Research IndicatorsGraph generated 27 August 2015 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 27 August, 2015 using data from PubMed, MeSH and CancerIndex
Specific Cancers (6)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: DUSP6 (cancer-related)
Díaz-García CV, Agudo-López A, Pérez C, et al.Prognostic value of dual-specificity phosphatase 6 expression in non-small cell lung cancer.
Tumour Biol. 2015; 36(2):1199-206 [PubMed
] Related Publications
Dual-specificity phosphatase 6 (DUSP6/MKP-3) is a mitogen-activated protein kinase phosphatase that regulates extracellular signal-regulated kinases (ERKs) activity via feedback mechanisms, with an increasingly recognized role in tumour biology. The aim of this study was to explore the role of DUSP6 expression in the prognosis of human non-small cell lung cancer (NSCLC). DUSP6 expression levels were evaluated by real-time quantitative reverse transcription polymerase chain reaction (PCR) in 60 NSCLC samples from patients who underwent pulmonary resection at 12 de Octubre University Hospital. We performed a statistical analysis to investigate the correlation of DUSP6 expression and the clinical outcomes. We found that 66.7% of the tumour samples show the downregulation of DUSP6 at the messenger RNA (mRNA) levels compared to benign epithelial lung tissues and 55% of them show at least twofold downregulation of DUSP6 gene expression. Patients were classified into three groups according to their DUSP6 expression levels and those with very low levels (at least twofold downregulation) had the worst outcomes. Using the value of twice below the mean value in benign epithelial lung tissue as a cutoff, the overall survival of patients with very low DUSP6 levels was significantly lower than that in the rest of patients (31.9 ± 18.8 months vs. not reached, P = 0.049). This was most pronounced in adenocarcinoma histology and high-stage tumour samples. Our results suggest that DUSP6 gene expression in tumour samples may be a prognostic marker in NSCLC.
AIM: Optimal molecular markers for detecting colorectal cancer (CRC) in a blood-based assay were evaluated.
METHODS: A matched (by variables of age and sex) case-control design (111 CRC and 227 non-cancer samples) was applied. Total RNAs isolated from the 338 blood samples were reverse-transcribed, and the relative transcript levels of candidate genes were analyzed. The training set was made of 162 random samples of the total 338 samples. A logistic regression analysis was performed, and odds ratios for each gene were determined between CRC and non-cancer. The samples (n = 176) in the testing set were used to validate the logistic model, and an inferred performance (generality) was verified. By pooling 12 public microarray datasets(GSE 4107, 4183, 8671, 9348, 10961, 13067, 13294, 13471, 14333, 15960, 17538, and 18105), which included 519 cases of adenocarcinoma and 88 controls of normal mucosa, we were able to verify the selected genes from logistic models and estimate their external generality.
RESULTS: The logistic regression analysis resulted in the selection of five significant genes (P < 0.05; MDM2, DUSP6, CPEB4, MMD, and EIF2S3), with odds ratios of 2.978, 6.029, 3.776, 0.538 and 0.138, respectively. The five-gene model performed stably for the discrimination of CRC cases from controls in the training set, with accuracies ranging from 73.9% to 87.0%, a sensitivity of 95% and a specificity of 95%. In addition, a good performance in the test set was obtained using the discrimination model, providing 83.5% accuracy, 66.0% sensitivity, 92.0% specificity, a positive predictive value of 89.2% and a negative predictive value of 73.0%. Multivariate logistic regressions analyzed 12 pooled public microarray data sets as an external validation. Models that provided similar expected and observed event rates in subgroups were termed well calibrated. A model in which MDM2, DUSP6, CPEB4, MMD, and EIF2S3 were selected showed the result in logistic regression analysis (H-L P = 0.460, R2= 0.853, AUC = 0.978, accuracy = 0.949, specificity = 0.818 and sensitivity = 0.971).
CONCLUSION: A novel gene expression profile was associated with CRC and can potentially be applied to blood-based detection assays.
The RAS/ERK pathway is commonly activated in carcinomas and promotes oncogenesis by altering transcriptional programs. However, the array of cis-regulatory elements and trans-acting factors that mediate these transcriptional changes is still unclear. Our genome-wide analysis determined that a sequence consisting of neighboring ETS and AP-1 transcription factor binding sites is enriched near cell migration genes activated by RAS/ERK signaling in epithelial cells. In vivo screening of candidate ETS proteins revealed that ETS1 is specifically required for migration of RAS/ERK activated cells. Furthermore, both migration and transcriptional activation through ETS/AP-1 required ERK phosphorylation of ETS1. Genome-wide mapping of multiple ETS proteins demonstrated that ETS1 binds specifically to enhancer ETS/AP-1 sequences. ETS1 occupancy, and its role in cell migration, was conserved in epithelial cells derived from multiple tissues, consistent with a chromatin organization common to epithelial cell lines. Genome-wide expression analysis showed that ETS1 was required for activation of RAS-regulated cell migration genes, but also identified a surprising role for ETS1 in the repression of genes such as DUSP4, DUSP6 and SPRY4 that provide negative feedback to the RAS/ERK pathway. Consistently, ETS1 was required for robust RAS/ERK pathway activation. Therefore, ETS1 has dual roles in mediating epithelial-specific RAS/ERK transcriptional functions.
Zhai X, Han Q, Shan Z, et al.Dual specificity phosphatase 6 suppresses the growth and metastasis of prostate cancer cells.
Mol Med Rep. 2014; 10(6):3052-8 [PubMed
] Related Publications
Dual specificity phosphatase 6 (DUSP6) is expressed at low levels in numerous types of human cancer. The loss of DUSP6 plays a pivotal role in tumor progression; however, the role of DUSP6 in prostate cancer remains unclear. In this study, in vitro invasion assays and in vivo metastasis experiments were used to investigate the effects of DUSP6 on prostate cancer cell invasion and metastasis. Furthermore, in vitro growth and soft agar assays and in vivo growth experiments were performed to determine the function of DUSP6 in cell proliferation. The results showed that the overexpression of DUSP6 suppressed the invasion and growth of DU‑145 human prostate cancer cells, whereas knockdown of DUSP6 promoted the invasion and proliferation of LNCap human prostate adenocarcinoma cells. Further experiments demonstrated that the overexpression of DUSP6 inhibited the proliferation and liver metastasis of DU‑145 cells in mice. In addition, DUSP6 downregulated the expression of matrix metallopeptidase 3 and interleukin 8 in prostate cancer cells. Taken together, these findings indicate that DUSP6 may act as a negative mediator in the regulation of prostate cancer cell growth and metastasis.
