Hindawi Evidence-Based Complementary and Alternative Medicine Volume 2021, Article ID 4341517, 12 pages https://doi.org/10.1155/2021/4341517
Research Article Network Pharmacology-Based Analysis of the Effects of Corydalis decumbens (Thunb.) Pers. in Non-Small Cell Lung Cancer
Jun Liu ,1 Zhibo He,2 Shan Li,1 Wenan Huang,1 and Zhongjie Ren1
1Medical School, Jiujiang University, Jiujiang 332005, China 2School of Literature and Communication, Jiujiang University, Jiujiang 332005, China
Correspondence should be addressed to Jun Liu; [email protected]
Received 3 May 2021; Revised 17 June 2021; Accepted 6 July 2021; Published 30 August 2021
Academic Editor: Jing Zhao
Copyright © 2021 Jun Liu et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Non-small cell lung cancer (NSCLC) is one of the most malignant tumors worldwide. *e main treatment for NSCLC is based on Western medicine; however, the overall effect is unsatisfactory. *is study aimed to investigate the potential therapeutic targets and pharmacological mechanisms of action of the traditional Chinese medicine Corydalis decumbens (*unb.) Pers. in NSCLC based on network pharmacology and bioinformatics. *e overlapping genes between Corydalis decumbens (*unb.) Pers. and NSCLCs were screened using Venn analysis. Cytoscape 3.7.1 software was used to analyze the overlapping target protein-protein interaction (PPI) network. Gene ontology and pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Ge- nomics database were performed to exploring biological functions of the overlapping genes. *e gene expression profiling interactive analysis dataset was used to analyze the correlation between hub gene expression and disease. *is study revealed 38 nodes with 191 edges, which may be therapeutic targets for NSCLC. PPI network analysis showed that the most likely association was between the genes AR and NCOA2, NCOA2, and RXRA and ESR1 and NCOA2. *ese overlapping genes were mainly enriched in the estrogen signaling pathway, calcium signaling pathway, cholinergic synapse, and PI3K-Akt signaling pathway. ESR2 mRNA levels were significantly downregulated in patients with lung adenocarcinoma (LUAD) getting worse, and KDR levels were lower in lung squamous cell carcinoma (LUSC) than those in normal tissue. PTGS2 expression was correlated with the median survival time of LUAD, and ESR1 expression was correlated with the median survival time of LUSC. *e application of network pharmacology revealed the potential mechanism underlying the effects of Corydalis decumbens (*unb.) Pers. in NSCLC treatment and provided a theoretical basis for further in-depth research in this field.
1. Introduction adverse reactions, easy recurrence and metastasis, poor prognosis, and high costs [4]. *us, actively exploring safe Lung cancer is one of the most malignant tumors with high and effective treatment methods is necessary to prevent and morbidity and mortality rates worldwide. It is divided into treat lung cancer [5]. non-small cell lung cancer (NSCLC) and small cell lung Traditional Chinese medicine (TCM) has a history of cancer (SCLC) based on its different morphological char- more than 2000 years in China and mainly includes bo- acteristics. NSCLC accounts for 80% of all lung cancer cases tanical, animal, and mineral medicines. It has been widely and mainly includes lung adenocarcinoma (LUAD), lung used to prevent and treat diseases, particularly in Asia [6, 7]. squamous cell carcinoma (LUSC), and large cell lung cancer Studies have shown that Chinese herbal medicines can di- [1]. Recent research showed that the main treatment for rectly inhibit malignant tumor growth and proliferation [6]. NSCLC is based on Western medicine, including surgery, For example, botanical ingredients such as alkaloids, dietary chemotherapy, radiotherapy, targeted therapy, and immu- polyphenols, and saponins are the main inhibitors of lung notherapy [2, 3]. However, the treatment for this disease is cancer [8–10]. Corydalis decumbens (*unb.) Pers. is bo- often accompanied by unsatisfactory outcomes, such as tanical medicine that is rich in alkaloids and has mainly 2 Evidence-Based Complementary and Alternative Medicine focused on treating cardiovascular and cerebrovascular 2.5. Functional Enrichment