CCND1

Gene Summary

Gene:CCND1; cyclin D1
Aliases: BCL1, PRAD1, U21B31, D11S287E
Location:11q13
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:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:G1/S-specific cyclin-D1
HPRD
Source:NCBIAccessed: 18 March, 2015

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 (1990-2015)
Graph generated 18 March 2015 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 18 March, 2015 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
Breast CancerCCND1 and Breast Cancer View Publications614
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 Publications497
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 Publications384
Lung CancerCCND1 and Lung Cancer View Publications176
Rectal CancerCCND1 and Rectal Cancer View Publications15
RhabdomyosarcomaCCND1 and Rhabdomyosarcoma View Publications8

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)

Al-Kawaaz M, Mathew S, Liu Y, et al.
Cyclin D1-positive diffuse large B-cell lymphoma with IGH-CCND1 translocation and BCL6 rearrangement: a report of two cases.
Am J Clin Pathol. 2015; 143(2):288-99 [PubMed] Related Publications
OBJECTIVES: To demonstrate and confirm the existence of cyclin D1-positive diffuse large B-cell lymphoma (DLBCL) with IGH-CCND1 rearrangement and discuss the rationale of differentiating this entity from blastoid and pleomorphic variants of mantle cell lymphoma (MCL).
METHODS: Two cyclin D1-positive lymphomas with morphologic features of DLBCL and IGH-CCND1 translocations were characterized with respect to clinical features, as well as morphologic, immunophenotypic, cytogenetic, and molecular findings.
RESULTS: The large tumor cells were CD20+, CD5-, CD10-, BCL6+, MUM1+, and cyclin D1+ in both cases. SOX11 was negative. Epstein-Barr virus-encoded RNA in situ hybridization demonstrated diffuse positivity in case 1. BCL6 and IGH-CCND1 rearrangements were identified by fluorescence in situ hybridization in both cases. Specifically, the diagnosis of a relapsed DLBCL with acquisition of IGH-CCND1 was rendered for case 1, molecularly confirmed by the detection of identical monoclonal IGH rearrangements between the initial diagnostic DLBCL and relapse lymphoma.
CONCLUSIONS: Our study demonstrates convincingly that IGH-CCND1 rearrangement leading to cyclin D1 overexpression can occur in DLBCL and pose a potential diagnostic pitfall, requiring thorough knowledge of the clinicopathologic findings to allow accurate discrimination from a blastoid or pleomorphic MCL. The coexistence of IGH-CCND1 and IGH-BCL6 rearrangements suggest that BCL6 and cyclin D1 may cooperate in the pathogenesis of DLBCL.

Xu Z, Zeng X, Tian D, et al.
MicroRNA-383 inhibits anchorage-independent growth and induces cell cycle arrest of glioma cells by targeting CCND1.
Biochem Biophys Res Commun. 2014; 453(4):833-8 [PubMed] Related Publications
In recent years, microRNAs (miRNAs) have been proved to be closely related to the tumorigenesis and progression. An increasing number of researches have shown that microRNAs function as oncogenes or tumor suppressor genes in human malignant tumors. This study aims to explore the effects of microRNA-383 (miR-383) on malignant biological function of human gliomas. We detected the expression of miR-383 in glioma tissues and normal brain tissues by quantitative real-time PCR. Anchorage-independent growth assays, and flow cytometry were used to evaluate the functions of miR-383 that involves in cell growth and cell cycle. Western blotting assay was used to examine protein expression levels of Cyclin D1 (CCND1), a cell cycle-associated oncogene which has a predicted binding site of miR-383 within its 3'-untranslated region (3'-UTR), and luciferase activity assay was used to evaluate the 3'-UTR activity of CCND1. In this study, we found that miR-383 expression level was lower in gliomas than normal brain tissues. Overexpression of miR-383 in U251 and U87 cells showed a significant inhibitory effect on cell growth, which accompanied with cell cycle G0/G1 arrest as well as downregulation of CCND1 expression. Moreover, CCND1 was verified to be one of the direct targets of miR-383. In summary, this study suggested that miR-383 plays the role of tumor suppressor by targeting CCND1 in glioma cells, and may be useful for developing a new therapeutic strategy for gliomas.

Zhong S, Ma T, Zhang X, et al.
MicroRNA expression profiling and bioinformatics analysis of dysregulated microRNAs in vinorelbine-resistant breast cancer cells.
Gene. 2015; 556(2):113-8 [PubMed] Related Publications
Vinorelbine (NVB) is one of the most active cytotoxic agents in breast cancer, especially metastatic breast cancer. However, breast cancer patients who are treated with the drug often develop resistance to it and some other drugs. Recently studies have shown that microRNAs (miRNAs) play an important role in drug resistance. In present study, miRNA expression profiles of breast cancer cells MDA-MB-231/S and its NVB-resistant variant MDA-MB-231/NVB cells were analyzed using microarray and the results were confirmed by real-time quantitative polymerase chain reaction. Bioinformatic analyses were carried out to predict gene targets of the dysregulated miRNAs and to analyze their potential roles in the development of drug resistance. Here, 123 differentially expressed miRNAs were identified in the resistant subline compared to MDA-MB-231/S. Networks of KEGG pathways, Gene Ontology (GO) terms, and protein-protein interaction (PPI) of 17 specific selected dysregulated miRNAs were constructed. The results showed that MAPK, mTOR, Wnt, and TGF-beta signaling pathways and several target genes such as CCND1, GRB2 and NT5E may associate with drug resistance of breast cancer cells to NVB. In summary, this study demonstrates that altered miRNA expression pattern is involved in acquiring resistance to NVB in breast cancer MDA-MB-231 cells. All these analysis results provided us a comprehensive view of the function of differential expression miRNAs related to drug resistance of breast cancer and may be helpful for the further study.

