Genes and Cancer最新文献

FOXP2 encodes a transcription factor involved in speech and language acquisition. Growing evidence now suggests that dysregulated FOXP2 activity may also be instrumental in human oncogenesis, along the lines of other cardinal developmental transcription factors such as DLX5 and DLX6 [1-4]. Several FOXP familymembers are directly involved during cancer initiation, maintenance and progression in the adult [5-8]. This may comprise either a pro-oncogenic activity or a deficient tumor-suppressor role, depending upon cell types and associated signaling pathways. While FOXP2 is expressed in numerous cell types, its expression has been found to be down-regulated in breast cancer [9], hepatocellular carcinoma [8] and gastric cancer biopsies [10]. Conversely, overexpressed FOXP2 has been reported in multiple myelomas, MGUS (Monoclonal Gammopathy of Undetermined Significance), several subtypes of lymphomas [5,11], as well as in neuroblastomas [12] and ERG fusion-negative prostate cancers [13]. According to functional evidences reported in breast cancer [9] and survey of recent transcriptomic and proteomic analyses of different tumor biopsies, we postulate that FOXP2 dysregulation may play a main role throughout cancer initiation and progression. In some cancer conditions, FOXP2 levels are now considered as a critical diagnostic marker of neoplastic cells, and in many situations, they even bear strong prognostic value [5]. Whether FOXP2 may further become a therapeutic target is an actively explored lead. Knowledge reviewed here may help improve our understanding of FOXP2 roles during oncogenesis and provide cues for diagnostic, prognostic and therapeutic analyses.

Ever since its initial discovery in Drosophila, hedgehog signaling has been linked to foregut development, The mammalian genome expresses three Hedgehog paralogues, sonic hedgehog (Shh), Indian Hedgehog, and desert hedgehog. In the mucosa of the embryonic and adult foregut, Shh expression is the highest. It has now become clear that hedgehog signaling is of pivotal importance in gastric homeostasis. Aberrant activation of hedgehog signaling is associated with a range of pathological consequences including various cancers. Also in gastric cancer, clinical and preclinical data support a role of Hedgehog signaling in neoplastic transformation, and gastrointestinal cancer development, also through cancer stroma interaction. Technological advance are facilitating monitoring Hedgehog signaling broadening options for the more efficient screening of individuals predisposed to eventually developing gastric cancer and targeting Hedgehog signaling may provide opportunities for prophylactic therapy once atrophic gastritis develops. Nevertheless, convincing evidence that Hedgehog antagonists are of clinically useful in the context of gastric cancer is still conspicuously lacking. Here we analyze review the role of Hedgehog in gastric physiology and the potential usefulness of targeting Hedgehog signaling in gastric cancer.

Uncontrolled cell replication is a key component of carcinogenesis. MicroRNAs (miRNAs) regulate genes involved in checkpoints, DNA repair, and genes encoding for key proteins regulating the cell cycle. We investigated how miRNAs and mRNAs in colorectal cancer subjects interact to regulate the cell cycle. Using RNA-Seq data from 217 individuals, we analyzed differential expression (carcinoma minus normal mucosa) of 123 genes within the cell cycle pathway with differential miRNA expression, adjusting for age and sex. Multiple comparison adjustments for gene/miRNA associations were made at the gene level using an FDR <0.05. Differentially expressed miRNAs and mRNAs were tested for associations with colorectal cancer survival. MRNA and miRNA sequences were compared to identify seed region matches to support biological interpretation of the observed associations. Sixty-seven mRNAs were dysregulated with a fold change (FC) <0.67 or >1.50. Thirty-two mRNAs were associated with 48 miRNAs; 102 of 290 total associations had identified seed matches; of these, ten had negative beta coefficients. Hsa-miR-15a-5p and hsa-miR-20b-5p were associated with colorectal cancer survival with an FDR <0.05 (HR 0.86 95% CI 0.79, 0.94; HR 0.83 95% CI 0.75, 0.91 respectively). Our findings suggest that miRNAs impact mRNA translation at multiple levels within the cell cycle.

Screening methods of High-Grade Serous Ovarian Cancer (HGSOC) lack specificity and sensitivity, partly due to benign tumors producing false-positive findings. We utilized a differential expression analysis pipeline on malignant tumor (MT) and normal epithelial (NE) samples, and also filtered the results to discriminate between MT and benign tumor (BT). We report that a panel of 26 dysregulated genes stratifies MT from both BT and NE. We further validated our findings by utilizing unsupervised clustering methods on two independent datasets. We show that the 26-genes panel completely distinguishes HGSOC from NE, and produces a more accurate classification between HGSOC and BT. Pathway analysis reveals that AKT3 is of particular significance, because of its high fold change and appearance in the majority of the dysregulated pathways. mRNA patterns of AKT3 suggest essential connections with tumor growth and metastasis, as well as a strong biomarker potential when used with 3 other genes (PTTG1, MND1, CENPF). Our results show that dysregulation of the 26-mRNA signature panel provides an evidence of malignancy and contribute to the design of a high specificity biomarker panel for detection of HGSOC, potentially in an early more curable stage.