Analysis. *e Database for diseases, arthritis, and myopia [11–13]; however, its use has Annotation, Visualization and Integrated Discovery (DA- been scarce in tumors. *e current study, using network VID, https://david.ncifcrf.gov) was used for functional en- pharmacology and bioinformatics, aimed to address the richment analysis of potential genes. “Homo sapiens” was following questions: does Corydalis decumbens (*unb.) selected as the species and “OFFICIAL GENE SYMBOL” Pers. play role in treating NSCLC? Which ingredients of was used for identification. Gene ontology (GO) functions Corydalis decumbens (*unb.) Pers. have an anti-NSCLC and the Kyoto Encyclopedia of Genes and Genomics effect? What is the molecular mechanism underlying the (KEGG) pathway enrichment analysis in the DAVID online effect of Corydalis decumbens (*unb.) Pers. in NSCLC tool were performed for exploring the biological function of treatment? the genes used in the treatment of NSCLC; P < 0.05 was considered as the cutoff criterion. In particular, GO func- tions include biological process (BP), molecular function 2. Materials and Methods (MF), and cellular component (CC). P < 0.01 was used as the 2.1. Ingredients of Corydalis decumbens (/unb.) Pers. We cutoff criterion. searched the active ingredients of Corydalis decumbens (*unb.) Pers. using the Traditional Chinese Medicine 2.6. Correlation Analysis of Hub Gene Expression and Disease. Systems Pharmacology Database and Analysis Platform *e top 10 hub genes in the PPI network were verified using (TCMSP, http://tcmspw.Com/tcmsp.php). *e Chinese the Cytoscape 3.7.1 plugin cytoHubba. *e gene expression pinyin name “xiatianwu” was entered in the “herb name” profiling interactive analysis dataset (GEPIA, http://gepia. column. *e filter conditions were oral bioavailability cancer-pku.cn/) was used to analyze the expression of hub (OB) ≥ 30% and drug similarity (DL) ≥ 0.18. genes, such as the differential expression analysis between NSCLC tissues and normal tissues, differential expression analysis according to pathological stages of cancer, and the 2.2. Drug Ingredient Target Network Construction. *e expression analysis associated with overall survival (OS) of corresponding targets of the active ingredients were ob- the NSCLC patients (P < 0.05). “MCC” was used as the tained from TCMSP, SymMap (https://www.symmap.org/), calculate mode, and the “display the shortest path” as the and the Encyclopedia of Traditional Chinese Medicine displayed options, LUAD and LUSC, were selected as the (ETCM, http://www.tcmip.cn/ETCM/index.php/Home/ cancer type dataset. Log2 FC cutoff � 2, q value cutoff � 0.05, Index/index.html). *e reviewed human database from and the other options were set as the default values. UniPort (http://www.Uniport.org/) was used to translate target names to gene names. Cytoscape 3.7.1 software was used to construct the drug ingredients target network. 3. Results 3.1. Potential Target Genes of Corydalis decumbens (/unb.) Pers. A total of 6 ingredients and 67 targets of Corydalis 2.3. Potential Target Genes of Corydalis decumbens (/unb.) decumbens (*unb.) Pers. were screened (Table 1, Figure 1, Pers. against Lung Cancer. We used online tools such as Table S1). A total of 3475 NSCLC target genes were obtained GeneCards (https://www.Genecards.org) to identify the from the GeneCards database. After the comparative symbols of genes reported in NSCLC using keyword analysis, the overlapping genes, which might be potential “NSCLC.” UniProt online databases were used to translate therapeutic targets for NSCLC, were also obtained. *e symbol names to gene names. *e overlapping genes of Venn diagram showed that 32 overlapping genes of Co- Corydalis decumbens (*unb.) Pers. and NSCLC were rydalis decumbens (*unb.) Pers. participated in the regu- identified by drawing a Venn diagram. *e overlapping lation of NSCLC progression (Figure 2, Table S2). *e genes were considered as potential Corydalis decumbens generated visual PPI network of potential therapeutic targets (*unb.) Pers. genes playing a role in treating NSCLC. for Corydalis decumbens (*unb.) Pers. contained 38 nodes Cytoscape 3.7.1 software was used to construct the ingre- and 191 edges (Figure 3). dients-potential target network.