Manzano RG, Martinez-Navarro EM, Forteza J, Brugarolas AMicroarray phosphatome profiling of breast cancer patients unveils a complex phosphatase regulatory role of the MAPK and PI3K pathways in estrogen receptor-negative breast cancers.
Int J Oncol. 2014; 45(6):2250-66 [PubMed
] Free Access to Full Article Related Publications
Phosphatases are proteins with the ability to dephosphorylate different substrates and are involved in critical cellular processes such as proliferation, tumor suppression, motility and survival. Little is known about their role in the different breast cancer (BC) phenotypes. We carried out microarray phosphatome profiling in 41 estrogen receptor-negative (ER-) BC patients, as determined by immunohistochemistry (IHC), containing both ERBB2+ and ERBB2- in order to characterize the differences between these two groups. We characterized and confirmed the distinct phosphatome of the two main ER- BC subgroups (in two independent microarrays series) and that of ER+ BC (in three large independent series). Our findings point to the importance of the MAPK and PI3K pathways in ER- BCs as some of the most differentially expressed phosphatases (like DUSP4 and DUSP6) sharing ERK as substrate, or regulating the PI3K pathway (INPP4B, PTEN). It was possible to identify a selective group of phosphatases upregulated only in the ER- ERBB2+ subgroup and not in ER+ (like DUSP6, DUSP10 and PPAPDC1A among others), suggesting a role of these phosphatases in specific BC subtypes, unlike other differentially expressed phosphatases (DUSP4 and ENPP1) that seemed to have a role in multiple BC subtypes. Significant correlation was found at the protein level by IHC between the expression of DUSP6 and phospho-ERK (p=0.04) but not of phospho-ERK with DUSP4. To show the potential prognostic relevance of phosphatases as a functional group of genes, we derived and validated in two large independent BC microarray series a multiphosphatase signature enriched in differentially expressed phosphatases, to predict distant metastasis-free survival (DMFS). ER- ERBB2+, ER- ERBB2- and ER+ BC patients have a distinct pattern of phosphatase RNA expression with a potential prognostic relevance. Further studies of the most relevant phosphatases found in this study are warranted.
Boeckx C, Op de Beeck K, Wouters A, et al.Overcoming cetuximab resistance in HNSCC: the role of AURKB and DUSP proteins.
Cancer Lett. 2014; 354(2):365-77 [PubMed
] Related Publications
Unraveling the underlying mechanisms of cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) is of major importance as many tumors remain non-responsive or become resistant. Our microarray results suggest that "resistant" cells still exhibit RAS-MAPK pathway signaling contributing to drug resistance, as witnessed by low expression of DUSP5 and DUSP6, negative regulators of ERK1/2, and increased expression of AURKB, a key regulator of mitosis. Therefore, interrupting the RAS-MAPK pathway by an ERK1/2 inhibitor (apigenin) or an AURKB inhibitor (barasertib) might be a new strategy for overcoming cetuximab resistance in HNSCC.
Abnormal expression of solute carrier family 34 (sodium phosphate), member 2 (SLC34A2) in the lung may induce abnormal alveolar type II (AT II) cells to transform into lung adenocarcinoma cells, and may also be important in biological process of lung adenocarcinoma. However, at present, the effects and molecular mechanisms of SLC34A2 in the initiation and progression of lung cancer remain to be elucidated. To the best of our knowledge, the present study revealed for the first time that the expression levels of SLC34A2 were downregulated in the A549 and H1299 lung adenocarcinoma cell lines. Further investigation demonstrated that the elevated expression of SLC34A2 in A549 cells was able to significantly inhibit cell viability and invasion in vitro. In addition, 10 upregulated genes between the A549‑P‑S cell line stably expressing SLC34A2 and the control cell line A549‑P were identified by microarray analysis and quantitative polymerase chain reaction, including seven tumor suppressor genes and three complement genes. Furthermore, the upregulation of complement gene C3 and complement 4B preproprotein (C4b) in A549‑P‑S cells was confirmed by ELISA analysis and was identified to be correlated with recovering Pi absorption in A549 cells by the phosphomolybdic acid method by enhancing the expression of SLC34A2. Therefore, it was hypothesized that the mechanisms underlying the effect of SLC34A2 on A549 cells might be associated with the activation of the complement alternative pathway (C3 and C4b) and upregulation of the expression of selenium binding protein 1, thioredoxin‑interacting protein, PDZK1‑interacting protein 1 and dual specificity protein phosphatase 6. Downregulation of SLC34A2 may primarily cause abnormal AT II cells to escape from complement‑associated immunosurveillance and abnormally express certain tumor‑suppressor genes inducing AT II cells to develop into lung adenocarcinoma. The present study further elucidated the effects and mechanisms of SLC34A2 in the generation and development of lung cancer.
Huerta M, Fernández-Márquez J, Cabello JL, et al.Analysis of gene expression for studying tumor progression: the case of glucocorticoid administration.
Gene. 2014; 549(1):33-40 [PubMed
] Related Publications
BACKGROUND: Glucocorticoids are commonly used as adjuvant treatment for side-effects and have anti-proliferative activity in several tumors but, on the other hand, their proliferative effect has been reported in several studies, some of them involving the spread of cancer. We shall attempt to reconcile these incongruities from the genomic and tissue-physiology perspectives with our findings.
METHODS: An accurate phenotype analysis of microarray data can help to solve multiple paradoxes derived from tumor-progression models. We have developed a new strategy to facilitate the study of interdependences among the phenotypes defined by the sample clusters obtained by common clustering methods (HC, SOTA, SOM, PAM). These interdependences are obtained by the detection of non-linear expression-relationships where each fluctuation in the relationship implies a phenotype change and each relationship typology implies a specific phenotype interdependence. As a result, multiple phenotypic changes are identified together with the genes involved in the phenotype transitions. In this way, we study the phenotypic changes from microarray data that describe common phenotypes in cancer from different tissues, and we cross our results with biomedical databases to relate the glucocorticoid activity to the phenotypic changes.
