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Current Drug Targets

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ISSN (Print): 1389-4501
ISSN (Online): 1873-5592

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Research Article

Molecular Targets and Mechanisms of Hedyotis diffusa Willd. for Esophageal Adenocarcinoma Treatment Based on Network Pharmacology and Weighted Gene Co-expression Network Analysis

Author(s): Yu Zhuang, Yun-Gang Sun, Chen-Guang Wang, Qiang Zhang, Chao Che and Feng Shao*

Volume 25, Issue 6, 2024

Published on: 11 January, 2024

Page: [431 - 443] Pages: 13

DOI: 10.2174/0113894501265851240102101122

Price: $65

Abstract

Background: Hedyotis diffusa Willd. (HDW) is a common anticancer herbal medicine in China, and its therapeutic effectiveness has been demonstrated in a range of cancer patients. There is no consensus about the therapeutic targets and molecular mechanisms of HDW, which contains many active ingredients.

Aim: To clarify the mechanism of HDW for esophageal adenocarcinoma (EAC), we utilized network pharmacology and weighted gene co-expression network analysis methods (WGCNA).

Methods: The gene modules that were linked with the clinical features of EAC were obtained through the WGCNA method. Then, the potential target genes were retrieved through the network pharmacology method in order to determine the targets of the active components. After enrichment analysis, a variety of signaling pathways with significant ratios of target genes were found, including regulation of trans-synaptic signaling, neuroactive ligand-receptor interaction and modulation of chemical synaptic transmission. By means of protein-protein interaction (PPI) network analysis, we have successfully identified the hub genes, which were AR, CNR1, GRIK1, MAPK10, MAPT, PGR and PIK3R1.

Result: Our study employed molecular docking simulations to evaluate the binding affinity of the active components with the hub gene. The identified active anticancer constituents in HDW are scopoletol, quercetin, ferulic acid, coumarin, and trans-4-methoxycinnamyl alcohol.

Conclusion: Our findings shed light on the molecular underpinnings of HDW in the treatment of EAC and hold great promise for the identification of potential HDW compounds and biomarkers for EAC therapy.

