Research IndicatorsGraph generated 10 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (7)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
TICdb, Universidad de Navarra
Search the database of Translocation breakpoints In Cancer for "CCND2"
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: CCND2 (cancer-related)
Zamani-Ahmadmahmudi M, Aghasharif S, Ilbeigi KPrognostic 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.
Yan L, Zhan C, Wang S, et al.Genetic analysis of radiation-specific biomarkers in sinonasal squamous cell carcinomas.
Tumour Biol. 2016; 37(9):12001-12009 [PubMed
] Related Publications
The aim of this study was to investigate the differences in the gene expression profiles of radiation-sensitive (RS) and radiation-resistant (RR) sinonasal squamous cell carcinoma (SNSCC) and to identify prognostic markers for the radiation reaction of SNSCC. We first examined the differentially expressed genes (DEGs) in RS and RR SNSCC tissues by analyzing clinical samples with GeneChip Human Transcriptome Array 2.0 (HTA 2.0).To understand the functional significance of the molecular changes, we examined the DEGs with Gene Ontology (GO) and pathway analyses to identify the core genes. The expression of several core genes (CCND2, COL5A2, GADD45B, and THBS2) was confirmed with reverse transcription quantitative PCR (RT-qPCR) in a larger series of tissues. We identified 208 DEGs, of which 76 were upregulated and 132 downregulated in the RS tissues relative to the RR tissues. The DEGs were mainly involved in the regulation of cell proliferation, the NF-kappaB signaling pathway, the cell adhesion molecule signaling pathway, and the extracellular matrix-receptor interaction signaling pathway. RT-qPCR confirmed that the CCND2, COL5A2, GADD45B, and THBS2 genes were significantly differentially expressed in the RS and RR tissues, consistent with the GeneChip data. These results extend our understanding of the molecular mechanisms underlying the sensitivity of SNSCC to radiation. The DEGs are involved in the differential response to radiation therapy and the dysregulated core genes identified in this study can be used to predict radiation sensitivity in SNSCC.
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.
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.
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.
Hille S, Dierck F, Kühl C, et al.Dyrk1a regulates the cardiomyocyte cell cycle via D-cyclin-dependent Rb/E2f-signalling.
Cardiovasc Res. 2016; 110(3):381-94 [PubMed
] Related Publications
AIMS: Down syndrome-associated dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (DYRK1A) is a ubiquitously expressed protein kinase. Up to date a variety of targets have been identified, establishing a key role for Dyrk1a in selected signalling pathways. In cardiomyocytes, Dyrk1a acts as a negative regulator of hypertrophy by phosphorylating transcription factors of the NFAT family, but its mechanistic function in the heart remains poorly understood. This study was designed to investigate a potential protective role of Dyrk1a in cardiac hypertrophy in vivo.
METHODS AND RESULTS: We generated transgenic mice with cardiac-specific overexpression of Dyrk1a. Counterintuitively, these mice developed severe dilated cardiomyopathy associated with congestive heart failure and premature death. In search for the cause of this unexpected phenotype, we found that Dyrk1a interacts with all members of the D-cyclin family and represses their protein levels in vitro and in vivo. Particularly, forced expression of Dyrk1a leads to increased phosphorylation of Ccnd2 on Thr280 and promotes its subsequent proteasomal degradation. Accordingly, cardiomyocytes overexpressing Dyrk1a display hypo-phosphorylated Rb1, suppression of Rb/E2f-signalling, and reduced expression of E2f-target genes, which ultimately results in impaired cell cycle progression.
CONCLUSIONS: We identified Dyrk1a as a novel negative regulator of D-cyclin-mediated Rb/E2f-signalling. As dysregulation of this pathway with impaired cardiomyocyte proliferation leads to cardiomyopathy, dose-specific Dyrk1a expression and activity appears to be critical for the hyperplastic and hypertrophic growth of the developing heart.
How chemotherapy affects carcinoma genomes is largely unknown. Here we report whole-exome and deep sequencing of 30 paired oesophageal adenocarcinomas sampled before and after neo-adjuvant chemotherapy. Most, but not all, good responders pass through genetic bottlenecks, a feature associated with higher mutation burden pre-treatment. Some poor responders pass through bottlenecks, but re-grow by the time of surgical resection, suggesting a missed therapeutic opportunity. Cancers often show major changes in driver mutation presence or frequency after treatment, owing to outgrowth persistence or loss of sub-clones, copy number changes, polyclonality and/or spatial genetic heterogeneity. Post-therapy mutation spectrum shifts are also common, particularly C>A and TT>CT changes in good responders or bottleneckers. Post-treatment samples may also acquire mutations in known cancer driver genes (for example, SF3B1, TAF1 and CCND2) that are absent from the paired pre-treatment sample. Neo-adjuvant chemotherapy can rapidly and profoundly affect the oesophageal adenocarcinoma genome. Monitoring molecular changes during treatment may be clinically useful.