RESULTS: 11,244 significant non-linear expression relationships, classified into 11 different typologies, have been detected from the data matrix analyzed. From them, 415 non-linear expression relationships were related to glucocorticoid activity. Studying them, we have found the possible reason for opposite effects of some stressor agents like dexamethasone on tumor progression and it has been confirmed by literature. This hidden reason has resulted in being linked with the type of tumor progression of the tissues. In the first type of tumor progression found, new cells can be stressed during proliferation and stressor agents increase tumor proliferation. In the second type, cell stress and tumor proliferation are antagonists so, therefore, stressor agents stop tumor proliferation in order to stress the cells. The non-linear expression relationships among DUSP6, FERMT2, FKBP5, EGFR, NEDD4L and CITED2 genes are used to synthesize these findings.
Lai AZ, Cory S, Zhao H, et al.Dynamic reprogramming of signaling upon met inhibition reveals a mechanism of drug resistance in gastric cancer.
Sci Signal. 2014; 7(322):ra38 [PubMed
] Related Publications
The Met receptor tyrosine kinase is activated or genetically amplified in some gastric cancers, but resistance to small-molecule inhibitors of Met often emerges in patients. We found that Met abundance correlated with a proliferation marker in patient gastric tumor sections, and gastric cancer cell lines that have MET amplifications depended on Met for proliferation and anchorage-independent growth in culture. Inhibition of Met induced temporal changes in gene expression in the cell lines, initiated by a rapid decrease in the expression of genes encoding transcription factors, followed by those encoding proteins involved in epithelial-mesenchymal transition, and finally those encoding cell cycle-related proteins. In the gastric cancer cell lines, microarray and chromatin immunoprecipitation analysis revealed considerable overlap between genes regulated in response to Met stimulation and those regulated by signal transducer and activator of transcription 3 (STAT3). The activity of STAT3, extracellular signal-regulated kinase (ERK), and the kinase Akt was decreased by Met inhibition, but only inhibitors of STAT3 were as effective as the Met inhibitor in decreasing tumor cell proliferation in culture and in xenografts, suggesting that STAT3 mediates the pro-proliferative program induced by Met. However, the phosphorylation of ERK increased after prolonged Met inhibition in culture, correlating with decreased abundance of the phosphatases DUSP4 and DUSP6, which inhibit ERK. Combined inhibition of Met and the mitogen-activated protein kinase kinase (MEK)-ERK pathway induced greater cell death in cultured gastric cancer cells than did either inhibitor alone. These findings indicate combination therapies that may counteract resistance to Met inhibitors.
The epithelial-to-mesenchymal transition (EMT) transcriptional program is characterized by repression of E-cadherin (CDH1) and induction of N-cadherin (CDH2), and mesenchymal genes like vimentin (VIM). Placenta-specific 8 (PLAC8) has been implicated in colon cancer; however, how PLAC8 contributes to disease is unknown, and endogenous PLAC8 protein has not been studied. We analyzed zebrafish and human tissues and found that endogenous PLAC8 localizes to the apical domain of differentiated intestinal epithelium. Colon cancer cells with elevated PLAC8 levels exhibited EMT features, including increased expression of VIM and zinc finger E-box binding homeobox 1 (ZEB1), aberrant cell motility, and increased invasiveness. In contrast to classical EMT, PLAC8 overexpression reduced cell surface CDH1 and upregulated P-cadherin (CDH3) without affecting CDH2 expression. PLAC8-induced EMT was linked to increased phosphorylated ERK2 (p-ERK2), and ERK2 knockdown restored cell surface CDH1 and suppressed CDH3, VIM, and ZEB1 upregulation. In vitro, PLAC8 directly bound and inactivated the ERK2 phosphatase DUSP6, thereby increasing p-ERK2. In a murine xenograft model, knockdown of endogenous PLAC8 in colon cancer cells resulted in smaller tumors, reduced local invasion, and decreased p-ERK2. Using MultiOmyx, a multiplex immunofluorescence-based methodology, we observed coexpression of cytosolic PLAC8, CDH3, and VIM at the leading edge of a human colorectal tumor, supporting a role for PLAC8 in cancer invasion in vivo.
Cossa G, Lanzi C, Cassinelli G, et al.Differential outcome of MEK1/2 inhibitor-platinum combinations in platinum-sensitive and -resistant ovarian carcinoma cells.
Cancer Lett. 2014; 347(2):212-24 [PubMed
] Related Publications
Deregulated pro-survival signalling plays a role in ovarian carcinoma drug resistance. Here, we show that cisplatin or oxaliplatin in combination with the MEK1/2 inhibitor CI-1040 resulted in a synergistic effect associated with enhanced apoptotic response in platinum-sensitive cells. The drug combinations were additive in platinum-resistant cells exhibiting increased phospho-ERK1/2, down-regulation of apoptosis-related factors (BAX, PUMA, FOXO1) and of phosphatases inhibiting ERK1/2 (DUSP5, DUSP6). Consistently, FOXO1 knockdown in sensitive cells reduced the efficacy of the combination treatment. Pharmacological targeting of ERK1/2 pathway increases cell sensitivity to platinum compounds by interfering with multiple events, ultimately favouring apoptosis induction in selected molecular backgrounds.
Lee EK, Chung KW, Yang SK, et al.DNA methylation of MAPK signal-inhibiting genes in papillary thyroid carcinoma.
Anticancer Res. 2013; 33(11):4833-9 [PubMed
] Related Publications
BACKGROUND: The purpose of this study was to identify the DNA methylation status of the mitogen-activated protein kinase (MAPK) signal-inhibiting genes dual-specificity phosphatase 4 (DUSP4) and 6 (DUSP6); and serpin peptidase inhibitor A member 5 (SERPINA5) in thyroid cancer.
MATERIALS AND METHODS: Using 76 papillary thyroid cancer(PTC) tissues and three thyroid cancer cell lines (TPC1, WRO82-1 and XTC), the expression of three genes and DNA methylation were determined by reverse transcription-PCR and methylation-specific PCR.
