Table 3.
Upstream regulators of metronomic CPA-responsive human genes
| Upstream regulator | Molecule type | p-value of overlap | # of target genes |
|---|---|---|---|
| A. Activated upstream regulators (human gene targets) | |||
| IFNL1/IL29 | Cytokine | 1.72E-29 | 36 |
| IFNG | Cytokine | 5.04E-23 | 68 |
| IFNA2 | Cytokine | 8.87E-23 | 36 |
| TGM2 | Enzyme | 6.30E-14 | 43 |
| IFNB1 | Cytokine | 7.98E-10 | 14 |
| Interferon alpha | Cytokine | 1.57E-07 | 23 |
| PAF1 | Transcription complex | 1.89E-07 | 14 |
| IRF1 | Transcription regulator | 1.25E-06 | 12 |
| IL27 | Cytokine | 1.65E-06 | 14 |
| Growth hormone | Protein hormone | 1.37E-05 | 12 |
| COL18A1 | Endostatin precursor | 9.08E-05 | 13 |
| B. Inhibited upstream regulators (human gene targets) | |||
| MAPK1 | Kinase | 4.88E-30 | 57 |
| IL1RN | Cytokine | 2.26E-15 | 26 |
| HIF1A | Transcription regulator | 1.09E-14 | 40 |
| EPAS1 | Transcription regulator | 6.48E-12 | 24 |
| NUPR1 | Transcription regulator | 3.60E-11 | 68 |
| GAPDH | Enzyme | 2.75E-10 | 14 |
| NEDD9 | Cell adhesion protein | 2.34E-08 | 13 |
| SOCS1 | Cytokine signaling inhibitor | 6.93E-08 | 12 |
| MAP3K7/TAK1 | Kinase | 1.05E-07 | 12 |
| ERK1/2 | Kinase | 1.47E-07 | 22 |
| RELA | Transcription regulator | 4.72E-07 | 24 |
| TGFB1 | Growth factor | 6.69E-06 | 37 |
Regulators were identified by IPA of the set of U251 human tumor cell genes up-regulated or down-regulated by metronomic CPA in common at both the day 12 and day 18 times points. Shown are the upstream regulators whose activation state is reliably predicated to be activated (A) or inhibited (B) by CPA treatment, based on a bias-corrected |Z-score| >2, and that meet the stringent threshold for overlap with the target gene set at p < E-04 and contain a minimum of 10 target genes in the regulated gene set. More complete information, including Z-scores, lists of target genes for each regulator, associated mechanistic networks, and other upstream regulators are shown in Additional file 1: Table S3.