Liu H, Shi D, Liu T, et al.
Lentivirus-mediated silencing of SCIN inhibits proliferation of human lung carcinoma cells.
Gene. 2015; 554(1):32-9 [PubMed] Related Publications
SCIN (scinderin) is a calcium-dependent actin severing and capping protein. Homologue in zebrafish has been found to be related with cell death. In the present study, we found that SCIN is highly expressed in human lung cancer specimens. However, the role of SCIN in lung cancer has not yet been determined. To investigate the function of SCIN in lung carcinoma cells, we took advantage of lentivirus-mediated RNA interference (RNAi) to knockdown SCIN expression in two lung carcinoma cell lines A549 and H1299. Silencing of SCIN significantly inhibited the proliferation and colony formation ability of both cell lines in vitro. Moreover, flow cytometry analysis showed that knockdown of SCIN led to G0/G1 phase cell cycle arrest as well as an excess accumulation of cells in the sub-G1 phase. Furthermore, depletion of SCIN resulted in a significant increase in Cyclin B1, p21 and PARP expression, and a little decrease in Cyclin D1 expression. These results suggest that SCIN plays an important role in lung carcinoma cell proliferation, and lentivirus-mediated silencing of SCIN might be a potential therapeutic approach for the treatment of lung cancer.

Pletneva MA, Andea A, Palanisamy N, et al.
Clear cell melanoma: a cutaneous clear cell malignancy.
Arch Pathol Lab Med. 2014; 138(10):1328-36 [PubMed] Related Publications
Clear cell melanoma is a rare clear cell malignancy. Accurate diagnosis of clear cell melanoma requires integration of immunohistochemical and morphologic findings, with molecular studies to rule out clear cell sarcoma. The differential diagnosis includes melanoma, carcinoma, perivascular epithelioid cell tumor, and epidermotropic clear cell sarcoma. We use a case of a lesion on the helix of an 86-year-old man as an example. Histologic examination revealed an ulcerated clear cell malignant tumor. Tumor cell cytoplasm contained periodic acid-Schiff-positive, diastase-sensitive glycogen. Tumor cells showed positive labeling for S100, HMB-45, and Melan-A, and negative labeling for cytokeratins, p63, and smooth muscle actin. Molecular studies demonstrated BRAF V600E mutation, copy gains at the 6p25 (RREB1) and 11q13 (CCND1) loci, and absence of EWSR1-ATF1 fusion. These findings supported a diagnosis of clear cell melanoma. The rare pure clear cell morphology occurs due to accumulation of intracytoplasmic glycogen. We review the differential diagnosis of clear cell melanoma and describe the utility of immunohistochemical and molecular studies in confirming this diagnosis.

Neves RP, Raba K, Schmidt O, et al.
Genomic high-resolution profiling of single CKpos/CD45neg flow-sorting purified circulating tumor cells from patients with metastatic breast cancer.
Clin Chem. 2014; 60(10):1290-7 [PubMed] Related Publications
BACKGROUND: Circulating tumor cells (CTCs) are promising surrogate markers for systemic disease, and their molecular characterization might be relevant to guide more individualized cancer therapies. To enable fast and efficient purification of individual CTCs, we developed a work flow from CellSearch(TM) cartridges enabling high-resolution genomic profiling on the single-cell level.
METHODS: Single CTCs were sorted from 40 CellSearch samples from patients with metastatic breast cancer using a MoFlo XDP cell sorter. Genomes of sorted single cells were amplified using an adapter-linker PCR. Amplification products were analyzed by array-based comparative genomic hybridization, a gene-specific quantitative PCR (qPCR) assay for cyclin D1 (CCND1) locus amplification, and genomic sequencing to screen for mutations in exons 1, 9, and 20 of the phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene and exons 5, 7, and 8 of the tumor protein p53 (TP53) gene.
RESULTS: One common flow-sorting protocol was appropriate for 90% of the analyzed CellSearch cartridges, and the detected CTC numbers correlated positively with those originally detected with the CellSearch system (R(2) = 0.9257). Whole genome amplification was successful in 72.9% of the sorted single CTCs. Over 95% of the cells displayed chromosomal aberrations typical for metastatic breast cancers, and amplifications at the CCND1 locus were validated by qPCR. Aberrant CTCs from 2 patients harbored mutations in exon 20 of the PIK3CA gene.
CONCLUSIONS: This work flow enabled effective CTC isolation and provided insights into genomic alterations of CTCs in metastatic breast cancer. This approach might facilitate further molecular characterization of rare CTCs to increase understanding of their biology and as a basis for their molecular screening in the clinical setting.

Andl T, Le Bras GF, Richards NF, et al.
Concerted loss of TGFβ-mediated proliferation control and E-cadherin disrupts epithelial homeostasis and causes oral squamous cell carcinoma.
Carcinogenesis. 2014; 35(11):2602-10 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Although the etiology of squamous cell carcinomas of the oral mucosa is well understood, the cellular origin and the exact molecular mechanisms leading to their formation are not. Previously, we observed the coordinated loss of E-cadherin (CDH1) and transforming growth factor beta receptor II (TGFBR2) in esophageal squamous tumors. To investigate if the coordinated loss of Cdh1 and Tgfbr2 is sufficient to induce tumorigenesis in vivo, we developed two mouse models targeting ablation of both genes constitutively or inducibly in the oral-esophageal epithelium. We show that the loss of both Cdh1 and Tgfbr2 in both models is sufficient to induce squamous cell carcinomas with animals succumbing to the invasive disease by 18 months of age. Advanced tumors have the ability to invade regional lymph nodes and to establish distant pulmonary metastasis. The mouse tumors showed molecular characteristics of human tumors such as overexpression of Cyclin D1. We addressed the question whether TGFβ signaling may target known stem cell markers and thereby influence tumorigenesis. From our mouse and human models, we conclude that TGFβ signaling regulates key aspects of stemness and quiescence in vitro and in vivo. This provides a new explanation for the importance of TGFβ in mucosal homeostasis.

