Table 5.
Upstream regulators of metronomic CPA-responsive mouse genes
| Upstream regulator | Molecule type | p-value of overlap | # of target genes |
|---|---|---|---|
| A. Activated upstream regulators (mouse gene targets) | |||
| IFNAR | Interferon receptor | 5.34E-14 | 31 |
| IRF3 | Transcription regulator | 5.62E-12 | 28 |
| IFNG | Interferon | 2.55E-11 | 80 |
| IL12 (complex) | Cytokine | 1.04E-10 | 24 |
| STAT1 | Transcription regulator | 1.32E-10 | 37 |
| IRF7 | Transcription regulator | 1.64E-10 | 23 |
| IFN alpha/beta | Interferon | 3.98E-09 | 20 |
| NFATC2 | Transcription regulator | 4.77E-09 | 26 |
| IFNB1 | Cytokine | 9.37E-09 | 34 |
| TLR4 | Toll-like receptor | 3.19E-08 | 42 |
| DOCK8 | other | 4.22E-08 | 21 |
| SASH1 | other | 7.34E-08 | 21 |
| TICAM1 | Adapter for TLR3 | 1.05E-07 | 28 |
| ITK | Kinase | 1.52E-07 | 22 |
| SAMSN1 | other | 2.20E-07 | 23 |
| mir-223 | MicroRNA | 3.67E-07 | 24 |
| DDX58 | Enzyme | 1.15E-06 | 14 |
| IL6 | Interleukin 6 | 1.22E-06 | 30 |
| SPI1 | Transcription regulator | 1.31E-06 | 19 |
| IKBKB | Kinase that activates REL/NF B | 3.41E-06 | 31 |
| NOS2 | Nitric oxide synthase; M1 macrophage marker | 3.83E-06 | 30 |
| MYD88 | Adapter for TLRs | 7.34E-06 | 32 |
| TLR3 | Transmembrane receptor | 8.10E-06 | 27 |
| BNIP3L | Pro-apoptotic factor | 9.69E-06 | 15 |
| TLR9 | Transmembrane receptor | 1.33E-05 | 25 |
| NLRP3 | Inflammasome | 1.59E-05 | 15 |
| IRF5 | Transcription regulator | 2.22E-05 | 12 |
| PPARG | Ligand-dependent nuclear receptor | 5.21E-05 | 40 |
| IL18 | Cytokine | 6.86E-05 | 11 |
| FADD | Transmembrane receptor adapter protein | 7.33E-05 | 15 |
| CD44 | Enzyme | 7.53E-05 | 22 |
| CDKN2A | Transcription regulator | 8.10E-05 | 20 |
| B. Inhibited upstream regulators (mouse gene targets) | |||
| CSF2/GM-CSF | Cytokine | 3.82E-15 | 45 |
| TRIM24 | Transcription regulator | 8.10E-13 | 32 |
| PTGER2 | G-protein coupled receptor | 1.65E-09 | 26 |
| DNASE2 | Enzyme | 4.26E-08 | 14 |
| ACKR2 | G-protein coupled receptor | 4.87E-08 | 15 |
| SOCS1 | other | 1.26E-07 | 20 |
| mir-21 | MicroRNA | 1.67E-06 | 25 |
| TGFB1 | Growth factor | 9.61E-06 | 19 |
| MYC | Transcription regulator | 1.46E-05 | 24 |
Upstream regulators were identified by IPA analysis of the set of mouse genes up-regulated or down-regulated by metronomic CPA in common in U251 tumors after three metronomic CPA treatments (day 18) and in 9L tumors after four metronomic CPA treatments (day 24), as described in Methods. Shown are the upstream regulators whose activation state is reliably predicated to be activated (A) or inhibited (B) by CPA treatment, with other details as described in Table 3. 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 S7.