival Genes with Prognostic Implications in Advanced Pancreatic Cancer.
Anticancer Res. 2016; 36(12):6347-6356 [PubMed] Related Publications
AIM: The aim of this study was to evaluate the mRNA expression pattern of growth- and survival-related genes and assess their prognostic significance in patients with advanced pancreatic cancer.
PATIENTS AND METHODS: In total, 98 patients were included in this retrospective translational research study and were evaluated for Kirsten rat sarcoma viral oncogene homolog (KRAS) mutational status, and v-akt murine thymoma viral oncogene homolog 1 (AKT1), AKT serine/threonine kinase 2 (AKT2), AKT serine/threonine kinase 3 (AKT3), cyclin D1 (CCND1), epidermal growth factor receptor (EGFR), mitogen-activated protein kinase 1 (MAPK1), hepatocellular growth factor receptor (MET), avian myelomatosis viral oncogene homolog (MYC), nuclear factor kappa B subunit 1 (NFKb1), phosphatase and tensin homolog (PTEN) and mechanistic target of rapamycin (FRAP1) genes mRNA expression. Among these patients, 73 received first-line gemcitabine combined with erlotinib (N=57) or gefitinib (N=16).
RESULTS: KRAS mutation did not correlate with mRNA gene expression. Unsupervised hierarchical clustering according to mRNA gene expression successfully distinguished four prognostically distinct groups of tumors. Overexpression of all genes was associated with best prognosis, while suppression or heterogeneous expression patterns of the examined genes were associated with expression patterns of growth- and survival-related genes, classifying pancreatic tumors into distinct groups with possibly different outcomes.

Liu L, Xu Y, Reiter RJ, et al.
Inhibition of ERK1/2 Signaling Pathway is Involved in Melatonin's Antiproliferative Effect on Human MG-63 Osteosarcoma Cells.
Cell Physiol Biochem. 2016; 39(6):2297-2307 [PubMed] Related Publications
BACKGROUND: In a previous study, we found that melatonin inhibits MG-63 osteosarcoma cell proliferation; however, the underlying mechanisms remain elusive. Mitogen-activated protein kinase (MAPK) and Akt signaling pathways play key roles in the anticancer effects of melatonin.
AIMS: The present study investigated whether MAPK and Akt signaling pathways are involved in melatonin's antiproliferative actions on the human MG-63 osteosarcoma cells.
METHODS/RESULTS: Western blot analysis confirmed that melatonin significantly inhibited phosphorylation of ERK1/2 but not p38, JNK, or Akt. The expression of ERK1/2, p38, JNK, and Akt was not altered by melatonin. PD98059 and melatonin alone, and especially in combination, significantly inhibited cell proliferation. The changes included G1 and G2/M phase arrest of the cell cycle, and a downregulation of the expression at both the protein and mRNA levels of cyclin D1 and CDK4 (related to the G1 phase) and of cyclin B1 and CDK1 (related to the G2/M phase) as measured by flow cytometry after propidium iodide staining, and both western blot and real-time PCR, respectively. Furthermore, the combination of PD98059 and melatonin synergistically and markedly augmented the action of either agent alone. Co-immunoprecipitation further confirmed that there was an interaction between p-ERK1/2 and cyclin D1, CDK4, cyclin B1, or CDK1, which was blunted in the presence of melatonin or PD98059.
CONCLUSION: These findings suggest that melatonin's antiproliferative action is mediated by inhibition of the ERK1/2 signaling pathway rather than the p38, JNK, or Akt pathways.

Ohtsuka M, Ling H, Ivan C, et al.
H19 Noncoding RNA, an Independent Prognostic Factor, Regulates Essential Rb-E2F and CDK8-β-Catenin Signaling in Colorectal Cancer.
EBioMedicine. 2016; 13:113-124 [PubMed] Free Access to Full Article Related Publications
The clinical significance of long noncoding RNAs (lncRNAs) in colorectal cancer (CRC) remains largely unexplored. Here, we analyzed a large panel of lncRNA candidates with The Cancer Genome Atlas (TCGA) CRC dataset, and identified H19 as the most significant lncRNA associated with CRC patient survival. We further validated such association in two independent CRC cohorts. H19 silencing blocked G1-S transition, reduced cell proliferation, and inhibited cell migration. We profiled gene expression changes to gain mechanism insight of H19 function. Transcriptome data analysis revealed not only previously identified mechanisms such as Let-7 regulation by H19, but also RB1-E2F1 function and β-catenin activity as essential upstream regulators mediating H19 function. Our experimental data showed that H19 affects phosphorylation of RB1 protein by regulating gene expression of CDK4 and CCND1. We further demonstrated that reduced CDK8 expression underlies changes of β-catenin activity, and identified that H19 interacts with macroH2A, an essential regulator of CDK8 gene transcription. However, the relevance of H19-macroH2A interaction in CDK8 regulation remains to be experimentally determined. We further explored the clinical relevance of above mechanisms in clinical samples, and showed that combined analysis of H19 with its targets improved prognostic value of H19 in CRC.

