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Machine Learning Discoveries of Wnt-X Synergy in ETC-1922159 Treated Colorectal Cancer Cells

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Advances in Colorectal Cancer Therapy

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05 September 2024

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05 September 2024

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Abstract
Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combinations of factors/genes/proteins that might be affecting the pathway under certain conditions. In colorectal cancer (CRC) cells treated with ETC-1922159, many genes were found up and down regu- lated, individually. A recently developed search engine ranked combinations of Wnt-X (X, a particular gene/protein) at 2nd order level after drug administration. These rank- ings reveal which Wnt-X combinations might be working synergistically in CRC. If found true, oncologists can further test the combination of interest in wet lab and deter- mine the mechanism of functioning between the Wnt and X. In this research work, we cover combinations of Wnt with Achaete-scute complex homolog 2 (ASCL2), ATP- binding cassette (ABC) domain transporters, Interleukin (IL), ubiquitin conjugating enzyme E2 (UBE2) family, exosome (EXOSC), caspase (CASP), TP53 and B-cell lymphoma (BCL) family.
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Subject: Computer Science and Mathematics  -   Mathematical and Computational Biology

1. Introduction

In the unpublished preprint [1], a frame work of a search engine was developed which can rank combinations of factors (genes/proteins) in a signaling pathway. Such combinations are of import due to the vast search space in which they exist and the difficulty to find them. The search engine facilitates in prioritizing the combinations as ranked biological hypotheses which the biologists might want to test in wet lab, to know if a synergistic combination is prevalent in a signaling pathway, in a direct or indirect manner. Interested readers are advised to go through unpublished preprints [1,2] for details regarding the search engine and the discoveries mentioned in there.

2. Materials and Methods

2.1. Combinatorial Search Problem and a Possible Solution

The issue of combinatorial search problem and a possible solution has been addressed in [2,3]. The details of the methodology of this manuscript have been explained in great detail in [3] & its application in [2]. Readers are requested to go through the same for gaining deeper insight into the working of the pipeline and its use of published data set generated after administration of ETC-1922159. In order to understand the significance of the solution proposed to the problem of combinatorial search that the biologists face in revealing unknown biological search problem, these works are of importance.
Briefly, from [2], the pipleline works by computing sensitivity indicies for each of these unique combinations and then vectorising these indices to connote and form discriminative feature vector for each combination. Since each combination is unique, the training and the test data are same. In the training data, the combinations are arranged and ranks from 1 to n are assigned. The ranking algorithm then learns the patterns from these combinations/sensitivity index vectors. Next the learned model is used to rank the test data by generating the ranking score for each of the unique combination. Sorting these shuffled scores of test data leads to prioritization of the combinations. [4] show an example of applying learned model to training data (same as the test data) in https://www.cs.cornell.edu/people/tj/svm_light/svm_rank.html. Note that these combinations are now ranked and give the biologists a chance to narrow down their focus on crucial biological hypotheses in the form of combinations which the biologists might want to test. Analogous to the webpage search engine, where the click of a button for a few key-words leads to a ranked list of web links, the pipeline uses sensitivity indices as an indicator of the strength of the influence of factors or their combinations, as a criteria to rank the combinations.

3. Results & Discussion

3.1. WNT Related Synergies

3.1.1. WNT10B-ASCL2

WNT10B has been found to be implicated in a range of cancers. In gastric cancer, the knockdown of WNT10B showed reduced expression of cell proliferation and migration as well as inhibition of epithelial-mesenchymal transition [5]. On the other hand, WNT10B is also involved in the formation of bone mass and progenitor maintenance of various kinds of tissue, while deletion of the same leads to loss of bone mass and mesenchymal progenitor cells [6]. Their contribution is also reported in axonal regeneration in injured CNS [7]. Furthermore, like WNT10B, WNT10A and WNT6 have shown to play a major role in inhibiting adipogenesis and stimulates osteoblastogenesis while regulating the mesenchymal stem cells [8,9]. Involvement in heptocellular carcinoma of WNT10B has been found wherein it is shown that stable silencing of WNT10B leads to significant reduction in proliferation, colony formation, migration and invasion in HepG2 HCC cell line [10]. Its implication in breast cancer [11,12] as well as endometrial cancer [13] has also been reported.
In colorectal cancer, WNT10B has shown to play a dual function of both oncogenesis promotion via β -catenin/TCF pathway and the inhibition of cell growth, possibly via FGF family of proteins [14]. Methylation of WNT10B has been found in the some of the cancer cell lines while its reversal has lead to over-expression of the WNT10B. However, the over-expression of WNT10B has lead to reduced cell growth in cancer, indicating a β -catenin independent component to be behind such a phenomena. Methylation of over-expressed WNT10B and synergistic work with FGF family of proteins later indicate the promotion of oncogenesis, as has been demonstrated in [14].
In a more recent work, ASCL2 has been found to play a major role in stemness in colon crypts and is implicated in colon cancer [15]. Switching off the ASCL2 leads to a literal blockage of the stemness process and vice versa. At the downstream level, ASCL2 is regulated by TCF4/ β -catenin via non-coding RNA target named WiNTRLINC1 [16]. Activation of ASCL2 leads to feedforward transcription of the non-coding RNA and thus a loop is formed which helps in the stemness and is highly effective in colon cancer. At the upstream level, ASCL2 is known act as a WNT/RSPONDIN switch that controls the stemness [17]. It has been shown that removal of RSPO1 lead to decrease in the Wnt signaling due to removal of the FZD receptors that led to reduced expression of ASCL2. Also, low levels of LGR5 were observed due to this phenomena. The opposite happened by increasing the RSPO1 levels. After the drug treatment, it was found that ASCL2 was highly suppressed pointing to the inhibition of stemness in the colorectal cancer cells. Also, [17] show that by genetically disrupting PORCN or inducing a PORCN inhibitor (like IWP-2), there is loss of stem cell markers like LGR5 and RNF43, which lead to disappearance of stem cells and moribund state of mice. A similar affect can be found with ETC-1922159, where there is suppression of RNF43 and LGR5 that lead to inhibition of the Wnt pathway and thus the ASCL2 regulation. These wet lab evidences are confirmed in the relatively low ranking of the combination ASCL2-RNF43 via the inhibition of PORCN-WNT that leads to blocking of the stemness that is induced by ASCL2. Since ASCL2 is directly mediated by the WNT proteins, the recorded ASCL2-WNT10B combination showed low priority ranking of 488, 497 and 321 for rbf, laplace and linear kernels, respectively, thus indicating a possible connection between WNT10B and ASCL2 activation. WNT10B might be playing a crucial role in stemness. This is further confirmed by wet lab experiments in [18], which show BVES deletion results in amplified stem cell activity and Wnt signaling after radiation. WNT10B has been implicated in colorectal cancer [14].

