1 Introduction

Ulcerative colitis (UC) is a common non-specific chronic protracting and relapsing inflammatory disease, which relates the large intestine mucosa and submucosa, and its most important clinical manifestations are characterized by diarrhoea, abdominal pain, mucus pus, and blood in the stool [1, 2]. And with its recurrent ymptoms, long-time treatment and significant morbidity [3, 4]. the effective treatment of UC is becoming more and more important.

At present, the precise cause of UC is unclear, and it may related to genetics, environment, leucocyte recruitment, disruption of colon barrier function and mucosal immune response [5]. The clinical treatment is mainly focus on medicine therapy, interleukin antagonist, immunosuppressive agents, corticosteroids and salicylates. Through previous studies, with various side effects in the treatment, it is necessary to explore more safe and effective ways to treat UC [6].

Traditional Chinese medicine (TCM) has developed for thousands of years, it is one of the greatest treasures of Chinese culture, and it is the crystallization of medical wisdom and experience of the Chinese nation which accumulated from large numbers of theories and rich clinical experience [7]. According to the theory of TCM, UC belongs to the category of dysentery, diarrhoea, and hematochezia, etc. TCM symptoms of UC include mainly types of dampness-heat in large intestine, excessive heat-toxin, dampness stagnancy due to spleen deficiency, Yang deficiency of spleen and kidney, cold-heat complicated symptom and so on, and the chief symptom of UC is dampness-heat in large intestine [8]. On the one hand, when evil heat attacks blood vessels, it will cause abnormal blood circulation, then it lead to force the blood to act recklessly, therefore, the patients with UC of dampness-heat symptom characterized by bloody stool. On the other hand, “Su Wen” has recorded that “Predominant dampness causing diarrhea”, and “Yizong Bidu” said “No diarrhea without dampness”. The dampness is heavy, turbid, sticky and stagnant, and it tends to move downward, so the intestinal symptoms of UC patients occurs repeatedly with protracted process [9, 10]. The possible pathogenetic mechanism is that while dampness-heat accumulated in large intestine, then fumigating intestine, it can cause the damage of collaterals in intestine, and during this process, the rottenness of blood and muscle forming pus, thus leading to pus and blood stools mixed with redness and whiteness [11]. And it exactly explained the basis of TCM therapeutic principles and methods in treating UC with dampness-heat symptom, therefore, based on this point, the central therapeutic principle is clearing heat and removing dampness.

Many clinical research has reported that it is effective for treating patients of UC with dampness-heat syndrome by using Chinese herbal medicine [12]. The large intestine is located in Lower-JIAO, in the findings of TCM research, Ermiaosan is a famous classic and common used prescription for dampness-heat in Lower-JIAO [13], and it is often used to treat disease caused by dampness-heat such as pain in tendons and bones, disabled wilted limbs, morbid vaginal discharge. Because of former researches of Ermiaosan whether used by enema therapy or oral therapy, it could ameliorate symptoms of UC effectively without side effects [14, 15]. In addition, UC is often accompanied by rheumatoid arthritis, ankylosing spondylitis and other diseases [16], and Ermiaosan is a classic prescription for treating damp-heat arthralgia [17].Therefore, we become so interested in this prescription in the treatment of UC with dampness-heat syndrome. And further more, we find out that the clinical application of these two drugs can significantly ameliorate the symptoms of abdominal pain, diarrhea and bloody stool in patients with UC, and thus to explore the active mechanism related to the treatment of UC.

The original name of Ermiaosan is Cang Zhu San, it first appeared in“Shi Yi De Xiao Fang”written by a famous physician named Wei yilin in the Yuan Dynasty (in 1345) . According to the record, it can treat the pain on feet and knees cause by Wind-cold and dampness-heat syndrome, or redness and swollening on these body parts, and thermal pain between feet bones. Then at the same period, an outstanding TCM physician named Zhu danxi, one of the "Four Great Masters of Jin and Yuan Dynasties" in Chinese medical history, he first changed the name of Cang Zhu San into Ermiaosan in his book “Danxi Xinfa”(in 1481), for it contains two herbs, and with its miraculous therapeutic effect in treating flaccidity of muscle and weakness of legs, pain between tendons and bones, wet sore on lower parts of the body, redness and swollening on feet and knees and so on caused by dampness-heat, so he gave this prescription a new name “Ermiaosan” [18].