RESULTS: In all cell lines, the expression of DUSP4 and DUSP6 increased; the corresponding gene promoters were unmethylated. However, SERPINA5 gene expression decreased and SERPINA5 DNA was methylated in the TPC1 cell line. With the de-methylating agent 5'-aza-2'-deoxycytidine, SERPINA5 gene expression was restored. In 82.9% of PTC tissues (63/76), the SERPINA5 DNA promoter was methylated, which was associated with a higher v-raf murine sarcoma viral oncogene homolog B1(BRAF) mutation rate in PTC tissues based on multivariate regression (odds ratio=3.573; 95% confidence interval=1.122-11.379; p=0.031).
CONCLUSION: The expression of the MAPK signal-inhibiting gene SERPINA5 decreased in the TPC1 cell line, SERPINA5 expression was regulated by DNA methylation, which was associated with a higher BRAF mutation rate in PTC.
Hagan CR, Knutson TP, Lange CAA Common Docking Domain in Progesterone Receptor-B links DUSP6 and CK2 signaling to proliferative transcriptional programs in breast cancer cells.
Nucleic Acids Res. 2013; 41(19):8926-42 [PubMed
] Free Access to Full Article Related Publications
Progesterone receptors (PR) are transcription factors relevant to breast cancer biology. Herein, we describe an N-terminal common docking (CD) domain in PR-B, a motif first described in mitogen-activated protein kinases. Binding studies revealed PR-B interacts with dual-specificity phosphatase 6 (DUSP6) via the CD domain. Mutation of the PR-B CD domain (mCD) attenuated cell cycle progression and expression of PR-B target genes (including STAT5A and Wnt1); mCD PR-B failed to undergo phosphorylation on Ser81, a ck2-dependent site required for expression of these genes. PR-B Ser81 phosphorylation was dependent on binding with DUSP6 and required for recruitment of a transcriptional complex consisting of PR-B, DUSP6 and ck2 to an enhancer region upstream of the Wnt1 promoter. STAT5 was present at this site in the absence or presence of progestin. Furthermore, phospho-Ser81 PR-B was recruited to the STAT5A gene upon progestin treatment, suggestive of a feed-forward mechanism. Inhibition of JAK/STAT-signaling blocked progestin-induced STAT5A and Wnt1 expression. Our studies show that DUSP6 serves as a scaffold for ck2-dependent PR-B Ser81 phosphorylation and subsequent PR-B-specific gene selection in coordination with STAT5. Coregulation of select target genes by PR-B and STAT5 is likely a global mechanism required for growth promoting programs relevant to mammary stem cell biology and cancer.
Skrzypski M, Dziadziuszko R, Jassem E, et al.Main histologic types of non-small-cell lung cancer differ in expression of prognosis-related genes.
Clin Lung Cancer. 2013; 14(6):666-673.e2 [PubMed
] Related Publications
BACKGROUND: There is increasing evidence that suggests that particular histopathologic types of non-small-cell lung cancer (NSCLC) display distinct molecular characteristics. We analyzed, in lung squamous cell carcinoma (SCC) and adenocarcinoma (AC), the expression of 8 genes that constitute 2 previously reported prognostic expression signatures in NSCLC.
METHODS: Fresh-frozen tumor and normal lung samples were obtained at surgery from 135 patients with stage I-III NSCLC (89 (65.9%) SCC, 46 (34.1%) AC). Expression of CSF1 (colony stimulating factor for macrophages), carbonic anhydrase 9 (CA9), epithelial growth factor receptor (EGFR), dual specificity phosphatase 6 (DUSP6), v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ERBB3), monocyte to macrophage differentiation-associated (MMD), lymphocyte-specific protein tyrosine kinase (LCK) and signal transducer and activator of transcription 1 (STAT1) was assessed in SCC, AC, and in normal lung by quantitative reverse transcriptase - polymerase chain reaction (qRT-PCR). Metastasis-free survival was analyzed according to the median value of gene expression in the entire NSCLC cohort and separately in SCC and AC.
RESULTS: Expression of CA9, CSF1, DUSP6, STAT1, and MMD differed between NSCLC and normal lung. EGFR was more abundant in SCC compared with AC, whereas the reverse was true for DUSP6 and ERBB3. A high expression of CSF1 correlated with shorter metastasis-free survival in the entire NSCLC group (P = .016) and in SCC (P = .049) and AC (P = .034) cohorts.
CONCLUSIONS: Several genes considered prognostic in NSCLC showed significantly different expression in SCC and AC, and thus should be analyzed separately in these 2 subtypes for their prognostic significance. CSF1 is similarly expressed in SCC and AC, and portends a poor outcome in the entire group of patients with NSCLC, and in SCC and AC when considered separately.
The zebrafish is a powerful genetic model that has only recently been used to dissect developmental pathways involved in oncogenesis. We hypothesized that operative pathways during embryogenesis would also be used for oncogenesis. In an effort to define RAS target genes during embryogenesis, gene expression was evaluated in Tg(hsp70-HRAS(G12V)) zebrafish embryos subjected to heat shock. dusp6 was activated by RAS, and this was used as the basis for a chemical genetic screen to identify small molecules that interfere with RAS signaling during embryogenesis. A KRAS(G12D)-induced zebrafish embryonal rhabdomyosarcoma was then used to assess the therapeutic effects of the small molecules. Two of these inhibitors, PD98059 and TPCK, had anti-tumor activity as single agents in both zebrafish embryonal rhabdomyosarcoma and a human cell line of rhabdomyosarcoma that harbored activated mutations in NRAS. PD98059 inhibited MEK1 whereas TPCK suppressed S6K1 activity; however, the combined treatment completely suppressed eIF4B phosphorylation and decreased translation initiation. Our work demonstrates that the activated pathways in RAS induction during embryogenesis are also important in oncogenesis and that inhibition of these pathways suppresses tumor growth.
Zhang H, Guo Q, Wang C, et al.Dual-specificity phosphatase 6 (Dusp6), a negative regulator of FGF2/ERK1/2 signaling, enhances 17β-estradiol-induced cell growth in endometrial adenocarcinoma cell.