3.1.2. ABC Transporters - WNT Cross Family Analysis

[19] have shown the role of ABC transporters in progression and clinical outcome of colorectal cancer. Work by [20] show that Wnt- β catenin signaling regulates ABCC3 (MRP3) transporter expression in colorectal cancer. ABCA2 belongs to the category of ABC transporters that play an essential role in the development of resistance by the efflux of anticancer agents outside of cancer cells [19]. [19] observed that ABCA2 had no significant change/affect in colorectal cancer cases. [20] found ABCA2 to be downregulated in colorectal cancer case. In ETC-1922159 affected CRC cells, down regulation of ABCA2 was observed, after the inhibition of proliferation in respective cells. Multiple members of ABC transporters and WNTs were found to be UP regulated after ETC-159 in CRC cells and WNTs are known to regulate ABCs. Below, we show a range of up regulated, possible unknown and unexplored synergistic 2nd order combinations that were ranked by the search engine. Note that the high numerical valued ranks (i.e nearing to 1800/2000 and above) indicate high potential of synergy that might be existing in CRC cells after the drug administration. Majority voting of rankings across the three different kernels point to the potential of the synergistic discovery. Wet labs investigations will assist in confirmation of these discoveries and if proven true, might lead to understanding of further mechanism between the components.
Table 1 and Table 2 show the rankings of ABC family w.r.t to WNT family members and WNT family w.r.t to ABC family members, respectively. From these two tables, we derive the plausible influences that might be existing in a two way format that is depicted in Table 3. In Table 1, WNT2B - ABC-C3 combination shows a majority voting of 1853 (laplace) and 2498 (rbf). Similarly, WNT7B - ABC-C13 shows a majority voting of 2245 (linear) and 2298 (rbf). These two combinations are depicted in Table 3 as ABC members influenced by WNT members (see under ABC w.r.t WNT). Reversibily, in Table 2 ABC-A5 - WNT2B shows a majority voting of 2018 (linear) and 2132 (rbf), ABC-A5 - WNT4 shows a majority voting of 2436 (linear) and 2449 (rbf), ABC-A5 - WNT9A shows a majority voting of 1989 (laplace), 2209 (linear) and 2365 (rbf), WNT2B - ABC-C5 shows a majority voting of 1970 (laplace), 2309 (linear) and 2248 (rbf), ABC-C5 - WNT9A shows a majority voting of 2183 (linear) and 2480 (rbf), WNT2B - ABC-C13 shows a majority voting of 2150 (linear) and 2048 (rbf), WNT7B - ABC-C13 shows a majority voting of 2508 (laplace) and 1830 (linear), WNT7B - ABC-D1 shows a majority voting of 2238 (laplace) and 2021 (linear), WNT7B - ABC-G1 shows a majority voting of 1808 (linear) and 1866 (rbf), WNT7B - ABC-G2 shows a majority voting of 2334 (linear) and 2145 (rbf) and WNT9A - ABC-G2 shows a majority voting of 1919 (laplace) and 2003 (rbf). These point to WNT members influenced by ABC members (see under WNT w.r.t ABC). Hypothetically, what we find is that the synergies can be bi-directional also and might contain various intermitent factors through which the factors might be working synergistically. These hypothese form present themselves as important combinations that might be of interest to biologists/oncologists.
One can also interpret the results of the Table 3 graphically, with the following influences - • ABC w.r.t WNT with WNT-2B − > ABC-C3; WNT-7B − > ABC-C13; and • WNT w.r.t ABC with ABC-A5 < − WNT-2B/4/9A; WNT-2B/9A < − ABC-C5; WNT-2B/7B < − ABC-C13; WNT-7B < − ABC-D1; WNT-7B < − ABC-G1; WNT-7B/9A < − ABC-G2. Thus, in this way, we can utilize the search engine to derive the various probable combinations between the factors of interest and their interdependent influences through the two-way cross family analysis.

3.1.3. IL - WNT Cross Family Analysis

Interleukin (IL) has been found in cross talk with WNT pathway. [21] show that NF κ B induced WNT signaling in colorectal cancer via interleukin-1 β IL1B. Further, [22] have shown that nitric oxide mediates crosstalk between interleukin 1 β and Wnt signaling in primary human chondrocytes by reducing DKK1 and FRZB expression. The role of IL-17 (Interleukin-17) family is known to be controversial in CRC, however there are cases were it has been reported to be a prognostic marker for colorectal cancer [23,24]. A homologue of the family, IL-17D a novel cytokine has been discovered [25] and found to play a role in many of the cancers. In cells treated with ETC-1922159, IL-17D was found to be down regulated and reversibly it must have been regulated in the colorectal cancer cases. Recently, crosstalk between WNT/ β -Catenin and NF- κ B signaling pathway during inflammation has been reported by [26]. [27] also show WNT/ β -catenin negative feedback loop inhibits IL-1 induced matrix metalloproteinase expression in human articular chondrocytes. [28] conclude that WNT/ β -catenin signaling promotes angiogenesis possibly via the induction of known angiogenic regulators such as Interleukin-8. In mouse colon, Interleukin-1 signaling is shown to mediate obesity-promoted elevations in inflammatory cytokines, WNT activation, and epithelial proliferation by [29]. In pulmonary fibrosis, [30] show that WNT/ β -Catenin signaling induces IL-1 β expression by alveolar epithelial cells. [31] show that IL-23 promotes the epithelial-mesenchymal transition of oesophageal carcinoma cells via the WNT/ β -catenin pathway. Finally, [32] show that IL-6/WNT interactions in rheumatoid arthritis.
Family members belonging to each of the factors like WNT, IL etc, might be involved synergistically in pathological case or otherwise. IL and WNT members were found to be up regulated after the treatment of ETC-1922159 in colorectal cancer cells. We present here, multiple plausible and alternative synergistic combinatorial biological hypotheses for IL-WNT combination, which emerge after a cross family member analysis of the in silico revelations pertaining to the components under investigation.
Table 4 shows IL-WNT two way cross family analysis. The left side of the table contains rankings of IL family with respect to WNTs and the right side of the table contains rankings of WNT family with respect to ILs. Depicted in table are the plausible combinatorial hypotheses derived from majority voting of the rankings in Table 4. On the left half, w.r.t WNT2B, IL-6ST/8/17REL show a synergy with WNT2B. These are reflected with rankings of 1797 (linear) and 2088 (rbf) for IL-6ST - WNT2B; rankings of 2107 (laplace), 1817 (linear) and 2088 (rbf) for IL-8 - WNT2B and rankings of 1824 (laplace) and 2241 (rbf) for IL-17REL - WNT2B, respectively. W.r.t WNT4, IL-1B/1RAP/15RA/17C show a synergy with WNT4. These are reflected with rankings of 1867 (laplace) and 1976 (linear) for IL-1B - WNT4; rankings of 2302 (laplace) and 1826 (linear) for IL-1RAP - WNT4; rankings of 1987 (laplace) and 2265 (linear) for IL-15RA - WNT4 and rankings of 2018 (laplace) and 1881 (linear) for IL-17C - WNT4, respectively. W.r.t WNT7B, IL-1RN/17REL show a synergy with WNT7B. These are reflected with rankings of 1882 (laplace) and 1796 (linear) for IL-1RN - WNT7B and rankings of 2053 (laplace), 2445 (linear) and 2489 (rbf) for IL-17REL - WNT4, respectively. W.r.t WNT9A, IL-1RAP/15RA show a synergy with WNT9A. These are reflected with rankings of 2273 (linear) and 2159 (rbf) for IL-1RAP - WNT9A and rankings of 1776 (laplace) and 2380 (linear) for IL-15RA - WNT9A, respectively.
On the right half, WNT2B w.r.t IL family, IL-1A/1RAP/8 show a synergy with WNT2B. These are reflected with rankings of 2290 (laplace) and 2427 (rbf) for IL-1A - WNT2B; rankings of 2488 (laplace) and 1892 (rbf) for IL-1RAP - WNT2B and rankings of 2157 1824 (laplace) and 2025 (linear) for IL-8 - WNT2B, respectively. WNT4 w.r.t IL family, IL-8/10RB show a synergy with WNT4. These are reflected with rankings of 1980 (laplace) and 2144 (linear) for IL-8 - WNT4 and rankings of 1828 (laplace), 2259 (linear) and 1993 (rbf) for IL-10RB - WNT4; respectively. WNT7B w.r.t IL family, IL-1A/1RN/6ST/17C show a synergy with WNT7B. These are reflected with rankings of 2134 (linear) and 2312 (rbf) for IL-1A - WNT7B; rankings of 1907 (laplace) and 2162 (linear) for IL-1RN - WNT7B; rankings of 1881 (linear) and 2020 (rbf) for IL-ST - WNT7B; and rankings of 1956 (laplace), 2388 (linear) and 1982 (rbf) for IL-17C - WNT7B, respectively. WNT9A w.r.t IL family, IL-1RAP/15RA/17REL show a synergy with WNT9A. These are reflected with rankings of 2003 (laplace) and 2179 (linear) for IL-1RAP - WNT9A; rankings of 2149 (laplace) and 2362 (linear) for IL-15RA - WNT9A; and rankings of 2101 (laplace) and 1940 (linear) for IL-17REL - WNT9A, respectively. One can also interpret the results of the Table 5 graphically, with the following influences - • IL w.r.t WNT with IL-6ST/8/17REL < − WNT-2B; IL-1B/1RAP/15RA/17C < − WNT-4; IL-1RN/17REL < − WNT-7B; IL-1RAP/15RA < − WNT-9A and • WNT w.r.t IL with IL-1A/1RAP/8 − > WNT-2B; IL-8/10RB − > WNT-4; IL-1A/1RN/6ST/17C − > WNT-7B and IL-1RAP/15RA/17REL − > WNT-9A.