Although microRNA-155 (miR-155) is known to play an important role in many cancers, its expression and function in oral squamous cell carcinoma (OSCC) was not fully understood. Thus, in the present study, we investigated the expression of miR-155 and also the role this miR plays in OSCC. We used the OSCC cell line (CAL27) and paired tumor and non-tumor tissue samples from patients with OSCC in order to detect the expression of miR-155. Cell proliferation, migration and invasion assays were then undertaken in order to determine the effect of miR-155 on the biological behavior of CAL27 cells following transient transfection with miR-155 mimic and antagomir. The regulatory effect of miR-155 on its target gene B-cell CLL/lymphoma 6 (BCL6) and downstream gene cyclin D2 (CCND2) was also analyzed. We found that miR-155 expression in OSCC cell and tumor tissues was significantly higher than that of the controls. We noted that the miR-155 mimic enhanced CAL27 cell proliferation, migration and invasion ability, downregulated BCL6 levels, and increased cyclin D2 expression. However, we noted that abrogating miR-155 with the miR-155 antagomir suppressed CAL27 cell proliferation, migration and invasion, upregulated BCL6 and reduced cyclin D2 expression. These results indicate that miR-155 plays a tumor-promoting role in OSCC by regulating the BCL6/cyclin D2 axis.
The oncogenic STAT3 signaling pathway is emerging as a promising target for the treatment of multiple myeloma (MM). In the present study, we identified a novel STAT3 inhibitor SC99 in a target-based high throughput screen. SC99 inhibited JAK2-STAT3 activation but had no effects on other transcription factors such as NF-κB, and kinases such as AKT, ERK, and c-Src that are in association with STAT3 signaling pathway. Furthermore, SC99 downregulated the expression of STAT3-modulated genes, including Bcl-2, Bcl-xL, VEGF, cyclin D2, and E2F-1. By inhibiting the STAT3 signaling, SC99 induced MM cell apoptosis which could be partly abolished by the ectopic expression of STAT3. Furthermore, SC99 displayed potent anti-MM activity in two independent MM xenograft models in nude mice. Oral administration of SC99 led to marked decrease of tumor growth within 10 days at a daily dosage of 30 mg/kg, but did not raise toxic effects. Taken together, this study identified a novel oral JAK2/STAT3 inhibitor that could be developed as an anti-myeloma agent.
Previous studies have shown that microRNA (miR)-610 is crucial in a variety of biological processes in various types of human cancer cells. However, the role of this microRNA in glioblastoma (GBM) is presently unclear. In this study, the role of miR‑610 in cell proliferation was investigated in GBM. It was demonstrated that miR‑610 expression is markedly downregulated in GBM cells and GBM tissues compared with normal human astrocytes (NHAs) and normal brain tissue, respectively. Ectopic expression of miR‑610 reduced the proliferation and anchorage‑independent growth of GBM cells, whereas inhibition of miR‑610 promoted this effect. Bioinformatics analysis further revealed cyclin D2 (CCND2) and AKT3, putative tumor promoters, as potential targets of miR‑610. Data from reporter assays showed that miR‑610 directly binds to the 3'‑untranslated region of CCND2 and AKT3 mRNA, and represses their expression at the transcriptional and translational levels. In conclusion, the data provide compelling evidence that miR‑610 functions as an anti‑onco‑miRNA, which is important in inhibiting cell proliferation in GBM, and its anti‑oncogenic effects are mediated chiefly through direct suppression of CCND2 and AKT3 expression.
Xu S, Zhao N, Hui L, et al.MicroRNA-124-3p inhibits the growth and metastasis of nasopharyngeal carcinoma cells by targeting STAT3.
Oncol Rep. 2016; 35(3):1385-94 [PubMed
] Related Publications
The present study investigated the effects of microRNA-124-3p (miR-124-3p) expression on nasopharyngeal carcinoma (NPC) cells and its relevant mechanism. A total of 90 NPC tissues and 85 postnasal catarrh tissues were collected. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect tissue samples and expression of miR-124-3p in CNE1, CNE2, SUNE1, H0NE1, 5-8F, 6-10B and C666-1 NPC cell line and immortalized nasopharyngeal epithelial cells line (NP69). Overexpressed miRNA-124-3p in CNE-2 was downregulated, and low-expressed miRNA‑124-3p in C666-1 was upregulated by liposome-mediated transfection. Cell Counting Kit-8 (CCK-8), flow cytometry, the scratch test, Transwell migration assay and Boyden chamber assays were used to detect cell proliferation, apoptosis, migration and invasion. The target gene of miRNA-124-3 calculated by bioinformatics was further determined using dual-luciferase system. Protein levels of the signal transducers and activators of transcription 3 (STAT3), phospho-STAT3 (p-STAT3), mouse anti-human cyclin D2 (CCND2) and matrix metalloproteinase-2 (MMP-2) were tested by western blotting. miRNA-124-3p expression in NPC was markedly downregulated compared to postnasal catarrh tissues (P<0.001); miRNA-124-3p expression showed close linkage with clinical stages, regional lymph node involvement and T stages (all P<0.001). miRNA-124-3p expression was lower in the 7 NPC cell lines than NP69 cells (all P<0.05). After upregulation of miR-124-3p, proliferation, apoptosis, migration and invasion of C666-1 cells were suppressed; while after downregulation of miR-124-3p, CNE2 cells were increased (all P<0.05). Expression of STAT3, p-STAT3, CCND2 and MMP-2 in C666-1 cells was decreased after transfection with miRNA-124-3p, and the above protein expression in CNE-2 cells was increased after inhibition of miRNA-124-3p (all P<0.05). To sum up, this study shows that miR-124-3p may negatively regulate the transcription of the STAT3 by interfering with its 3'UTR, and the degradation of STAT3 affects its downstream expression of such as p-STAT3, CCND2 and MMP-2, thereby promoting NPC cells apoptosis and inhibiting proliferation, migration and invasion of NPC cells.