As for Ermiaosan, it consists of just two herbs, Huang Bo (Phellodendri Chinrnsis Cortex) and Cang Zhu (Atractylodes lancea), Huang Bo tastes bitter, and it is classified as a kind of cold medicine that can clear heat and remove dampness, purge fire and detoxification, expel hectic fever, treat sore, with a meridian tropism in the kidney and bladder, it is mainly used to treat diarrhoea with dampness-heat syndrome, jaundice, urine red, gynecological illness, morbid vaginal discharge and pruritus vulvae, heat stangury, roughness and pain in the urethra, night sweet, spermatorrhea, carbuncle toxin and swelling sores and so on. Cang Zhu has a slightly warm nature, and its flavor is pungent and bitter, with a meridian tropism in the liver, stomach and spleen, it can invigorate spleen and eliminate dampness, dispel pathogenic wind and cold, and improve eyesight, it can be used to treat dampness retention in Middle-JIAO, abdominal fullness and distention, diarrhoea, edema, atrophy and flaccidity on feet, pain due to wind-dampness, anemofrigid cold, nyctalopia, clouded vision and dry eye [19].“Zhen Zhu Nang” has referred that Huang Bo can clear the heat from the bladder, diuresis, remove dampness and edema in Lower-JIAO, and help with blood stool in dysentery [20]. And it is mostly used for diarrhea, leucorrhea mixed with redness and whiteness, feet and knees flaccidity caused by dampness and heat of Lower-JIAO [21, 22].

Former researches have shown that Huang Bo has many pharmacological effects, such as anti-ulcer, anti-inflammatory, antibacterial, antioxidant, anti-tumor, stop diarrhea and so on [23]. Previous studies has confirmed that the bioactive components of Huang Bo can be used for the treatment of bacillary dysentery, gastroenteritis, etc., and they have gained very obvious curative effect [24].

“Wenbing Tiaobian” has elaborated “The dampness does not fade away while just only clearing away the heat, and the heat will be more exuberant while just only eliminating the dampness” written by Wu Jutong in the Qing Dynasty [25]. As “Bencao Gangmu” recorded “Zhenheng said that Cang Zhu can treat dampness from upper-JIAO to lower-JIAO” [26], it is really useful in treating dampness of all Sanjiao. “Bencao Xinbian” has discribed that Cang Zhu is good at eliminating dampness by circulating in the large intestine, and that is its special effect actually [27, 28].

In recent studies, The digestive system pharmacological effects of Cang Zhu and its active ingredients mainly include anti gastrointestinal ulcer, regulating gastrointestinal propulsion and anti diarrhea [29]. Modern pharmacological studies have reported that Cang Zhu has a variety of pharmacological activities, that including anti-inflammatory, anti ulcer [30]. Network pharmacology and molecular docking are brand new technologies that based on systems biology, database molecular correlation analysis, they are applied to exploring the potential new drugs and prediction of their related main compounds and targets [31]. Our study not only explains the molecular mechanism of Ermiaosan acting on UC but also offers the theoretical basis and effective strategy for further clinical and experimental research in the future [32].

2 Materials and methods

2.1 Screening of main component and targets

The main active chemical components of Ermiaosan were screened through Traditional Chinese Medicine Systems Pharmacology database (TCMSP, http:// tcmspw.com/tcmsp.php) [33] and selected by using the thresholds of oral bioavailability (OB) ≥ 30% and drug-likeness (DL) ≥ 18%, the targets of Ermiaosan were obtained from TCMSP, the SwissTargetPrediction (http://www.swisstargetprediction.ch.) [34], Therapeutic Targets Database (TTD, http://bidd.nus.edu.sg/group/ttd/ttd.asp) [35] and the DrugBank database (www.drugbank.ca) [36]. Subsequently the corresponding genes of the candidate targets were retrieved by UniProt database (https://www.uniprot.org/) [37], the targets related to ulcerative colitis were obtained from TTD and Genecard database (https://www.genecards.org/) [38]. Then the candidate targets of Ermiaosan against ulcerative colitis were obtained by taking an intersection of the above targets with a Venn diagram tool (http://bioinfogp.cnb.csic.es/tools/venny/index.html) [39].