3.1.4. UBE2 - WNT Cross Family Analysis

[33] observed balanced ubiquitylation and deubiquitylation of Frizzled regulate cellular responsiveness to Wg/Wnt. Family members belonging to each of the factors like UBE2, WNT etc, might be involved synergistically in pathological case or otherwise. UBE2 and WNT members were found to be up regulated after the treatment of ETC-159 in colorectal cancer cells. However, not much is known about interation between the UBE2 family members and WNTs. Here we present a range of synergies that were ranked highly for up regulation. Table 6 presents the rankings of UBE family VS WNT family. Following this, is the Table 7 which derives the necessary influences via majority voting of rankings in Table 6.
On the left half, w.r.t WNT family, UBE2A show a synergy with WNT4. These are reflected with rankings of 2314 (linear) and 2279 (rbf) for UBE2A - WNT4; UBE2B show a synergy with WNT4/7B. These are reflected with rankings of 2260 (laplace), 2008 (linear) and 2141 (rbf) for UBE2B - WNT4 and rankings of 2116 (laplace) and 2206 (rbf) for UBE2B - WNT7B, respectively; UBE2F show a synergy with WNT4/7B. These are reflected with rankings of 2135 (laplace) and 2505 (linear) for UBE2F - WNT4 and rankings of 2423 (laplace) and 2077 (rbf) for UBE2F - WNT7B, respectively; UBE2H show a synergy with WNT2B. These are reflected with rankings of 1841 (laplace) and 2178 (linear) for UBE2H - WNT2B; UBE2J1 show a synergy with WNT-7B/9A. These are reflected with rankings of 2349 (laplace) and 2183 (rbf) for UBE2J1 - WNT7B and rankings of 1835 (laplace) and 2053 (rbf) for UBE2J1 - WNT9A, respectively. UBE2Z show a synergy with WNT-2B/4/9A. These are reflected with rankings of 1756 (linear) and 1878 (rbf) for UBE2J1 - WNT2B, rankings of 2195 (laplace) and 2468 (rbf) for UBE2J1 - WNT4, and 2343 (laplace) and 1973 (rbf) for UBE2J1 - WNT9A, respectively.
On the right half, w.r.t UBE2, UBE2A shows a synergy with WNT4. These are reflected with rankings of 2345 (linear) and 2151 (rbf) for UBE2A - WNT7B; UBE2B shows a synergy with WNT-7B/9A. These are reflected with rankings of 2052 (linear) and 1903 (rbf) for UBE2B - WNT7B and rankings of 2300 (laplace), 2476 (linear) and 2326 (rbf) for UBE2B - WNT9A, respectively; UBE2F shows a synergy with WNT-7B/9A. These are reflected with rankings of 2236 (laplace) and 1751 (rbf) for UBE2F - WNT7B and rankings of 2251 (linear) and 2179 (rbf) for UBE2F - WNT9A, respectively; UBE2H shows a synergy with WNT4. These are reflected with rankings of 2248 (linear) and 2155 (rbf) for UBE2H - WNT4; UBE2J1 shows a synergy with WNT-7B/9A. These are reflected with rankings of 1877 (llinear) and 1846 (rbf) for UBE2J1 - WNT7B and rankings of 2471 (laplace), 2137 (linear) and 2469 (rbf) for UBE2J1 - WNT9A, respectively. UBE2Z shows a synergy with WNT-9A. These are reflected with rankings of 1972 (laplace) and 1800 (linear) for UBE2Z - WNT7B, respectively.
One can also interpret the results of the Table 7 graphically, with the following influences - • UBE2 w.r.t WNT with WNT-4 − > UBE2-A; WNT-4/7 − > UBE2-B; WNT-4/7B − > UBE2-F; WNT-2B − > UBE2-H; WNT-7B/9B − > UBE2-J1; WNT-2B/4/7B − > UBE2-Z and • WNT w.r.t UBE2 with WNT-7B < − UBE2-A; WNT-7B/9A < − UBE2-B; WNT-7B/9A < − UBE2-F; WNT-4 < − UBE2-H; WNT-7B/9A < − UBE2-J1; WNT-7B < − UBE2-Z;

3.1.5. EXOSC - WNT10B Cross Family Analysis

Recently, emerging role of exosome (EXOSC) has been studied in WNT secretion and transportation by [34]. It has been found that exosomes play a critical role in morphogen signaling during embryonic development and cancer progression. In injured CNS, exosomes mediate mobilization of WNT10B to promote axonal regeneration as shown by [35]. [36] show the importance of exsosomes in WNT transportation. Emerging on these lines, we conducted a small two-way analysis of EXOSC components and WNT10B which were found to be down regulated in CRC cells after administration of ETC-1922159. Note that here, the interpretation of the rankings changes as the low numerical valued ranks (nearing to 1) are considered of high importance as they point to the synergistic down regulation after the drug administration. In line with the experiments, as ETC-1922159 a PORCN-WNT inhibitor block the transportation of WNTs, it might be that the affects of EXOSC components are also down regulated. These were rightly allocated with the low numerical valued in-silico ranks by the engine, thus pointing to the experimental down regulation in cells also. This confirmatory results also helps us in exploring the unknown combinations that might be prevailing synergistically when the WNT-EXOSC were up regulated before the administration of ETC-1922159 in CRC cells.
Table 8 shows the rankings of EXOSC family w.r.t WNT10B and vice versa. Followed by this is the unexplored combinatorial hypotheses in Table 9 generated from two-way analysis of the ranks in Table 8. On the left half of the Table 8, except for EXOSC7 - WNT10B, all other combinations of EXOSC family show high synergy with WNT10B. This is depicted by the low numerical valued ranks allocated by the search engine for EXOSC-2/3/5/6/8/9 with WNT10B, via majority voting across the ranking methods using laplace, linear and rbf kernels. This shows that EXOSC-2/3/5/6/8/9 had a critical role in the transport of WNT10B. On the right half of the same table, EXOSC-2/5/6/7/9 show synergistic affiliation with respect to WNT10B, via low numerical valued ranks. These are translated to graphical influences in Table 9. One can also interpret the results of the Table 9 graphically, with the following influences - • EXOSC w.r.t WNT10B with EXOSC-2/5/6/7/9 < − WNT10B and • WNT10B w.r.t EXOSC with EXOSC-2/3/5/6/8/9 − > WNT10B. Further analyses of these combinations in wet lab might help biologists explore the deeper mechanism of exosome components and WNT10B in CRC cells.