Mol Cell Endocrinol. 2013; 376(1-2):60-9 [PubMed
] Related Publications
Dual-specificity phosphatase 6 (Dusp6) is a negative feedback mechanism of fibroblast growth factors (FGFs)/mitogen-activated protein kinase (MAPK)/ERK1/2 signaling. The aim of this study was to explore the expression of Dusp6 in human endometrial adenocarcinomas and the role of Dusp6 expression in the growth regulation of endometrial adenocarcinoma cell. We found that Dusp6 was over-expressed in human endometrial adenocarcinomas. In Ishikawa cells, plasmid-driven Dusp6 expression efficiently blocked the activity of FGF2-induced MAPK/ERK1/2 signaling. Unexpectedly, Dusp6 expression significantly enhanced the growth of Ishikawa cells. In Dusp6 forced-expression cells, 17β-estradiol stimulation increased the cell growth by all most threefolds. In addition, progesterone treatment reduced the cell growth to about half both in Ishikawa cells with and without forced-Dusp6-expression. Dusp6 over-expression is involved in the pathogenesis and development of human endometrial adenocarcinomas. Dusp6 functions as a negative regulator of FGF2/ERK1/2 signaling but enhances the growth and 17β-estradiol-induced cell growth in endometrial adenocarcinoma cell.
BACKGROUND: Breast cancer, a heterogeneous disease has been broadly classified into oestrogen receptor positive (ER+) or oestrogen receptor negative (ER-) tumour types. Each of these tumours is dependent on specific signalling pathways for their progression. While high levels of survivin, an anti-apoptotic protein, increases aggressive behaviour in ER- breast tumours, oxidative stress (OS) promotes the progression of ER+ breast tumours. Mechanisms and molecular targets by which OS promotes tumourigenesis remain poorly understood.
RESULTS: DETA-NONOate, a nitric oxide (NO)-donor induces OS in breast cancer cell lines by early re-localisation and downregulation of cellular survivin. Using in vivo models of HMLE(HRAS) xenografts and E2-induced breast tumours in ACI rats, we demonstrate that high OS downregulates survivin during initiation of tumourigenesis. Overexpression of survivin in HMLE(HRAS) cells led to a significant delay in tumour initiation and tumour volume in nude mice. This inverse relationship between survivin and OS was also observed in ER+ human breast tumours. We also demonstrate an upregulation of NADPH oxidase-1 (NOX1) and its activating protein p67, which are novel markers of OS in E2-induced tumours in ACI rats and as well as in ER+ human breast tumours.
CONCLUSION: Our data, therefore, suggest that downregulation of survivin could be an important early event by which OS initiates breast tumour formation.
Degl'Innocenti D, Romeo P, Tarantino E, et al.DUSP6/MKP3 is overexpressed in papillary and poorly differentiated thyroid carcinoma and contributes to neoplastic properties of thyroid cancer cells.
Endocr Relat Cancer. 2013; 20(1):23-37 [PubMed
] Related Publications
Thyroid carcinomas derived from follicular cells comprise papillary thyroid carcinoma (PTC), follicular thyroid carcinoma, poorly differentiated thyroid carcinoma (PDTC) and undifferentiated anaplastic thyroid carcinoma (ATC). PTC, the most frequent thyroid carcinoma histotype, is associated with gene rearrangements that generate RET/PTC and TRK oncogenes and with BRAF-V600E and RAS gene mutations. These last two genetic lesions are also present in a fraction of PDTCs. The ERK1/2 pathway, downstream of the known oncogenes activated in PTC, has a central role in thyroid carcinogenesis. In this study, we demonstrate that the BRAF-V600E, RET/PTC, and TRK oncogenes upregulate the ERK1/2 pathway's attenuator cytoplasmic dual-phase phosphatase DUSP6/MKP3 in thyroid cells. We also show DUSP6 overexpression at the mRNA and protein levels in all the analysed PTC cell lines. Furthermore, DUSP6 mRNA was significantly higher in PTC and PDTC in comparison with normal thyroid tissues both in expression profile datasets and in patients' surgical samples analysed by real-time RT-PCR. Immunohistochemical and western blot analyses showed that DUSP6 was also overexpressed at the protein level in most PTC and PDTC surgical samples tested, but not in ATC, and revealed a positive correlation trend with ERK1/2 pathway activation. Finally, DUSP6 silencing reduced the neoplastic properties of four PTC cell lines, thus suggesting that DUSP6 may have a pro-tumorigenic role in thyroid carcinogenesis.
Kim SH, Lee HY, Yi H, et al.Haloperidol induces demethylation and expression of the dual specificity phosphatase 6 gene in MIA PaCa-2 human pancreatic cancer cells.
Life Sci. 2012; 91(25-26):1317-22 [PubMed
] Related Publications
AIMS: The effects of antipsychotics on various gene expressions through change in DNA methylation have been reported. Dual-specificity phosphatase 6 (DUSP6) is an extracellular signal regulated kinase 1/2 (ERK1/2)-selective phosphatase, and its expression can be suppressed by intronic methylation. Antipsychotic agent haloperidol affects ERK1/2 activity and could induce changes in DNA methylation as well as histone acetylation. In this study, we examined the effects of haloperidol on DUSP6 expression related to DNA methylation changes.
MAIN METHODS: The effects of haloperidol and 5-azacytidine, a demethylating agent, on expression and methylation of DUSP6 were quantitatively measured in MIA PaCa-2 human pancreatic carcinoma cells, in which DUSP6 expression is suppressed due to intronic hypermethylation. The growth rate of MIA PaCa-2 cells was also examined after treatment with haloperidol or 5-azacytidine.
KEY FINDINGS: Haloperidol increased DUSP6 expression in a concentration-dependent manner and inhibited MIA PaCa-2 cell proliferation; effects were comparable to those of 5-azacytidine. However, haloperidol did not induce DUSP6 expression in PANC-1 cells, another pancreatic cancer cell line without transcriptional suppression of DUSP6. Pyrosequencing methylation analysis confirmed the intronic hypermethylation of DUSP6 in MIA PaCa-2 and revealed that haloperidol and 5-azcytidine induced demethylation of CpG sequences in this region.
