Fig 6. Oscillating hypoxic response dynamics regulates gene expression congruent to many human cancers.

(A-C) Genes downregulated by oscillating hypoxia show a correlatively downregulated signature in many human cancer types. (A) Heatmap showing genes upregulated by hypoxia, but downregulated by oscillatory hypoxia (Osc^down genes), and (B) their relative expression in cancers vs normal tissue in the TCGA tumor database; colors refer to a TCGA study where the given gene is expressed significantly higher (red), or significantly lower (green) in tumor compared to normal tissue sample, with significance for the whole set of Osc^down genes in (C). (D-F) Genes upregulated by oscillating hypoxia also show a correlatively upregulated signature in many human cancer types: (D) Heatmap showing genes downregulated in hypoxia, but upregulated in oscillatory hypoxia (Osc^up genes), and (E) direction of their expression in TCGA tumors vs normal samples; color code same as B. (F) Significance of the whole set of Osc^up genes shown in tumor vs normal; In C, and F, bars show overall fold change of the geneset, colorbar represents the mean log₂fold change between cancer and normal samples. (G-H) Genes differentially regulated by oscillatory hypoxia are significantly downregulated (G), or upregulated (H) when compared against the directional expression of all other genes in those TCGA tumors vs control samples; In both G, and H, each dot represents a tumor comparison with normal tissue; x-axis refer to log(pvalue) of tumor vs normal comparison; bars show 95% confidence interval for mean vs all genes difference; vertical red line marks threshold of pvalue = 0.05. (I-L) Representative examples of Osc^down and Osc^up gene sets in breast cancer BRCA, and liver hepatocellular carcinoma LIHC: (I) Histogram showing density of Osc^down genes (green), or all genes (pink); Genes are normalized by total gene numbers; BRCA tumor samples = 1085, normal breast samples = 291. (J) GSEA enrichment analysis in Osc^down gene expression in BRCA vs normal samples; all genes are ranked in order of decreasing tumor/normal fold changes on x-axis, with bars representing Osc^down genes. (K) Histogram showing relative distribution of fold change of Osc^down genes (green), or all genes (pink); Genes are normalized by total gene numbers; LIHC tumor samples = 369, normal breast samples = 160. In I, and K, asterisk represents the mean log₂fold change between cancer and normal samples for the corresponding gene set (all or Osc^down /Osc^up). (L) GSEA enrichment analysis in Osc^up gene expression in LIHC cancers. (M) Osc^down genes are significantly downregulated in many TCGA cancer types when compared to all the other genes; bars show a 95% confidence interval for the difference. (N) Many Osc^up genes are significantly upregulated in many TCGA cancer types compared to all the other genes; bars show a 95% confidence interval.