3.1.6. CASP - WNT Cross Family Analysis

[37] show that a caspase-dependent pathway is involved in Wnt/ β -catenin signaling promoted apoptosis in Bacillus Calmette-Guerin infected RAW264.7 macrophages. [38] have shown that WNT11 promotes cardiomyocyte development by caspase-mediated suppression of canonical WNT signals. Additionally, [39] show that Wnt5a and Wnt11 inhibit the canonical Wnt pathway and promote cardiac progenitor development via the Caspase-dependent degradation of AKT. These findings indicate probable interplay of Caspase and WNTs in various pathological cases. In mice, caspase-1 activation and IL-1 β secretion together have shown to contribute to inflammatory condition of acute arthritis (see [40]). Recently, Caspase-3 inhibition has been found to be a therapeutic approach in colorectal cancer as shown by [41]. [42] also show synergistic role of Caspase-8 and Caspase-3 expressions as biomarkers in colorectal cancer. Family members belonging to each of the factors like CASP, WNT etc, might be involved synergistically in pathological case or otherwise. CASP and WNT members were found to be up regulated after the treatment of colorectal cancer cells with ETC-1922159.
Table 10 shows the rankings of CASP family w.r.t WNTs and vice versa. Followed by this is the unexplored combinatorial hypotheses in Table 11 generated from two-way analysis of the ranks in Table 10. On the first three tabular rows of the Table 10 show rankings of CASP family w.r.t WNT family. Here we present the possible interdependent WNT-CASP combinations that might be working synergistically in CRC cells. Considering CASP5 w.r.t WNTs, CASP5 - WNT2B show up regulated synergy through rankings of 2171 (laplace) and 2366 (linear). Considering CASP9 w.r.t WNTs, CASP9 - WNT-4/7B/9A show up regulated synergy through rankings of 2472 (laplace) and 2200 (linear) for CASP9 - WNT4; 2196 (laplace) and 1935 (linear) for CASP9 - WNT7B; and 1863 (laplace) and 2002 (linear) for CASP9 - WNT9A, respectively. Finally, considering CASP16 w.r.t WNTs, CASP16 - WNT4 showed up regulated synergy with rankings of 2070 (laplace) and 1783 (linear).
The next three tabular rows show rankings of WNT family w.r.t CASP family. W.r.t CASP4, WNT-7B/9A show promise of up regulation. These are reflected with rankings of 2479 (linear) and 1739 (rbf) for WNT7B - CASP4 and rankings of 2278 (linear) and 1939 (rbf) for WNT9A - CASP4, respectively. W.r.t CASP5, WNT-7B shows promise of up regulation. This is reflected with rankings of 2112 (laplace), 1919 (linear) and 2440 (rbf) for WNT7B - CASP5. W.r.t CASP7, WNT-2B/4/9A show promise of up regulation. These are reflected with rankings of 2505 (laplace) and 1891 (linear) for WNT2B - CASP7; rankings of 2456 (linear) and 2455 (rbf) for WNT4 - CASP7; and rankings of 2183 (laplace) and 1941 (linear) for WNT9A - CASP7, respectively. W.r.t CASP9, WNT-9A shows promise of up regulation. This is reflected with rankings of 2378 (laplace), 2396 (linear) and 2058 (rbf) for WNT9A - CASP9. W.r.t CASP10, WNT-4/9A show promise of up regulation. These are reflected with rankings of 1830 (laplace), 2229 (linear) and 1847 (rbf) for WNT4 - CASP10; and rankings of 2185 (laplace) and 1977 (linear) for WNT9A - CASP10, respectively. Finally, w.r.t CASP16, WNT-2B/4/9A show promise of up regulation. These are reflected with rankings of 2197 (laplace), 2489 (linear) and 1775 (rbf) for WNT2B - CASP16; rankings of 2508 (laplace), 1820 (linear) and 1867 (rbf) for WNT7B - CASP16; and rankings of 1943 (laplace) and 1839 (linear) for WNT9A - CASP16, respectively.
One can also interpret the results of the Table 11 graphically, with the following influences - • CASP w.r.t WNT with CASP5 < − WNT2B; CASP9 < − WNT-4/7B/9A; CASP16 < − WNT4 and • WNT w.r.t CASP with. WNT-7B/9A < − CASP4; WNT7B < − CASP5; WNT-2B/4/9A < − CASP7; WNT9A < − CASP9; WNT-4/9A < − CASP10; WNT-2B/7B/9A < − CASP16.

3.1.7. TP53 - WNT Cross Family Analysis

[43] have shown that down regulation of β -catenin is activated by TP53. Wnt/ β -catenin signaling is known to regulate the proliferation and differentiation of mesenchymal progenitor cells through the TP53 Pathway, as shown by [44]. [45] show that WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma. In mouse cochlea, [46] show that WNT signaling activates TP53-induced glycolysis and apoptosis regulator and protects against cisplatin-induced spiral ganglion neuron damage. These range of interactions of TP53 with WNT points towards definite synergy. [47] show that TP53 protein regulates Hsp90 ATPase activity and thereby Wnt signaling by modulating Aha1 expression. Family members belonging to each of the factors like TP53, WNT etc, might be involved synergistically in pathological case or otherwise. TP53 and WNT members were found to be up regulated after the treatment of ETC-159 in colorectal cancer cells.
Table 12 contains rankings of TP53 w.r.t WNTs and vice versa. Followed by this is the unexplored combinatorial hypotheses in Table 13 generated from two-way analysis of the ranks in Table 12. On the left half of Table 12 are rankings of TP53 w.r.t WNTs and on the right half are the rankings of WNTs w.r.t TP53 family. Beginning with the left half, TP53I3 - WNT2B shows synergistic up regulation with rankings of 2056 (laplace) and 1712 (linear); TP53INP1 - WNT2B shows synergistic up regulation with rankings of 1805 (linear) and 2056 (rbf) and TP53BP2 - WNT9A shows synergistic up regulation with rankings of 2232 (linear) and 2143 (rbf). On the right half the table, TP53INP1 - WNT2B shows synergistic up regulation with rankings of 1853 (laplace) and 2089 (linear); TP53INP2 - WNT2B shows synergistic up regulation with rankings of 1723 (linear) and 2335 (rbf); TP53INP1 - WNT4 shows synergistic up regulation with rankings of 2414 (linear) and 2493 (rbf); TP53I3 - WNT7B shows synergistic up regulation with rankings of 1988 (laplace) and 2393 (rbf) and finally, TP53INP1 - WNT9A shows synergistic up regulation with rankings of 2045 (linear) and 2437 (rbf).
One can also interpret the results of the Table 11 graphically, with the following influences - • TP53 family w.r.t WNTs with TP53I3 < − WNT2B; TP53INP1 < − WNT2B and TP53BP2 < − WNT9A; and • WNT family VS TP53 with TP53INP1 − > WNT2B; TP53INP2 − > WNT2B; TP53INP1 − > WNT4; TP53I3 − > WNT7B and TP53INP1 − > WNT9A.