SIGNIFICANCE: Haloperidol induced DUSP6 expression related to intronic demethylation and inhibited MIA PaCa-2 cell proliferation, which suggests demethylating activity and anti-cancer effects of haloperidol. These findings suggest the possible involvement of epigenetic regulatory mechanisms in the action mechanism of haloperidol.
Mitogen-activated protein kinase (MAPK) pathways regulate many cellular functions including cell proliferation, differentiation, migration and apoptosis. We evaluate genetic variation in the c-Jun-N-terminal kinases, p38, and extracellular regulated kinases 1/2 MAPK-signaling pathways and colon and rectal cancer risk using data from population-based case-control studies (colon: n = 1555 cases, 1956 controls; rectal: n = 754 cases, 959 controls). We assess 19 genes (DUSP1, DUSP2, DUSP4, DUSP6, DUSP7, MAP2K1, MAP3K1, MAP3K2, MAP3K3, MAP3K7, MAP3K9, MAP3K10, MAP3K11, MAPK1, MAPK3, MAPK8, MAPK12, MAPK14 and RAF1). MAP2K1 rs8039880 [odds ratio (OR) = 0.57, 95% confidence interval (CI) = 0.38, 0.83; GG versus AA genotype] and MAP3K9 rs11625206 (OR = 1.41, 95% CI = 1.14, 1.76; recessive model) were associated with colon cancer (P (adj) value < 0.05). DUSP1 rs322351 (OR = 1.43, 95% CI = 1.09, 1.88; TT versus CC) and MAPK8 rs10857561 (OR = 1.48, 95% CI 1.08, 2.03; AA versus GG/GA) were associated with rectal cancer (P (adj) < 0.05). Aspirin/non-steroidal anti-inflammatory drug, cigarette smoking and body mass index interacted with several genes to alter cancer risk. Genetic variants had unique associations with KRAS, TP53 and CIMP+ tumors. DUSP2 rs1724120 [hazard rate ratio (HRR) = 0.72, 95%CI = 0.54, 0.96; AA versus GG/GA), MAP3K10 rs112956 (HRR = 1.40, 95% CI = 1.10, 1.76; CT/TT versus CC) and MAP3K11 (HRR = 1.76, 95% CI 1.18, 2.62 TT versus GG/GT) influenced survival after diagnosis with colon cancer; MAP2K1 rs8039880 (HRR = 2.53, 95% CI 1.34, 4.79 GG versus AG/GG) and Raf1 rs11923427 (HRR = 0.59 95% CI = 0.40, 0.86; AA versus TT/TA) were associated with rectal cancer survival. These data suggest that genetic variation in the MAPK-signaling pathway influences colorectal cancer risk and survival after diagnosis. Associations may be modified by lifestyle factors that influence inflammation and oxidative stress.
BACKGROUND: Several studies have shown the prognostic and predictive potential of molecular markers in combined therapy for lung cancer. Most of them referred, however, to operable early stage NSCLC. The aim of the present study is to correlate the expression of multiple mRNA markers in bronchoscopy obtained cancer specimens with clinical outcome of advanced lung cancer.
METHODS: Bronchoscopy cancer specimens were taken from 123 patients with radiological diagnosis of advanced lung tumor. Out of 123 patients 50 were diagnosed with squamous cell cancer, 17 with adenocarcinoma, 12 with NOS, 32 with SCLC and one with large cell neuroendocrinal cancer. In 11 patients other tumours were diagnosed. The group was heterogeneous with respect to clinical stage, performance of the patients and treatment. Quantitative real time PCR was carried out by ABI 7900 HT machine, with Universal Probe Library (Roche) fluorescent probes. The genes selected for the analysis were ERCC1, EGFR, BRCA1, CSF1, CA9, DUSP6, STAT1, ERBB3, MMD, FN1, and CDKN1B.
RESULTS: More than 50 ng of RNA (the amount considered sufficient for the analysis) was isolated in 82 out of 112 lung cancer specimens (73%), including 60/80 (75.0%) of NSCLC specimens and 22/32 (68,7%) of SCLC samples. The highest Cohen's κ coefficient for discrimination between small cell, squamous cell and adenocarcinoma was found for CDKN1B, CSF and EGFR1 (κ = 0.177, p = 0.0041). A multivariate Cox regression model has shown a significant impact of clinical stage (p<0.001, RR = 4.19), ERCC1 (p = 0.01, RR = 0.43) and CA9 (p = 0.03, RR = 2.11) expression on overall survival in a group of 60 patients with NSCLC.
CONCLUSION: These results show the feasibility of multiple gene expression analysis in bronchoscopy obtained cancer specimens as prognostic markers in radiotherapy and chemotherapy for advanced lung cancer. A limiting factor was relatively high proportion of samples from which sufficient amount of RNA could not be isolated.
UNLABELLED: The antidiabetic drug metformin has antitumor activity in a variety of cancers because it blocks cell growth by inhibiting TORC1. Here, we show that melanoma cells that are driven by oncogenic BRAF are resistant to the growth-inhibitory effects of metformin because RSK sustains TORC1 activity even when AMP-activated protein kinase (AMPK) is activated. We further show that AMPK targets the dual-specificity protein phosphatase DUSP6 for degradation and this increases ERK activity, which then upregulates the VEGF-A protein. Critically, this drives angiogenesis and accelerates the growth of BRAF-driven tumors in mice. Unexpectedly, however, when VEGF signaling is inhibited, instead of accelerating tumor growth, metformin inhibits tumor growth. Thus, we show that BRAF-driven melanoma cells are resistant to the antigrowth effects of AMPK and that AMPK mediates cell-autonomous and cell-nonautonomous effects that accelerate the growth of these cells in vivo.
SIGNIFICANCE: Metformin inhibits the growth of most tumor cells, but BRAF-mutant melanoma cells are resistant to metformin in vitro, and metformin accelerates their growth in vivo. Unexpectedly, VEGF inhibitors and metformin synergize to suppress the growth of BRAF-mutant tumors, revealing a combination of drugs that may be effective in these patients.
Toriseva M, Ala-aho R, Peltonen S, et al.Keratinocyte growth factor induces gene expression signature associated with suppression of malignant phenotype of cutaneous squamous carcinoma cells.