2.2 Construction of network and hub genes selection

We input these overlapped targets into STRING tools (https://string-db.org) [40] to construct the Protein–protein interactions (PPI) network, the required score to be greater than 0.4 and the species was selected as “Homo sapiens”, and the drug-compound-target-disease network was built and visualized using Cytoscape 3.8.2 software [41]. CytoHubba plugin was used to explore the core genes, main methods Degree greater than fourfold above the average was used to evaluate and sequence the central genes [42], and then the main related core genes were successfully selected. At the same time, we construct drug-compound-target network, and we choose the top 3 main compounds ranked by degree.

2.3 Enrichment analysis

Bioinformatic analysis was performed using the OECloud tools at https://cloud.oebiotech.cn. to explore the enrichment analyses of gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), hence to predict the potential roles of Ermiaosan against ulcerative colitis. We set P value < 0.05 as the default option to visualize the results. As for GO enrichment analysis, there were three selected analysis categories: biological processes, cell components and molecular functions, and top 10 main items of each categories choose to visualize the results. Next, as for KEGG enrichment analysis, we choose top 20 important pathways to explore the specific mechanism of Ermiaosan against ulcerative colitis, and the targets genes were subjected to pathway annotations using the Kyoto Encyclopedia of Genes and Genomes (KEGG).

2.4 Molecular Docking verification

The three-dimensional (3D) structure of the target proteins were downloaded from Protein Data Bank (PDB, https:// www.rcsb.org/) [43], the source of organism was set as “Homo sapiens”, and precised at resolutions of 2.0–3.0 Å, and the candidate active compounds were downloaded from TCMSP (all saved as *.mol2 format) thus they were prepared as ligands. Docking results were decorated by PyMOL 2.3.0 to show the 3D protein–ligand complex, and AutoDock Tools 1.5.6 software was used to add the nonpolar hydrogen, isolate proteins, remove the water molecules, and then we calculated the affinities between these ligands and proteins to verify their correlation of binding. Hydrogenation and charge calculation of these 7 main target proteins were totally carried out specifically, the docking binding energy based on the threshold level of ≤  − 5.0 kcal/mol, which was considered successfully to indicated a well certain compound-protein binding affinity, and the the lower the binding energy, the better the docking effect [44], and finally, PyMOL 2.3.0. was reused to visualize the related conformations with good affinity.

3 Results

3.1 Targets of ermiaosan against ulcerative colitis

A total of forty-six main chemical compounds of Ermiaosan were obtained from TCMSP database, and 704 targets (removed out duplicate targets) were identified by searching the TCMSP database, Swiss, TTD and DrugBank database, the candidate targets were put into the UniProt database, the species option was set as “Homo sapiens”. Cytoscape 3.8.2 software was used to construct drug-compound-target network, and the top 3 active compounds were dihydroniloticin, quercetin and beta-sitosterol 3-O-glucoside_qt, the detailed information of selected compounds is shown in Table 1, the result of drug-compound-target relationship and top 3 active compounds were shown in Fig. 1,Table 2. As for disease gene, a total of 4872 ulcerative colitis-related genes were obtained from TTD and GeneCards database. Finally, we obtained 408 overlapping genes through Venn diagram, as shown in Fig. 2.

Table 1 The information of 46 candidate compounds in Ermiaosan
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Fig. 1
figure 1

The result of drug-compound-target network (Light blue ellipses represent the drugs of Ermiaosan, fuchsia diamonds represent compounds of Ermiaosan, yellow round rectangles represent potential targets of Ermiaosan)

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Table 2 Top 3 candidate compounds of Ermiaosan
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Fig. 2
figure 2

Venny diagram of Ermiaosan (medicine gene) and ulcerative colitis (disease gene) intersection targets. 408 overlapping targets represent the candidate targets of Ermiaosan against ulcerative colitis

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3.2 Network of intersection targets

3.2.1 PPI network of targets

To get further understanding about the interaction of these 408 overlapping targets, the STRING tool was applied to construct PPI network of the relationships of herb compounds-disease-tergets for these targets. We set the confidence score > 0.7, the analysis of PPI network shown that there were 408 nodes and the number of edges was 9421, the average node degree was 46.2, and the average local clustering coefficient was 0.534 ( As shown in Fig. 3).