3.1.8. BCL - WNT Cross Family Analysis

[48] observed that silencing Wnt2B by siRNA interference inhibits metastasis and enhances chemotherapy sensitivity in ovarian cancer. More specifically, [48] show that in the presence of Wnt2B siRNA treatment, the caspase-9/B-cell lymphoma 2 (BCL2)/B-cell lymphoma-xL (BCL-xL) pathway and the epithelial-mesenchymal transition/phosphorylated protein kinase B pathway were inhibited. [49] show that targeted disruption of the BCL9/ β -catenin complex inhibits oncogenic WNT signaling. CDK1-mediated BCL9 phosphorylation inhibits clathrin to promote mitotic Wnt signaling as shown by [50]. These findings point to the existing synergy of BCL family with WNTs. Family members belonging to each of the factors like BCL, WNT etc, might be involved synergistically in pathological case or otherwise. BCL and WNT members were found to be up regulated after the treatment of ETC-159 in colorectal cancer cells.
Table 14 contains rankings of BCL w.r.t WNTs and vice versa. Followed by this is the unexplored combinatorial hypotheses in Table 15 generated from two-way analysis of the ranks in Table 14. On the left half of Table 14 are rankings of BCL w.r.t WNTs. WNT4 - BCL2L2 shows high ranking with 2364 (laplace) and 2042 (linear); WNT7B - BCL2L2 shows high ranking with 1877 (laplace) and 2456 (linear); WNT9A - BCL2L2 shows high ranking with 1877 (laplace) and 2447 (linear); WNT4 - BCL2L13 shows high ranking with 1938 (laplace), 2425 (linear) and 1900 (rbf); WNT7B - BCL2L13 shows high ranking with 1993 (linear) and 2284 (rbf) and WNT2B - BCL10 shows high ranking with 2321 (laplace) and 2023 (linear).
On the right side are rankings of WNTs w.r.t BCL. WNT7B - BCL2L1 shows high ranking with 2213 (laplace) and 2266 (linear); WNT7B - BCL2L2 shows high ranking with 2456 (laplace), 2512 (linear) and 2286 (rbf); WNT9A - BCL2L2 shows high ranking with 1868 (laplace) and 2333 (rbf); WNT9A - BCL2L13 shows high ranking with 1858 (laplace), 2422 (linear) and 1934 (rbf); WNT2B - BCL3 shows high ranking with 1846 (laplace), 2056 (linear) and 1896 (rbf); WNT4 - BCL6 shows high ranking with 2483 (laplace) and 2488 (linear); WNT7B - BCL6 shows high ranking with 1893 (laplace) and 2284 (linear); WNT9A - BCL6 shows high ranking with 2098 (linear) and 1905 (rbf); WNT2B - BCL9L shows high ranking with 1918 (laplace) and 1882 (rbf) and WNT4 - BCL9L shows high ranking with 2498 (linear) and 2509 (rbf);
One can also interpret the results of the Table 15 graphically, with the following influences - • BCL family w.r.t WNTs with WNT4 − > BCL2L2; WNT7B − > BCL2L2; WNT9A − > BCL2L2; WNT4 − > BCL2L13; WNT7B − > BCL2L13; WNT2B − > BCL10 and • WNT family w.r.t BCL with WNT7B < − BCL2L1; WNT7B < − BCL2L2; WNT9A < − BCL2L2; WNT9A < − BCL2L13; WNT2B < − BCL3; WNT4 < − BCL6; WNT7B < − BCL6; WNT9A < − BCL6; WNT2B < − BCL9L; WNT4 < − BCL9L.

Conclusions

Presented here are a range of multiple synergistic WNT 2nd order combinations that were ranked via a search engine. Later, two way cross family analysis between components of these combinations were conducted. Via majority voting across the ranking methods, it was possible to find plausible unexplored synergistic combinations that might be prevalent in CRC cells after treatment with ETC-1922159 drug. The two-way cross family analysis also assists in deriving influences between components which serve as hypotheses for further tests. If found true, it paves way for biologists/oncologists to further investigate and understand the mechanism behind the synergy through wet experiments.

Author Contributions

Concept, design, in silico implementation - SS. Analysis and interpretation of results - SS. Manuscript writing - SS. Manuscript revision - SS. Approval of manuscript - SS.

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.

Source of Data

Data used in this research work was released in a publication in [51]. 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).

