Meta-analysis of archived DNA microarrays identifies genes regulated by hypoxia and involved in a metastatic phenotype in cancer cells

<p>Abstract</p> <p>Background</p> <p>Metastasis is a major cancer-related cause of death. Recent studies have described metastasis pathways. However, the exact contribution of each pathway remains unclear. Another key feature of a tumor is the presence of hypoxic areas caused by a lack of oxygen at the center of the tumor. Hypoxia leads to the expression of pro-metastatic genes as well as the repression of anti-metastatic genes. As many Affymetrix datasets about metastasis and hypoxia are publicly available and not fully exploited, this study proposes to re-analyze these datasets to extract new information about the metastatic phenotype induced by hypoxia in different cancer cell lines.</p> <p>Methods</p> <p>Affymetrix datasets about metastasis and/or hypoxia were downloaded from GEO and ArrayExpress. AffyProbeMiner and GCRMA packages were used for pre-processing and the Window Welch <it>t </it>test was used for processing. Three approaches of meta-analysis were eventually used for the selection of genes of interest.</p> <p>Results</p> <p>Three complementary approaches were used, that eventually selected 183 genes of interest. Out of these 183 genes, 99, among which the well known <it>JUNB</it>, <it>FOS </it>and <it>TP63</it>, have already been described in the literature to be involved in cancer. Moreover, 39 genes of those, such as <it>SERPINE1 </it>and <it>MMP7</it>, are known to regulate metastasis. Twenty-one genes including <it>VEGFA </it>and <it>ID2 </it>have also been described to be involved in the response to hypoxia. Lastly, DAVID classified those 183 genes in 24 different pathways, among which 8 are directly related to cancer while 5 others are related to proliferation and cell motility. A negative control composed of 183 random genes failed to provide such results. Interestingly, 6 pathways retrieved by DAVID with the 183 genes of interest concern pathogen recognition and phagocytosis.</p> <p>Conclusion</p> <p>The proposed methodology was able to find genes actually known to be involved in cancer, metastasis and hypoxia and, thus, we propose that the other genes selected based on the same methodology are of prime interest in the metastatic phenotype induced by hypoxia.</p

Maternal ethanol exposure is associated with decreased plasma zinc and increased fetal abnormalities in normal but not metallothionein-null mice

BackgroundEthanol profoundly affects fetal development, and this is proposed to be due primarily to a transient fetal zinc (Zn) deficiency that arises from the binding of Zn by metallothionein (MT) in the maternal liver. Zn homeostasis and fetal outcome were investigated in normal (MT+/+) and metallothionein-null (MT-/-) mice in response to ethanol exposure.Methods/resultsMice were treated with saline or ethanol (0.015 m/g intraperitoneally at 0 and 4 hr) on day 8 of gestation (Gd8), and the degree of fetal dysmorphology was assessed on Gd18. The incidence of external abnormalities was significantly increased in offspring from MT+/+ dams exposed to ethanol, where 27.4% of fetuses were affected. MT-/- ethanol-, MT+/+ saline-, and MT-/- saline-treated dams had fetuses in which the frequencies of abnormalities were 2.2, 6.4, and 6.9%, respectively. To investigate Zn homeostasis, nonpregnant mice were killed at intervals over 16 hr after ethanol injection. Liver MT concentrations in MT+/+ mice were increased 20-fold by 16 hr, with a significant elevation evident by 4 hr, whereas liver Zn levels were also significantly increased by 2 hr and maintained for 16 hr. In parallel with these changes, plasma Zn concentrations in MT+/+ mice decreased by 65%, with minimum levels of 4.5+/-0.3 micromol/liter at 8 hr. Conversely, MT-/- mice exhibited increased plasma Zn concentrations, with peak values of 20.8+/-0.3 observed at 4 hr.ConclusionThese findings link the teratogenic effect of ethanol to the induction of maternal MT and the limitation of fetal Zn supply from the plasma.Carey, Luke C. ; Coyle, Peter ; Philcox, Jeffrey C. ; Rofe, Allan M