Wang G, Wang H, Zhang C, et al.
Rac3 regulates cell proliferation through cell cycle pathway and predicts prognosis in lung adenocarcinoma.
Tumour Biol. 2016; 37(9):12597-12607 [PubMed] Related Publications
Lung cancer is still the leading cause of malignant deaths in the world. It is of great importance to find novel functional genes for the tumorigenesis of lung cancer. We demonstrated that Rac3 could promote cell proliferation and inhibit apoptosis in lung adenocarcinoma cell line A549 previously. The aim of this study was to investigate the function and mechanism of Rac3 in lung adenocarcinoma cell lines. Immunohistochemistry staining was performed in 107 lung adenocarcinoma tissues and matched non-tumor tissues. Multivariate analysis and Kaplan-Meier analysis were used to investigate the correlation between Rac3 expression and the clinical outcomes. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay, and flow cytometry analysis were employed to determine the proliferative ability, cell cycle distribution, and apoptosis in H1299 and H1975 cell lines. Gene expression microarray and pathway analysis between the Rac3-siRNA group and the control group in A549 cells were performed to investigate the pathways and mechanism of Rac3 regulation. Rac3 was shown to be positively expressed in lung adenocarcinoma tissues, and the expression of Rac3 associates with longer survival in lung adenocarcinoma patients. Silencing of Rac3 significantly induced cell growth inhibition, colony formation decrease, cell cycle arrest, and apoptosis of lung adenocarcinoma cell lines, which accompanied by obvious downregulation of CCND1, MYC, and TFDP1 of cell cycle pathway involving in the tumorigenesis of lung adenocarcinoma based on the gene expression microarray. In conclusion, these findings suggest that Rac3 has the potential of being a therapeutic target for lung adenocarcinoma.

Rosales-Reynoso MA, Arredondo-Valdez AR, Juárez-Vázquez CI, et al.
TCF7L2 and CCND1 polymorphisms and its association with colorectal cancer in Mexican patients.
Cell Mol Biol (Noisy-le-grand). 2016; 62(11):13-20 [PubMed] Related Publications
Accumulative evidence suggests that alterations due to mutations or genetic polymorphisms in the TCF7L2 and CCND1 genes, which are components of the Wnt signaling pathway, contributes to carcinogenesis. The present study was designated to clarify whether common single nucleotide polymorphisms (SNPs) of the transcription factor 7- like 2 (TCF7L2) and cyclin D1 (CCND1) genes are associated with colorectal cancer risk in Mexican patients. A case-control study including 197 colorectal cancer patients and 100 healthy subjects was conducted in a Mexican population. Identification of polymorphisms was made by the polymerase chain reaction-restriction fragment length polymorphism methodology. The association was calculated by the odds ratio (OR) test. The results demonstrate that patients with the T/T genotype for the rs12255372 polymorphism of the TCF7L2 gene present an increased colorectal cancer risk (OR=2.64, P=0.0236). Also, the risk analysis for Tumor-Nodule-Metastasis (TNM) stage and tumor location showed association with this polymorphism under the over-dominant model of inheritance (OR=1.75, P=0.0440). A similar relation was observed for the genotype T/T of the rs7903146 polymorphism and the rectal location of cancer (OR=7.57, P=0.0403). For the rs603965 polymorphism of the CCND1 gene, we observed a protection effect for the colon cancer location under the dominant model (OR=0.49, P=0.0477). These results reveal a significant role of the analyzed polymorphisms in the TCF7L2 and CCND1 genes on the susceptibility or protection for developing colorectal cancer in the Mexican population.

Shi Q, Shi X, Zuo G, et al.
Anticancer effect of 20(S)-ginsenoside Rh2 on HepG2 liver carcinoma cells: Activating GSK-3β and degrading β-catenin.
Oncol Rep. 2016; 36(4):2059-70 [PubMed] Related Publications
20(S)-ginsenoside Rh2 [(S)Rh2] possesses potential to prevent cancer in vitro as well as in vivo, but the underlying mechanism is still unknown. First, we infected HepG2 cells with lentivirus which carries β‑catenin. We detected the pharmacological effects of (S)Rh2 on HepG2 and HepG2‑β‑catenin cells and found that the IC50 of (S)Rh2 exposure on HepG2-β-catenin cells was higher than HepG2 cells. Flow cytometry (FCM) indicated that (S)Rh2 could be arrested in G0/G1 phase and induce early apoptosis in HepG2 and HepG2‑β‑catenin cells. Second, ELISA kit was used to check the activity of glycogen synthase kinase‑3β (GSK‑3β), which was upregulated by (S)Rh2. GSK‑3β inhibitor BIO, was used to verify that (S)Rh2 activated GSK‑3β. PCR and western blotting results indicated that (S)Rh2 could degrade the expression of β‑catenin, which combined with TCF in the nucleus and activate transcription of Wnt target genes, such as Bax, Bcl‑2, cyclin D1, MMP3, which were checked by chromatin immunoprecipitation (ChIP), PCR and western blotting. The results showed that the expression of Bax mRNA and proteins increased, while the cyclin D1, Bcl‑2, MMP3 mRNA and proteins were downregulated in HepG2 and HepG2‑β‑catenin cells which was induced by (S)Rh2. By contrast, with the HepG2-β-catenin + (S)Rh2 group, the expression of other mRNA and proteins in HepG2 + (S)Rh2 group changed significantly. In vivo, experiments were performed using a nude mouse xenograft model to investigate the (S)Rh2 effect. So these results suggested that (S)Rh2 could suppress proliferation, promote apoptosis and inhibit metastasis of HepG2, decrease weight of tumor by downregulating β‑catenin through activating GSK‑3β and the pharmacological effect of (S)Rh2 on HepG2 cells might be weakened by overexpression of β‑catenin.

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.