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Table 1. 2nd order interaction ranking between ABC w.r.t WNT family members.
Table 1. 2nd order interaction ranking between ABC w.r.t WNT family members.
Ranking ABC family w.r.t WNT family
Ranking of ABC family w.r.t WNT-2B Ranking of ABC family w.r.t WNT4
laplace linear rbf laplace linear rbf
WNT2B - ABC-A5 2108 310 72 ABC-A5 - WNT4 359 1285 433
ABC-B11 - WNT2B 319 2132 18 ABC-B11 - WNT4 872 1284 867
WNT2B - ABC-C3 1853 262 2498 ABC-C3 - WNT4 10 617 296
WNT2B - ABC-C5 2213 1685 840 WNT4 - ABC-C5 1383 2119 215
WNT2B - ABC-C13 1149 1191 2175 WNT4 - ABC-C13 1649 1814 542
WNT2B - ABC-D1 1119 177 2163 ABC-D1 - WNT4 1041 1171 1740
WNT2B - ABC-G1 1068 1583 214 ABC-G1 - WNT4 1020 1146 2025
WNT2B - ABC-G2 1500 1533 172 ABC-G2 - WNT4 784 1431 435
Ranking of ABC family w.r.t WNT-7B Ranking of ABC family w.r.t WNT-9A
laplace linear rbf laplace linear rbf
ABC-A5 - WNT7B 1550 516 995 ABC-A5 - WNT9A 735 349 1479
ABC-B11 - WNT7B 968 599 324 ABC-B11 - WNT9A 843 1647 689
ABC-C3 - WNT7B 694 1668 695 ABC-C3 - WNT9A 1590 359 2136
WNT7B - ABC-C5 979 1715 2268 ABC-C5 - WNT9A 1295 368 2265
WNT7B - ABC-C13 950 2245 2298 ABC-C13 - WNT9A 1394 2294 1134
ABC-D1 - WNT7B 252 850 1215 ABC-D1 - WNT9A 910 2367 675
ABC-G1 - WNT7B 269 733 1160 ABC-G1 - WNT9A 426 2457 1074
ABC-G2 - WNT7B 1717 224 264 ABC-G2 - WNT9A 1108 2350 960
Table 2. 2nd order interaction ranking between WNT w.r.t ABC family members.
Table 2. 2nd order interaction ranking between WNT w.r.t ABC family members.
Ranking WNT family w.r.t ABC family
Ranking of WNT family w.r.t ABC-A5 Ranking of WNT family w.r.t ABC-B11
laplace linear rbf laplace linear rbf
ABC-A5 - WNT2B 1549 2018 2132 WNT2B - ABC-B11 1083 703 1887
ABC-A5 - WNT4 1375 2436 2449 WNT4 - ABC-B11 156 298 1517
ABC-A5 - WNT7B 2420 1527 460 WNT7B - ABC-B11 1134 204 2323
ABC-A5 - WNT9A 1989 2209 2365 WNT9A - ABC-B11 226 2134 1480
Ranking of WNT family w.r.t ABC-C3 Ranking of WNT family w.r.t ABC-C5
laplace linear rbf laplace linear rbf
ABC-C3 - WNT2B 1127 1482 1905 WNT2B - ABC-C5 1970 2309 2248
ABC-C3 - WNT4 897 1454 489 WNT4 - ABC-C5 2129 229 230
ABC-C3 - WNT7B 656 2080 772 WNT7B - ABC-C5 1539 756 1258
ABC-C3 - WNT9A 2339 1616 814 ABC-C5 - WNT9A 213 2183 2480
Ranking of WNT family w.r.t ABC-C13 Ranking of WNT family w.r.t ABC-D1
laplace linear rbf laplace linear rbf
WNT2B - ABC-C13 950 2150 2048 WNT2B - ABC-D1 1751 1370 1174
WNT4 - ABC-C13 538 326 2242 WNT4 - ABC-D1 45 1784 101
WNT7B - ABC-C13 2508 1830 1219 WNT7B - ABC-D1 2238 2021 1121
WNT9A - ABC-C13 738 2501 634 WNT9A - ABC-D1 732 1526 1759
Ranking of WNT family w.r.t ABC-G1 Ranking of WNT family w.r.t ABC-G2
laplace linear rbf laplace linear rbf
WNT2B - ABC-G1 318 775 2040 WNT2B - ABC-G2 1342 1987 1230
WNT4 - ABC-G1 2169 157 39 WNT4 - ABC-G2 862 1352 1985
WNT7B - ABC-G1 587 1808 1866 WNT7B - ABC-G2 2334 2145 1526
WNT9A - ABC-G1 856 2350 920 WNT9A - ABC-G2 1919 1284 2003
Table 3. 2nd order combinatorial hypotheses between ABC and WNT family members.
Table 3. 2nd order combinatorial hypotheses between ABC and WNT family members.
Unexplored combinatorial hypotheses
ABC w.r.t WNT
WNT-2B ABC-C3
WNT-7B ABC-C13
WNT w.r.t ABC
ABC-A5 WNT-2B/4/9A
WNT-2B/9A ABC-C5
WNT-2B/7B ABC-C13
WNT-7B ABC-D1
WNT-7B ABC-G1
WNT-7B/9A ABC-G2
Table 4. 2nd order interaction ranking between ABC w.r.t IL family members.
Table 4. 2nd order interaction ranking between ABC w.r.t IL family members.
Ranking IL family VS WNT family
Ranking of IL family w.r.t WNT-2B Ranking of WNT-2B w.r.t IL family
laplace linear rbf laplace linear rbf
IL1A - WNT2B 6 2363 924 IL1A - WNT2B 2290 1360 2427
IL1B - WNT2B 1015 1278 794 IL1B - WNT2B 847 2168 1369
IL1RAP - WNT2B 1481 1391 799 IL1RAP - WNT2B 2488 35 1892
IL1RN - WNT2B 1229 1967 1582 IL1RN - WNT2B 1307 43 2514
IL2RG - WNT2B 1434 1100 2335 IL2RG - WNT2B 1384 1255 1283
IL6ST - WNT2B 1157 1797 2088 IL6ST - WNT2B 776 242 1481
IL8 - WNT2B 2107 1817 2251 IL8 - WNT2B 2157 2025 593
IL10RB - WNT2B 961 2494 512 IL10RB - WNT2B 2419 856 1419
IL15 - WNT2B 1008 1214 1714 IL15 - WNT2B 1171 625 1215
IL15RA - WNT2B 728 1782 1382 IL15RA - WNT2B 2262 1021 657
IL17C - WNT2B 477 2357 1483 IL17C - WNT2B 1947 1304 1331
IL17REL - WNT2B 1824 12 2241 IL17REL - WNT2B 1980 919 1617
Ranking of IL family w.r.t WNT-4 Ranking of WNT-4 w.r.t IL family
laplace linear rbf laplace linear rbf
IL1A - WNT4 2500 1346 955 IL1A - WNT4 507 221 91
IL1B - WNT4 1867 1976 1682 IL1B - WNT4 129 250 291
IL1RAP - WNT4 2302 1826 803 IL1RAP - WNT4 74 19 1553
IL1RN - WNT4 1314 856 104 IL1RN - WNT4 851 1218 2029
IL2RG - WNT4 1289 590 319 IL2RG - WNT4 520 920 424
IL6ST - WNT4 1315 273 2422 IL6ST - WNT4 991 1443 2454
IL8 - WNT4 1722 549 11 IL8 - WNT4 1980 2144 1267
IL10RB - WNT4 1700 153 1055 IL10RB - WNT4 1828 2259 1993
IL15 - WNT4 1012 871 1658 IL15 - WNT4 959 553 448
IL15RA - WNT4 1987 2265 819 IL15RA - WNT4 788 139 645
IL17C - WNT4 2018 1639 1881 IL17C - WNT4 406 276 232
IL17REL - WNT4 1019 425 893 IL17REL - WNT4 955 595 1689
Ranking of IL family w.r.t WNT-7B Ranking of WNT-7B w.r.t IL family
laplace linear rbf laplace linear rbf
IL1A - WNT7B 662 950 149 IL1A - WNT7B 1058 2134 2312
IL1B - WNT7B 290 167 502 IL1B - WNT7B 1683 1871 1575
IL1RAP - WNT7B 872 1976 789 IL1RAP - WNT7B 381 1728 1517
IL1RN - WNT7B 1882 1796 503 IL1RN - WNT7B 1907 2162 1605
IL2RG - WNT7B 1381 446 482 IL2RG - WNT7B 1070 1695 2245
IL6ST - WNT7B 819 1284 1528 IL6ST - WNT7B 1268 1881 2020
IL8 - WNT7B 2232 220 701 IL8 - WNT7B 1551 58 2149
IL10RB - WNT7B 1318 1198 656 IL10RB - WNT7B 375 2145 803
IL15 - WNT7B 1000 290 245 IL15 - WNT7B 2307 1524 1687
IL15RA - WNT7B 1535 1054 2204 IL15RA - WNT7B 1575 191 1949
IL17C - WNT7B 515 263 113 IL17C - WNT7B 1956 2388 1982
IL17REL - WNT7B 2053 2445 2489 IL17REL - WNT7B 322 859 1631
Ranking of IL family w.r.t WNT-9A Ranking of WNT-9A w.r.t IL family
laplace linear rbf laplace linear rbf
IL1A - WNT9A 199 2228 1270 IL1A - WNT9A 597 1322 469
IL1B - WNT9A 305 2266 466 IL1B - WNT9A 776 652 1010