Di Fiore R, Drago-Ferrante R, Pentimalli F, et al.Let-7d miRNA Shows Both Antioncogenic and Oncogenic Functions in Osteosarcoma-Derived 3AB-OS Cancer Stem Cells.
J Cell Physiol. 2016; 231(8):1832-41 [PubMed
] Related Publications
Osteosarcoma (OS), an aggressive highly invasive and metastatic bone-malignancy, shows therapy resistance and recurrence, two features that likely depend on cancer stem cells (CSCs), which hold both self-renewing and malignant potential. So, effective anticancer therapies against OS should specifically target and destroy CSCs. We previously found that the let-7d microRNA was downregulated in the 3AB-OS-CSCs, derived from the human OS-MG63 cells. Here, we aimed to assess whether let-7d modulation affected tumorigenic and stemness properties of these OS-CSCs. We found that let-7d-overexpression reduced cell proliferation by decreasing CCND2 and E2F2 cell-cycle-activators and increasing p21 and p27 CDK-inhibitors. Let-7d also decreased sarcosphere-and-colony forming ability, two features associated with self-renewing, and it reduced the expression of stemness genes, including Oct3/4, Sox2, Nanog, Lin28B, and HMGA2. Moreover, let-7d induced mesenchymal-to-epithelial-transition, as shown by both N-Cadherin-E-cadherin-switch and decrease in vimentin. Surprisingly, such switch was accompanied by enhanced migratory/invasive capacities, with a strong increase in MMP9, CXCR4 and VersicanV1. Let-7d- overexpression also reduced cell sensitivity to apoptosis induced by both serum-starvation and various chemotherapy drugs, concomitant with decrease in caspase-3 and increase in BCL2 expression. Our data suggest that let-7d in 3AB-OS-CSCs could induce plastic-transitions from CSCs-to-non-CSCs and vice-versa. To our knowledge this is the first study to comprehensively examine the expression and functions of let-7d in OS-CSCs. By showing that let-7d has both tumor suppressor and oncogenic functions in this context, our findings suggest that, before prospecting new therapeutic strategies based on let-7d modulation, it is urgent to better define its multiple functions. J. Cell. Physiol. 231: 1832-1841, 2016. © 2015 Wiley Periodicals, Inc.
BACKGROUND: Tobacco smoke, diet and indoor/outdoor air pollution, all major sources of polycyclic aromatic hydrocarbons (PAHs), have been associated with breast cancer. Aberrant methylation may be an early event in carcinogenesis, but whether PAHs influence the epigenome is unclear, particularly in breast tissue where methylation may be most relevant. We aimed to evaluate the role of methylation in the association between PAHs and breast cancer.
METHODS: In a population-based case-control study, we measured promoter methylation of 13 breast cancer-related genes in breast tumor tissue (n=765-851 cases) and global methylation in peripheral blood (1055 cases/1101 controls). PAH sources (current active smoking, residential environmental tobacco smoke (ETS), vehicular traffic, synthetic log burning, and grilled/smoked meat intake) were evaluated separately. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs).
RESULTS: When comparing methylated versus unmethylated genes, synthetic log use was associated with increased ORs for CDH1 (OR=2.26, 95%CI=1.06-4.79), HIN1 (OR=2.14, 95%CI=1.34-3.42) and RARβ (OR=1.80, 95%CI=1.16-2.78) and decreased ORs for BRCA1 (OR=0.44, 95%CI=0.30-0.66). Residential ETS was associated with decreased ORs for ESR1 (OR=0.74, 95%CI=0.56-0.99) and CCND2 methylation (OR=0.65, 95%CI=0.44-0.96). Current smoking and vehicular traffic were associated with decreased ORs for DAPK (OR=0.53, 95%CI=0.28-0.99) and increased ORs for TWIST1 methylation (OR=2.79, 95%CI=1.24-6.30), respectively. In controls, synthetic log use was inversely associated with LINE-1 (OR=0.59, 95%CI=0.41-0.86).
DISCUSSION: PAH sources were associated with hypo- and hypermethylation at multiple promoter regions in breast tumors and LINE-1 hypomethylation in blood of controls. Methylation may be a potential biologic mechanism for the associations between PAHs and breast cancer incidence.
Xu H, Moni MA, Liò PNetwork regularised Cox regression and multiplex network models to predict disease comorbidities and survival of cancer.
Comput Biol Chem. 2015; 59 Pt B:15-31 [PubMed
] Related Publications
In cancer genomics, gene expression levels provide important molecular signatures for all types of cancer, and this could be very useful for predicting the survival of cancer patients. However, the main challenge of gene expression data analysis is high dimensionality, and microarray is characterised by few number of samples with large number of genes. To overcome this problem, a variety of penalised Cox proportional hazard models have been proposed. We introduce a novel network regularised Cox proportional hazard model and a novel multiplex network model to measure the disease comorbidities and to predict survival of the cancer patient. Our methods are applied to analyse seven microarray cancer gene expression datasets: breast cancer, ovarian cancer, lung cancer, liver cancer, renal cancer and osteosarcoma. Firstly, we applied a principal component analysis to reduce the dimensionality of original gene expression data. Secondly, we applied a network regularised Cox regression model on the reduced gene expression datasets. By using normalised mutual information method and multiplex network model, we predict the comorbidities for the liver cancer based on the integration of diverse set of omics and clinical data, and we find the diseasome associations (disease-gene association) among different cancers based on the identified common significant genes. Finally, we evaluated the precision of the approach with respect to the accuracy of survival prediction using ROC curves. We report that colon cancer, liver cancer and renal cancer share the CXCL5 gene, and breast cancer, ovarian cancer and renal cancer share the CCND2 gene. Our methods are useful to predict survival of the patient and disease comorbidities more accurately and helpful for improvement of the care of patients with comorbidity. Software in Matlab and R is available on our GitHub page: https://github.com/ssnhcom/NetworkRegularisedCox.git.
