Translational oncogenomics最新文献

The Y-box Binding Protein-1 (YB-1) is a highly conserved oncogenic transcription/translation factor that is expressed in cancers affecting adults and children. It is now believed that YB-1 plays a causal role in the development of cancer given recent work showing that its expression drives the tumorigenesis in the mammary gland. In human breast cancers, YB-1 is associated with rapidly proliferating tumors that are highly aggressive. Moreover, expression of YB-1 promotes the growth of breast cancer cell lines both in monolayer and anchorage independent conditions. The involvement of YB-1 in breast cancer pathogenesis has made it a putative therapeutic target; however, the mechanism(s) that regulate YB-1 are poorly understood. This review first describes the oncogenic properties of YB-1 in cancer. It also highlights the importance of YB-1 in hardwiring signal transduction pathways to the regulation of genes involved in the development of cancer.

There is a growing body of literature suggesting that signaling based therapy might be a potential approach for medullary thyroid cancer (MTC). In this review we focus on the tumor suppressor role of Notch1 and Raf-1 signaling in MTC. Interestingly these two pathways are minimally active or absent in these tumors and activation of Notch1 and Raf-1 significantly reduces tumor growth in vitro. Therefore, identification of compounds that induce these pathways could be a potential strategy to treat patients with MTC.

The increasing number of proteomic and DNA-microarray studies is continually providing a steady acquisition of data on the molecular abnormalities associated with human tumors. Rapid translation of this accumulating biological information into better diagnostics and more effective cancer therapeutics in the clinic depends on the use of robust function-testing strategies. Such strategies should allow identification of molecular lesions that are essential for the maintenance of the transformed phenotype and enable validation of potential drug-targets. The tetracycline regulated gene expression/ suppression systems (Tet-systems) developed and optimized by bioengineers over recent years seem to be very well suited for the function-testing purposes in cancer research. We review the history and latest improvements in Tet-technology in the context of functional oncogenomics.

Many tumor markers for bladder cancer have been evaluated for use in detecting and monitoring bladder cancers tissue specimens, bladder washes, and urine specimens. However, none of the biomarkers reported to date has shown sufficient sensitivity and specificity to detect the entire spectrum of bladder cancers in routine clinical practice. The limited value of the established prognostic markers demands analysis of new molecular parameters having the potential to predict the prognosis of bladder cancer patients, particularly, the high-risk patients at risk of cancer progression and recurrence. Abnormal methylation of CpG islands can efficiently repress transcription of the associated gene in a manner akin to mutations and deletions. Several tumor suppressor genes correlated with bladder cancer contain CpG islands in their promoters. Markers for aberrant methylation may be a potential gateway for monitoring bladder cancer. Hypermethylation of several gene promoters was detected in urine sediment DNA from bladder cancer patients. Detection of DNA methylation in voided urine is feasible and noninvasive. Methylation is an important molecular mechanism in the development of bladder cancer and could be used as a prognostic and diagnostic marker. Aberrant patterns of epigenetic modification could, in the near future, be crucial indicators in cancer diagnosis, prognosis, and may additionally be good targets for developing novel therapies while maintaining quality of life.

Specific combinations of transcription-factor binding sites in the promoter regions of genes regulate gene expression, and thus key functional processes in cells. Analysis of such promoter regions in specific functional contexts can be used to delineate novel disease-associated genes based on shared phenotypic properties. The aim of this study was to utilize promoter analysis to predict cell proliferation-associated genes and to test this method in colon cancer cell lines. We used freely-available bioinformatic techniques to identify cell-proliferation-associated genes expressed in colon cancer, extract a shared promoter module, and identify novel genes that also contain this module in the human genome. An EGRF/ETSF promoter module was identified as prevalent in proliferation-associated genes from a colon cancer cDNA library. We detected 30 other genes, from the known promoters of the human genome, which contained this proliferation-associated module. This group included known proliferation-associated genes, such as HERG1 and MCM7, and a number of genes not previously implicated in cell proliferation in cancer, such as TSPAN3, Necdin and APLP2. Suppression of TSPAN3 and APLP2 by siRNA was performed and confirmed by RT-PCR. Inhibition of these genes significantly inhibited cell proliferation in colon cancer cell lines. This study demonstrates that promoter analysis can be used to identify novel cancer-associated genes based on shared functional processes.

Chronic eosinophilic leukemia is a clonal disease characterized by hypereosinophilia and eosinophilia-related pathologic manifestations. Recently, the fusion gene FIP1L1/PDGFRA was found in the long arm of chromosome 4 and its expression has been shown to be associated with development of a clinical hypereosinophilic syndrome (HES) in a significant proportion of patients. FIP1L1/PDGFRα, the product of the gene FIP1L1/PDGFRA, is a constitutively activated tyrosine kinase and can be inhibited by imatinib mesylate. Several investigations have tried to dissect the mechanism of leukemogenesis and signaling induced by FIP1L1/PDGFRα in cell lines, primary human eosinophils and in murine myeloproliferative models. In this review, we analyzed the current knowledge on the relationship between FIP1L1/PDGFRα-induced signaling and eosinophil proliferation, survival and activation, specially focusing on its possible role in the modulation of cytokine and chemoattractant signaling pathways.

