Submitted:
24 December 2024
Posted:
26 December 2024
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Abstract
Six-transmembrane epithelial antigen of prostate 3 (STEAP3) is a metalloreductase that is capable of converting iron from an insoluble ferric (Fe3+) to a soluble ferrous (Fe2+) form. It has been found to be overexpressed in colorectal cancer. In colorectal cancer cells treated with ETC-1922159, it was found to be down-regulated. A recently developed search engine ranked combinations of STEAP3-X (X, a particular gene/protein) at 2nd order level after drug administration. In this research work, I cover combinations of STEAP3 with cyclin dependent kinase inhibitor (CDKN), glutathione peroxidase (GPX), solute carrier family (SLC), methyltransferase N6 adenosine methyltransferase complex catalytic subunit (METTL), b-cell leukemia / lymphoma protein (BCL), interleukin (IL) and transferrin receptor protein (TFR) family.
Keywords:
STEAP3
; Porcupine inhibitor ETC-1922159
; Sensitivity analysis
; Colorectal cancer
1. Introduction
1.1. Six-Transmembrane Epithelial Antigen of Prostate (STEAP)
Sendamarai et al. [1] discuss the role of STEAP3 as a metalloreductase. They state that erythroid precursor cells uptake iron (Fe3+) by loading it to transferrin (TF) which then binds to the transferrin receptor (TFR) at the cell surface. This TF-TFR complex then enters the endosome. Upon endosomal acidification, iron is released from TF, reduced to Fe2+ by STEAP3, and transported across the endosomal membrane by a divalent metal iron transporter. Ohgami et al. [2] further characterize and demonstrate that STEAP2, STEAP3, and STEAP4 not only reduce iron but also copper. Zhou et al. [3] and Lv et al. [4] show that STEAP3 promotes colorectal cancer. In colorectal cancer cells treated with ETC-1922159, STEAP3 was found to be down regulated, along with other genes. I present here machine learning based discoveries of STEAP3-X combinations that might be working synergistically in colorectal cancer. Some of these combinations have already been tested in wet lab, however many others remain unexplored/untested. To address this, I use the following search engine, in the next section.
1.2. Combinatorial Search Problem and a Possible Solution
In a recently published work Sinha [5], a frame work of a search engine was developed which can rank combinations of factors (genes/proteins) in a signaling pathway. Readers are requested to go through the adaptation of the above mentioned work for gaining deeper insight into the working of the pipeline and its use of published data set generated after administration of ETC-1922159, Sinha [6]. The work uses SVM package by Joachims [7] in https://www.cs.cornell.edu/people/tj/svm_light/svm_rank.html. I use the adaptation to rank 2nd order gene combinations.
2. Results & Discussion
2.1. STEAP3 Related Synergies
2.1.1. STEAP3-CDKN Family
In colon cancer, Na et al. [8] STEAP3 overexpression upregulated the expression of CDKN1C. In colorectal cancer cells treated with ETC-1922159, some of the family members of CDKN were down regulated, along with STEAP3. Individual recordings of these down regulations have been documented. I was able to rank 2nd order combination of CDKN family members with STEAP3, that were down regulated.
Table 1 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 2 generated from analysis of the ranks in Table 1. The Table 1 shows rankings of CDKN family w.r.t STEAP3. CDKN2C - STEAP3 shows low ranking of 906 (laplace) and 118 (linear). CDKN3 - STEAP3 shows low ranking of 1369 (laplace) and 223 (linear). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment. CDKN2AIPNL did not show synergistic down regulation with STEAP3.
One can also interpret the results of the Table 1 graphically, with the following influences - • CDKN family w.r.t STEAP3 with STEAP3 CDKN-2C/3.
2.1.2. STEAP3-GPX family
In renal cell carcinoma, Ye et al. [9] show that in STEAP3 knockdown group, expression of othe ferroptosis-related protein GPX4 was decreased. Similarly, Han et al. [10] show that knockdown of STEAP3 decreased the expression of GPX4 in ovarian cancer cells. In colorectal cancer cells treated with ETC-1922159, some of the family members of GPX were down regulated, along with STEAP3. Individual recordings of these down regulations have been documented. I was able to rank 2nd order combination of GPX family members with STEAP3, that were down regulated.
Table 3 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 4 generated from analysis of the ranks in Table 3. The Table 3 shows rankings of GPX family w.r.t STEAP3. GPX1 - STEAP3 shows low ranking of 333 (linear) and 812 (rbf). GPX1P1 - STEAP3 shows low ranking of 1064 (linear) and 1610 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
One can also interpret the results of the Table 3 graphically, with the following influences - • GPX family w.r.t STEAP3 with STEAP3 GPX-1/1P1.