Branham MT, Campoy E, Laurito S, et al.Epigenetic regulation of ID4 in the determination of the BRCAness phenotype in breast cancer.
Breast Cancer Res Treat. 2016; 155(1):13-23 [PubMed
] Related Publications
BRCAness breast tumors represent a group of sporadic tumors characterized by a reduction in BRCA1 gene expression. As BRCA1 is involved in double-strand breaks (DSBs) repair, dysfunctional BRCA pathway could make a tumor sensitive to DNA damaging drugs (e.g., platinum agents). Thus, accurately identifying BRCAness could contribute to therapeutic decision making in patients harboring these tumors. The purpose of this study was to identify if BRCAness tumors present a characteristic methylation profile and/or were related to specific clinico-pathological features. BRCAness was measured by MLPA in 63 breast tumors; methylation status of 98 CpG sites within 84 cancer-related genes was analyzed by MS-MLPA. Protein and mRNA expressions of the selected genes were measured by quantitative real-time PCR and Western Blot. BRCAness was associated with younger age, higher nuclear pleomorphism, and triple-negative (TN) status. Epigenetically, we found that the strongest predictors for BRCAness tumors were the methylations of MLH1 and PAX5 plus the unmethylations of CCND2 and ID4. We determined that ID4 unmethylation correlated with the expression levels of both its mRNA and protein. We observed an inverse relation between the expressions of ID4 and BRCA1. To the best of our knowledge, this is the first report suggesting an epigenetic regulation of ID4 in BRCAness tumors. Our findings give new information of BRCAness etiology and encourage future studies on potential drug targets for BRCAness breast tumors.
Saponara M, Urbini M, Astolfi A, et al.Molecular characterization of metastatic exon 11 mutant gastrointestinal stromal tumors (GIST) beyond KIT/PDGFRα genotype evaluated by next generation sequencing (NGS).
Oncotarget. 2015; 6(39):42243-57 [PubMed
] Free Access to Full Article Related Publications
About 85% of GISTs are associated with KIT and PDGFRα gene mutations, which predict response to tyrosine kinase inhibitors. Although the outcomes in patients affected by GIST have dramatically improved, tumor progression control still remains a challenge. The aim of this study is the genomic characterization of individual metastatic KIT-exon 11-mutant GIST to identify additional aberrations and simultaneous molecular events representing potential therapeutic targets.Seven patients with metastatic GIST were studied with whole transcriptome sequencing and copy number analysis. Somatic single nucleotide variations were called; however, no shared mutated genes were detected except KIT. Almost all patients showed loss of genomic regions containing tumor suppressor genes, sometimes coupled with single nucleotide mutation of the other allele. Additionally, six fusion transcripts were found and three patients showed amplifications involving known oncogenes.Evaluating the concordance between CN status and mRNA expression levels, we detected overexpression of CCND2 and EGFR and silencing of CDKN2A, CDKN2C, SMARCB1, PTEN and DMD. Altered expression of these genes could be responsible for aberrant activation of signaling pathways that support tumor growth. In this work, we assessed the effect of Hedgehog pathway inhibition in GIST882 cells, which causes decrement of cell viability associated with reduction of KIT expression.Additional genomic alterations not previously reported in GIST were found even if not shared by all samples. This contributes to a more detailed molecular understanding of this disease, useful for identification of new targets and novel therapeutics and representing a possible point of departure for a truly individualized clinical approach.
Dodurga Y, Seçme M, Eroğlu C, et al.Investigation of the effects of a sulfite molecule on human neuroblastoma cells via a novel oncogene URG4/URGCP.
Life Sci. 2015; 143:27-34 [PubMed
] Related Publications
AIM: The aim of this study is to determine the anticancer effect of sulfite on SH-SY5Y neuroblastoma cells in vitro conditions and elucidate underlying molecular mechanism of sulfite and explore its therapeutic activity.
MAIN METHODS: In this study, cytotoxic effects of sulfite in SH-SY5Y cels were detected over time in a dose dependent manner with the IC50 doses ranging from 0.5 to 10 mM. Genotoxic effect of sulfite was shown by comet assay. IC50 doses in the SH-SY5Y cells were detected as 5 mM. Expression profiles of the target genes related to apoptosis and cell cycle control were determined by quantitative RT-PCR. Protein changes were determined by western blot analysis.
KEY FINDINGS: URG4/URGCP, CCND1, CCND2, CDK4, CDK6, E2F4 and BCL-2 gene expression levels were significantly reduced and RB1, TP53, BAX, BID, CASP2, CASP3, CASP9 and DIABLO gene expressions were significantly increased in dose group cells. The mechanism of this result may be related to sulfite dependent inhibition of cell cycle at the G1 phase by down-regulating URG4/URGCP or CCND1, CDK4, CDK6 gene expression and stimulating apoptosis via the intrinsic pathway. Sulfite suppressed invasion and colony formation in SH-SY5Y cell line using matrigel invasion chamber and colony formation assay, respectively.
SIGNIFICANCE: It is thought that sulfite demonstrates anticarcinogenesis activity by affecting cell cycle arrest, apoptosis s, invasion, and colony formation on SH-SY5Y cells. Sulfite may be an effective agent for treatment of neuroblastoma as a single agent or in combination with other agents.