Circulating Tumor Cells (CTCs) are floating cell populations, which are resistant to anoikis after detachment from the primary sites and travel through the circulatory and lymphatic systems to disseminate throughout the body. CTCs are considered as seed cells for metastasis, and thus isolation of CTCs does not require any invasive procedure. Based on the nature and location of ovarian cancer and glioblastoma, the role of CTCs and hematogenous (carried by blood) spreading of tumor cells in these cancers were not understood well. Dysregulation of epidermal growth factor receptor (EGFR/ERBB) family members due to their overexpression and/or mutation have been known to contribute to the etiology and progression of ovarian cancer and glioblastoma. However, the role of ERBB receptors on CTC formation of ovarian cancer and glioblastoma is not well established. This report highlights the role of ERBB family receptors on resistance to anoikis and CTC formation in ovarian cancer and glioblastoma. Recent research on CTCs demonstrates that capturing ERBB receptor positive cells from circulating system is an efficient approach to isolate CTCs for genomic and proteomic characterization of tumor cells. Therefore, ERBB-targeted isolation of CTCs would help to design therapy to treat cancer, determine drug responses and drug-resistant mechanisms in cancer patients.

Ewing sarcoma is an aggressive cancer of bone and soft tissue in children with poor prognosis. It is characterized by the chromosomal translocation between EWS and an Ets family transcription factor, most commonly FLI-1. EWS-FLI-1 fusion accounts for 85% of Ewing sarcoma cases. EWS-FLI-1 regulates the expression of a number of genes important for sarcomagenesis, can transform NIH3T3 and C3H10T1/2 cells, and is necessary for proliferation and tumorigenicity of Ewing sarcoma cells, suggesting that EWS-FLI-1 is the causative oncoprotein. Here we report that EWS-FLI-1 induces the expression of pappalysin-1 (PAPPA), a cell surface protease that degrades IGF binding proteins (IGFBPs) and increases the bioavailability of IGF. EWS-FLI-1 binds to the pappalysin-1 gene promoter and stimulates the expression of pappalysin-1, leading to degradation of IGFBPs and enhanced IGF signaling. Silencing of pappalysin-1 strongly inhibited anchorage-dependent and anchorage-independent growth as well as xenograft tumorigenicity of Ewing sarcoma cells. These results suggest that EWS-FLI-1 creates a cell surface microenvironment conducive to IGF signaling by inducing pappalysin-1, which emerged as a novel target to inhibit IGF signaling in Ewing sarcoma.

Several studies have demonstrated that specific 14-3-3 isoforms are frequently elevated in cancer and that these proteins play a role in human tumorigenesis. 14-3-3γ, an isoform recently demonstrated to function as an oncoprotein, is overexpressed in a variety of human cancers; however, its role in promoting tumorigenesis remains unclear. We previously reported that overexpression of 14-3-3γ caused the appearance of polyploid cells, a phenotype demonstrated to have profound tumor promoting properties. Here we examined the mechanism driving 14-3-3γ-induced polyploidization and the effect this has on genomic stability. Using FUCCI probes we showed that these polyploid cells appeared when diploid cells failed to enter mitosis and subsequently underwent endoreduplication. We then demonstrated that 14-3-3γ-induced polyploid cells experience significant chromosomal segregation errors during mitosis and observed that some of these cells stably propagate as tetraploids when isolated cells were expanded into stable cultures. These data lead us to conclude that overexpression of the 14-3-3γ promotes endoreduplication. We further investigated the role of 14-3-3γ in human NSCLC samples and found that its expression is significantly elevated in polyploid tumors. Collectively, these results suggests that 14-3-3γ may promote tumorigenesis through the production of a genetically unstable polyploid intermediate.

The proto-oncogene MYC is a transcription factor over-expressed in many cancers and required for cell survival. Its function is regulated by histone acetyltransferase (HAT) complexes, such as the GCN5 complex and the NuA4/Tip60 complex. However, the roles of the HAT complexes during MYC function in cancer have not been well characterized. We recently showed that adenovirus E1A and its N-terminal 80 aa region, E1A 1-80, interact with the NuA4 complex, through the E1A TRRAP-targeting (ET) domain, and enhance MYC association with the NuA4 complex. We show here that the ET domain mainly targets the MYC-NuA4 complex. By global gene expression analysis using E1A 1-80 and deletion mutants, we have identified a panel of genes activated by targeting the MYC-NuA4 complex and notably enriched for genes involved in ribosome biogenesis and gene expression. A second panel of genes is activated by E1A 1-80 targeting of both the MYC-NuA4 complex and p300, and is enriched for genes involved in DNA replication and cell cycle processes. Both panels of genes are highly expressed in cancer cells. Since the ET domain is essential for E1A-mediated cellular transformation, our results suggest that MYC and the NuA4 complex function cooperatively in cell transformation and cancer.

Aim: To assess the association of GLO1 C332C gene polymorphism with breast cancer risk at different stages of the disease and to investigate the effect of this gene polymorphism on its mRNA expression and enzyme activity.

Methods: GLO1 C332C gene polymorphism was analyzed by PCR-RFLP in 100 healthy controls and 200 patients with breast cancer (100 patients with stage I & II and 100 patients with stage III & IV). GLO1 mRNA expression was measured by real time PCR. Serum GLO1 enzyme activity was measured colorimetrically.

Results: GLO1 A allele was associated with increased risk of breast cancer [OR (95%CI)= 2.8(1.9-4.1), P < 0.001]. Its frequency was significantly higher among advanced stages of breast cancer compared with localized tumors (OR (95%CI)= 1.9(1.3-2.9), p < 0.001). GLO1 mRNA expression and enzyme activity were significantly higher in breast cancer patients compared to controls and they were much higher in the advanced stages of the disease (P < 0.001). Carriers of AA genotype showed higher GLO1 expression and enzyme activity compared with carriers of CC genotype.

Conclusion: GLO1 C332C SNP was associated with overexpression of GLO1 mRNA and higher enzyme activity in breast cancer patients suggesting its role in the development of breast cancer and its progression from localized to advanced.