3.2. PPI Network Analysis. Based on the potential phar- 2.4. Construction of the Overlapping Target Protein-Protein macodynamics of Corydalis decumbens (*unb.) Pers. Interaction (PPI) Network. *e STRING database (http:// against NSCLC, the interacting proteins were screened using www.string-db.org/) and Cytoscape 3.7.1 software were used the STRING online tool. We found 31 nodes (PRSS1 did not to elucidate the molecular mechanism underlying the anti- interact with any of the genes) with 90 PPI relationships in NSCLC effect of Corydalis decumbens (*unb.) Pers. the network (Figure 4(a)). *e PPI network was constructed According to the STRING database with the species limited using Cytoscape 3.7.1 software for further visualization and to “Homo sapiens” and a confidence score >0.4, the inter- analysis (Figure 4(b)). *e results showed 15 genes whose action proteins were screened. *e PPI network was con- degree was greater than or equal to 5.8 (average score) structed using Cytoscape 3.7.1 for further visualization and (Table S3) and 40 edges whose combined score was greater analysis (PPI node degree, node interaction scores, and hub than or equal to 0.69 (average score) (Table S4). We found genes). possible PPIs between Corydalis decumbens (*unb.) Pers. Evidence-Based Complementary and Alternative Medicine 3
Table 1: Information of Corydalis decumbens (*unb.) Pers. ingredients. Mol. ID Name OB (100%) DL MOL000781 PDSP1_000624 33.45 0.69 MOL000785 Palmatine 64.6 0.65 MOL000787 Fumarine 59.26 0.83 MOL000790 Isocorypalmine 35.77 0.59 MOL000791 Bicuculline 69.67 0.88 MOL000793 C09367 47.54 0.69
Figure 1: *e ingredient-target network in the current study. *e yellow diamond represents targets, and the purple rectangle represents the ingredients of Corydalis decumbens (*unb.) Pers. *e line between the two nodes represents the interaction. and NSCLC-associated targets. *e most likely association ESR1 (interacts with) NCOA2, CALM1 (interacts with) was between AR and NCOA2 (score � 0.999). *e remaining NOS2, CALM1 (interacts with) NOS3, ESR1 (interacts with) interactions were as follows: NCOA2 (interacts with) RXRA, NOS3. 4 Evidence-Based Complementary and Alternative Medicine
Drug NSCLC
35 32 3443 (1%) (0.9%) (98.1%)
Figure 2: *e overlapping genes in the Venn diagram.
Figure 3: *e ingredient-potential target network. *e green rectangle represents the ingredients of Corydalis decumbens (*unb.) Pers., and the red diamond represents the overlapping targets; the line between two nodes represents the interaction.
3.3. Functional Enrichment Analysis of Corydalis decumbens Figure 5. For biological processes, potential therapeutic (/unb.) Pers. Potential targets of Corydalis decumbens targets of Corydalis decumbens (*unb.) Pers. were signif- (*unb.) Pers. were used for further GO function and icantly enriched in “adenylate cyclase-inhibiting G-protein pathway enrichment analyses using the DAVID online tool. coupled acetylcholine receptor signaling pathway” and *e results showed that the genes could be assigned to “phospholipase C-activating G-protein coupled acetylcho- different GO terms, which mainly involved biological pro- line receptor signaling pathway.” For cell components, cesses (BP) (90 items), cell components (CC) (27 items), and “axon terminus” and “asymmetric synapse” were mainly molecular functions (MF) (41 items). *e cutoff for statis- enriched. In addition, “RNA polymerase II transcription tical significance was set P < 0.01, and the top 20 items with factor activity,” ligand-activated sequence-specific DNA significant enrichment in biological processes, cell compo- binding,” “steroid hormone receptor activity”, and “G- nents, and molecular functions were screened, as shown in protein coupled acetylcholine receptor activity” belonged to Evidence-Based Complementary and Alternative Medicine 5
SLC6A3
ACHE
OPRM1 CHRM2
PTGS1 ADRB2 GJB1 CHRM1
PTGS2 GJA1 CALM1 CHRM3 FOS NOS3 NOS2 GNRH1
PTPN1 KDR
ESR2 RXRA PRKACA ESR1 CDK2 NCOA2 PDE3A RXRB
AR PRSS1 BMPR2
VCP
PIM1
CA2
(a) (b)
Figure 4: *e protein-protein interaction network of overlapping genes. (a) Result from the STRING online tool. (b) Result from Cytoscape 3.7.1 software. *e darker the color is, the greater the degree is.