Fig. 3
figure 3

Protein–protein interaction networks of Ermiaosan and ulcerative colitis

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3.2.2 Result of cytoscape network of targets and the hub genes

We used Cytoscape3.8.2 software to visualise the combined score of the STRING database of Ermiaosan and ulcerative colitis ( As shown in Fig. 4), and then we set the node size and color to map the degree value and score value to construct drug-target interaction of the drug and disease, it contained 411 nodes and the number of edges was 951, the average node degree was 92.6, with the methods Degree greater than fourfold above the average was set to select core genes by cytoHubba plugin, these top 7 targets were the key targets of Ermiaosan against ulcerative colitis, the darker the color, the higher the correlation. ( As shown in Fig. 5 and Table 3).

Fig. 4
figure 4

Drug-disease-tergets interaction of Ermiaosan and ulcerative colitis. (Red diamonds represent ulcerative colitis, light blue ellipses represent the drug of Ermiaosan, grass green round rectangles represent potential common targets of Ermiaosan and ulcerative colitis.)

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Fig. 5
figure 5

Top 7 key targets in PPI network

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Table 3 Key targets in PPI network that are Degree greater than fourfold above the average (Top 7)
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3.3 The results of enrichment analysis

The multiple potential mechanisms of Ermiaosan against ulcerative colitis through Bioinformatic analysis which was performed using the OECloud tools at https://cloud.oebiotech.cn., with the default option was P value < 0.05. And the results of top 10 main items of each categories of GO terms were: protein phosphorylation, positive regulation of cell proliferation, positive regulation of angiogenesis, inflammatory response, vascular endothelial growth factor receptor signaling pathway, positive regulation of gene expression, negative regulation of apoptotic process and so on ( As shown in Fig. 6a), and then top 20 important GO enrichment analysis items were selected (As shown in Fig. 6b, Table 4). As for KEGG enrichment analysis, the top 20 key pathways were identified (As shown in Fig. 7, Table 5), and the main pathways included PI3K–Akt, TNF and HIF-1 signaling pathway, the detail targets of regulation roles of these pathways are shown in Fig. 8a–f. The maps of KEGG pathway showed that the related targets of regulation roles were AKT, TNF, IL6, P53, VEGF, IL1B and so on.

Fig. 6
figure 6

a Results of biological process (top 10), cellular components (top 10), molecular function (top 10). b Top 20 items of GO enrichment analysis

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Table 4 Results of KEGG enrichment analysis (top 20)
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Fig. 7
figure 7

Top 20 items of KEGG enrichment analysis

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Table 5 The binding energies of top 3 main active compounds with top 7 key targets
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Fig. 8
figure 8figure 8figure 8

a KEGG pathway annotations of PI3K-Akt signaling pathway of Ermiaosan in the regulation of ulcerative colitis. Red rectangles represent the targets of regulation roles. b KEGG pathway annotations of PI3K-Akt signaling pathway of Ermiaosan in the regulation of ulcerative colitis. Green rectangles represent the targets of potential roles. c KEGG pathway annotations of TNF signaling pathway of Ermiaosan in the regulation of ulcerative colitis. Red rectangles represent the targets of regulation roles. d KEGG pathway annotations of TNF signaling pathway of Ermiaosan in the regulation of ulcerative colitis. Green rectangles represent the targets of potential roles. e KEGG pathway annotations of HIF-1 signaling pathway of Ermiaosan in the regulation of ulcerative colitis.Red rectangles represent the targets of regulation roles. f KEGG pathway annotations of HIF-1 signaling pathway of Ermiaosan in the regulation of ulcerative colitis.Green rectangles represent the targets of potential roles.

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3.4 The results of molecular docking verification

The top three main active compounds dihydroniloticin, quercetin, and beta-sitosterol 3-O-glucoside_qt had a tight linkage with ulcerative colitis verified through molecular docking, Among all docking of protein–ligands, the results showed that these 3 compounds had a strong affinity with the selected top 7 key targets, except for CTNNB1(PDB ID:6o9c), the binding energy with quercetin and beta-sitosterol 3-O-glucoside_qt were -4.29 kcal/mol and -4.89 kcal/mol, the rest target proteins are all less than -5 kcal/mol, all the detail information of binding energy with these 3 compounds of top 7 key targets are shown in Table 4, and the docking conformations of these targets of regulation roles AKT1, TNF, IL6,TP53, VEGFA, IL1B and CTNNB1 are shown in Fig. 9a–u.