Farhadi E, Zaker F, Safa M, Rezvani MR
miR-101 sensitizes K562 cell line to imatinib through Jak2 downregulation and inhibition of NF-κB target genes.
Tumour Biol. 2016; 37(10):14117-14128 [PubMed] Related Publications
Imatinib mesylate (IM) is a frontline treatment in the early chronic phase of chronic myeloid leukemia (CML). However, intrinsic and acquired resistance against this drug has been defined and this issue has become a problem and a challenge in CML treatment. According to new findings, the inhibition of Janus kinase 2 (Jak2) in Bcr-Abl+ cells can promote apoptosis in IM-resistant cells. microRNAs (miRNAs) regulate the gene expression by targeting the messenger RNA (mRNA) for degradation. Recently, a growing body of evidence has implicated that dysregulation of miRNAs is associated with cancer initiation and development. In this report, we proposed that miRNA-101 targets Jak2 mRNA and regulates its expression and induces K562 leukemia cell apoptosis. Here, we transduced the K562 cell line with a miR-101-overexpressing vector and evaluated the Jak2 mRNA level. Our results showed that miR-101 overexpression in Bcr-Abl+ cells reduced the Jak2 mRNA level. Moreover, imatinib treatment and miR-101 upregulation led to miR-23a overexpression, which has putative binding site(s) on 3'-untranslated regions (3'-UTRs) of STAT5, CCND1, and Bcl-2 genes. Our results also indicated that miR-101 overexpression inhibited cell proliferation indicated by the MTT assay and promoted apoptosis detected via flow cytometry. Importantly, mRNA expression of NF-kappa B-regulated anti-apoptotic (Bcl-2, Bcl-xl, MCL-1, XIAP, and survivin) and proliferative (c-Myc and CCND1) genes was decreased. These findings suggest that miR-101 acts as a tumor suppressor by downregulating Jak2 expression and sensitizing K562 cells to imatinib. Therefore, restoration of miR-101 may be a therapeutic approach for CML treatment.

Wang Z, Ying M, Wu Q, et al.
Overexpression of myosin VI regulates gastric cancer cell progression.
Gene. 2016; 593(1):100-9 [PubMed] Related Publications
Myosin VI (MYO6) is a unique member of the myosin superfamily. Although it has been reported to participate in human cancer progression, the role of MYO6 in gastric cancer remains unclear. In this study, we found the expression of MYO6 gene was higher in gastric cancer tissues than in the normal tissues by Oncomine database mining and affects patient overall survival using the Kaplan-Meier plotter online analysis. Additionally, the expression levels of MYO6 were widely expressed in gastric cancer cells by quantitative real-time Polymerase Chain Reaction (qRT-PCR) and western blot assay. Then knockdown of MYO6 significantly suppressed the proliferation and colony formation abilities of AGS and MGC80-3 cells. Moreover, cell cycle analysis showed that inhibition of MYO6 induced cell cycle arrested in G0/G1 phase in AGS and MGC80-3 cells. Further analysis showed knockdown of MYO6 downregulated cell-cycle activators cyclin A and cyclin D1 and upregulated cell-cycle inhibitor p21, as determined by qRT-PCR and western blot analysis in MGC80-3 cells. Meanwhile, MYO6 inhibition significantly induced apoptosis in AGS and MGC80-3 cells. Also, knockdown of MYO6 increased the expression of apoptosis-related proteins Bax and cleaved Caspase-3, and decreased Bcl-2 expression by western blot analysis in MGC80-3 cells. In addition, MYO6 knockdown also inhibited cell migration ability in MGC80-3 cells. Taken together, our study indicates that MYO6 may play an important role in gastric cancer tumorigenesis and may serve as a potential therapeutic target in human gastric cancer.

Pirtoli L, Belmonte G, Toscano M, et al.
Cyclin D1 Co-localizes with Beclin-1 in Glioblastoma Recurrences: A Clue to a Therapy-induced, Autophagy-mediated Degradative Mechanism?
Anticancer Res. 2016; 36(8):4057-62 [PubMed] Related Publications
BACKGROUND: Glioblastoma (GB) recurrences are rarely removed, therefore, tissue modifications induced by radiotherapy, and temozolomide chemotherapy are scarcely known. Nuclear cyclin D1 is associated with GB progression and resistance to therapy. We previously found that the expression of autophagic protein beclin-1 is a major determinant of prognosis in GB.
PATIENTS AND METHODS: In 31 patients with primary GB and their recurrences, we investigated the protein expression of cyclin D1 and beclin-1, before and after radiotherapy-temozolomide therapy by immunohistochemistry.
RESULTS: Most (20/31) primary GBs were negative for nuclear cyclin D1, and highly expressed beclin-1. In their recurrences, cytoplasmic cyclin D1 positivity was observable, which co-localized with beclin-1. Eleven primary GBs instead exhibited low beclin-1 expression and were positive for nuclear cyclin D1; three of their recurrences exhibited an increase of beclin-1, which co-localized with cyclin D1 in the cytoplasm.
CONCLUSION: Our results suggest therapy-induced degradation of cyclin D1 via autophagy.