Hoskins JW, Jia J, Flandez M, et al.
Transcriptome analysis of pancreatic cancer reveals a tumor suppressor function for HNF1A.
Carcinogenesis. 2014; 35(12):2670-8 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is driven by the accumulation of somatic mutations, epigenetic modifications and changes in the micro-environment. New approaches to investigating disruptions of gene expression networks promise to uncover key regulators and pathways in carcinogenesis. We performed messenger RNA-sequencing in pancreatic normal (n = 10) and tumor (n = 8) derived tissue samples, as well as in pancreatic cancer cell lines (n = 9), to determine differential gene expression (DE) patterns. Sub-network enrichment analyses identified HNF1A as the regulator of the most significantly and consistently dysregulated expression sub-network in pancreatic tumor tissues and cells (median P = 7.56×10(-7), median rank = 1, range = 1-25). To explore the effects of HNF1A expression in pancreatic tumor-derived cells, we generated stable HNF1A-inducible clones in two pancreatic cancer cell lines (PANC-1 and MIA PaCa-2) and observed growth inhibition (5.3-fold, P = 4.5×10(-5) for MIA PaCa-2 clones; 7.2-fold, P = 2.2×10(-5) for PANC-1 clones), and a G0/G1 cell cycle arrest and apoptosis upon induction. These effects correlated with HNF1A-induced down-regulation of 51 of 84 cell cycle genes (e.g. E2F1, CDK2, CDK4, MCM2/3/4/5, SKP2 and CCND1), decreased expression of anti-apoptotic genes (e.g. BIRC2/5/6 and AKT) and increased expression of pro-apoptotic genes (e.g. CASP4/9/10 and APAF1). In light of the established role of HNF1A in the regulation of pancreatic development and homeostasis, our data suggest that it also functions as an important tumor suppressor in the pancreas.

Liu Y, Patel L, Mills GB, et al.
Clinical significance of CTNNB1 mutation and Wnt pathway activation in endometrioid endometrial carcinoma.
J Natl Cancer Inst. 2014; 106(9) [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Endometrioid endometrial carcinoma (EEC) is the most common form of endometrial carcinoma. The heterogeneous clinical course of EEC is an obstacle to individualized patient care.
METHODS: We performed an integrated analysis on the multiple-dimensional data types including whole-exome and RNA sequencing, RPPA profiling, and clinical data from 271 EEC cases in The Cancer Genome Atlas (TCGA) to identify molecular fingerprints that may account for this clinical heterogeneity. Significance analysis of microarray was used to identify marker genes of each subtype that were subject to pathway analysis. Association of molecular subtypes with clinical features and mutation data was analyzed with the Mann Whitney, Chi-square, Fisher's exact, and Kruskal-Wallis tests. Survival analysis was evaluated with log-rank test. All statistical tests were two-sided.
RESULTS: Four transcriptome subtypes with distinct clinicopathologic characteristics and mutation spectra were identified from the TCGA dataset and validated in an independent sample cohort of 184 EEC cases. Cluster II consisted of younger, obese patients with low-grade EEC but diminished survival. CTNNB1 exon 3 mutations were present in 87.0% (47/54) of Cluster II (P < .001) that exhibited a low overall mutation rate; this was statistically significantly associated with Wnt/β-catenin signaling activation (P < .001). High expression levels of CTNNB1 (P = .001), MYC (P = .01), and CCND1 (P = .01) were associated with poorer overall survival in low-grade EEC tumors.
CONCLUSIONS: CTNNB1 exon 3 mutations are likely a driver that characterize an aggressive subset of low-grade and low-stage EEC occurring in younger women.

Kuo HW, Huang CY, Fu CK, et al.
The significant association of CCND1 genotypes with gastric cancer in Taiwan.
Anticancer Res. 2014; 34(9):4963-8 [PubMed] Related Publications
BACKGROUND AND AIM: Gastric cancer is one of the most common malignant tumors worldwide. Due to the complex initiation and intricate progression mechanisms, early detection and effective treatment of gastric cancer are both difficult to achieve. The genetic polymorphisms encoding critical protein cyclin D1 (CCND1) to regulate cell cycle transition from G1 phase to S phase may determine the susceptibility of individuals to gastric cancer. The study aimed to examine the contribution of CCND1 genotypes to gastric cancer risk in Taiwan.
MATERIALS AND METHODS: The genotypes of CCND1 A870G (rs9344) and G1722C (rs678653) were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis among 358 gastric patients and 358 cancer-free controls, and the distribution of genotypic and allelic frequencies among the two groups were compared.
RESULTS: The results showed that there were significant differences between gastric cancer and control groups in the distribution of the genotypes (p=6.86×10(-4)) and allelic frequency (p=0.0016) in the CCND1 A870G genotype. In addition, individuals who carried the AG or GG genotype had 0.55- and 0.51-fold of odds ratios of developing gastric cancer compared to those who carried the AA genotype (95% confidence intervals [CI]=0.39-0.76 and 0.32-0.81, respectively). There was no such association of CCND1 G1722C with gastric cancer. Furthermore, there was an obvious interaction of the CCND1 A870G genotype with personal smoking habit on gastric cancer risk (p=0.0005).
CONCLUSION: Cell-cycle regulation may play a role in gastric cancer initiation and development and the CCND1 A870G genotype maybe a useful biomarker for detection of early gastric cancer.

Gao YB, Chen ZL, Li JG, et al.
Genetic landscape of esophageal squamous cell carcinoma.
Nat Genet. 2014; 46(10):1097-102 [PubMed] Related Publications
Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers. We performed exome sequencing on 113 tumor-normal pairs, yielding a mean of 82 non-silent mutations per tumor, and 8 cell lines. The mutational profile of ESCC closely resembles those of squamous cell carcinomas of other tissues but differs from that of esophageal adenocarcinoma. Genes involved in cell cycle and apoptosis regulation were mutated in 99% of cases by somatic alterations of TP53 (93%), CCND1 (33%), CDKN2A (20%), NFE2L2 (10%) and RB1 (9%). Histone modifier genes were frequently mutated, including KMT2D (also called MLL2; 19%), KMT2C (MLL3; 6%), KDM6A (7%), EP300 (10%) and CREBBP (6%). EP300 mutations were associated with poor survival. The Hippo and Notch pathways were dysregulated by mutations in FAT1, FAT2, FAT3 or FAT4 (27%) or AJUBA (JUB; 7%) and NOTCH1, NOTCH2 or NOTCH3 (22%) or FBXW7 (5%), respectively. These results define the mutational landscape of ESCC and highlight mutations in epigenetic modulators with prognostic and potentially therapeutic implications.