Fig. 9
figure 9figure 9

a Dihydroniloticin with AKT1. b Dihydroniloticin with TNF. c Dihydroniloticin with IL6. d Dihydroniloticin with TP53. e Dihydroniloticin with VEGFA. f. Dihydroniloticin with IL1B. g Dihydroniloticin with CTNNB1. h Quercetin with AKT1. i Quercetin with TNF. j Quercetin with IL6. k Quercetin with TP53. l Quercetin with VEGFA. m Quercetin with IL1B. n Quercetin with CTNNB1. o Beta-sitosterol 3-O-glucoside_qt with AKT1. p Beta-sitosterol 3-O-glucoside_qt with TNF. q Beta-sitosterol 3-O-glucoside_qt with IL6. r Beta-sitosterol 3-O-glucoside_qt with TP53. s Beta-sitosterol 3-O-glucoside_qt with VEGFA. t Beta-sitosterol 3-O-glucoside_qt with IL1B. u Beta-sitosterol 3-O-glucoside_qt with CTNNB1

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4 Discussion

The incidence of UC is increasing year by year around the world, and it is listed as one of the most challenge and refractory diseases by World Health Organization [45, 46]. Pharmacotherapy is still the main measure in the treatment of UC, and the therapeutic goal is to control intestinal inflammation and improve immune disorders [47].

The combination of dampness and heat is the basic pathological factor of UC based on the theory of TCM, on the one hand, the main pathogenesis of recurrent bloody purulent stool is that the blood stasis caused by dampness-heat, and then blood stasis-heat impairs collaterals [48], thus the symptom of abdominal pain due to the blockage of blood vesselson. On the other hand, while intestinal mucosa steeped by dampness-heat, then the colon mucosa appears hyperemia and edema, and subsequently, after a long period of time, the rottenness of blood and muscle could result in ulcer or erosion on the colon mucosa [49].

Another physician who was also listed as one of the "Four Great Masters of Jin and Yuan Dynasties" named Li Dongyuan, he used Ermiaosan as the main prescription to treat diarrhea caused by dampness-heat, the good curative effect provides a reference for the treatment of diarrhea in later generations [50]. The flexible application of traditional Chinese medicine in the dialectic-al treatment of UC has gained well clinical effects [51].

In the prescription of Ermiaosan, Cang Zhu could invigorate Spleen and eliminate dampness, then the dampness can't be generated without source(in TCM, the dampness comes from the dysfunction of spleen in transportation), and the heat can not be attached as the dampness is removed. As for Huang Bo, with its cold and bitter nature, it can restrain the warm and dry nature of Cang Zhu. When these two medicines are used together, one is warm and the other is cold, the combination use of them can clear away dampness, remove heat and thus dispel all symptoms [52].

Recent studies have found out that while Cang Zhu or Huang Bo used alone, there is no strong efficacy, but only when they are used together can the maximum pharmacodynamics be achieved, some components of the two medicinal materials interact with each other to make the effect more predominant [53].

Network pharmacology and molecular docking methods were useful tools that used to explore the possible pharmacological mechanisms of Ermiaosan against UC in our study, which showed that 46 compounds and 408 target genes were related to UC. The results of GO and KEGG pathway enrichment analyses indicates that the effects of Ermiaosan against UC may be due to the active compounds of Ermiaosan, especially for dihydroniloticin, quercetin and beta-sitosterol 3-O-glucoside_qt which could influence the regulation of the PI3K–Akt, TNF and HIF-1 signaling pathway. They may also be related to protein phosphorylation, positive regulation of cell proliferation, positive regulation of angiogenesis, inflammatory response, vascular endothelial growth factor receptor signaling pathway, positive regulation of gene expression, negative regulation of apoptotic process and so on. According to the results of PPI analysis and Cytoscape Hub, AKT1, TNF, IL6, TP53, VEGFA, IL1B and CTNNB1 were selected as key targets, and they reflect a strong affinity with dihydroniloticin, quercetin and beta-sitosterol 3-O-glucoside_qt as the results of the molecular docking method.