Kurita D, Takeuchi K, Kobayashi S, et al.
A cyclin D1-negative mantle cell lymphoma with an IGL-CCND2 translocation that relapsed with blastoid morphology and aggressive clinical behavior.
Virchows Arch. 2016; 469(4):471-6 [PubMed] Related Publications
Mantle cell lymphoma (MCL) is a B cell neoplasm characterized by cyclin D1 overexpression; its prognosis is poor, especially when it exhibits a blastoid morphology. Cyclin D1-negative MCL is rare, and its pathogenesis and progression remain unclear. Herein, we describe a cyclin D1-negative, cyclin D2-positive MCL with a CCND2 and immunoglobulin lambda light chain (IGL) translocation. The patient was initially diagnosed with cyclin D1-negative MCL and achieved complete remission via combination chemotherapy and autologous stem cell transplantation. After relapsing, he was diagnosed with a blastoid variant of MCL that showed lymphoid cells with dispersed chromatin and more mitotic figures and higher p53 expression compared with the initial MCL. Despite salvage therapies, the disease became refractory, and the patient died 28 months after initiating chemotherapy. This case demonstrates that blastoid morphology in cyclin D1-negative MCL with IGL-CCND2 translocation indicates progression to a more aggressive neoplasm, similar to cyclin D1-positive MCL.

Park S, Hong JP, Lee JK, et al.
Associations between the neuron-specific glucocorticoid receptor (NR3C1) Bcl-1 polymorphisms and suicide in cancer patients within the first year of diagnosis.
Behav Brain Funct. 2016; 12(1):22 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cancer diagnosis is associated with an increased suicide risk, particularly within the first 1 year after diagnosis of cancer. Abnormal function of the hypothalamic-pituitary-adrenal axis has been implicated in the pathophysiology of depression and suicide. We examined genetic associations of the functional Bcl-1 polymorphism of (rs41423247) neuron-specific glucocorticoid receptor (NR3C1) gene, with death by suicide in cancer patients. Suicides occurring within a year of cancer diagnosis ('early suicide') were considered separately from those suicides during the second or subsequent year ('late suicide') after cancer diagnosis.
METHODS: The subjects consisted of 343 cancer patients admitted to a general hospital in Seoul, South Korea from 1996 to 2009, of which 182 had died by suicide and 161 were alive on December 31, 2009. Genomic DNA was extracted from formalin-fixed paraffin-embedded tissue sample of patients with cancer. We conducted a case-control association analysis of Bcl-1 polymorphism of NR3C1 gene.
RESULTS: Subjects carrying the GG genotype of Bcl-1 polymorphism were at increased risk of early suicide when compared to those carrying the CC genotype (OR 3.80, 95 % CI 1.02-14.16, p = .047). Similarly, those individuals carrying the GG genotype (recessive mode) had an increased risk of early suicide relative to the CC or CG genotype (OR 3.71, 95 % CI 1.03-13.43, p = .045). However, there were no differences in the genotype distributions of the NR3C1 Bcl-1 polymorphism between late suicide cases and controls.
CONCLUSIONS: Our findings suggest that the NR3C1 Bcl-1 polymorphisms may be involved in the susceptibility to suicide within the first year after cancer diagnosis among cancer patients in Korean population.

Koide R, Kulkeaw K, Tanaka Y, et al.
Aryl Hydrocarbon Receptor Antagonist StemRegenin 1 Promotes the Expansion of Human Promyelocytic Leukemia Cell Line, NB4.
Anticancer Res. 2016; 36(7):3635-43 [PubMed] Related Publications
BACKGROUND/AIM: StemRegenin 1 (SR1), an antagonist of aryl hydrocarbon receptor (AHR), reportedly promotes expansion of hematopoietic stem cells but its effect on leukemia cells is unclear. This study focused on the role of SR1 in leukemia cell proliferation.
MATERIALS AND METHODS: AHR expression was compared in the cell lines Jurkat, Kasumi-1, NB4 and K562, using real-time polymerase chain reaction. Highly AHR-expressing NB4 cells were cultured with SR1 for 2 and 4 days, and evaluated for viability and gene expression. DNA microarray was also performed.
RESULTS: The viability of NB4 cells treated with 1.5 μM SR1 increased at day 4. Expression of B-cell CLL/lymphoma 2 (BCL2) was up-regulated, while that of BCL2 associated X protein (BAX) was down-regulated at day 2. Increased cyclin D1 (CCND1), CCND2 and v-myc avian myelocytomatosis viral oncogene homolog (MYC) expressions were observed at day 4. Global gene expression profiles showed up-regulation of splice variant-related genes and down-regulation of inflammation-related genes.
CONCLUSION: SR1 promotes the expansion of NB4 cells in vitro, implying the need for caution regarding in vivo use of R1.

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

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

Jiang S, Zhao C, Yang X, et al.
miR-1 suppresses the growth of esophageal squamous cell carcinoma in vivo and in vitro through the downregulation of MET, cyclin D1 and CDK4 expression.
Int J Mol Med. 2016; 38(1):113-22 [PubMed] Free Access to Full Article Related Publications
Several aberrant microRNAs (miRNAs or miRs) have been implicated in esophageal cancer (EC), which is widely prevalent in China. However, their role in EC tumorigenesis has not yet been fully elucidated. In the present study, we determined that miR‑1 was downregulated in esophageal squamous cell carcinoma (ESCC) tissues compared with adjacent non-neoplastic tissues using RT-qPCR, and confirmed this using an ESCC cell line. Using a nude mouse xenograft model, we confirmed that the re-expression of miR‑1 significantly inhibited ESCC tumor growth. A tetrazolium assay and a trypan blue exclusion assay revealed that miR‑1 suppressed ESCC cell proliferation and increased apoptosis, whereas the silencing of miR‑1 promoted cell proliferation and decreased apoptosis, suggesting that miR‑1 is a novel tumor suppressor. To elucidate the molecular mechanisms of action of miR‑1 in ESCC, we investigated putative targets using bioinformatics tools. MET, cyclin D1 and cyclin-dependent kinase 4 (CDK4), which are involved in the hepatocyte growth factor (HGF)/MET signaling pathway, were found to be targets of miR‑1. miR‑1 expression inversely correlated with MET, cyclin D1 and CDK4 expression in ESCC cells. miR‑1 directly targeted MET, cyclin D1 and CDK4, suppressing ESCC cell growth. The newly identified miR‑1/MET/cyclin D1/CDK4 axis provides new insight into the molecular mechanisms of ESCC pathogenesis and indicates a novel strategy for the diagnosis and treatment of ESCC.