Govatati S, Singamsetty GK, Nallabelli N, et al.
Contribution of cyclin D1 (CCND1) and E-cadherin (CDH1) alterations to colorectal cancer susceptibility: a case-control study.
Tumour Biol. 2014; 35(12):12059-67 [PubMed] Related Publications
Cyclin D1 (CCND1) and E-cadherin (CDH1) are two important genes of the β-catenin/LEF pathway that is involved in tumorigenesis of various cancers including colorectal cancer (CRC). However, studies of the association between genetic variants of these two genes and CRC have shown conflicting results. We conducted a genetic association study in South Indian population (cases, 103; controls, 107) to assess the association of CCND1 870G/A and CDH1 -160C/A single nucleotide polymorphisms (SNPs) with CRC risk. Genotyping of SNPs was performed by PCR sequencing analysis. Haplotype frequencies for multiple loci and the standardized disequilibrium coefficient (D') for pair-wise linkage disequilibrium (LD) were assessed by Haploview Software. In addition, to better understand the role of CCND1 and CDH1 in the pathophysiology of CRC, the expression pattern was evaluated in analogous tumor and adjacent normal tissues from 23 CRC patients by Western blot analysis. The frequencies of CCND1 870A/A (P = 0.045) genotype, CDH1 -160A allele (P = 0.042), and 870A/-160A haplotype (P = 0.002) were significantly higher in patients as compared with controls. Strong LD was observed between 870G/A and -160C/A SNPs in cases (D' = 0.76) as compared to controls (D' = 0.32). Furthermore, elevated CCND1 and diminished CDH1 expression was observed in tumor tissue as compared with analogous normal tissue of CRC patients. Interestingly, advanced-stage tumors showed wider expression alterations than in early-stage tumors. In conclusion, CCND1 870G/A and CDH1 -160C/A SNPs may modify the risk of CRC susceptibility in South Indian population. In addition, elevated CCND1 and diminished CDH1 expression appears to be useful prognostic markers for CRC.

Shuai S, Yan X, Zhang J, et al.
TIP30 nuclear translocation negatively regulates EGF-dependent cyclin D1 transcription in human lung adenocarcinoma.
Cancer Lett. 2014; 354(1):200-9 [PubMed] Related Publications
Aberrant epidermal growth factor (EGF)-dependent signaling plays a key role in the progression of human carcinomas. We found that TIP30, a tumor suppressor protein, translocated into the nucleus of human lung adenocarcinoma cells following EGF treatment, and the selective inhibitors of EGFR signaling pathways blocked this effect. Chromatin immunoprecipitation assays revealed that TIP30 negatively regulated EGF-dependent transcriptional activation of CCND1 through a HDAC1-dependent mechanism. In lung adenocarcinoma patients, the level of nuclear TIP30 was inversely correlated with that of EGFR and cyclin D1. These findings suggest that nuclear TIP30-induced downregulation of cyclin D1 transcription antagonizes EGFR signaling and suppresses tumorigenesis.

Li Z, Li X, Li C, et al.
Transcription factor OCT4 promotes cell cycle progression by regulating CCND1 expression in esophageal carcinoma.
Cancer Lett. 2014; 354(1):77-86 [PubMed] Related Publications
The CCND1 gene is overexpressed in esophageal cancer and accelerates cell cycle progression. However, the mechanism whereby the upstream genes or factors directly regulate CCND1 expression remains unknown. By analyzing the 5'-UTR region of the CCND1 gene, we found that this region contains an octamer motif (ATTTTGCAT), which suggests that the expression of CCND1 might be directly associated with octamer-binding transcription factor 4 (OCT4). In this study, the wild-type and the octamer motif-mutanted CCND1 promoters were cloned, and their corresponding luciferase reporter vectors were then constructed to study the molecular mechanism by which OCT4 regulates the expression of CCND1 and influences the biological behaviors of esophageal cancer cells. The results indicated that suppressing the expression of CCND1 and OCT4 in esophageal cancer cells reduced cell proliferative and invasive abilities, induced cell cycle G1-phase arrest, and slowed the growth of xenografts in nude mice. Suppression of OCT4 expression significantly decreased the wild-type CCND1 promoter activity and down-regulated the expression of CCND1, but did not affect the activity of the mutant promoter. Whereas, suppression of CCND1 did not affect OCT4 expression, suggesting that OCT4 regulates CCND1 expression by activating the CCND1 promoter and subsequently promoting cell cycle progression. The results revealed and confirmed that OCT4 is the upstream factor that directly binds to the CCND1 promoter to regulate CCND1 expression, then to promote cell cycle progression and accelerate the proliferation and invasion of esophageal cancer cells. This finding may significantly contribute to elucidating the regulatory mechanism involved in the cell cycle progression of esophageal cancer cells and may aid in screening potential gene targets for the biological therapy of esophageal cancer.

Ali A, Shah AS, Ahmad A
Gain-of-function of mutant p53: mutant p53 enhances cancer progression by inhibiting KLF17 expression in invasive breast carcinoma cells.
Cancer Lett. 2014; 354(1):87-96 [PubMed] Related Publications
Kruppel-like-factor 17 (KLF17) is a negative regulator of metastasis and epithelial-mesenchymal-transition (EMT). However, its expression is downregulated in metastatic breast cancer that contains p53 mutations. Here, we show that mutant-p53 plays a key role to suppress KLF17 and thereby enhances cancer progression, which defines novel gain-of-function (GOF) of mutant-p53. Mutant-p53 interacts with KLF17 and antagonizes KLF17 mediated EMT genes transcription. Depletion of KLF17 promotes cell viability, decreases apoptosis and induces drug resistance in metastatic breast cancer cells. KLF17 suppresses cell migration and invasion by decreasing CD44, PAI-1 and Cyclin-D1 expressions. Taken together, our results show that KLF17 is important for the suppression of metastasis and could be a potential therapeutic target during chemotherapy.