The previous study shows IL-1β,VEGF, tumor necrosis factor-αand IL-6 are expressed at higher levels in the patients with UC [54, 55]. Modern medical research verified that Ermiaosan can inhibit the expression of inflammatory factors and regulate immunity [56], And has an impact on the gastrointestinal tract [57]. And currently, animal experiment study indicates that quercetinin could play a prophylactic effect in terms of disease activity and bowel length in UC model of mice [58]. Scholars in recent years had proved that Ermiaosan can inhibit IL-1β, IL6, IL8, TNF- α, VEGF and other inflammatory factors, thus it can reduce the occurrence and development of inflammation, and promote neovascularization [59,60,61,62,63].

When ulcerative colitis occurs, more inflammatory mediators are involved in the lesion, and during the active phase of the inflammatory lesion, the expression of active inflammatory factors is more pronounced. The increased expression of VEGF in lesions can directly stimulate the division and proliferation of vascular endothelial cells, increase the gap between endothelial cells, increase vascular permeability, and exude fibrinogen, which can provide support for vascular structures and promote angiogenesis [64],

There are literature studies reporting that angiogenesis plays an important role in its pathological mechanism and mucosal repair. VEGF is currently considered the strongest and most specific proangiogenic factor, which can promote tissue repair and induce capillary regeneration [65]. And the viewpoint of preventing blood from overflowing out of the veins and alleviating intestinal bleeding is coincidental with TCM.

PPI network analysis shows that AKT1, TNF, IL6, TP53, VEGFA, IL1B and CTNNB1 may be important targets of Ermiaosan in the treatment of ulcerative colitis, and combined with the results of GO enrichment analysis, these targets involve in protein phosphorylation, positive regulation of cell proliferation, positive regulation of angiogenesis, inflammatory response, vascular endothelial growth factor receptor signaling pathway, positive regulation of gene expression, negative regulation of apoptotic process.

It explains that the blood entering components of Ermiaosan can alleviate the progression of UC by regulating AKT1, TNF, IL6, TP53, VEGFA, IL1B, CTNNB1 and other target proteins mainly related to positive regulation of cell proliferation, positive regulation of angiogenesis, inflammatory response, vascular endothelial growth factor receptor signaling pathway, positive regulation of gene expression to reduce inflammation, regulate immunity, promote cell regeneration and angiogenesis and other processes. And this process coincides with the view of traditional Chinese medicine to eliminate dampness-heat, then fundamentally prevent it from hurting collaterals, and promote muscle production to stop bleeding, promote the dissipation of pathological products, and prevent blood from overflowing the collaterals, thus accelerating intestinal healing.

KEGG pathway analysis shows that Ermiaosan plays therapeutic role in treating UC may be related to the regulation on PI3K–Akt, TNF and HIF-1 signaling pathways. It has been reported that PI3K/AKT/mTOR signaling pathway plays a significant role in the regulation of cell activation and inflammatory response [66], and some scientific tests estabblished that the expression of IL-1β, IL-6 and TNF-α can be down-regulated by inhibiting PI3K–Akt signal pathway, thus, which can play a protective, anti-inflammatory and anti-apoptotic role in intestinal mucosa of UC rats [67]. And it can inhibit the secretion of the inflammatory factor TNF-α and IL-6 by regulating HIF-1related signal pathway, then to ameliorate the inflammatory reaction of UC [68]. Further more, in our previous research, we found out that in the pathogenesis of UC, the immune response mediated by TNF signal pathway is closely related to it, while inhibiting the expression of this pathway can effectively reduce the content of IL-1, IL-6 and so on [69].

The above results indicate that Ermiaosan may regulate PI3K–Akt, TNF and HIF-1 signaling pathways by acting on key targets such as AKT1, TNF, IL6, TP53, VEGFA, IL1B and CTNNB1 can inhibit inflammation, regulate immunity, positive regulation of cell proliferation, positive regulation of angiogenesis improve mucosal barrier and etc., so as to exert therapeutic effect in UC with dampness-heat syndrome based on active compounds of dihydroniloticin, quercetin and beta-sitosterol 3-O-glucoside_qt, and they reflect a strong affinity with each other.

5 Conclusions

In conclusion, the results of our study show that Ermiaosan may play therapeutic role in treating UC with dampness-heat syndrome based on active compounds of dihydroniloticin, quercetin and beta-sitosterol 3-O-glucoside_qt, and they mainly acting on seven targets AKT1, TNF, IL6, TP53, VEGFA, IL1B and CTNNB1 may be related to the regulation on PI3K–Akt, TNF and HIF-1 signaling pathways.