ATP1B1 encodes the Na,K-ATPase β subunit, a key regulator of the Na+ and K+ electrochemical gradients across the plasma membrane and an essential regulator of cellular activity. We used several microarray datasets to test the prognostic efficacy of ATP1B1 expression in cytogenetically normal acute myeloid leukemia (CN-AML). Within the primary cohort (n = 157), high ATP1B1 expression (ATP1B1(high)) was associated with shorter overall survival (OS) and event-free survival (EFS) (P = 0.0068, P = 0.0039, respectively). Similar results were also obtained in the European Leukemia Net (ELN) Intermediate-I genetic category (OS: P = 0.0035, EFS: P = 0.0007). Multivariable analyses confirmed ATP1B1(high) is an independent predictor of shorter OS (P = 0.042) and EFS (P = 0.035). Analysis of another CN-AML cohort confirmed that ATP1B1(high) is associated with shorter OS (P = 0.0046, n = 162). In addition, up-regulation of oncogenes/onco-microRNAs such as MYCN, CCND2, CDK6, KIT and miR-155, among others, was associated with ATP1B1(high), which may be indicative of ATP1B1's leukemogenicity. Our results may improve risk stratification and indicate new therapeutic targets for CN-AML.
Afify A, Huang EC, Jeong M, Urayama SImmunoisolation of pancreatic epithelial cells from endoscopic ultrasound-guided fine needle aspirates with magnetic beads for downstream molecular application.
Diagn Cytopathol. 2016; 44(1):32-8 [PubMed
] Related Publications
BACKGROUND: Evaluation of pancreatic mass is routinely performed by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). However, molecular analyses of the tumor cells on FNA samples are limited by the significant cellular heterogeneity. The goal of the current study is to evaluate a magnetic immunoconcentration technique in isolating pancreatic epithelial cells from needle aspirates, and to demonstrate that the isolated cells could be utilized for molecular analysis.
METHODS: Pancreatic EUS-FNA specimens were processed and stored at -80°C. Based on the cytopathological diagnosis, 17 adenocarcinoma, 3 lymphoproliferative, and 3 benign cases were retrieved from the collection for further analyses. Epithelial cells were isolated using antihuman epithelial cell specific antibody-bound magnetic beads, and the isolated cellular component was confirmed cytologically. Genomic DNA was extracted, quantitated, and evaluated with methylation-specific PCR for cyclin D2 in 8 adenocarcinoma cases.
RESULTS: After optimization, malignant epithelial cells were successfully isolated from all adenocarcinoma cases. Normal pancreatic ductal cells were isolated from three benign cases. No cells were retrieved after immunomagnetic isolation in all three lymphoproliferative cases. DNA yields were 5-2646 ng, with a mean of 357 ng. Methylation-specific PCR for cyclin D2 on the 8 carcinoma cases showed methylated state at the promoter region, demonstrating feasible evaluation of the methylation status.
CONCLUSION: The magnetic immunoconcentration of pancreatic EUS-FNA specimen described here is a practical method of isolating pancreatic epithelial cells from needle aspirates. Isolated cells were sufficient for performing subsequent molecular analysis.
UNLABELLED: Epigenetic regulators have emerged as critical factors governing the biology of cancer. Here, in the context of melanoma, we show that RNF2 is prognostic, exhibiting progression-correlated expression in human melanocytic neoplasms. Through a series of complementary gain-of-function and loss-of-function studies in mouse and human systems, we establish that RNF2 is oncogenic and prometastatic. Mechanistically, RNF2-mediated invasive behavior is dependent on its ability to monoubiquitinate H2AK119 at the promoter of LTBP2, resulting in silencing of this negative regulator of TGFβ signaling. In contrast, RNF2's oncogenic activity does not require its catalytic activity nor does it derive from its canonical gene repression function. Instead, RNF2 drives proliferation through direct transcriptional upregulation of the cell-cycle regulator CCND2. We further show that MEK1-mediated phosphorylation of RNF2 promotes recruitment of activating histone modifiers UTX and p300 to a subset of poised promoters, which activates gene expression. In summary, RNF2 regulates distinct biologic processes in the genesis and progression of melanoma via different molecular mechanisms.
SIGNIFICANCE: The role of epigenetic regulators in cancer progression is being increasingly appreciated. We show novel roles for RNF2 in melanoma tumorigenesis and metastasis, albeit via different mechanisms. Our findings support the notion that epigenetic regulators, such as RNF2, directly and functionally control powerful gene networks that are vital in multiple cancer processes.
Kawano M, Tanaka K, Itonaga I, et al.c-Myc Represses Tumor-Suppressive microRNAs, let-7a, miR-16 and miR-29b, and Induces Cyclin D2-Mediated Cell Proliferation in Ewing's Sarcoma Cell Line.