Cui YM, Jiang D, Zhang SH, et al.
FOXC2 promotes colorectal cancer proliferation through inhibition of FOXO3a and activation of MAPK and AKT signaling pathways.
Cancer Lett. 2014; 353(1):87-94 [PubMed] Related Publications
Abnormal expression of FOXC2 has been found in several human cancers. However, the role of FOXC2 in the progression of colorectal cancer (CRC) has not been well characterized. In analysis of 206 CRC specimens, we revealed that both high expression and nuclear localization of FOXC2 were correlated to aggressive characteristics and poor survival of patients with CRC. FOXC2 promoted cell proliferation through activation of MAPK and AKT pathways, subsequently down-regulating p27, up-regulating cyclin D1 and p-FOXO3a. Furthermore, FOXC2 nuclear localization was required for its promotion of cell proliferation. These findings suggest that FOXC2 plays an essential role in CRC progression and may serve as a valuable clinical prognostic marker of this disease.

Georgiadou D, Sergentanis TN, Sakellariou S, et al.
Cyclin D1, p16(INK) (4A) and p27(Kip1) in pancreatic adenocarcinoma: assessing prognostic implications through quantitative image analysis.
APMIS. 2014; 122(12):1230-9 [PubMed] Related Publications
The prognostic significance of cyclin D1, p16(INK) (4A) and p27(Kip1) expression has been documented in several human malignancies; however, their prognostic potential in pancreatic adenocarcinoma is still unclear. This study aimed to assess the correlation of the aforementioned molecules with clinicopathological parameters and prognosis. Sixty patients with pancreatic ductal adenocarcinoma underwent surgical resection at a single institution; immunohistochemical staining of the studied markers was quantified by Ιmage analysis system. Cyclin D1 overexpression was positively associated with grade, neural infiltration and vascular invasion, whereas p27 positively correlated with age. Higher cyclin D1 expression indicated poorer survival (adjusted HR = 9.75, 95%CI: 1.48-64.31, p = 0.018, increment: one unit in H-score), whereas a marginal trend toward an association between p16 positivity and improved survival was observed (adjusted HR = 0.58, 95%CI: 0.32-1.05, p = 0.072 regarding positive vs negative cases). No significant association with overall survival was noted regarding p27. In conclusion, cyclin D1 overexpression and possibly p16 loss of expression in pancreatic adenocarcinoma seem to be adverse prognostic factors, whereas p27 expression did not seem to possess such prognostic properties. Further validation of the present findings in studies encompassing larger samples seems to be needed.

Malik D, Kaul D, Chauhan N, Marwaha RK
miR-2909-mediated regulation of KLF4: a novel molecular mechanism for differentiating between B-cell and T-cell pediatric acute lymphoblastic leukemias.
Mol Cancer. 2014; 13:175 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: microRNAs (miRNAs) play both oncogenic and oncostatic roles in leukemia. However, the molecular details underlying miRNA-mediated regulation of their target genes in pediatric B- and T-cell acute lymphoblastic leukemias (ALLs) remain unclear. The present study investigated the relationship between miR-2909 and Kruppel-like factor 4 (KLF4), and its functional relevance to cell cycle progression and immortalization in patients with pediatric ALL.
METHODS: Elevated levels of miR-2909 targeted the tumor suppressor gene KLF4 in pediatric B-cell, but not pediatric T-cell ALL, as detected by pMIR-GFP reporter assay. Expression levels of genes including apoptosis-antagonizing transcription factor (AATF), MYC, B-cell lymphoma (BCL3), P21CIP, CCND1 and SP1 in B- and T-cells from patients with pediatric ALL were compared with control levels using real-time quantitative reverse transcription polymerase chain reaction, western blotting, and reporter assays.
RESULTS: We identified two novel mutations in KLF4 in pediatric T-ALL. A mutation in the 3' untranslated region of the KLF4 gene resulted in loss of miR-2909-mediated regulation, while mutation in its first or third zinc-finger motif (Zf1/Zf3) rendered KLF4 transcriptionally inactive. This mutation was a frameshift mutation resulting in alteration of the Zf3 motif sequence in the mutant KLF4 protein in all pediatric T-ALL samples. Homology models, docking studies and promoter activity of its target gene P21CIP confirmed the lack of function of the mutant KLF4 protein in pediatric T-ALL. Moreover, the inability of miR-2909 to regulate KLF4 and its downstream genes controlling cell cycle and apoptosis in T-cell but not in B-ALL was verified by antagomiR-2909 transfection. Comprehensive sequence analysis of KLF4 identified the predominance of isoform 1 (~55 kDa) in most patients with pediatric B-ALL, while those with pediatric T-ALL expressed isoform 2 (~51 kDa).
CONCLUSIONS: This study identified a novel miR-2909-KLF4 molecular axis able to differentiate between the pathogeneses of pediatric B- and T-cell ALLs, and which may represent a new diagnostic/prognostic marker.

Wang X, Qian H, Zhang S
Discovery of significant pathways in breast cancer metastasis via module extraction and comparison.
IET Syst Biol. 2014; 8(2):47-55 [PubMed] Related Publications
Discovering significant pathways rather than single genes or small gene sets involved in metastasis is becoming more and more important in the study of breast cancer. Many researches have shed light on this problem. However, most of the existing works are relying on some priori biological information, which may bring bias to the models. The authors propose a new method that detects metastasis-related pathways by identifying and comparing modules in metastasis and non-metastasis gene co-expression networks. The gene co-expression networks are built by Pearson correlation coefficients, and then the modules inferred in these two networks are compared. In metastasis and non-metastasis networks, 36 and 41 significant modules are identified. Also, 27.8% (metastasis) and 29.3% (non-metastasis) of the modules are enriched significantly for one or several pathways with p-value <0.05. Many breast cancer genes including RB1, CCND1 and TP53 are included in these identified pathways. Five significant pathways are discovered only in metastasis network: glycolysis pathway, cell adhesion molecules, focal adhesion, stathmin and breast cancer resistance to antimicrotubule agents, and cytosolic DNA-sensing pathway. The first three pathways have been proved to be closely associated with metastasis. The rest two can be taken as a guide for future research in breast cancer metastasis.