IL1RAP - WNT9A 1773 2273 2159 IL1RAP - WNT9A 2003 2179 964
IL1RN - WNT9A 2479 1506 1503 IL1RN - WNT9A 1363 1829 1632
IL2RG - WNT9A 1489 598 865 IL2RG - WNT9A 186 260 1276
IL6ST - WNT9A 2229 761 1103 IL6ST - WNT9A 2099 1416 1674
IL8 - WNT9A 346 1103 1910 IL8 - WNT9A 589 1751 1529
IL10RB - WNT9A 1836 1556 1006 IL10RB - WNT9A 1021 2127 1534
IL15 - WNT9A 168 1445 855 IL15 - WNT9A 1357 1025 1709
IL15RA - WNT9A 1776 206 2380 IL15RA - WNT9A 2149 2362 737
IL17C - WNT9A 72 2442 569 IL17C - WNT9A 1532 2465 1607
IL17REL - WNT9A 2512 24 580 IL17REL - WNT9A 2101 1940 313
Table 5. 2nd order combinatorial hypotheses between IL and WNT family members.
Table 5. 2nd order combinatorial hypotheses between IL and WNT family members.
Unexplored combinatorial hypotheses
IL w.r.t WNT
IL-6ST/8/17REL WNT-2B
IL-1B/1RAP/15RA/17C WNT-4
IL-1RN/17REL WNT-7B
IL-1RAP/15RA WNT-9A
WNT w.r.t IL
IL-1A/1RAP/8 WNT-2B
IL-8/10RB WNT-4
IL-1A/1RN/6ST/17C WNT-7B
IL-1RAP/15RA/17REL WNT-9A
Table 6. 2nd order interaction ranking between WNT w.r.t UBE2 family members.
Table 6. 2nd order interaction ranking between WNT w.r.t UBE2 family members.
Ranking UBE2 family VS WNT family
Ranking of UBE2-A w.r.t WNT family Ranking of WNT family w.r.t UBE2-A
laplace linear rbf laplace linear rbf
WNT2B - UBE2A 1608 203 181 WNT2B - UBE2A 1677 899 1671
WNT4 - UBE2A 1293 2314 2279 WNT4 - UBE2A 424 1062 545
WNT7B - UBE2A 1139 1217 1961 WNT7B - UBE2A 392 2345 2151
WNT9A - UBE2A 443 1705 287 WNT9A - UBE2A 806 1581 1098
Ranking of UBE2-B w.r.t WNT family Ranking of WNT family w.r.t UBE2-B
laplace linear rbf laplace linear rbf
WNT2B - UBE2B 1473 2220 599 WNT2B - UBE2B 2020 553 73
WNT4 - UBE2B 2260 2008 2141 WNT4 - UBE2B 301 334 47
WNT7B - UBE2B 2116 2206 1454 WNT7B - UBE2B 1336 2052 1903
WNT9A - UBE2B 2291 79 1381 WNT9A - UBE2B 2300 2476 2326
Ranking of UBE2-F w.r.t WNT family Ranking of WNT family w.r.t UBE2-F
laplace linear rbf laplace linear rbf
WNT2B - UBE2F 1246 833 2387 WNT2B - UBE2F 1006 1917 49
WNT4 - UBE2F 2135 2505 1762 WNT4 - UBE2F 63 1109 664
WNT7B - UBE2F 2423 1673 2077 WNT7B - UBE2F 2236 1660 1751
WNT9A - UBE2F 2032 1165 128 WNT9A - UBE2F 1014 2251 2179
Ranking of UBE2-H w.r.t WNT family Ranking of WNT family w.r.t UBE2-H
laplace linear rbf laplace linear rbf
WNT2B - UBE2H 1841 351 2178 WNT2B - UBE2H 2015 1019 1331
WNT4 - UBE2H 1090 778 1224 WNT4 - UBE2H 218 2248 2155
WNT7B - UBE2H 1505 1215 527 WNT7B - UBE2H 2294 1209 1367
WNT9A - UBE2H 605 332 2479 WNT9A - UBE2H 437 1202 2379
Ranking of UBE2-J1 w.r.t WNT family Ranking of WNT family w.r.t UBE2-J1
laplace linear rbf laplace linear rbf
WNT2B - UBE2J1 1539 1251 1814 WNT2B - UBE2J1 1500 1562 1255
WNT4 - UBE2J1 1583 2478 1604 WNT4 - UBE2J1 292 62 65
WNT7B - UBE2J1 2349 1207 2183 WNT7B - UBE2J1 552 1877 1846
WNT9A - UBE2J1 1835 2053 1652 WNT9A - UBE2J1 2471 2137 2469
Ranking of UBE2-Z w.r.t WNT family Ranking of WNT family w.r.t UBE2-Z
laplace linear rbf laplace linear rbf
WNT2B - UBE2Z 58 1756 1878 WNT2B - UBE2Z 1576 1171 1543
WNT4 - UBE2Z 2195 2468 938 WNT4 - UBE2Z 896 132 186
WNT7B - UBE2Z 2343 1973 723 WNT7B - UBE2Z 1972 1800 1399
WNT9A - UBE2Z 136 1986 4 WNT9A - UBE2Z 1149 865 813
Table 7. 2nd order combinatorial hypotheses between UBE2 and WNT family members.
Table 7. 2nd order combinatorial hypotheses between UBE2 and WNT family members.
Unexplored combinatorial hypotheses
UBE2 w.r.t WNT
WNT-4 UBE2-A
WNT-4/7 UBE2-B
WNT-4/7B UBE2-F
WNT-2B UBE2-H
WNT-7B/9B UBE2-J1
WNT-2B/4/7B UBE2-Z
WNT w.r.t UBE2
WNT-7B UBE2-A
WNT-7B/9A UBE2-B
WNT-7B/9A UBE2-F
WNT-4 UBE2-H
WNT-7B/9A UBE2-J1
WNT-7B UBE2-Z
Table 8. 2nd order interaction ranking between WNT w.r.t EXOSC family members.
Table 8. 2nd order interaction ranking between WNT w.r.t EXOSC family members.
Ranking EXOSC family VS WNT10B
Ranking of WNT10B w.r.t EXOSC family Ranking of EXOSC family w.r.t WNT10B
laplace linear rbf laplace linear rbf
EXOSC2 - WNT10B 221 433 699 EXOSC2 - WNT10B 1695 1077 992
EXOSC3 - WNT10B 906 1292 860 EXOSC3 - WNT10B 610 2496 2428
EXOSC5 - WNT10B 919 484 997 EXOSC5 - WNT10B 832 1445 1589
EXOSC6 - WNT10B 407 1195 1747 EXOSC6 - WNT10B 1319 1738 1689
EXOSC7 - WNT10B 2599 2571 2584 EXOSC7 - WNT10B 2710 13 4
EXOSC8 - WNT10B 336 1437 391 EXOSC8 - WNT10B 451 2284 2493
EXOSC9 - WNT10B 222 701 732 EXOSC9 - WNT10B 1378 1501 1651
Table 9. 2nd order combinatorial hypotheses between EXOSC and WNT10B family members.
Table 9. 2nd order combinatorial hypotheses between EXOSC and WNT10B family members.
Unexplored combinatorial hypotheses
EXOSC w.r.t WNT10B
EXOSC-2/5/6/7/9 WNT10B
WNT10B w.r.t EXOSC
EXOSC-2/3/5/6/8/9 WNT10B
Table 10. 2nd order interaction ranking between WNT VS CASP family members.
Table 10. 2nd order interaction ranking between WNT VS CASP family members.
Ranking CASP family VS WNT family
Ranking of CASP4 w.r.t WNTs family Ranking of CASP5 w.r.t WNTs family
laplace linear rbf laplace linear rbf
CASP4 - WNT2B 2265 320 1517 CASP5 - WNT2B 975 2171 2366
CASP4 - WNT4 1050 1081 558 CASP5 - WNT4 1788 1356 569
CASP4 - WNT7B 622 9 632 CASP5 - WNT7B 716 978 606
CASP4 - WNT9A 446 1413 583 CASP5 - WNT9A 383 808 147
Ranking of CASP7 w.r.t WNTs family Ranking of CASP9 w.r.t WNTs family
laplace linear rbf laplace linear rbf
CASP7 - WNT2B 1152 305 248 CASP9 - WNT2B 1345 1501 1328
CASP7 - WNT4 936 1260 1787 CASP9 - WNT4 1344 2472 2200
CASP7 - WNT7B 901 1403 1303 CASP9 - WNT7B 2196 1935 1713
CASP7 - WNT9A 1330 1527 2436 CASP9 - WNT9A 1863 428 2002
Ranking of CASP10 w.r.t WNTs family Ranking of CASP16 w.r.t WNTs family
laplace linear rbf laplace linear rbf
CASP10 - WNT2B 1607 1108 739 CASP16 - WNT2B 240 621 193
CASP10 - WNT4 432 689 132 CASP16 - WNT4 2070 1783 711
CASP10 - WNT7B 1906 1171 1165 CASP16 - WNT7B 411 713 103
CASP10 - WNT9A 1611 2152 1451 CASP16 - WNT9A 14 2512 181
Ranking of WNTs family w.r.t CASP4 Ranking of WNTs family w.r.t CASP5
laplace linear rbf laplace linear rbf
CASP4 - WNT2B 609 1317 2372 CASP5 - WNT2B 1849 1192 1590
CASP4 - WNT4 105 711 1062 CASP5 - WNT4 890 682 714
CASP4 - WNT7B 1093 2479 1739 CASP5 - WNT7B 2112 1919 2440