0.00200
0.00175
0.00150
0.00125
0.00100 P value
0.00075
0.00050
0.00025
0.00000
Nucleus
Drug binding
Axon terminus
Steroid binding Steroid
Enzyme binding
Cell-cell signaling
Plasma membrane
Asymmetric synapse
receptor signalingreceptor pathway signalingreceptor pathway
Transcription factor binding Transcription
Nervous system development
sequence-specifc binding DNA
Steroid hormone receptor activity hormone receptor Steroid
Positive regulation of vasodilation of regulation Positive
Intergal component of the of plasma component membraneIntergal
G protein-coupled acetylcholine activityG protein-coupled receptor
Transcription initiation from RNA polymerase initiation from RNA II promoter Transcription
Phospholipase C-activating acetylcholine G protein-coupled
G protein-coupled acetylcholine signallingG protein-coupled receptor pathway
Adenylate cyclase-inhibiting Adenylate acetylcholine G protein-coupled
RNA polymerase II transcription factor activity, ligand-activated polymeraseRNA II transcription factor activity,
Positive regulation of transcription from RNA polymerase transcription RNA from of regulation II promoter Positive
BP CC MF Figure 5: Gene Ontology analysis of potential target genes of Corydalis decumbens (*unb.) Pers. against non-small cell lung cancer. 6 Evidence-Based Complementary and Alternative Medicine
Pathways in cancer Calcium signaling pathway Estrogen signaling pathway cAMP signaling pathway PI3K-Akt signaling pathway Count Neuroactive ligand-receptor interaction 3 Cholinergic synapse 4 yroid hormone signaling pathway 5 Small cell lung cancer 6 Oxytocin signaling pathway 7 Salivary secretion 8 Renin secretion Regulation of lipolysis in adipocytes –Log10 (p value) Oocyte meiosis Gastric acid secretion 5 Dopaminergic synapse 4 cGMP-PKG signaling pathway 3 Amphetamine addiction 2 VEGF signaling pathway Prolactin signaling pathway Pertussis Leishmaniasis Bile secretion
10 15 20 25 Gene ratio Figure 6: Pathway enrichment analysis of potential target genes of Corydalis decumbens (*unb.) Pers. against non-small cell lung cancer using the Kyoto Encyclopedia of Genes and Genomics. molecular functions. Additionally, the KEGG pathway en- richment analysis (P < 0.01) showed that these overlapping AR GJA1 FOS genes were mainly enriched in pathways such as the estrogen signaling pathway, calcium signaling pathway, cholinergic synapse, cAMP signaling pathway, PI3K-Akt signaling CALM1 ESR1 PTGS2 pathway, and VEGF signaling pathway (Figure 6).
3.4. Hub Genes Analysis. *e hub genes of Corydalis KDR ESR2 PRKACA decumbens (*unb.) Pers. for treating NSCLC were selected based on the Cytoscape 3.7.1 plugin cytoHubba (Figure 7). Potential therapeutic targets of Corydalis decumbens NOS3 (*unb.) Pers. included CALM1, AR, ESR1, ESR2, FOS, GJA1, KDR, NOS3, OPRM1, and PRKACA. Using the Figure 7: Top 10 hub genes of the potential target genes of Co- GEPIA dataset, we compared the mRNA expression of hub rydalis decumbens (*unb.) Pers. against non-small cell lung genes among NSCLC (LUAD and LUSC) at different stages. cancer. *e darker the color is, the greater the degree is. *e results showed that not all of the ESR2 mRNA ex- pression levels were the same in different stage LUAD of median survival time of the group with a high expression of patients (P < 0.05) (Figure 8). Additionally, we compared the PTGS2 mRNA in LUAD was lower than that of the group