Thomas C, Robinson C, Dessauvagie B, et al.
Expression of proliferation genes in formalin-fixed paraffin-embedded (FFPE) tissue from breast carcinomas. Feasibility and relevance for a routine histopathology laboratory.
J Clin Pathol. 2017; 70(1):25-32 [PubMed] Related Publications
AIM: Breast carcinoma proliferative activity, histological grade and commercial molecular tests are all important in prognostication and treatment. There is a particular need for improved, standardised techniques for subclassification of grade 2 breast cancers into low-risk and high-risk prognostic groups. In this study we investigated whether gene expression profiling of five proliferation genes was feasible using breast cancer tissue in a clinical setting and whether these profiles could enhance pathological assessment.
METHODS: Expression of five proliferation gene mRNAs; Ki-67, STK 15, CCNB1, CCND1 and MYBL2, was quantified in 27 breast carcinomas and compared with Ki-67 proliferation index (PI) and Nottingham mitotic score.
RESULTS: Expression of Ki-67, STK15 and MYBL2 mRNA showed moderate Spearman's correlation with Ki-67 PI (p<0.01), but CCND1 and CCNB1 showed weak, non-significant correlation. Individual gene expression did not associate with mitotic score but combined mRNA expression correlated with both Ki-67 PI (p=0.018) and mitotic score (p=0.03; 0.007).
CONCLUSIONS: This study confirms mRNA analysis in breast carcinoma formalin-fixed, paraffin-embedded samples is feasible and suggests gene expression profiling, using a small set of five proliferation genes, has potential in aiding histological grading or assessment of proliferative activity of breast cancers. To fully evaluate the clinical applicability of this approach, a larger cohort study with long-term follow-up data is required.

Ye J, Li L, Feng P, et al.
Downregulation of miR-34a contributes to the proliferation and migration of laryngeal carcinoma cells by targeting cyclin D1.
Oncol Rep. 2016; 36(1):390-8 [PubMed] Related Publications
Laryngeal carcinoma is one of the most common head and neck cancers. MicroRNAs are a class of small non-coding RNAs 18-25 nucleotides in length that post-transcriptionally regulate gene expression and have a pivotal role in many biological processes including cancer development. In this study, we investigated the role of miR-34a in laryngeal carcinoma and confirmed the regulation of cyclin D1 (CCND1) by miR-34a. We examined miR-34a expression levels in 71 laryngeal carcinoma patient specimens by quantitative reverse transcription-PCR, and analyzed the clinicopathological significance of the obtained data. Then, functional assays were performed to investigate the potential effects of miR-34a on cancer cell proliferation and migration. In addition, western blotting, luciferase reporter assay and several algorithms were conducted to confirm that CCND1 is directly regulated by miR-34a. We demonstrated that the miR-34a expression level was significantly downregulated in laryngeal carcinoma clinical specimens compared with that observed in their paired adjacent normal tissues. Additionally, miR-34a expression was also inversely correlated with lymph node metastasis and clinical stage. Functional assays showed that ectopic expression of miR-34a inhibited cell proliferation and migration in laryngeal carcinoma cells. Bioinformatic analysis identified CCND1 as a potential target of miR-34a. Moreover, we confirmed that miR-34a inhibited the expression of CCND1 by directly binding to its 3'-untranslated region. Silencing of CCND1 induced effects similar to those of miR-34a ectopic expression, and in laryngeal carcinoma tissues, miR-34a and CCND1 were inversely correlated. Our data suggest that tumor suppressor miR-34a could serve as a new potential diagnostic marker and that ectopic expression of miR-34a may be used as a therapeutic target for laryngeal carcinoma.

Heilmann AM, Subbiah V, Wang K, et al.
Comprehensive Genomic Profiling of Clinically Advanced Medullary Thyroid Carcinoma.
Oncology. 2016; 90(6):339-46 [PubMed] Article available free on PMC after 21/05/2017 Related Publications
OBJECTIVE: The aim of this study was to determine the genomic alterations of cancer-related genes in advanced medullary thyroid carcinoma during the course of clinical care.
METHODS: Hybrid-capture-based comprehensive genomic profiling was performed on 34 consecutive medullary thyroid carcinoma cases to identify all four classes of genomic alterations, and outcome for an index patient was collected.
RESULTS: RET was mutated in 88% (30/34) of cases, with RET M918T being responsible for 70% (21/30) of the RET alterations. The other RET alterations were RET E632_L633del, C634R, C620R, C618G/R/S, V804M, and RET amplification. Two of the four RET wild-type patients harbored mutations in KRAS or HRAS (1/34 each). The next most frequent genomic alterations were amplifications of CCND1, FGF3, and FGF19 and alterations in CDKN2A (3/34 each). One case with a RET M918T mutation developed acquired resistance to progressively dose-escalated vandetanib. When the mTOR inhibitor everolimus was added to continued vandetanib treatment, the patient achieved a second 25% reduction of tumor volume (RECIST 1.1) for 8 months.
CONCLUSIONS: Comprehensive genomic profiling identified the full breadth of RET alterations in metastatic medullary thyroid carcinoma and possible cooperating oncogenic driver alterations. This approach may refine the use of targeted therapy for these patients.