2.1.3. STEAP3-SLC family
Han et al. [10] show that knockdown of STEAP3 decreased the expression of SLC7A11 in ovarian cancer cells. In colorectal cancer cells treated with ETC-1922159, some of the family members of SLC were down regulated, along with STEAP3. Individual recordings of these down regulations have been documented. I was able to rank 2nd order combination of SLC family members with STEAP3, that were down regulated.
Table 5 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 6 generated from analysis of the ranks in Table 5. The Table 5 shows rankings of SLC family w.r.t STEAP3. SLC19A3 - STEAP3 shows low ranking of 3 (laplace) and 58 (rbf). SLC25A19 - STEAP3 shows low ranking of 56 (laplace) and 600 (rbf). SLC39A10 - STEAP3 shows low ranking of 79 (laplace) and 292 (rbf). SLC12A8 - STEAP3 shows low ranking of 104 (laplace) and 846 (rbf). SLC25A35 - STEAP3 shows low ranking of 259 (laplace), 651 (linear) and 728 (rbf). SLC28A3 - STEAP3 shows low ranking of 272 (laplace), 1113 (linear) and 458 (rbf). SLC7A8 - STEAP3 shows low ranking of 368 (laplace), 559 (linear) and 887 (rbf). SLC19A1 - STEAP3 shows low ranking of 429 (laplace) and 1395 (linear). SLC25A26 - STEAP3 shows low ranking of 548 (laplace), 230 (linear) and 982 (rbf). SLC16A1.AS1 - STEAP3 shows low ranking of 690 (laplace), 1232 (linear) and 541 (rbf). SLC25A27 - STEAP3 shows low ranking of 1105 (laplace), 380 (linear) and 1569 (rbf). SLC35G1 - STEAP3 shows low ranking of 1108 (laplace) and 1302 (rbf). SLC39A8 - STEAP3 shows low ranking of 1175 (laplace) and 1564 (linear). SLC17A9 - STEAP3 shows low ranking of 1319 (laplace), 777 (linear) and 191 (rbf). SLC43A3 - STEAP3 shows low ranking of 1336 (laplace) and 341 (linear). SLC35E3 - STEAP3 shows low ranking of 922 (linear) and 690 (rbf). SLC12A2 - STEAP3 shows low ranking of 150 (linear) and 1223 (rbf). SLC25A32 - STEAP3 shows low ranking of 1203 (linear) and 1426 (rbf). SLC38A5 - STEAP3 shows low ranking of 1151 (linear) and 1343 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment.
On the other hand, SLC4A7, SLC1A4, SLC18B1, SLC25A38, SLC28A2, SLC41A1, SLC25A15, SLC5A6, SLC35F2, SLC7A2, SLC43A1, SLC2A11, SLC25A14, SLC26A2, SLC25A40 and SLC6A6 do not show synergy with STEAP3 while synergistic down regulation.
One can also interpret the results of the Table 5 graphically, with the following influences - • SLC family w.r.t STEAP3 with STEAP3 SLC-19A3 / 25A19 / 39A10 / 12A8 / 25A35 / 28A3 / 7A8 / 19A1 / 25A26 / 16A1.AS1 / 25A27 / 35G1 / 39A8 / 17A9 / 43A3 / 35E3 / 12A2 / 25A32 / 38A5.
2.1.4. STEAP3-METTL family
In colorectal cancer, Zhou et al. [3] determined the related regulators for STEAP3 m6A modification, by knocking down m6A writers (METTL3, METTL14) and m6A readers (YTHDF1, YTHDF2). Their experiments shows that the protein level and mRNA level of STEAP3 were decreased by METTL14 and YTHDF2. In colorectal cancer cells treated with ETC-1922159, some of the family members of METTL were down regulated, along with STEAP3. Individual recordings of these down regulations have been documented. I was able to rank 2nd order combination of METTL family members with STEAP3, that were down regulated.
Table 7 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 8 generated from analysis of the ranks in Table 7. The Table 7 shows rankings of METTL family w.r.t STEAP3. METTL3 - STEAP3 shows low ranking of 156 (laplace) and 326 (rbf). METTL16 - STEAP3 shows low ranking of 799 (laplace) and 654 (rbf). METTL12 - STEAP3 shows low ranking of 884 (laplace), 1147 (linear) and 687 (rbf). METTL21B - STEAP3 shows low ranking of 1228 (laplace) and 995 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment. However, METTL1, METTL8, METTL13, METTL5, METTL21A, METTL17 and METTL2B did not show any down regulation synergy with STEAP3.