transcriptional levels of hub genes between NSCLC and with low expression of PTGS2 (Figure 10(a)). *e group with normal samples using the GEPIA dataset. *e results in- high expression of ESR1 in LUSC had a lower median dicated that the expression levels of KDR were lower in survival time than the group with low expression of ESR1 LUSC than in normal tissue (Figure 9). We further explored (Figure 10(b)). the critical efficiency of hub genes in the survival of patients with NSCLC. GEPIA “Survival analysis” tools were used to analyze the correlation of hub genes’ mRNA levels in the 4. Discussion survival of patients with NSCLC (LUAD and LUSC). *e Kaplan–Meier curve and log-rank test analyses revealed that Lung cancer is one of the most malignant cancers world- the expression of PTGS2 was correlated with the median wide, and the effect of clinical treatment for this disease is survival time of LUAD and the expression of ESR1 was not satisfactory [4]; therefore, this study explored the po- correlated with the median survival time of LUSC. *e tential therapeutic effects of Corydalis decumbens (*unb.) Evidence-Based Complementary and Alternative Medicine 7
12 F value = 0.823 7 F value = 0.325 F value = 0.34 F value = 6.93 5 Pr (>F) = 0.482 Pr (>F) = 0.807 Pr (>F) = 0.796 Pr (>F) = 0.000143 11 6 2.0 4 5 10 1.5 3 4 9 3 1.0 2 8 2 1 0.5 7 1
6 0 0 0.0
Stage I Stage II Stage III Stage IV Stage I Stage II Stage III Stage IV Stage I Stage II Stage III Stage IV Stage I Stage II Stage III Stage IV
CALM1 AR ESR1 ESR2
12 F value = 1.81 F value = 1.95 F value = 0.252 F value = 0.138 Pr (>F) = 0.144 Pr (>F) = 0.121 8 Pr (>F) = 0.86 10 Pr (>F) = 0.937 10 8 8 6 8 6 6 4 6 4 4
2 4 2 2
Stage I Stage II Stage III Stage IV Stage I Stage II Stage III Stage IV Stage I Stage II Stage III Stage IV Stage I Stage II Stage III Stage IV
FOS GJA1 KDR NOS3
7 F value = 0.281 10 F value = 1.39 Pr (>F) = 0.839 Pr (>F) = 0.246 8 6
6 5
4 4 2 3 0
Stage I Stage II Stage III Stage IV Stage I Stage II Stage III Stage IV
PRKACA PTGS2 (a)
4 12 F F value = 1.79 value = 1.06 F value = 0.21 3.0 F value = 0.581 Pr (>F) = 0.149 Pr (>F) = 0.366 3.0 Pr (>F) = 0.89 Pr (>F) = 0.628 2.5 3 2.5 10 2.0 2.0 2 1.5 8 1.5
1.0 1.0 1 6 0.5 0.5
0 0.0 0.0
Stage I Stage II Stage III Stage IV Stage I Stage II Stage III Stage IV Stage I Stage II Stage III Stage IV Stage I Stage II Stage III Stage IV
CALM1 AR ESR1 ESR2
12 F F F F value = 2.08 value = 2.5 6 value = 1.08 7 value = 1.61 Pr (>F) = 0.101 Pr (>F) = 0.059 Pr (>F) = 0.356 Pr (>F) = 0.187 10 10 5 6 5 8 4 8 4 3 6 6 3 2 2 4 4 1 1
Stage I Stage II Stage III Stage IV Stage I Stage II Stage III Stage IV Stage I Stage II Stage III Stage IV Stage I Stage II Stage III Stage IV
FOS GJA1 KDR NOS3
F F 8 value = 0.953 value = 1.07 Pr (>F) = 0.415 10 Pr (>F) = 0.362
7 8
6 6
5 4 4 2 3 0
Stage I Stage II Stage III Stage IV Stage I Stage II Stage III Stage IV
PRKACA PTGS2 (b)
Figure 8: Correlation analysis among hub genes expression and tumor stage in non-small cell lung cancer patients. (a) LUAD patients. (b) LUSC patients. 8 Evidence-Based Complementary and Alternative Medicine