Poi MJ, Knobloch TJ, Sears MT, et al.
Coordinated expression of cyclin-dependent kinase-4 and its regulators in human oral tumors.
Anticancer Res. 2014; 34(7):3285-92 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
BACKGROUND/AIM: While aberrant expression of cyclin-dependent kinase-4 (CDK4) has been found in squamous cell carcinoma of the head and neck (SCCHN), the associations between CDK4 and its regulators, namely, cyclin D1, cyclin E, gankyrin, SEI1, and BMI1 in gene expression remain to be explored. Herein we investigated the mRNA profiles of these oncogenes and their interrelations in different oral lesion tissues.
MATERIALS AND METHODS: Thirty SCCHN specimens and patient-matched high at-risk mucosa (HARM) and 16 healthy control specimens were subjected to quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses.
RESULTS: The mRNA levels of CDK4, cyclin D1, gankyrin, SEI1, BMI1 were significantly elevated in both HARM and SCCHN (in comparison with control specimens), and statistically significant correlations were found among these markers in gene expression.
CONCLUSION: Up-regulation of CDK4 and its regulators takes place in oral cancer progression in a coordinate manner, and HARM and SCCHN share a similar molecular signature within the CDK4-pRB pathway.

Ross JS, Wang K, Elkadi OR, et al.
Next-generation sequencing reveals frequent consistent genomic alterations in small cell undifferentiated lung cancer.
J Clin Pathol. 2014; 67(9):772-6 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
AIMS: Small cell lung cancer (SCLC) carries a poor prognosis, and the systemic therapies currently used as treatments are only modestly effective, as demonstrated by a low 5-year survival at only ∼5%. In this retrospective collected from March 2013 to study, we performed comprehensive genomic profiling of 98 small cell undifferentiated lung cancer (SCLC) samples to identify potential targets of therapy not currently searched for in routine clinical practice.
METHODS: DNA from 98 SCLC was sequenced to high, uniform coverage (Illumina HiSeq 2500) and analysed for all classes of genomic alterations.
RESULTS: A total of 386 alterations were identified for an average of 3.9 alterations per tumour (range 1–10). Fifty-two (53%) of cases harboured at least 1 actionable alteration with the potential to personalise therapy including base substitutions, amplifications or homozygous deletions in RICTOR (10%), KIT (7%), PIK3CA (6%), EGFR (5%), PTEN (5%), KRAS (5%), MCL1 (4%), FGFR1 (4%), BRCA2, (4%), TSC1 (3%), NF1 (3%), EPHA3 (3%) and CCND1. The most common non-actionable genomic alterations were alterations in TP53 (86% of SCLC cases), RB1 (54%) and MLL2 (17%).
CONCLUSIONS: Greater than 50% of the SCLC cases harboured at least one actionable alteration. Given the limited treatment options and poor prognosis of patients with SCLC, comprehensive genomic profiling has the potential to identify new treatment paradigms and meet an unmet clinical need for this disease.

Wang T, Li Y, Wang W, et al.
Twist2, the key Twist isoform related to prognosis, promotes invasion of cervical cancer by inducing epithelial-mesenchymal transition and blocking senescence.
Hum Pathol. 2014; 45(9):1839-46 [PubMed] Related Publications
In response to tumor development, cells initially undergo invasion and metastasis followed by epithelial-mesenchymal transition (EMT, a process by which cells acquire motility) and overriding senescence (an endogenous defense mechanism against tumor progression). Oncogenic activation of Twist1 and Twist2 is essential for EMT and senescence; however, little is known about the specific contributions of Twist1 versus Twist2 to prognosis, metastasis, and the mechanism underlying cervical carcinoma. Here, we investigated the similarities and differences between Twist1 and Twist2 in assessing prognosis and promoting invasion and metastasis of cervical carcinoma as well as their roles in the underlying molecular mechanisms. By monitoring the survival of 144 clinical cervical cancer patients, we demonstrated that Twist2 shows more effective predictive performance compared with Twist1 and is more closely correlated with International Federation of Gynecology and Obstetrics stage and lymph node metastasis. Compared with Twist1, Twist2 more strongly promotes invasivity and motility by inducing EMT and overriding senescence. Differences between Twist1 and Twist2 in regulating senescence and the cell cycle might be due to their individual roles in regulating the cyclin D1/cyclin dependent kinase 4 (Cdk4) pathway. Overall, our data indicate that Twist2 is the key Twist isoform coupling aberrant signals from EMT to senescence and is an important candidate biomarker for cervical cancer prognosis.

Weilandt M, Koch A, Rieder H, et al.
Target genes of recurrent chromosomal amplification and deletion in urothelial carcinoma.
Cancer Genomics Proteomics. 2014 May-Jun; 11(3):141-53 [PubMed] Related Publications
BACKGROUND: Urothelial carcinoma (UC) is characterized by multiple recurrent chromosomal changes on a background of increasing genomic instability. To define target genes of recurrent deletions and amplifications, we explored which gene alterations are common in UC, in two recently established cell lines, BC44 and BC61.
MATERIALS AND METHODS: Genes located in regions of gain or deletion in the cell lines were identified by array comparative genomic hybridization (aCGH). Six published microarray datasets were analyzed for genes differentially expressed between urothelial tumor vs. normal tissues. Gene expression and chromosomal changes were compared in BC61 cells.
RESULTS: The cell lines share homozygous deletions at 9p21 around CDKN2A and amplifications at 11q13.2 around CCND1. In both cell lines 11 genes were commonly lost and 115 gained. Across UC in general, 230 genes were expressed stronger and 349 weaker; a subset displaying corresponding genetic changes in the cell lines. The commonly affected subset contains well-investigated genes like E2F1 and CCNE1, but also several genes not yet sufficiently investigated in UC.
DISCUSSION: Our approach highlights genes involved in cell cycle regulation, apoptosis and signal transduction as commonly deregulated across UC. Nevertheless, many chromosomal regions undergoing recurrent changes harbor several commonly deregulated genes that may act jointly in UC development and progression.