PLoS One. 2012; 7(3):e33041 [PubMed
] Free Access to Full Article Related Publications
Keratinocyte growth factor (KGF, fibroblast growth factor-7) is a fibroblast-derived mitogen, which stimulates proliferation of epithelial cells. The expression of KGF by dermal fibroblasts is induced following injury and it promotes wound repair. However, the role of KGF in cutaneous carcinogenesis and cancer progression is not known. We have examined the role of KGF in progression of squamous cell carcinoma (SCC) of the skin. The expression of KGF receptor (KGFR) mRNA was lower in cutaneous SCCs (n = 6) than in normal skin samples (n = 6). Expression of KGFR mRNA was detected in 6 out of 8 cutaneous SCC cell lines and the levels were downregulated by 24-h treatment with KGF. KGF did not stimulate SCC cell proliferation, but it reduced invasion of SCC cells through collagen. Gene expression profiling of three cutaneous SCC cell lines treated with KGF for 24 h revealed a specific gene expression signature characterized by upregulation of a set of genes specifically downregulated in SCC cells compared to normal epidermal keratinocytes, including genes with tumor suppressing properties (SPRY4, DUSP4, DUSP6, LRIG1, PHLDA1). KGF also induced downregulation of a set of genes specifically upregulated in SCC cells compared to normal keratinocytes, including genes associated with tumor progression (MMP13, MATN2, CXCL10, and IGFBP3). Downregulation of MMP-13 and KGFR expression in SCC cells and HaCaT cells was mediated via ERK1/2. Activation of ERK1/2 in HaCaT cells and tumorigenic Ha-ras-transformed HaCaT cells resulted in downregulation of MMP-13 and KGFR expression. These results provide evidence, that KGF does not promote progression of cutaneous SCC, but rather suppresses the malignant phenotype of cutaneous SCC cells by regulating the expression of several genes differentially expressed in SCC cells, as compared to normal keratinocytes.
Cisplatin is an effective anticancer drug used to treat many types of cancer, including non-small cell lung carcinoma (NSCLCs), but development of resistance is the primary impediment in cancer treatment. Insulin-like growth factor-binding protein 7 (IGFBP7) is a secreted tumor suppressor that is inactivated in human lung cancer. IGFBP7 is known to alter sensitivity to interferon-based anticancer therapy, and here, we examined loss of IGFBP7 as a potential contributor to chemo-resistance to cisplatin. The transcriptional level of IGFBP7 was decreased in cisplatin-resistant human cancer cell lines and NSCLC xenografts. IGFBP7 knock-down increased cellular resistance to cisplatin and increased the level of mitogen-activated protein kinase phosphatases (MKP) 3 levels. The expression of MKP3 increased in a cisplatin-resistant NSCLC cell line and lung xenografts. MKP3 knock-down increased IGFBP7 level, indicating that MKP3 regulates IGFBP7. These findings suggest a novel molecular mechanism responsible for the tumor suppressive function of IGFBP7 in cisplatin-resistant human lung cancer and could lead to the development of IGFBP7 as a cisplatin-sensitizing agent.
Holt SV, Logie A, Davies BR, et al.Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055).
Cancer Res. 2012; 72(7):1804-13 [PubMed
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The mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/AKT signaling pathways interact at multiple nodes in cancer, including at mTOR complexes, suggesting an increased likelihood of redundancy and innate resistance to any therapeutic effects of single pathway inhibition. In this study, we investigated the therapeutic effects of combining the MAPK extracellular signal-regulated kinase (MEK)1/2 inhibitor selumetinib (AZD6244) with the dual mTORC1 and mTORC2 inhibitor (AZD8055). Concurrent dosing in nude mouse xenograft models of human lung adenocarcinoma (non-small cell lung cancers) and colorectal carcinoma was well tolerated and produced increased antitumor efficacy relative to the respective monotherapies. Pharmacodynamic analysis documented reciprocal pathway inhibition associated with increased apoptosis and Bim expression in tumor tissue from the combination group, where key genes such as DUSP6 that are under MEK functional control were also modulated. Our work offers a strong rationale to combine selumetinib and AZD8055 in clinical trials as an attractive therapeutic strategy.
Baba T, Kawaguchi M, Fukushima T, et al.Loss of membrane-bound serine protease inhibitor HAI-1 induces oral squamous cell carcinoma cells' invasiveness.
J Pathol. 2012; 228(2):181-92 [PubMed
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A loss of balance between cell membrane-associated proteases and their inhibitors may underlie cancer invasion and metastasis. We analysed the roles of a membrane- associated serine protease inhibitor, HAI-1, in oral squamous cell carcinoma (OSCC). While membranous HAI-1 was widely observed in cancer cells of human OSCC tissues, this was significantly reduced at the infiltrative invasion front. In vitro, HAI-1 was detected in all eight OSCC cell lines examined, in which its cognate membrane protease, matriptase was also expressed. HAI-1 expression knock-down (KD) in OSCC lines, SAS and HSC-3, reduced the growth of both lines in vitro but significantly enhanced SAS tumourigenicity in vivo, which was accompanied by histological changes suggestive of the epithelial-mesenchymal transition. Both HAI-1-KD lines also exhibited significantly enhanced migratory capability, and membrane-associated but not truncated HAI-1 was required to rescue this phenotype. Other OSCC lines (HSC-2, Sa3, Ca9-22) also showed enhanced migration in response to HAI-1 KD. The enhanced migration is partly attributed to dysregulation of matriptase, as simultaneous matriptase KD alleviated the migration of HAI-1-KD cells. HAI-1 deficiency also altered the expression of CD24, S100A4, CCND2 and DUSP6, all of which are involved in tumour progression. While matriptase was involved in the increased CD24 expression associated with HAI-1 deficiency, the protease appeared to be not responsible for the altered expression of other genes. Therefore, a matriptase-independent mechanism for the invasiveness associated with HAI-1 KD is also present. Together, these observations suggest that HAI-1 has a crucial suppressive role in OSCC cell invasiveness.