CASP4 - WNT9A 456 2278 1939 CASP5 - WNT9A 315 1880 1437
Ranking of WNTs family w.r.t CASP7 Ranking of WNTs family w.r.t CASP9
laplace linear rbf laplace linear rbf
CASP7 - WNT2B 2505 1891 1120 CASP9 - WNT2B 282 639 1414
CASP7 - WNT4 108 2456 2455 CASP9 - WNT4 572 1788 378
CASP7 - WNT7B 1380 1559 1681 CASP9 - WNT7B 979 901 676
CASP7 - WNT9A 2183 1941 1632 CASP9 - WNT9A 2378 2396 2058
Ranking of WNTs family w.r.t CASP10 Ranking of WNTs family w.r.t CASP16
laplace linear rbf laplace linear rbf
CASP10 - WNT2B 625 1471 81 CASP16 - WNT2B 2197 2489 1775
CASP10 - WNT4 1830 2229 1847 CASP16 - WNT4 1382 954 1017
CASP10 - WNT7B 1965 937 147 CASP16 - WNT7B 2508 1820 1867
CASP10 - WNT9A 2185 1977 1350 CASP16 - WNT9A 1943 1154 1839
Table 11. 2nd order combinatorial hypotheses between CASP and WNT family members.
Table 11. 2nd order combinatorial hypotheses between CASP and WNT family members.
Unexplored combinatorial hypotheses
CASP w.r.t WNT
CASP5 WNT2B
CASP9 WNT4/WNT7B/WNT9A
CASP16 WNT4
WNT w.r.t CASP
WNT7B/WNT9A CASP4
WNT7B CASP5
WNT2B/WNT4/WNT9A CASP7
WNT9A CASP9
WNT4/WNT9A CASP10
WNT2B/WNT7B/WNT9A CASP16
Table 12. 2nd order interaction ranking between WNT VS TP53 family members.
Table 12. 2nd order interaction ranking between WNT VS TP53 family members.
Ranking TP53 family VS WNT
Ranking of TP53 family w.r.t WNT2B Ranking of WNT2B w.r.t TP53 family
laplace linear rbf laplace linear rbf
TP53BP2 - WNT2B 2286 234 1550 TP53BP2 - WNT2B 313 908 2457
TP53I3 - WNT2B 2056 1712 1461 TP53I3 - WNT2B 713 1223 1720
TP53INP1 - WNT2B 945 1805 2056 TP53INP1 - WNT2B 1853 2089 762
TP53INP2 - WNT2B 369 1277 453 TP53INP2 - WNT2B 754 1723 2335
Ranking of TP53 family w.r.t WNT4 Ranking of WNT4 w.r.t TP53 family
laplace linear rbf laplace linear rbf
TP53BP2 - WNT4 1034 315 1734 TP53BP2 - WNT4 678 1464 2500
TP53I3 - WNT4 1738 1631 232 TP53I3 - WNT4 297 319 493
TP53INP1 - WNT4 645 498 450 TP53INP1 - WNT4 131 2414 2493
TP53INP2 - WNT4 671 1440 405 TP53INP2 - WNT4 529 467 154
Ranking of TP53 family w.r.t WNT7B Ranking of WNT7B w.r.t TP53 family
laplace linear rbf laplace linear rbf
TP53BP2 - WNT7B 2333 1282 1673 TP53BP2 - WNT7B 1442 2217 1068
TP53I3 - WNT7B 324 712 284 TP53I3 - WNT7B 1712 1988 2393
TP53INP1 - WNT7B 1227 1585 1019 TP53INP1 - WNT7B 1226 1685 1497
TP53INP2 - WNT7B 845 1004 470 TP53INP2 - WNT7B 1017 1746 1925
Ranking of TP53 family w.r.t WNT9A Ranking of WNT9A w.r.t TP53 family
laplace linear rbf laplace linear rbf
TP53BP2 - WNT9A 908 2232 2143 TP53BP2 - WNT9A 1035 371 1218
TP53I3 - WNT9A 1707 2297 1018 TP53I3 - WNT9A 1351 1281 1695
TP53INP1 - WNT9A 447 243 1245 TP53INP1 - WNT9A 295 2045 2437
TP53INP2 - WNT9A 22 2497 1138 TP53INP2 - WNT9A 421 1765 1121
Table 13. 2nd order combinatorial hypotheses between TP53 and WNT family members.
Table 13. 2nd order combinatorial hypotheses between TP53 and WNT family members.
Unexplored combinatorial hypotheses
TP53 family w.r.t WNT
TP53I3 WNT2B
TP53INP1 WNT2B
TP53BP2 WNT9A
WNT family w.r.t TP53
TP53INP1 WNT2B
TP53INP2 WNT2B
TP53INP1 WNT4
TP53I3 WNT7B
TP53INP1 WNT9A
Table 14. 2nd order interaction ranking between WNT VS BCL family members.
Table 14. 2nd order interaction ranking between WNT VS BCL family members.
Ranking BCL family VS WNT
Ranking of BCL2L1 w.r.t WNT family Ranking of WNT family w.r.t BCL2L1
laplace linear rbf laplace linear rbf
WNT2B - BCL2L1 1884 101 966 WNT2B - BCL2L1 1854 1666 1699
WNT4 - BCL2L1 98 1162 719 WNT4 - BCL2L1 21 107 16
WNT7B - BCL2L1 1434 1891 620 WNT7B - BCL2L1 2213 2266 1511
WNT9A - BCL2L1 1088 1020 1318 WNT9A - BCL2L1 1019 1462 1345
Ranking of BCL2L2 w.r.t WNT family Ranking of WNT family w.r.t BCL2L2
laplace linear rbf laplace linear rbf
WNT2B - BCL2L2 625 2204 1677 WNT2B - BCL2L2 1574 2206 955
WNT4 - BCL2L2 2364 2042 1610 WNT4 - BCL2L2 160 590 316
WNT7B - BCL2L2 843 1877 2456 WNT7B - BCL2L2 2456 2512 2286
WNT9A - BCL2L2 1877 538 2447 WNT9A - BCL2L2 1868 2333 990
Ranking of BCL2L13 w.r.t WNT family Ranking of WNT family w.r.t BCL2L13
laplace linear rbf laplace linear rbf
WNT2B - BCL2L13 201 1862 1353 WNT2B - BCL2L13 1256 1254 1490
WNT4 - BCL2L13 1938 2425 1900 WNT4 - BCL2L13 922 270 187
WNT7B - BCL2L13 1105 1993 2284 WNT7B - BCL2L13 1610 1319 954
WNT9A - BCL2L13 1855 268 2387 WNT9A - BCL2L13 1858 2422 1934
Ranking of BCL3 w.r.t WNT family Ranking of WNT family w.r.t BCL3
laplace linear rbf laplace linear rbf
WNT2B - BCL3 950 1328 2482 WNT2B - BCL3 1846 2056 1896
WNT4 - BCL3 1228 1562 1353 WNT4 - BCL3 591 359 1932
WNT7B - BCL3 591 615 553 WNT7B - BCL3 1687 2160 1428
WNT9A - BCL3 1037 1410 1102 WNT9A - BCL3 1539 1424 398
Ranking of BCL6 w.r.t WNT family Ranking of WNT family w.r.t BCL6
laplace linear rbf laplace linear rbf
WNT2B - BCL6 455 2426 1529 WNT2B - BCL6 52 107 170
WNT4 - BCL6 256 486 787 WNT4 - BCL6 2483 2488 1273
WNT7B - BCL6 2147 1466 1105 WNT7B - BCL6 975 1893 2284
WNT9A - BCL6 1547 734 2012 WNT9A - BCL6 1558 2098 1905
Ranking of BCL9L w.r.t WNT family Ranking of WNT family w.r.t BCL9L
laplace linear rbf laplace linear rbf
WNT2B - BCL9L 2348 804 1558 WNT2B - BCL9L 1918 700 1882
WNT4 - BCL9L 1446 657 309 WNT4 - BCL9L 303 2498 2509
WNT7B - BCL9L 1539 253 1279 WNT7B - BCL9L 1608 811 2168
WNT9A - BCL9L 1923 677 688 WNT9A - BCL9L 941 1843 1238
Ranking of BCL10 w.r.t WNT family Ranking of WNT family w.r.t BCL10
laplace linear rbf laplace linear rbf
WNT2B - BCL10 2321 69 2023 WNT2B - BCL10 1951 1101 1599
WNT4 - BCL10 285 1170 465 WNT4 - BCL10 2032 34 406
WNT7B - BCL10 1847 606 1252 WNT7B - BCL10 1297 74 2009
WNT9A - BCL10 217 798 1649 WNT9A - BCL10 1771 335 861
Table 15. 2nd order combinatorial hypotheses between TP53 and WNT family members.
Table 15. 2nd order combinatorial hypotheses between TP53 and WNT family members.
Unexplored combinatorial hypotheses
BCL w.r.t WNT family
WNT-4/7B/9A BCL2L2
WNT-4/7B BCL2L13
WNT-2B BCL10
WNT family w.r.t BCL
WNT-7B BCL2L1
WNT-7B/9A BCL2L2
WNT-9A BCL2L13
WNT-2B BCL3
WNT-4/7B/9A BCL6
WNT-2B/4 BCL9L
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