Background: Potassium bromate (KBrO3), used in both the food and cosmetics industry, and a drinking water disinfection by-product, is a nephrotoxic compound and rodent carcinogen. To gain insight into the carcinogenic mechanism of action and provide possible biomarkers of KBrO3 exposure, the gene expression in kidneys from chronically exposed male F344 rats was investigated.

Methods: Male F344 rats were exposed to KBrO3 in drinking water for 52 and 100 wk. Kidneys were removed, frozen, and stored at -80°C, then used for Affymetrix microarray analysis. Gene expression patterns were examined using a non-carcinogenic (20 ppm) and carcinogenic dose (400 ppm) at 52 wk, and compared to 100 wk high dose (400 ppm) and adenoma gene expression.

Results: Statistical analysis revealed 144, 224, 43, and 994 genes out of 15866 from the 52 wk low, 52 wk high, 100 wk high, and adenomas respectively, were differentially expressed when compared to control kidneys. Gene ontology classification of the 52 wk high dose showed alterations of gene transcripts involved in oxidative stress, lipid metabolism, kidney function/ion transport, and cellular function. In a comparison of kidney development gene expression, alterations were seen in the adenomas but not in the 52 wk bromate-treated kidneys. However, the normal kidney from the high dose group resembled the adenoma expression pattern with early kidney development genes being up-regulated and adult phase genes being down-regulated. Moreover, eight genes were identified which could serve as biomarkers of carcinogenic exposure to bromate. The most promising of these was Pendrin, or Slc26a4, a solute carrier of chloride and iodide active in the kidney, thyroid, and inner ear. All these tissues are targets of KBrO3 toxicity. Expression array results were verified with quantitative real-time rtPCR.

Conclusions: These data demonstrate that the 400 ppm carcinogenic dose of KBrO3 showed marked gene expression differences from the 20 ppm non-carcinogenic dose. Comparison of kidney development gene expression showed that the adenoma patterns were more characteristic of embryonic than adult kidneys, and that the normal kidney from the high dose group resembled the adenoma-like gene expression pattern. Taken together, the analysis from this study identifies potential biomarkers of exposure and illuminates a possible carcinogenic mode of action for KBrO3.

Unlabelled: Multiple lines of evidence implicate over-expression and activation of the androgen receptor (AR) in the progression of prostate cancer (PC) to androgen-independence (AI) and resistance to therapy. The mechanisms leading to AR over-expression are not fully understood but binding of Sp1 to specific Sp1-binding sites in the AR promoter and 5'-untranslated region (5'-UTR) was shown to up-regulate AR transcription. In this work, we further characterized the role of Sp1 in the control of AR transcription and explored its potential as a therapeutic target in androgen-dependent (AD) and independent (AI) LNCaP cells. We identified a pair of new Sp1-binding site in the 5'-UTR of AR which we named ARSp1-3. ARSp1-3 binds Sp1 with higher affinity than other known Sp1-binding sites in the promoter/5'-UTR and in transfection experiments, the ARSp1-3 reporter showed higher transcriptional activity in AI than in AD cells. Treatment of these cells with nanomolar concentrations of Mithramycin inhibited binding of Sp1 to its binding sites in the promoter/5'-UTR of the AR gene but more specifically the binding of ARSp1-3 while other regulatory elements of the AR promoter were not affected. Inhibition of Sp1 binding by Mithramycin decreased the AR transcription and transactivation of PSA reporter constructs. At the lowest concentrations, Mithramycin decreased endogenous AR protein and proliferation of AD and AI LNCaP cells. The combinations of Mithramycin with either paclitaxel or bicalutamide were highly synergistic.

Conclusion: Sp1 binding induces AR transcription in LNCaP cells. The higher affinity of ARSp1-3 for Sp1 may support higher AR mRNA levels in AI than AD LNCaP cells. Mithramycin is a potent and specific inhibitor of Sp1 and AR transcription with potential, at very low concentrations, to enhance the efficacy of hormones or taxane based therapy in patients with recurrent or androgen-independent progression that sustain AR expression.

Background: c-Met mutations play a critical role in the development and progression of primary tumors and metastases. Activation of the HGF/SF-c-Met pathway determines a poor prognosis in non-small-cell and small-cell lung cancer (SCLC) patients. Missense mutations of c-Met have been identified in SCLC patients located in the juxtamembrane (JM) and in the Sema domain. To determine the role of the c-Met pathway in SCLC, we have investigated the presence of c-Met mutations in SCLC patients.

Patients and methods: Forty-four tumor tissue samples from SCLC patients were obtained with bronchoscopy before beginning treatment. Analysis of c-Met mutations was performed in exon 2 and exon 14.

Results: Of the 44 patients included in this study, 23 were classified as limited disease and were treated with sequential or concurrent chemotherapy and thoracic radiotherapy. Twenty-one patients with extensive disease received chemotherapy alone, the majority with cisplatin or carboplatin plus etoposide. The median survival was 14 months (95% CI: 9.4 to 18.5 months) and the 2- and 5-year survival rates were 24% and 15%, respectively. Previously identified missense mutations E168D, R988C and T1010I in c-Met were not found in our study. However, novel mutations were identified, including T995I in the juxtamembrane domain (T995I) and a mutation which does not change amino acid in codon 178 in the Sema domain.

Conclusion: In SCLC patients, the presence of mutations in c-Met gene is a rare event. Other genetic alterations involved in the HGF/SF-c-Met pathway should be assessed to define the role of this signaling pathway in SCLC.