One can also interpret the results of the Table 7 graphically, with the following influences - • METTL family w.r.t STEAP3 with STEAP3 METTL-3/16/12/21B.
2.1.5. STEAP3-BCL family
In hepatocellular carcinoma, citetWang:2021steap3 STEAP3 promotes cancer cell proliferation. They found that anti-apoptotic protein BCL2 was substantially transcriptionally upregulated by STEAP3. In colorectal cancer cells treated with ETC-1922159, some of the family members of BCL were down regulated, along with STEAP3. Individual recordings of these down regulations have been documented. I was able to rank 2nd order combination of BCL family members with STEAP3, that were down regulated.
Table 9 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 10 generated from analysis of the ranks in Table 9. The Table 9 shows rankings of BCL family w.r.t STEAP3. BCL6B - STEAP3 shows low ranking of 65 (laplace) and 100 (rbf). BCL11A - STEAP3 shows low ranking of 854 (laplace) and 1322 (rbf). BCL11B - STEAP3 shows low ranking of 1026 (laplace) and 691 (rbf). BCL2L12 - STEAP3 shows low ranking of 1035 (laplace) and 1292 (linear). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment. However, BCL9 and BCL7A did not show any down regulation synergy with STEAP3.
One can also interpret the results of the Table 9 graphically, with the following influences - • BCL family w.r.t STEAP3 with STEAP3 BCL-6B/11A/11B/2L12.
2.1.6. STEAP3-IL family
In hepatocellular carcinoma, Wang et al. [11] STEAP3 promotes cancer cell proliferation. They found that inflammatory factors like IL-8 and IL-18 were substantially transcriptionally upregulated by STEAP3. In colorectal cancer cells treated with ETC-1922159, some of the family members of IL were down regulated, along with STEAP3. Individual recordings of these down regulations have been documented. I was able to rank 2nd order combination of IL family members with STEAP3, that were down regulated.
Table 11 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 12 generated from analysis of the ranks in Table 11. The Table 11 shows rankings of IL family w.r.t STEAP3. ILF3 - STEAP3 shows low ranking of 121 (laplace) and 926 (rbf). IL17RB - STEAP3 shows low ranking of 208 (laplace) and 404 (rbf). IL17D - STEAP3 shows low ranking of 596 (laplace) and 705 (linear). IL33 - STEAP3 shows low ranking of 1070 (laplace) and 57 (linear). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment. However, IL1RL2, ILF2 and IL17RD did not show any down regulation synergy with STEAP3.
One can also interpret the results of the Table 11 graphically, with the following influences - • IL family w.r.t STEAP3 with STEAP3 IL-F3/17RB/17D/33.
2.1.7. STEAP3-TFR Family
Ohgami et al. [2], show that the expression of STEAP2 and STEAP4 in erythropoietic tissues, their partial colocalization with TF and TFR1, and the demonstration that they have ferrireductase activity in vitro, indicate that STEAP2 and STEAP4 are reasonable candidates for redundant ferrireductases in the erythroid TF-cycle endosome. In colorectal cancer cells treated with ETC-1922159, some of the family members of TFR were down regulated, along with STEAP3. Individual recordings of these down regulations have been documented. I was able to rank 2nd order combination of TFR family members with STEAP3, that were down regulated.
Table 13 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in Table 14 generated from analysis of the ranks in Table 13. The Table 13 shows rankings of TFR family w.r.t STEAP3. TFR2 - STEAP3 shows low ranking of 1063 (laplace) and 1169 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment. However, TFRC did not show any down regulation synergy with STEAP3.
One can also interpret the results of the Table 13 graphically, with the following influences - • TFR family w.r.t STEAP3 with STEAP3 TFR-2.
3. Conclusion
Presented here are a range of multiple synergistic STEAP3 2nd order combinations that were ranked via a machine learning based search engine. Via majority voting across the ranking methods, it was possible to find plausible unexplored synergistic combinations of STEAP3-X that might be prevalent in CRC cells after treatment with ETC-1922159 drug.
Author Contributions
Concept, design, in silico implementation - SS. Analysis and interpretation of results - SS. Manuscript writing - SS. Manuscript revision - SS. Approval of manuscript - SS.
Data Availability Statement
Data used in this research work was released in a publication in Madan et al. [12]. The ETC-1922159 was released in Singapore in July 2015 under the flagship of the Agency for Science, Technology and Research (A*STAR) and Duke-National University of Singapore Graduate Medical School (Duke-NUS).