12 5 3.5 6 10 2.5 4 5 8 2.0 (TPM + 1) (TPM + 1) (TPM + 1) (TPM + 1) 2 2 2 2 3 4 6 3 1.5 2 4 2 1.0 2 1 1 0.5 Expression–log Expression–log Expression–log Expression–log 0 0 0 0.0 LUAD LUSC LUAD LUSC LUAD LUSC LUAD LUSC (num(T) = 483; (num(T) = 486; (num(T) = 483; (num(T) = 486; (num(T) = 483; (num(T) = 486; (num(T) = 483; (num(T) = 486; num(N) = 347) num(N) = 338) num(N) = 347) num(N) = 338) num(N) = 347) num(N) = 338) num(N) = 347) num(N) = 338) CALM1 AR ESR1 ESR2 8 12 10 10 10 8 6 8 (TPM + 1) (TPM + 1) 8 (TPM + 1) (TPM + 1) 2 2 6 2 2 6 6 4 4 4 4 2 2 2 2 0 0 0 0 Expression–log Expression–log Expression–log Expression–log LUAD LUSC LUAD LUSC LUAD LUSC LUAD LUSC (num(T) = 483; (num(T) = 486; (num(T) = 483; (num(T) = 486; (num(T) = 483; (num(T) = 486; (num(T) = 483; (num(T) = 486; num(N) = 347) num(N) = 338) num(N) = 347) num(N) = 338) num(N) = 347) num(N) = 338) num(N) = 347) num(N) = 338) FOS GJA1 KDR NOS3
8 10
6 8 (TPM + 1) (TPM + 1) 2 2 6 4 4 2 2 Expression–log Expression–log 0 0 LUAD LUSC LUAD LUSC (num(T) = 483; (num(T) = 486; (num(T) = 483; (num(T) = 486; num(N) = 347) num(N) = 338) num(N) = 347) num(N) = 338) PRKACA PTGS2 Figure 9: *e expression of hub genes in non-small cell lung cancer. “T” indicates tumor tissue, and “N” indicates normal tissue.
Pers. against NSCLC based on network pharmacology the occurrence and metastasis of NSCLC. Shi et al. [18] analysis and bioinformatics. Network pharmacology is an found that, in nonsmoking female patients with lung ade- interdisciplinary subject that combines systems biology and nocarcinoma, Ca2+ is an important small-molecule signal pharmacology using high-throughput sequencing, geno- that regulates cell function. *e high expression of the Ca2+ mics, and other technologies to analyze and explore the pathway transcription factor NFATc2 is considered to be a multichannel regulation of signaling pathways [14]. In this new regulator for lung cancer to initiate cell phenotype, and study, we predicted a potential PPI network between NSCLC high NFATc2 expression predicted poor tumor differenti- and Corydalis decumbens (*unb.) Pers. based on network ation, adverse recurrence-free, and cancer-specific overall pharmacology analysis. *e results showed that the main survivals in human lung cancers [19]. *e increase in Ca2+ ingredients of Corydalis decumbens (*unb.) Pers. were concentration in the cytoplasm of cancer cells can also PDSP1_000624, palmatine, fumarine, isocorypalmine, induce apoptosis [20]. Increasing evidence suggests that the bicuculline, and C09367. Studies have shown that alkaloids estrogen signaling pathway may be a therapeutic target for exhibit good antitumor activity. Bicuculline can effectively metastatic NSCLC [21]. Babita et al. [22] indicated that, in a inhibit the migration and invasion of human hepatocellular preclinical model of NSCLC, estrogen promoted the growth carcinoma MHCC97-H cells which is related to the of NSCLC and increased tumor microvessel density. In the downregulation of VEGF, MMP-2, and MMP-9 gene ex- estrogen signaling pathway, estrogen and estrogen receptors pression and inhibition of JAK2/STAT3 signaling pathway are thought to play an important role in NSCLC [23]. activation [15]. Fumarine exerts antiproliferative effects by Hormone receptors are prognostic factors indicating met- stimulating the p53 pathway in human colon cancer [16], astatic tropism to the bones and comparably outcome in and the apoptotic rate of HT-29 cells increased significantly NSCLC early stage [24]. *e PI3K-AKT signaling pathway after photodynamic treatment with palmatine [17]. plays a major role whole in the occurrence and development A total of 32 overlapping genes were identified between of NSCLC [25, 26]. *erefore, it is speculated that the po- the drug targets and NSCLC molecular targets. GO and tentially effective ingredients of Corydalis decumbens KEGG analyses showed that they were mainly assigned to (*unb.) Pers. mainly act on the key factors in the above different GO terms and pathways. For example, transcrip- pathways to effectively treat NSCLC. tion factor binding, protein binding, drug binding, estrogen Furthermore, we analyzed the top 10 potential thera- signaling pathway, and calcium signaling pathway promote peutic targets of Corydalis decumbens (*unb.) Pers.: Evidence-Based Complementary and Alternative Medicine 9
Overall survival Overall survival Overall survival
1.0 Logrank p = 0.24 1.0 Logrank p = 0.77 1.0 Logrank p = 0.94 HR(high) = 1.2 HR(high) = 1 HR(high) = 1 p(HR) = 0.24 p(HR) = 0.77 p(HR) = 0.94 0.8 n(high) = 239 0.8 n(high) = 239 0.8 n(high) = 239 n(low) = 239 n(low) = 238 n(low) = 236 0.6 0.6 0.6
0.4 0.4 0.4 Percent survival Percent survival Percent survival Percent 0.2 0.2 0.2
0.0 0.0 0.0
0 50 100 150 200 250 0 50 100 150 200 250 0 50 100 150 200 250 Months Months Months
Low CALM1 group Low AR group Low ESR1 group High CALM1 group High AR group High ESR1 group
Overall survival Overall survival Overall survival
1.0 Logrank p = 0.063 1.0 Logrank p = 0.1 1.0 Logrank p = 0.59 HR(high) = 0.76 HR(high) = 0.78 HR(high) = 0.92 p(HR) = 0.065 p(HR) = 0.1 p(HR) = 0.59 0.8 n(high) = 239 0.8 n(high) = 239 0.8 n(high) = 239 n(low) = 238 n(low) = 239 n(low) = 239 0.6 0.6 0.6
0.4 0.4 0.4 Percent survival Percent survival Percent survival Percent 0.2 0.2 0.2
0.0 0.0 0.0
0 50 100 150 200 250 0 50 100 150 200 250 0 50 100 150 200 250 Months Months Months
Low ESR2 group Low FOS group Low NOS3 group High ESR2 group High FOS group High NOS3 group
Overall survival Overall survival Overall survival
1.0 Logrank p = 0.54 1.0 Logrank p = 0.24 1.0 Logrank p = 0.029 HR(high) = 0.91 HR(high) = 1.2 HR(high) = 1.4 p(HR) = 0.54 p(HR) = 0.24 p(HR) = 0.03 0.8 n(high) = 239 0.8 n(high) = 239 0.8 n(high) = 239 n(low) = 239 n(low) = 239 n(low) = 239 0.6 0.6 0.6
0.4 0.4 0.4 Percent survival Percent survival Percent survival Percent 0.2 0.2 0.2
0.0 0.0 0.0
0 50 100 150 200 250 0 50 100 150 200 250 0 50 100 150 200 250 Months Months Months
Low PRKACA group Low NCOA2 group Low PTGS2 group High PRKACA group High NCOA2 group High PTGS2 group (a) Figure 10: Continued. 10 Evidence-Based Complementary and Alternative Medicine
Overall survival Overall survival Overall survival
1.0 Logrank p = 0.72 1.0 Logrank p = 0.21 1.0 Logrank p = 0.007 HR(high) = 0.95 HR(high) = 1.2 HR(high) = 1.5 p(HR) = 0.72 p(HR) = 0.21 p(HR) = 0.0072 0.8 n(high) = 241 0.8 n(high) = 240 0.8 n(high) = 241 n(low) = 241 n(low) = 236 n(low) = 238 0.6 0.6 0.6
0.4 0.4 0.4 Percent survival Percent survival Percent survival Percent 0.2 0.2 0.2
0.0 0.0 0.0
0 50 100 150 0 50 100 150 0 50 100 150 Months Months Months
Low CALM1 group Low AR group Low ESR1 group High CALM1 group High AR group High ESR1 group
Overall survival Overall survival Overall survival
1.0 Logrank p = 0.76 1.0 Logrank p = 0.34 1.0 Logrank p = 0.29 HR(high) = 0.96 HR(high) = 1.1 HR(high) = 1.2 p(HR) = 0.75 p(HR) = 0.34 p(HR) = 0.29 0.8 n(high) = 234 0.8 n(high) = 241 0.8 n(high) = 241 n(low) = 237 n(low) = 241 n(low) = 241 0.6 0.6 0.6
0.4 0.4 0.4 Percent survival Percent survival Percent survival Percent 0.2 0.2 0.2
0.0 0.0 0.0