Li XC, Liu C, Huang T, Zhong Y
The Occurrence of Genetic Alterations during the Progression of Breast Carcinoma.
Biomed Res Int. 2016; 2016:5237827 [PubMed] Article available free on PMC after 21/05/2017 Related Publications
The interrelationship among genetic variations between the developing process of carcinoma and the order of occurrence has not been completely understood. Interpreting the mechanisms of copy number variation (CNV) is absolutely necessary for understanding the etiology of genetic disorders. Oncogenetic tree is a special phylogenetic tree inferential pictorial representation of oncogenesis. In our present study, we constructed oncogenetic tree to imitate the occurrence of genetic and cytogenetic alterations in human breast cancer. The oncogenetic tree model was built on CNV of ErbB2, AKT2, KRAS, PIK3CA, PTEN, and CCND1 genes in 963 cases of tumors with sequencing and CNA data of human breast cancer from TCGA. Results from the oncogenetic tree model indicate that ErbB2 copy number variation is the frequent early event of human breast cancer. The oncogenetic tree model based on the phylogenetic tree is a type of mathematical model that may eventually provide a better way to understand the process of oncogenesis.

Nie X, Wang X, Lin Y, et al.
SNP rs1059234 in CDKN1A Gene Correlates with Prognosis in Resected Gastric Adenocarcinoma.
Clin Lab. 2016; 62(3):409-16 [PubMed] Related Publications
BACKGROUND: Cyclin-dependent kinase inhibitor 1A (CDKN1A) and Cyclin D1 (CCND1) play essential roles in the regulation of cell cycle progression and are closely associated with human cancer. CDKN1A and CCND1 single nucleotide polymorphisms (SNPs) have been demonstrated to influence the prognosis in humans with different cancers. However, their roles in the prognosis of patients with resected gastric adenocarcinoma (RGA) remain to be determined.
METHODS: Genotypes of CDKN1A rs1059234 and CCND1 rs603965 SNPs were performed in 235 tissue samples from RGA. The association of the genotypes of these two SNPs with the prognosis in the patients with RGA was analyzed by X2 test, multivariate Cox regression analyses, and Kaplan Meier curves.
RESULTS: During the 50 months of median follow-up time, the overall recurrence and survival rate in the whole group was 57.4% and 46.8%, respectively. Whereas, recurrence and survival rate in patients with CC genotype of rs1059234 located in 3'UTR of CDKN1A were 78.0% and 27.1% (p = 0.004; p = 0.006). Multivariate analyses further confirmed that the CC genotype was significantly related with both increased recurrence and death risk (HR 3.33, 95% CI 1.95-5.70; p = 1.07 x 10⁻⁵, and HR 3.45, 95% CI 1.95-6.10; p = 2.03 x 10⁻⁵). No significant difference among CCND1 rs603965 SNP with the prognosis was determined.
CONCLUSIONS: rs1059234 of CDKN1A is closely associated with the prognosis in patients with RGA.

Xiang J, Guo S, Jiang S, et al.
Silencing of Long Non-Coding RNA MALAT1 Promotes Apoptosis of Glioma Cells.
J Korean Med Sci. 2016; 31(5):688-94 [PubMed] Article available free on PMC after 21/05/2017 Related Publications
The metastasis-associated lung adenocarcinoma transcription 1 (MALAT1) is a highly conserved long non-coding RNA (lncRNA) gene. However, little is known about the pathological role of lncRNA MALAT1 in glioma. In the present study, we explored the expression level of lncRNA MALAT1 in primary glioma tissues as well as in U87 and U251 glioma cell lines. Using qRT-PCR, we found that the expression of lncRNA MALAT1 was significantly increased in glioma tissues compared with that of paracancerous tissues. Meanwhile, the expression of MALAT1 was highly expressed in U98 and U251 cells. In order to explore the function of MALAT1, the expression of MALAT1 was greatly reduced in U87 and U251 cells transfected with siRNA specifically targeting MALAT1. Consequently, cell viability of U87 and U251 cells were drastically decreased after the knockdown of MALAT1. Concomitantly, the apoptosis rate of the two cell lines was dramatically increased. Furthermore, the expression levels of some tumor markers were reduced after the knockdown of MALAT1, such as CCND1 and MYC. In summary, the current study indicated a promoting role of MALAT1 in the development of glioma cell.

Zhou JJ, Meng Z, Zhou Y, et al.
Hepatitis C virus core protein regulates OCT4 expression and promotes cell cycle progression in hepatocellular carcinoma.
Oncol Rep. 2016; 36(1):582-8 [PubMed] Related Publications
Hepatitis C virus (HCV) core protein plays an important role in the development of hepatocellular carcinoma. octamer-binding protein 4 (OCT4) is critically essential for the pluripotency and self-renewal of embryonic stem cells. Abnormal expression of OCT4 has been detected in several human solid tumors. However, the relationship between HCV core and OCT4 remains uncertain. In the present study, we found that HCV core is capable of upregulating OCT4 expression. The effect of HCV core-induced OCT4 overexpression was abolished by RNAi-mediated scilencing of HCV core. In addition, HCV core-induced OCT4 overexpression resulted in enhanced cell proliferation and cell cycle progression. Inhibition of OCT4 reduced the CCND1 expression and induced G0/G1 cell cycle arrest. Furthermore, OCT4 protein directly binds to CCND1 promoter and transactivates CCND1. These findings suggest that HCV core protein regulates OCT4 expression and promotes cell cycle progression in hepatocellular carcinoma providing new insight into the mechanism of hepatocarcinogenesis by HCV infection.