PLoS One. 2015; 10(9):e0138560 [PubMed
] Free Access to Full Article Related Publications
Myc oncogenic transcription factor is known to inhibit tumor suppressive microRNAs (miRNAs), resulting in greater expression of their target protein related to cell cycle, invasion or anti-apoptotic factors in human cancer cells. To explore possible oncogenic factors in Ewing's sarcoma (ES), we conducted microarray-based approach to profile the changes in the expression of miRNAs and its downstream mRNAs in five ES cell lines and human mesenchymal stem cells (hMSCs). Three miRNAs, let-7a, miR-16 and miR-29b were significantly down-regulated, whereas c-Myc and cyclin D2 (CCND2) were significantly up-regulated in all tested ES cells compared with hMSCs. To verify that let-7a, miR-16 and miR-29b were the targets of c-Myc in ES cell lines, we transfected siRNA against c-Myc and confirmed the coordinate up-regulation of let-7a, miR-16 and miR-29b through the repression of c-Myc. The ES cells transfected with c-Myc-siRNA and let-7a, miR-16 and miR-29b exhibited the inhibition of the cell cycle progression. The increased expression of let-7a, miR-16 and miR-29b resulted in the reduction of CCND2 protein expression. We also demonstrated that c-Myc-siRNA treatment of ES cells was associated with the decreased expression of CCND2 as a down-stream of three miRNAs. Furthermore, the introduction of let-7a, miR-16 and miR-29b in ES cells could inhibit the c-Myc-mediated up-regulation of CCND2 resulted in the prevention of cell cycle progression. In addition, the transfection of let-7a, miR-16 and miR-29b in ES cells suppressed tumor growth ex vivo treatment. These findings suggests that the up-regulation of c-Myc inhibited the expression of let-7a, miR-16 and miR-29b subsequently induced CCND2 expression in ES cells. The present study might identify a novel oncogenic axis that c-Myc regulates the expression of CCND2 via let-7a, miR-16 and miR-29b, leading to the development new therapeutic targets for ES.
INTRODUCTION: It has been shown in some articles that genetic and epigenetic abnormalities cannot only be found in tumor tissues but also in adjacent regions that appear histologically normal. This phenomenon is metaphorically called field cancerization or field defect. Field cancerization is regarded as clinically significant because it is assumed to be an important factor in local recurrence of cancer. As the field showing these molecular abnormalities may not be removed completely by surgery, these changes might lead to neoplasms and subsequent transformation to a tumor. We aimed to investigate the applicability of the methylation status of six tumor suppressor genes as biomarkers for detecting field cancerization in breast cancer.
METHODS: The promoter methylation status of CCND2, DAPK1, GSTP1, HIN-1, MGMT and RASSF1A was determined by methylation-sensitive high-resolution melting (MS-HRM) analysis. MS-HRM methods for CCND2, MGMT and RASSF1A were developed in-house, primer sequences for DAPK1, GSTP1 and HIN-1 have already been published. Biopsy samples were taken from tumor, tumor-adjacent and tumor-distant tissue from 17 breast cancer patients. Normal breast tissues of four healthy women served as controls.
RESULTS: All MS-HRM methods proved to be very sensitive. LODs were in the range from 0.1 to 1.5 %, LOQs ranged from 0.3 to 5.3 %. A total of 94 %, 82 % and 65 % of the tumors showed methylation of RASSF1A, HIN-1 and MGMT promoters, respectively. The methylation status of these promoters was significantly lower in tumor-distant tissues than in tumor tissues. Tumor-adjacent tissues showed higher methylation status of RASSF1A, HIN-1 and MGMT promoters than tumor-distant tissues, indicating field cancerization. The methylation status of the HIN-1 promoter in tumor-adjacent tissues was found to correlate strongly with that in the corresponding tumors (r = 0.785, p < 0.001), but not with that in the corresponding tumor-distant tissues (r = 0.312, p = 0.239).
CONCLUSIONS: Among the gene promoters investigated, the methylation status of the HIN-1 promoter can be considered the best suitable biomarker for detecting field cancerization. Further investigation is needed to test whether it can be used for defining surgical margins in order to prevent future recurrence of breast cancer.
Misiewicz-Krzeminska I, Sarasquete ME, Vicente-Dueñas C, et al.Post-transcriptional Modifications Contribute to the Upregulation of Cyclin D2 in Multiple Myeloma.
Clin Cancer Res. 2016; 22(1):207-17 [PubMed
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PURPOSE: Dysregulation of one of the three D-cyclin genes has been observed in virtually all multiple myeloma tumors. The mechanisms by which CCND2 is upregulated in a set of multiple myeloma are not completely deciphered. We investigated the role of post-transcriptional regulation through the interaction between miRNAs and their binding sites at 3'UTR in CCND2 overexpression in multiple myeloma.
EXPERIMENTAL DESIGN: Eleven myeloma cell lines and 45 primary myeloma samples were included in the study. Interactions between miRNAs deregulated in multiple myeloma and mRNA targets were analyzed by 3'UTR-luciferase plasmid assay. The presence of CCND2 mRNA isoforms different in length was explored using qRT-PCR, Northern blot, mRNA FISH, and 3' rapid amplification of cDNA ends (RACE)-PCR.
RESULTS: We detected the presence of short CCND2 mRNA, both in the multiple myeloma cell lines and primary cells. The results obtained by 3'RACE experiments revealed that changes in CCND2 3'UTR length are explained by alternative polyadenylation. The luciferase assays using plasmids harboring the truncated CCND2 mRNA strongly confirmed the loss of miRNA sites in the shorter CCND2 mRNA isoform. Those multiple myelomas with greater abundance of the shorter 3'UTR isoform were associated with significant higher level of total CCND2 mRNA expression. Furthermore, functional analysis showed significant CCND2 mRNA shortening after CCND1 silencing and an increased relative expression of longer isoform after CCND1 and CCND3 overexpression, suggesting that cyclin D1 and D3 could regulate CCND2 levels through modifications in polyadenylation-cleavage reaction.