0 50 100 150 0 50 100 150 0 50 100 150 Months Months Months
Low ESR2 group Low FOS group Low NOS3 group High ESR2 group High FOS group High NOS3 group
Overall survival Overall survival Overall survival
1.0 Logrank p = 0.76 1.0 Logrank p = 0.62 1.0 Logrank p = 0.97 HR(high) = 1 HR(high) = 1.1 HR(high) = 0.99 p(HR) = 0.76 p(HR) = 0.62 p(HR) = 0.97 0.8 n(high) = 241 0.8 n(high) = 241 0.8 n(high) = 241 n(low) = 241 n(low) = 241 n(low) = 241 0.6 0.6 0.6
0.4 0.4 0.4 Percent survival Percent survival Percent survival Percent 0.2 0.2 0.2
0.0 0.0 0.0
0 50 100 150 0 50 100 150 0 50 100 150 Months Months Months
Low PRKACA group Low NCOA2 group Low PTGS2 group High PRKACA group High NCOA2 group High PTGS2 group (b)
Figure 10: *e prognostic value of mRNA of the hub factors in non-small cell lung cancer patients. (a) LUAD patients. (b) LUSC patients. *e hub genes were CALM1, AR, ESR1, ESR2, FOS, NOS3, PRKACA,NCOA2, and PTGS2.
CALM1, AR, ESR1, ESR2, FOS, GJA1, KDR, NOS3, Studies have found that vascular epidermal growth factor OPRM1, and PRKACA. *e PPI network showed that the receptor 2 (VEGFR-2) plays a key role in the occurrence and most likely association was between AR and NCOA2; development of tumors including NSCLC [31–33]. VEGFR- NCOA2 and RXRA, ESR1 and NCOA2, FOS and ESR2, 2 is also known as the KDR in the human body. Several ESR2 and NCOA2, and FOS and ESR2. In tumor models, the studies have shown that the estrogen receptor beta (ESR2) adrenaline signaling pathway plays a regulatory role in tu- appeared in many tumors, including lung cancer, wherein mor growth and development. Moreover, the activation of ESR2 and interleukin 6 receptor (IL-6R) interacts to mediate β-adrenergic receptors promotes tumor progression and lung cancer progression. Cell proliferation, invasion, and cell development of resistance to treatment [27, 28]. Fos/Jun- cycle were significantly increased, and cell apoptosis was dependent signal transduction pathways are thought to be markedly inhibited by the concurrent action of ESR2 and IL- major effects of oncogene action in NSCLC [29]; moreover, 6 in A549 cells [34]. Chen et al. [35] showed that phos- exosome-derived miR-224-5p induced NSCLC cell prolif- phorylated ESR1 could directly bind to the promoter of eration and metastasis by directly suppressing AR [30]. FOSL1 (FOS-like 1) in ESCs/DSCs. Moreover, silencing of Evidence-Based Complementary and Alternative Medicine 11
ESR1 expression indirectly abrogated FOSL1 expression at [4] J. Zheng, T. Xu, F. Chen, and Y. Zhang, “Correction to: the transcript and protein levels. MiRNA-195-5p functions as a tumor suppressor and a pre- dictive of poor prognosis in non-small cell lung cancer by directly targeting CIAPIN1,” Pathology Oncology Research: 5. Conclusions POR, vol. 26, no. 3, p. 2015, 2020. *is study is used the network pharmacology analysis to [5] L.-Q. Wan, Y. Tan, M. Jiang, and Q. Hua, “*e prognostic impact of traditional Chinese medicine monomers on tumor- understand the mechanism of action of Corydalis decumbens associated macrophages in non-small cell lung cancer,” (*unb.) Pers. and preliminarily verified the effects of Co- Chinese Journal of Natural Medicines, vol. 17, no. 10, rydalis decumbens (*unb.) Pers. in multicomponent, pp. 729–737, 2019. multitarget, and multichannel treatment of lung cancer. *e [6] F. Qi, L. Zhao, A. 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