Kim CW, Go RE, Lee HM, et al.
Cigarette smoke extracts induced the colon cancer migration via regulating epithelial mesenchymal transition and metastatic genes in human colon cancer cells.
Environ Toxicol. 2017; 32(2):690-704 [PubMed] Related Publications
There was considerable evidence that exposure to cigarette smoke is associated with an increased risk for colon cancer. Nevertheless, the mechanism underlying the relationship between cigarette smoking and colon cancer remains unclear. Moreover, there were only a few studies on effects of complexing substance contained in cigarette smoke on colon cancer. Thus, we further investigated whether cigarette smoke extract (CSE) affects the cell cycle, apoptosis and migration of human metastatic colon cancer cells, SW-620. MTT assay revealed that SW-620 cell proliferation was significantly inhibited following treatments with all CSEs, 3R4F, and two-domestic cigarettes, for 9 days in a concentration-dependent manner. Moreover, CSE treatments decreased cyclin D1 and E1, and increased p21 and p27 proteins by Western blot analysis in SW-620 cells. Additionally, the treatment of the cells with CSE contributed to these effects expressing by apoptosis-related proteins. An increased migration or invasion ability of SW-620 cells following CSE treatment was also confirmed by a scratch or fibronectin invasion assay in vitro. In addition, the protein levels of E-cadherin as an epithelial maker were down-regulated, while the mesenchymal markers, N-cadherin, snail, and slug, were up-regulated in a time-dependent manner. A metastatic marker, cathepsin D, was also down-regulated by CSE treatment. Taken together, these results indicate that CSE exposure in colon cancer cells may deregulate the cell growth by altering the expression of cell cycle-related proteins and pro-apoptotic protein, and stimulate cell metastatic ability by altering epithelial-mesenchymal transition (EMT) markers and cathepsin D expression. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 690-704, 2017.

Shivakumar BM, Chakrabarty S, Rotti H, et al.
Comparative analysis of copy number variations in ulcerative colitis associated and sporadic colorectal neoplasia.
BMC Cancer. 2016; 16:271 [PubMed] Article available free on PMC after 21/05/2017 Related Publications
BACKGROUND: The incidence of and mortality from colorectal cancers (CRC) can be reduced by early detection. Currently there is a lack of established markers to detect early neoplastic changes. We aimed to identify the copy number variations (CNVs) and the associated genes which could be potential markers for the detection of neoplasia in both ulcerative colitis-associated neoplasia (UC-CRN) and sporadic colorectal neoplasia (S-CRN).
METHODS: We employed array comparative genome hybridization (aCGH) to identify CNVs in tissue samples of UC nonprogressor, progressor and sporadic CRC. Select genes within these CNV regions as a panel of markers were validated using quantitative real time PCR (qRT-PCR) method along with the microsatellite instability (MSI) in an independent cohort of samples. Immunohistochemistry (IHC) analysis was also performed.
RESULTS: Integrated analysis showed 10 overlapping CNV regions between UC-Progressor and S-CRN, with the 8q and 12p regions showing greater overlap. The qRT-PCR based panel of MYC, MYCN, CCND1, CCND2, EGFR and FNDC3A was successful in detecting neoplasia with an overall accuracy of 54% in S-CRN compared to that of 29% in UC neoplastic samples. IHC study showed that p53 and CCND1 were significantly overexpressed with an increasing frequency from pre-neoplastic to neoplastic stages. EGFR and AMACR were expressed only in the neoplastic conditions.
CONCLUSION: CNVs that are common and unique to both UC-associated and sporadic colorectal neoplasm could be the key players driving carcinogenesis. Comparative analysis of CNVs provides testable driver aberrations but needs further evaluation in larger cohorts of samples. These markers may help in developing more effective neoplasia-detection strategies during screening and surveillance programs.

Norton N, Advani PP, Serie DJ, et al.
Assessment of Tumor Heterogeneity, as Evidenced by Gene Expression Profiles, Pathway Activation, and Gene Copy Number, in Patients with Multifocal Invasive Lobular Breast Tumors.
PLoS One. 2016; 11(4):e0153411 [PubMed] Article available free on PMC after 21/05/2017 Related Publications
BACKGROUND: Invasive lobular carcinoma (ILC) comprises approximately ~10-20% of breast cancers. In general, multifocal/multicentric (MF/MC) breast cancer has been associated with an increased rate of regional lymph node metastases. Tumor heterogeneity between foci represents a largely unstudied source of genomic variation in those rare patients with MF/MC ILC.
METHODS: We characterized gene expression and copy number in 2 or more foci from 11 patients with MF/MC ILC (all ER+, HER2-) and adjacent normal tissue. RNA and DNA were extracted from 3x1.5 mm cores from all foci. Gene expression (730 genes) and copy number (80 genes) were measured using Nanostring PanCancer and Cancer CNV panels. Linear mixed models were employed to compare expression in tumor versus normal samples from the same patient, and to assess heterogeneity (variability) in expression among multiple ILC within an individual.
RESULTS: 35 and 34 genes were upregulated (FC>2) and down-regulated (FC<0.5) respectively in ILC tumor relative to adjacent normal tissue, q<0.05. 9/34 down-regulated genes (FIGF, RELN, PROM1, SFRP1, MMP7, NTRK2, LAMB3, SPRY2, KIT) had changes larger than CDH1, a hallmark of ILC. Copy number changes in these patients were relatively few but consistent across foci within each patient. Amplification of three genes (CCND1, FADD, ORAOV1) at 11q13.3 was present in 2/11 patients in both foci. We observed significant evidence of within-patient between-foci variability (heterogeneity) in gene expression for 466 genes (p<0.05 with FDR 8%), including CDH1, FIGF, RELN, SFRP1, MMP7, NTRK2, LAMB3, SPRY2 and KIT.
CONCLUSIONS: There was substantial variation in gene expression between ILC foci within patients, including known markers of ILC, suggesting an additional level of complexity that should be addressed.