Acknowledgments
Special thanks to Mrs. Rita Sinha and Mr. Prabhat Sinha for supporting the author financially, without which this work could not have been made possible.
Conflicts of Interest
There are no conflicts to declare.
References
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Table 1.
2nd order interaction ranking between STEAP3 VS CDKN family members.
| Ranking CDKN family VS STEAP3 | |||
|---|---|---|---|
| Ranking of CDKN family w.r.t STEAP3 | |||
| laplace | linear | rbf | |
| CDKN2C - STEAP3 | 906 | 118 | 2200 |
| CDKN3 - STEAP3 | 1369 | 223 | 2556 |
| CDKN2AIPNL - STEAP3 | 2353 | 1642 | 1362 |
Table 2.
2nd order combinatorial hypotheses between STEAP3 and CDKN family members.
| Unexplored combinatorial hypotheses | |
|---|---|
| CDKN family w.r.t STEAP3 | |
| CDKN-2C/3 | STEAP3 |
Table 3.
2nd order interaction ranking between STEAP3 VS GPX family members.
| Ranking GPX family VS STEAP3 | |||
|---|---|---|---|
| Ranking of GPX family w.r.t STEAP3 | |||
| laplace | linear | rbf | |
| GPX1 - STEAP3 | 2124 | 333 | 812 |
| GPX1P1 - STEAP3 | 2328 | 1064 | 1610 |
Table 4.
2nd order combinatorial hypotheses between STEAP3 and GPX family members.
| Unexplored combinatorial hypotheses | |
|---|---|
| GPX family w.r.t STEAP3 | |
| GPX-1/1P1 | STEAP3 |
Table 5.
2nd order interaction ranking between STEAP3 VS SLC family members.
| Ranking SLC family VS STEAP3 | |||||||
|---|---|---|---|---|---|---|---|
| Ranking of SLC family w.r.t STEAP3 | |||||||
| laplace | linear | rbf | laplace | linear | rbf | ||
| SLC19A3 - STEAP3 | 3 | 2632 | 58 | SLC25A19 - STEAP3 | 56 | 2618 | 600 |
| SLC39A10 - STEAP3 | 79 | 1648 | 292 | SLC12A8 - STEAP3 | 104 | 2463 | 846 |
| SLC25A35 - STEAP3 | 259 | 651 | 728 | SLC28A3 - STEAP3 | 272 | 1113 | 458 |
| SLC7A8 - STEAP3 | 368 | 559 | 887 | SLC4A7 - STEAP3 | 417 | 2258 | 2277 |
| SLC19A1 - STEAP3 | 429 | 1395 | 2288 | SLC25A26 - STEAP3 | 548 | 230 | 982 |
| SLC1A4 - STEAP3 | 654 | 1931 | 1557 | SLC16A1.AS1 - STEAP3 | 690 | 1232 | 541 |
| SLC25A27 - STEAP3 | 1105 | 380 | 1569 | SLC35G1 - STEAP3 | 1108 | 1654 | 1302 |
| SLC39A8 - STEAP3 | 1175 | 1564 | 1803 | SLC18B1 - STEAP3 | 1318 | 1670 | 1853 |
| SLC17A9 - STEAP3 | 1319 | 777 | 191 | SLC43A3 - STEAP3 | 1336 | 341 | 1777 |
| SLC25A38 - STEAP3 | 1519 | 1768 | 1697 | SLC28A2 - STEAP3 | 1573 | 2082 | 931 |
| SLC35E3 - STEAP3 | 1589 | 922 | 690 | SLC41A1 - STEAP3 | 1591 | 2516 | 1965 |
| SLC25A15 - STEAP3 | 1623 | 1703 | 624 | SLC5A6 - STEAP3 | 1671 | 1866 | 1668 |
| SLC35F2 - STEAP3 | 1734 | 107 | 1842 | SLC43A1 - STEAP3 | 1832 | 431 | 2423 |
| SLC7A2 - STEAP3 | 1942 | 302 | 2648 | SLC12A2 - STEAP3 | 1991 | 150 | 1223 |
| SLC25A32 - STEAP3 | 2063 | 1203 | 1426 | SLC2A11 - STEAP3 | 2101 | 1991 | 1404 |
| SLC25A14 - STEAP3 | 2120 | 308 | 2254 | SLC26A2 - STEAP3 | 2240 | 1658 | 964 |
| SLC25A40 - STEAP3 | 2269 | 1371 | 2206 | SLC6A6 - STEAP3 | 2576 | 1519 | 2482 |
| SLC38A5 - STEAP3 | 2682 | 1151 | 1343 | ||||
Table 6.