Li W, Li K, Zhao L, Zou H
Bioinformatics analysis reveals disturbance mechanism of MAPK signaling pathway and cell cycle in Glioblastoma multiforme.
Gene. 2014; 547(2):346-50 [PubMed] Related Publications
BACKGROUND & OBJECTIVES: To analyze the reversal gene pairs and identify featured reversal genes related to mitogen-activated protein kinases (MAPK) signaling pathway and cell cycle in Glioblastoma multiforme (GBM) to reveal its pathogenetic mechanism.
METHODS: We downloaded the gene expression profile GSE4290 from the Gene Expression Omnibus database, including 81 gene chips of GBM and 23 gene chips of controls. The t test was used to analyze the DEGs (differentially expressed genes) between 23 normal and 81 GBM samples. Then some perturbing metabolic pathways, including MAPK (mitogen-activated protein kinases) and cell cycle signaling pathway, were extracted from KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway database. Cancer genes were obtained from the database of Cancer Gene Census. The reversal gene pairs between DEGs and cancer genes were further analyzed in MAPK and cell cycle signaling pathway.
RESULTS: A total 8523 DEGs were obtained including 4090 up-regulated and 4433 down-regulated genes. Among them, ras-related protein rab-13(RAB13), neuroblastoma breakpoint family member 10 (NBPF10) and disks large homologue 4 (DLG4) were found to be involved in GBM for the first time. We obtained MAPK and cell cycle signaling pathways from KEGG database. By analyzing perturbing mechanism in these two pathways, we identified several reversal gene pairs, including NRAS (neuroblastoma RAS) and CDK2 (cyclin-dependent kinase 2), CCND1 (cyclin D1) and FGFR (fibroblast growth factor receptor). Further analysis showed that NRAS and CDK2 were positively related with GBM. However, FGFR2 and CCND1 were negatively related with GBM.
INTERPRETATION & CONCLUSIONS: These findings suggest that newly identified DEGs and featured reversal gene pairs participated in MAPK and cell cycle signaling pathway may provide a new therapeutic line of approach to GBM.

Guo L, Chen S, Jiang H, et al.
The expression of S100P increases and promotes cellular proliferation by increasing nuclear translocation of β-catenin in endometrial cancer.
Int J Clin Exp Pathol. 2014; 7(5):2102-12 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
There is increasing evidence suggesting that S100P has a significant role in cancer, and is associated with poor clinical outcomes. The expression of S100P mRNA and protein in endometrial cancer and normal endometrium tissues was detected by real-time quantitative RT-PCR and immunohistochemistry. Moreover, we reduced the expression of S100P in HEC-1A and Ishikawa endometrial cancer cell lines by siRNA transfection. Based on the reduced S100P mRNA expression, we measured the effects of S100P on cellular proliferation by the cell-counting kit-8. Nuclear β-catenin protein level was detected by western blotting. Cyclin D1 and c-myc mRNA expression regulated by β-catenin was detected by real-time quantitative RT-PCR. We found that the expression of S100P mRNA and protein increased in endometrial cancer tissues compared with the normal endometrium. Local S100P expression progressively increased from pathologic differenciation grade 1 to 3. After reducing the S100P expression, the cellular proliferation ability, nuclear β-catenin protein level, cyclin D1 and c-myc mRNA levels reduced. It indicated that S100P could promote cell proliferation by increasing nuclear translocation of β-catenin. The expression of S100P mRNA and protein in endometrial cancer significantly increased and is associated with pathologic differenciation grade. S100P may promote endometrial cell proliferation by increasing nuclear translocation of β-catenin.

Pysz MA, Hao F, Hizli AA, et al.
Differential regulation of cyclin D1 expression by protein kinase C α and ϵ signaling in intestinal epithelial cells.
J Biol Chem. 2014; 289(32):22268-83 [PubMed] Article available free on PMC after 08/08/2015 Related Publications
Cellular accumulation of cyclin D1, a key regulator of cell proliferation and tumorigenesis, is subject to tight control. Our previous studies have identified PKCα as a negative regulator of cyclin D1 in the intestinal epithelium. However, treatment of non-transformed IEC-18 ileal crypt cells with PKC agonists has a biphasic effect on cyclin D1 expression. Initial PKCα-mediated down-regulation is followed by recovery and subsequent accumulation of the cyclin to levels markedly higher than those seen in untreated cells. Using protein overexpression strategies, siRNA, and pharmacological inhibitors, we now demonstrate that the recovery and hyperinduction of cyclin D1 reflect the combined effects of (a) loss of negative signals from PKCα due to agonist-induced PKCα down-regulation and (b) positive effects of PKCϵ. PKCϵ-mediated up-regulation of cyclin D1 requires sustained ERK stimulation and transcriptional activation of the proximal cyclin D1 (CCDN1) promoter, without apparent involvement of changes in protein stability or translation. PKCϵ also up-regulates cyclin D1 expression in colon cancer cells, through mechanisms that parallel those in IEC-18 cells. Although induction of cyclin D1 by PKCϵ is dependent on non-canonical NF-κB activation, the NF-κB site in the proximal promoter is not required. Instead, cyclin D1 promoter activity is regulated by a novel interaction between NF-κB and factors that associate with the cyclic AMP-response element adjacent to the NF-κB site. The differential effects of PKCα and PKCϵ on cyclin D1 accumulation are likely to contribute to the opposing tumor-suppressive and tumor-promoting activities of these PKC family members in the intestinal epithelium.