CONCLUSIONS: Overall, these results highlight the impact of CCND2 3'UTR shortening on miRNA-dependent regulation of CCND2 in multiple myeloma.
Osteosarcoma remains a leading cause of cancer death in children and young adolescents. Although the introduction of multiagent chemotherapy, survival rates have not improved in two decades. Therefore, it is urgently needed to know the details regarding molecular etiology to driving therapeutic inroads for this disease. In this study we performed an integrated analysis of miRNA and mRNA expression data to explore the dysregulation of miRNA and miRNA-target gene regulatory network underlying OS. 59 differentially expressed miRNAs were identified, with 28 up-regulated and 31 down-regulated miRNAs by integrating OS miRNA expression data sets available. Using miRWalk databases prediction, we performed an anticorrelated analysis of miRNA and genes expression identified by a integrated analysis of gene expression data to identify 109 differently expressed miRNA target genes. A novel miRNA-target gene regulatory network was constructed with the miRNA-target gene pairs. miR-19b-3p, miR-20a-5p, miR-124-3p and their common target CCND2, the nodal points of regulatory network, may play important roles in OS. Bioinformatics analysis of biological functions and pathways demonstrated that target genes of miRNAs are highly correlated with carcinogenesis. Our findings may help to understand the molecular mechanisms of OS and identify targets of effective targeted therapies for OS.
Hsa-miRNA-206 (miR-206), highly expressed in skeletal muscle, has recently been discovered to have anticancer properties in different tissues. However, the role of miR-206 on lung cancer is still ambiguous. In this study, we investigated the role of miR-206 on the development of lung cancer. The results indicated that miR-206 expression was suppressed in lung cancer tissues and very low levels were found in non-small cell lung cancer (NSCLS) cell lines. Transient transfection of miR-206 into cultured A549 and SK-MES-1 cells led to significant decrease in cell growth, migration, invasion and colony formation, and promoted cell apoptosis. Using bioinformatics, we identified putative miR-206 binding sites within the 3'-untranslated region (3'-UTR) of the human c-Met and Bcl2 mRNA. The expression of c-Met and Bcl2 proteins were shown to be down-regulated after treated with miR-206 by subsequent Western blot and qRT-PCR analysis. Conversely, up-regulation of c-Met and Bcl2 were confirmed in tissue samples of human lung cancer, with its level inversely correlated with miR-206 expression. In addition, miR-206 also decreased the gene expression of MMP-9, CCND1 and CCND2 while increased the gene expression of p57 (Kip2) in A549 and SK-MES-1 cells. Taken together, our results demonstrated that miR-206 suppressed c-Met and Bcl2 expression in NSCLS and could function as a potent tumor suppressor in c-Met/Bcl2-over expressing tumors. Inhibition of miR-206 function could contribute to aberrant cell proliferation, migration, invasion and apoptosis, leading to NSCLS development.
The central role of the microRNA (miR) 15a/16-1 cluster in B-cell oncogenesis has been extensively demonstrated, with over two-thirds of B-cell chronic lymphocytic leukemia characterized by the deletion of the miR-15a/16-1 locus at 13q14. Despite the well-established understanding of the molecular mechanisms occurring during miR-15a/16-1 dysregulation, the oncogenic role of other miR-15/16 family members, such as the miR-15b/16-2 cluster (3q25), is still far from being elucidated. Whereas miR-15a is highly similar to miR-15b, miR-16-1 is identical to miR-16-2; thus, it could be speculated that both clusters control a similar set of target genes and may have overlapping functions. However, the biological role of miR-15b/16-2 is still controversial. We generated miR-15b/16-2 knockout mice to better understand the cluster's role in vivo. These mice developed B-cell malignancy by age 15-18 mo with a penetrance of 60%. At this stage, mice showed significantly enlarged spleens with abnormal B cell-derived white pulp enlargement. Flow cytometric analysis demonstrated an expanded CD19+ CD5+ population in the spleen of 40% knockout mice, a characteristic of the chronic lymphocytic leukemia-associated phenotype found in humans. Of note, miR-15b/16-2 modulates the CCND2 (Cyclin D2), CCND1 (Cyclin D1), and IGF1R (insulin-like growth factor 1 receptor) genes involved in proliferation and antiapoptotic pathways in mouse B cells. These results are the first, to our knowledge, to suggest an important role of miR-15b/16-2 loss in the pathogenesis of B-cell chronic lymphocytic leukemia.
Dahlin AM, Hollegaard MV, Wibom C, et al.CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 gene variants and risk of childhood medulloblastoma.
J Neurooncol. 2015; 125(1):75-8 [PubMed
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Recent studies have described a number of genes that are frequently altered in medulloblastoma tumors and that have putative key roles in the development of the disease. We hypothesized that common germline genetic variations in these genes may be associated with medulloblastoma development. Based on recent publications, we selected 10 genes that were frequently altered in medulloblastoma: CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 (now renamed as KMT2D). Common genetic variants (single nucleotide polymorphisms) annotating these genes (n = 221) were genotyped in germline DNA (neonatal dried blood spot samples) from 243 childhood medulloblastoma cases and 247 control subjects from Sweden and Denmark. Eight genetic variants annotating three genes in the sonic hedgehog signaling pathway; CCND2, PTCH1, and GLI2, were found to be associated with the risk of medulloblastoma (P(combined) < 0.05). The findings were however not statistically significant following correction for multiple testing by the very stringent Bonferroni method. The results do not support our hypothesis that common germline genetic variants in the ten studied genes are associated with the risk of developing medulloblastoma.