Wang Y, Fan H, Zhou B, et al.Fusion of human umbilical cord mesenchymal stem cells with esophageal carcinoma cells inhibits the tumorigenicity of esophageal carcinoma cells.
Int J Oncol. 2012; 40(2):370-7 [PubMed
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Prior studies on the biology and therapeutic application of human stem cells in human malignancies have reported mixed results. Some evidence shows the use of stem cell transplantation is an important tool in the treatment of several hematologic and non-hematologic malignancies while some others suggest both human stem cells and mature stromal cells can contribute to the development and growth of human malignancies. Aiming to provide more evidence on this controversial issue, we investigated the effect of cell fusion of mesenchymal stem cells with esophageal carcinoma cells on tumorigenesis. Results suggest that artificial fusion of human umbilical cord mesenchymal stem cells with esophageal carcinoma cells resulted in hybrids with declined cell growth, increased apoptosis and suppressed tumorigenicity. The comparison of gene expression profiles of human mesenchymal stem cells, esophageal carcinoma cells and hybrids indicated that fusion induced activation of apoptosis. Furthermore, the expression of DUSP6/MKP3 in MAPK pathway increased strikingly and the exogenous overexpression confirmed the growth suppression. Our results demonstrate fusion of human mesenchymal stem cells with esophageal carcinoma cells induced apoptosis and benign transdifferentiation rather than reprogramming to cancer stem cells.
Li W, Melton DWCisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance.
Oncogene. 2012; 31(19):2412-22 [PubMed
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The incidence of malignant melanoma is growing rapidly worldwide and there is still no effective therapy for metastatic disease. Melanoma is the second most common cancer among young adults in the UK, where incidence rates have more than quadrupled since the 1970s. Increased expression of a number of DNA repair genes has been reported in melanoma and this likely contributes to its extreme resistance to conventional DNA-damaging chemotherapeutics. One such chemotherapeutic that is effective against a range of other cancers, but not melanoma, is cisplatin. The DNA repair proteins ERCC1 and XPF are needed to remove cisplatin-induced DNA damage and we have investigated the response of these proteins to cisplatin in melanoma. The expression of both genes is induced by cisplatin. Use of a MEK inhibitor showed that ERCC1, but not XPF induction was regulated by the mitogen-activated protein kinase (MAPK) pathway, with reduction in expression of DUSP6, the phosphatase that inactivates the extracellular signal-regulated kinase (ERK), being particularly important. DUSP6 overexpression prevented cisplatin induction of both ERCC1 and XPF, resulting in increased sensitivity to cisplatin. A novel ERCC1 mRNA was found that initiated upstream of the normal transcription initiation site, and was strongly regulated by both cisplatin and the MAPK pathway and its role in cisplatin resistance merits further study. The cisplatin induction of ERCC1 and XPF provides important insights into the resistance of melanoma to DNA-damaging chemotherapeutics, which is one of the major obstacles to melanoma treatment.
Messina S, Frati L, Leonetti C, et al.Dual-specificity phosphatase DUSP6 has tumor-promoting properties in human glioblastomas.
Oncogene. 2011; 30(35):3813-20 [PubMed
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Dual-specificity phosphatase 6 (DUSP6, mitogen-activated protein kinase (MAPK) phosphatase 3 or PYST1) dephosphorylates phosphotyrosine and phosphothreonine residues on extracellular signal-regulated kinase (ERK1/2; MAPK1/2) to inactivate the ERK1/2 kinase. DUSP6 is a critical regulator of the ERK signaling cascade and has been implicated as a tumor suppressor. We report here experimental evidences that DUSP6 is transcriptionally upregulated in primary and long-term cultures of human glioblastoma, as assayed by northern hybridization and real-time quantitative PCR, producing constitutive high level of protein expression. Functional assays were performed with adenovirus-mediated expression of DUSP6 in glioblastoma cultures. Protein overexpression inhibits growth by inducing G1-phase delay and increased mitogenic/anchorage dependence and clonogenic potential in vitro. Changes in cell morphology were associated with an increased tumor growth in vivo. Chemoresistance is a major cause of treatment failure and poor outcome in human glioblastomas. Importantly, DUSP6 overexpression increased resistance to cisplatin-mediated cell death in vitro and in vivo. Antisense-mediated depletion of DUSP6 acted in lowering the threshold to anticancer DNA-damaging drugs. We conclude that upregulation of DUSP6 exerts a tumor-promoting role in human glioblastomas exacerbating the malignant phenotype.
Wong VC, Chen H, Ko JM, et al.Tumor suppressor dual-specificity phosphatase 6 (DUSP6) impairs cell invasion and epithelial-mesenchymal transition (EMT)-associated phenotype.
Int J Cancer. 2012; 130(1):83-95 [PubMed
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Suppressive effects of DUSP6 in tumorigenesis and EMT-associated properties were observed. Dual-specificity phosphatase (DUSP6) is a MAP kinase phosphatase (MKP) negatively regulating the activity of ERK, one of the major molecular switches in the MAPK signaling cascade propagating the signaling responses during malignancies. The impact of DUSP6 in EMT and its contribution to tumor dissemination has not yet been characterized. Due to differences in tumor microenvironments affecting cell signaling during cancer progression, DUSP6 may play varying roles in tumor development. We sought to examine the potential role of DUSP6-mediated tumorigenesis and EMT-associated properties in two aerodigestive tract cancers, namely, esophageal squamous cell carcinoma (ESCC) and nasopharyngeal carcinoma (NPC). Significant loss of DUSP6 was observed in 100% of 11 ESCC cell lines and 71% of seven NPC cell lines. DUSP6 expression was down-regulated in 40% of 30 ESCC tumor tissues and 75% of 20 NPC tumor tissues compared to their respective normal counterparts. Suppressive effects of DUSP6 in tumor formation and cancer cell mobility are seen in in vivo tumorigenicity assay and in vitro colony formation, three-dimensional Matrigel culture, cell migration and invasion chamber tests. Notably, overexpression of DUSP6 impairs EMT-associated properties. Furthermore, tissue microarray analysis reveals a clinical association of DUSP6 expression with better patient survival. Taken together, our study provides a novel insight into understanding the functional impact of DUSP6 in tumorigenesis and metastasis of ESCC and NPC.