Liu Q, Boudot A, Ni J, et al.
Cyclin D1 and C/EBPβ LAP1 operate in a common pathway to promote mammary epithelial cell differentiation.
Mol Cell Biol. 2014; 34(16):3168-79 [PubMed] Article available free on PMC after 08/08/2015 Related Publications
Both cyclin D1 and the transcription factor C/EBPβ are required for mammary epithelial cell differentiation; however, the pathway in which they operate is uncertain. Previous analyses of the patterns of gene expression in human tumors suggested a connection between cyclin D1 overexpression and C/EBPβ, but whether this represents a cancer-specific gain of function for cyclin D1 is unknown. C/EBPβ is an intronless gene encoding three protein isoforms--LAP1, LAP2, and LIP. Here, we provide evidence that cyclin D1 engages C/EBPβ in an isoform-specific manner. Cyclin D1 binds to LAP1, an event that activates the transcriptional function of LAP1 by relieving its autoinhibited state effected by intramolecular interactions. Reexpression of LAP1 but not LAP2 or LIP restores the ability of C/EBPβ-deficient mammary epithelial cells to differentiate and does so in a manner dependent on cyclin D1. And cyclin D1-mediated activation of LAP1 participates in mammary epithelial cell differentiation. Our findings indicate that cyclin D1 and C/EBPβ LAP1 operate in a common pathway to promote mammary epithelial cell differentiation.

Tajiri R, Inokuchi M, Sawada-Kitamura S, et al.
Clonal profiling of mixed lobular and ductal carcinoma revealed by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization.
Pathol Int. 2014; 64(5):231-6 [PubMed] Related Publications
A needle biopsy of a mass in the right breast of a 36-year-old woman revealed invasive ductal carcinoma (IDC), and approximately 20% of cancer cells showed unequivocal membranous staining with the HercepTest. After systemic therapy with trastuzumab and paclitaxel followed by FEC (fluorouracil + epirubicin + cyclophosphamide), a right mastectomy was performed. By histological and immunohistochemical examinations, the resected tumor consisted mainly of E-cadherin-negative invasive lobular carcinoma (ILC), and the rest was ERBB2-positive IDC; thus, the diagnosis was mixed ductal and lobular carcinoma. Multiplex ligation-dependent probe amplification and fluorescence in situ hybridization (FISH) analyses revealed that ILC and IDC shared high-level amplification of CCND1 in homogeneously staining regions (HSR) and that IDC had an additional HSR-type amplicon of ERBB2. These findings strongly indicate that IDC and ILC had a common precursor cell with CCND1 amplification. Review of the biopsy specimen with FISH showed IDC with gene amplifications of CCND1 and ERBB2 as a minor component, IDC without amplification of CCND1 or ERBB2 as a major component, and a minute portion of ILC with CCND1 amplification. We speculate that chemotherapy and trastuzumab caused a marked reduction in IDC; however, ILC with CCND1 amplification was resistant to chemotherapy and grew.

Jung K, Wu F, Wang P, et al.
YB-1 regulates Sox2 to coordinately sustain stemness and tumorigenic properties in a phenotypically distinct subset of breast cancer cells.
BMC Cancer. 2014; 14:328 [PubMed] Article available free on PMC after 08/08/2015 Related Publications
BACKGROUND: Sox2, a transcription factor and an embryonic stem cell marker, has been implicated in the pathogenesis of breast cancer (BC). YB-1 is another transcription factor that has been shown to promote stemness in BC cells.
METHODS: Western blotting, quantitative PCR, and siRNAs were used to query the regulatory relationships between YB-1, Sox2, and their downstream targets. Chromatin immunoprecipitation was used to detect YB-1 interactions at the Sox2 promoter. Mammosphere and soft agar assays were used to assess the phenotypic consequences of YB-1 knockdown.
RESULTS: Here, we report that YB-1 regulates Sox2. YB-1 was found to bind to the SOX2 promoter and down-regulate its expression in MCF7 and ZR751. The regulatory interaction between YB-1 and Sox2 was drastically different between the two phenotypically distinct cell subsets, purified based on their differential response to a Sox2 reporter. They are referred to as the reporter unresponsive (RU) cells and the reporter responsive (RR) cells. Upon siRNA knockdown of YB-1, RU cells showed an increase in Sox2 expression but no change in Sox2 reporter activity; in contrast, RR cells exhibited increased expression and reporter activity of Sox2. Correlating with these findings, YB-1 knockdown induced a differential response in the expression of genes known to be regulated by both Sox2 and YB-1 (e.g. CCND1 and ITGA6). For instance, in response to YB-1 knockdown, CCND1 and ITGA6 expression were decreased or unchanged in RU cells but paradoxically increased in RR cells. Compared to RU cells, RR cells were significantly more resistant to the suppression of mammosphere formation due to YB-1 knockdown. Importantly, mammospheres derived from parental MCF7 cells treated with YB-1 siRNA knockdown exhibited higher expression levels of SOX2 and its downstream targets.
CONCLUSIONS: To conclude, in a subset of BC cells, namely RR cells, YB-1 regulates Sox2 to coordinately maintain stemness and tumorigenic properties.

Wang JL, Chen ZF, Chen HM, et al.
Elf3 drives β-catenin transactivation and associates with poor prognosis in colorectal cancer.
Cell Death Dis. 2014; 5:e1263 [PubMed] Article available free on PMC after 08/08/2015 Related Publications
Aberrant regulation of the Wnt/β-catenin pathway plays important roles in colorectal carcinogenesis, with over 90% of cases of sporadic colon cancer featuring β-catenin accumulation. While ubiquitination-mediated degradation is widely accepted as a major route for β-catenin protein turnover, little is known about the regulation of β-catenin in transcriptional level. Here we show that Elf3, a member of the E-twenty-six family of transcription factors, drives β-catenin transactivation and associates with poor survival of colorectal cancer (CRC) patients. We first found recurrent amplification and upregulation of Elf3 in CRC tissues, and further Gene Set Enrichment Analysis identified significant association between Elf3 expression and activity of WNT/β-catenin pathway. Chromatin immunoprecipitation and electrophoretic mobility shift assay consistently revealed that Elf3 binds to and transactivates β-catenin promoter. Ectopic expression of Elf3 induces accumulation of β-catenin in both nucleus and cytoplasm, causing subsequent upregulation of several effector genes including c-Myc, VEGF, CCND1, MMP-7 and c-Jun. Suppressing Elf3 in CRC cells attenuates β-catenin signaling and decreases cell proliferation, migration and survival. Targeting Elf3 in xenograft tumors suppressed tumor progression in vivo. Taken together, our data identify Elf3 as a pivotal driver for β-catenin signaling in CRC, and highlight potential prognostic and therapeutic significance of Elf3 in CRC.

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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