Wang L, Zhang Y, Zhao L, et al.
MicroRNA-193b inhibits the proliferation, migration and invasion of gastric cancer cells via targeting cyclin D1.
Acta Histochem. 2016; 118(4):323-30 [PubMed] Related Publications
MicroRNAs have been involved in RNA silencing and post-transcriptional regulation of gene expression and also play important roles in tumorigenesis and tumor progression. MiR-193b was previously reported to act as tumor suppressor in diverse cancers. However, little is known about the expression, function and mechanism of miR-193b in gastric cancer (GC). In this study, we investigated the expression of miR-193b in 50 GC cases and found that miR-193b was significantly reduced in GC tissues compared with the adjacent normal gastric tissues. Moreover, lower-level of miR-193b was also associated with a more aggressive GC phenotype. We further demonstrated that miR-193b can inhibit the proliferation, migration and invasion of HGC-27 and MGC-803 GC cells. Further mechanism study indicated that CCND1 was a direct target of miR-193b in GC. Overexpression of miR-193b inhibited the expression of CCND1, and knock-down of CCND1 inhibited the proliferation of GC cells, suggesting that miR-193b exerted its anti-tumorigenic role in GC cells through targeting CCND1 gene.

Further References

Stamatopoulos K, Kosmas C, Belessi C, et al.
Molecular analysis of bcl-1/IgH junctional sequences in mantle cell lymphoma: potential mechanism of the t(11;14) chromosomal translocation.
Br J Haematol. 1999; 105(1):190-7 [PubMed] Related Publications
Mantle cell lymphoma (MCL) is characterized by the t(11;14) translocation that juxtaposes the bcl-1 locus to immunoglobulin (Ig) gene sequences and leads to deregulation of cyclin D1 gene. t(11;14) is thought to result from an error of the recombinase during D-JH Ig gene assembly; however, data on the underlying mechanism and candidate recombination-targeting motifs in the major translocation cluster (MTC) of the bcl-1 gene are lacking. bcl-1/IgH junctional sequences from seven MCL patients were amplified by PCR using primers targeting MTC and JH sequences on chromosomes 11q13 and 14q32, respectively. PCR products were directly sequenced and junctional sequences were searched for homology to known germline D genes. bcl-t MTC breakpoints were searched for the presence of possible recombination target motifs; heptamers, nonamers, binding sequence of the bp45 nuclease, x-like sequences and D gene segments. bcl-1/JH junctions were found to bear homology to D gene segments (DLR3, DM and DIR5) in 3/7 MCL samples. A computer-based search in previously published and/or submitted to GenBank bcl-1/JH junctional sequences identified homology to D genes in 1/4 MCL tumour samples and 1/4 MCl cell lines; DXP4 or D23/7 and DHQ52 or D22/21 or DXP5, respectively. The MTC locus contained motifs with homology to bp45 nuclease binding sequence, x-like sequences, heptamers/nonamers, D-like DIR genes and non-homologous recombination short (6 bp) DNA sequences. The above data indicate that the t(11;14) translocation in MCL may also occur at a more mature stage of B-cell ontogeny than previously thought, i.e. during VH-to-DJH rearrangement. Various known recombination motifs within MTC may contribute to an illegitimate recombination event between bcl-1 and DJH.

Espinet B, Solé F, Woessner S, et al.
Translocation (11;14)(q13;q32) and preferential involvement of chromosomes 1, 2, 9, 13, and 17 in mantle cell lymphoma.
Cancer Genet Cytogenet. 1999; 111(1):92-8 [PubMed] Related Publications
We have studied 13 cases of histologically confirmed mantle cell lymphomas (MCL) combining cytological-immunological features with conventional cytogenetics and in situ hybridization (ISH) techniques. Peripheral blood smears and lymph node biopsies expressed the typical mantle zone pattern with alpha B-cell phenotype. Most of the cases (11 of 13) had lymphomatous cells in the peripheral blood. Chromosome analysis was carried out on lymphoid cells from peripheral blood and/or lymph node biopsies. Phytohemagglutinin (PHA) and phorbol 12-myristate 13 acetate (TPA) were used as mitogens. Biotin-labeled libraries of whole chromosomes implicated in complex karyotypes were used to improve their interpretation. Clonal chromosome abnormalities were found in 10 of 13 patients (77%); 7 of these had a complex abnormality. The most frequent recurrent structural abnormalities were: t(11;14)(q13;q32), involvement of chromosome 1 (der[1], del[1], dup[1]), chromosome 2 (del[2], der[2]), chromosome 9 (der[9], -9), chromosome 13 (add[13], t[13q]), and chromosome 17 (add[17], der[17], t[17q]). The most frequent numerical abnormalities were monosomy 21 and loss of the Y chromosome.

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