Zhao S, Han J, Zheng L, et al.MicroRNA-203 Regulates Growth and Metastasis of Breast Cancer.
Cell Physiol Biochem. 2015; 37(1):35-42 [PubMed
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BACKGROUNDS/AIMS: MicroRNAs (MiRNAs) control many biological events and play critical roles in the development of tumor. Among all miRNAs, miR203 has been recently shown to have an inhibitory effect on prostate cancer. However, its involvement in the carcinogenesis of breast cancer has not been reported.
METHODS: We examined the levels of miR203 in the breast cancer from the patients compared to the paired normal breast tissue. We also examined the levels of miR203 in several commonly used breast cancer cell lines. The effects of overexpression or depletion of miR203 on breast cancer cell growth were analyzed by a MTT assay, and on breast cancer cell invasion were examined by a scratch wound healing assay and a transwell cell migration assay. MiR203-targeted genes were analyzed by Western blot.
RESULTS: We detected significantly lower levels of miR203 in the breast cancer from the patients compared to the paired normal breast tissue. Moreover, the levels of miR203 were significantly lower in breast cancer tissue from the patients with cancer metastasis. Decreased miR203 levels were detected in all examined breast cancer lines. Overexpression of miR203 inhibited breast cancer cell growth and invasion, while antisense-mediated inhibition of miR203 enhanced cancer cell growth and invasion. Further analyses show that miR203 may inhibit cell growth through decreasing cell-cycle activator cyclinD2 and CDK6, increasing cell-cycle suppressor p21 and p27, and increasing apoptosis-associated protein Bcl-2. MiR203 may also inhibit cell metastasis through suppressing matrix metalloproteinase 2 (MMP2), MMP7 and MMP9.
CONCLUSION: Our data thus highlight miR203 as a novel therapeutic target for breast cancer.
Miao Y, Wang R, Fan L, et al.Detection of t(12;14)(p13;q32) in a patient with IGH-CCND1 negative mantle cell lymphoma resembling ultra-high risk chronic lymphocytic leukemia.
Int J Clin Exp Pathol. 2015; 8(6):7494-8 [PubMed
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T(12;14)(p13;q32) is a rare recurrent chromosomal translocation, which has only been identified in a small subgroup of mantle cell lymphoma (MCL) without typical t(11;14)(q13;q32). This rearrangement causes aberrant over-expression of cyclin D2 (CCND2), which disrupts the normal cell cycle. Here we report a subtle case of MCL with t(12;14)(p13;q32) that was initially misdiagnosed as ultra-high risk chronic lymphocytic leukemia (CLL). A 60-year-old male patient presented with obvious leukocytosis and progressive weakness. Morphology of peripheral blood and immunophenotyping by flow cytometry pointed to a diagnosis of chronic lymphocytic leukemia. Fluorescence in situ hybridization (FISH) using IGH-CCND1 probe was negative for CCND1 abnormality, but demonstrated IGH breakapart signals. The initial diagnosis of CLL was established and the patient was treated with six courses of immunochemotherpy with fludarabine, cyclophosphamide and rituximab (FCR). Complete remission (CR) was achieved at the end of treatment, but disease relapsed quickly. The patient was transferred to our hospital, flow cytometry using additional markers showed that the clonal cells were CD200+(dim), CD148+(strong), and chromosome analysis revealed a complex karyotype, 47, XY, t(12;14)(p13;q32), +12, del(9p21), which indicated over-expression of CCND2, and immunostaining showed strong positivity of SOX11 further confirming the characteristics of CCND1-negtive MCL. The final diagnosis was revised to rare subtype of MCL with CCND2 translocation and intensive regimens were employed. This confusable MCL case illustrates the importance of cytogenetic analysis and clinicopathologic diagnosis of this rare category of MCL.
Yu WF, Wang HM, Lu BC, et al.miR-206 inhibits human laryngeal squamous cell carcinoma cell growth by regulation of cyclinD2.
Eur Rev Med Pharmacol Sci. 2015; 19(14):2697-702 [PubMed
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OBJECTIVE: Accumulating evidence has shown that microRNAs (miRNAs) are aberrantly expressd in many malignancies and crucial to tumorigenesis. Herein, we identified the role and mechanism of miR-206 in laryngeal squamous cell carcinoma (LSCC) growth.
PATIENTS AND METHODS: Quantitative real-time PCR was performed to detect the relative expression level of miR-206 in LSCC tissues. Crystal violet and flow cytometry were conducted to explore the effects of miR-206 on the proliferation and cell cycle of human LSCC cell line, respectively. The impact of miR-206 overexpression on putative target cyclinD2 were subsequently verified via Western blot. Tumor growth assay was performed to testify the effect of miR-206 on the tumor growth in vivo.
RESULTS: MiR-206 expression was frequently (p < 0.05) down-regulated in LSCC specimens. Overexpression of miR-206 in Hep-2 cell inhibited the proliferation by blocking the G1/S transition as well as suppressed the growth of xenograft tumors in mice, implying that miR-206 functions as a tumour suppressor in the progression of LSCC. Overexpression of miR-206 significantly decreased (p < 0.05) the protein level of cyclinD2, which has previously been identified as a direct targets of miR-206.
CONCLUSIONS: Altogether, our results identify a crucial tumour suppressive role of miR-206 in LSCC growth, at least partly via up-regulation of cyclinD2 protein levels, and suggest that miR-206 might be a candidate prognostic predictor or an anticancer therapeutic target for LSCC patients.