2nd order combinatorial hypotheses between STEAP3 and SLC family members.
| Unexplored combinatorial hypotheses | |
|---|---|
| SLC family w.r.t STEAP3 | |
| SLC-19A3/25A19/39A10/12A8/25A35/28A3/7A8/19A1 | STEAP3 |
| SLC-25A26/16A1.AS1/25A27/35G1/39A8/17A9/43A3 | STEAP3 |
| SLC-35E3/12A2/25A32/38A5 | STEAP3 |
Table 7.
2nd order interaction ranking between STEAP3 VS METTL family members.
| Ranking METTL family VS STEAP3 | |||
|---|---|---|---|
| Ranking of METTL family w.r.t STEAP3 | |||
| laplace | linear | rbf | |
| METTL3 - STEAP3 | 156 | 1958 | 326 |
| METTL16 - STEAP3 | 799 | 2196 | 654 |
| METTL12 - STEAP3 | 884 | 1147 | 687 |
| METTL21B - STEAP3 | 1228 | 2012 | 995 |
| METTL1 - STEAP3 | 1579 | 1553 | 689 |
| METTL8 - STEAP3 | 1659 | 2592 | 1638 |
| METTL13 - STEAP3 | 1721 | 2335 | 1346 |
| METTL5 - STEAP3 | 1960 | 1544 | 2485 |
| METTL21A - STEAP3 | 2154 | 1937 | 1446 |
| METTL17 - STEAP3 | 2239 | 1126 | 2370 |
| METTL2B - STEAP3 | 2689 | 74 | 2242 |
Table 8.
2nd order combinatorial hypotheses between STEAP3 and METTL family members.
| Unexplored combinatorial hypotheses | |
|---|---|
| METTL family w.r.t STEAP3 | |
| METTL-3/16/12/21B | STEAP3 |
Table 9.
2nd order interaction ranking between STEAP3 VS BCL family members.
| Ranking BCL family VS STEAP3 | |||
|---|---|---|---|
| Ranking of BCL family w.r.t STEAP3 | |||
| laplace | linear | rbf | |
| BCL6B - STEAP3 | 65 | 2708 | 100 |
| BCL11A - STEAP3 | 854 | 1793 | 1322 |
| BCL11B - STEAP3 | 1026 | 2624 | 691 |
| BCL2L12 - STEAP3 | 1035 | 1292 | 2235 |
| BCL9 - STEAP3 | 2265 | 558 | 1963 |
| BCL7A - STEAP3 | 2597 | 739 | 2309 |
Table 10.
2nd order combinatorial hypotheses between STEAP3 and BCL family members.
| Unexplored combinatorial hypotheses | |
|---|---|
| BCL family w.r.t STEAP3 | |
| BCL-6B/11A/11B/2L12 | STEAP3 |
Table 11.
2nd order interaction ranking between STEAP3 VS IL family members.
| Ranking IL family VS STEAP3 | |||
|---|---|---|---|
| Ranking of IL family w.r.t STEAP3 | |||
| laplace | linear | rbf | |
| ILF3 - STEAP3 | 121 | 2314 | 926 |
| IL17RB - STEAP3 | 208 | 2462 | 404 |
| IL17D - STEAP3 | 596 | 705 | 2273 |
| IL1RL2 - STEAP3 | 835 | 2234 | 1733 |
| IL33 - STEAP3 | 1070 | 57 | 2098 |
| ILF2 - STEAP3 | 1986 | 1029 | 2474 |
| IL17RD - STEAP3 | 2352 | 589 | 2233 |
Table 12.
2nd order combinatorial hypotheses between STEAP3 and IL family members.
| Unexplored combinatorial hypotheses | |
|---|---|
| IL family w.r.t STEAP3 | |
| IL-F3/17RB/17D/33 | STEAP3 |
Table 13.
2nd order interaction ranking between STEAP3 VS TFR family members.
| Ranking TFR family VS STEAP3 | |||
|---|---|---|---|
| Ranking of TFR family w.r.t STEAP3 | |||
| laplace | linear | rbf | |
| TFR2 - STEAP3 | 1063 | 2487 | 1169 |
| TFRC - STEAP3 | 1946 | 663 | 2255 |
Table 14.
2nd order combinatorial hypotheses between STEAP3 and TFR family members.
| Unexplored combinatorial hypotheses | |
|---|---|
| TFR family w.r.t STEAP3 | |
| TFR-2 | STEAP3 |
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