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[1]
Uhlenhopp DJ, Then EO, Sunkara T, Gaduputi V. Epidemiology of esophageal cancer: update in global trends, etiology and risk factors. Clin J Gastroenterol 2020; 13(6): 1010-21.
[http://dx.doi.org/10.1007/s12328-020-01237-x] [PMID: 32965635]
[2]
Yang J, Liu X, Cao S, Dong X, Rao S, Cai K. Understanding esophageal cancer: The challenges and opportunities for the next decade. Front Oncol 2020; 10: 1727.
[http://dx.doi.org/10.3389/fonc.2020.01727] [PMID: 33014854]
[3]
Cao W, Chen HD, Yu YW, Li N, Chen WQ, Jing N. Changing profiles of cancer burden worldwide and in China: A secondary analysis of the global cancer statistics 2020. Chin Med J 2021; 134(7): 783-91.
[http://dx.doi.org/10.1097/CM9.0000000000001474] [PMID: 33734139]
[4]
Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021; 71(3): 209-49.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[5]
Zheng RS, Sun KX, Zhang SW, et al. [Report of cancer epidemiology in China, 2015]. Zhonghua Zhong Liu Za Zhi 2019; 41(1): 19-28.
[http://dx.doi.org/10.3760/cma.j.issn.0253-3766.2019.01.005] [PMID: 30678413]
[6]
Abnet CC, Arnold M, Wei WQ. Epidemiology of esophageal squamous cell carcinoma. Gastroenterology 2018; 154(2): 360-73.
[http://dx.doi.org/10.1053/j.gastro.2017.08.023] [PMID: 28823862]
[7]
Codipilly DC, Qin Y, Dawsey SM, et al. Screening for esophageal squamous cell carcinoma: recent advances. Gastrointest Endosc 2018; 88(3): 413-26.
[http://dx.doi.org/10.1016/j.gie.2018.04.2352] [PMID: 29709526]
[8]
Coleman HG, Xie SH, Lagergren J. The epidemiology of esophageal adenocarcinoma. Gastroenterology 2018; 154(2): 390-405.
[http://dx.doi.org/10.1053/j.gastro.2017.07.046] [PMID: 28780073]
[9]
Manabe N, Matsueda K, Haruma K. Epidemiological review of gastroesophageal junction adenocarcinoma in asian countries. Digestion 2022; 103(1): 29-36.
[http://dx.doi.org/10.1159/000519602] [PMID: 34718236]
[10]
Zhang HZ, Jin GF, Shen HB. Epidemiologic differences in esophageal cancer between Asian and Western populations. Chin J Cancer 2012; 31(6): 281-6.
[http://dx.doi.org/10.5732/cjc.011.10390] [PMID: 22507220]
[11]
McColl KEL. What is causing the rising incidence of esophageal adenocarcinoma in the West and will it also happen in the East? J Gastroenterol 2019; 54(8): 669-73.
[http://dx.doi.org/10.1007/s00535-019-01593-7] [PMID: 31172291]
[12]
Sun LP, Yan LB, Liu ZZ, et al. Dietary factors and risk of mortality among patients with esophageal cancer: A systematic review. BMC Cancer 2020; 20(1): 287.
[http://dx.doi.org/10.1186/s12885-020-06767-8] [PMID: 32252671]
[13]
Xue Y, Zhou X, Xue L, Zhou R, Luo J. The role of pretreatment prognostic nutritional index in esophageal cancer: A meta-analysis. J Cell Physiol 2019; 234(11): 19655-62.
[http://dx.doi.org/10.1002/jcp.28565] [PMID: 31344989]
[14]
Kouzu K, Tsujimoto H, Sugasawa H, et al. Modified geriatric nutrition risk index as a prognostic predictor of esophageal cancer. Esophagus 2021; 18(2): 278-87.
[http://dx.doi.org/10.1007/s10388-020-00795-w] [PMID: 33170460]
[15]
Tramontano AC, Sheehan DF, Yeh JM, et al. The impact of a prior diagnosis of barrett’s esophagus on esophageal adenocarcinoma survival. Am J Gastroenterol 2017; 112(8): 1256-64.
[http://dx.doi.org/10.1038/ajg.2017.82] [PMID: 28374815]
[16]
Lagergren J, Smyth E, Cunningham D, Lagergren P. Oesophageal cancer. Lancet 2017; 390(10110): 2383-96.
[http://dx.doi.org/10.1016/S0140-6736(17)31462-9] [PMID: 28648400]
[17]
Cao L, Wang X, Zhu G, et al. Traditional chinese medicine therapy for esophageal cancer: A literature review. Integr Cancer Ther 2021; 20
[http://dx.doi.org/10.1177/15347354211061720] [PMID: 34825600]
[18]
Guerra-Martín MD, Tejedor-Bueno MS, Correa-Casado M. Effectiveness of complementary therapies in cancer patients: A systematic review. Int J Environ Res Public Health 2021; 18(3): 1017.
[http://dx.doi.org/10.3390/ijerph18031017] [PMID: 33498883]
[19]
Liu L, Fan J, Ai G, et al. Berberine in combination with cisplatin induces necroptosis and apoptosis in ovarian cancer cells. Biol Res 2019; 52(1): 37.
[http://dx.doi.org/10.1186/s40659-019-0243-6] [PMID: 31319879]
[20]
Lin S, An X, Guo Y, et al. Meta-analysis of astragalus-containing traditional chinese medicine combined with chemotherapy for colorectal cancer: Efficacy and safety to tumor response. Front Oncol 2019; 9: 749.
[http://dx.doi.org/10.3389/fonc.2019.00749] [PMID: 31456940]
[21]
Wang J, Luo J, Yin X, et al. Jiedu granule combined with transcatheter arterial chemoembolization and gamma knife radiosurgery in treating hepatocellular carcinoma with portal vein tumor thrombus. BioMed Res Int 2019; 2019: 1-8.
[http://dx.doi.org/10.1155/2019/4696843] [PMID: 31341898]
[22]
Del-Toro-Sánchez CL, Rodríguez-Félix F, Cinco-Moroyoqui FJ, et al. Recovery of phytochemical from three safflower ( Carthamus tinctorius L.) by-products: Antioxidant properties, protective effect of human erythrocytes and profile by UPLC-DAD-MS. J Food Process Preserv 2021; 45(9): e15765.
[http://dx.doi.org/10.1111/jfpp.15765]
[23]
Chen R, He J, Tong X, Tang L, Liu M. The hedyotis diffusa willd. (Rubiaceae): A review on phytochemistry, pharmacology, quality control and pharmacokinetics. Molecules 2016; 21(6): 710.
[http://dx.doi.org/10.3390/molecules21060710] [PMID: 27248992]
[24]
Niu Y, Meng QX. Chemical and preclinical studies on Hedyotis diffusa with anticancer potential. J Asian Nat Prod Res 2013; 15(5): 550-65.
[http://dx.doi.org/10.1080/10286020.2013.781589] [PMID: 23600735]
[25]
Han X, Zhang X, Wang Q, Wang L, Yu S. Antitumor potential of Hedyotis diffusa Willd: A systematic review of bioactive constituents and underlying molecular mechanisms. Biomed Pharmacother 2020; 130: 110735.
[http://dx.doi.org/10.1016/j.biopha.2020.110735] [PMID: 34321173]
[26]
Zhang R, Ma C, Wei Y, et al. Isolation, purification, structural characteristics, pharmacological activities, and combined action of Hedyotis diffusa polysaccharides: A review. Int J Biol Macromol 2021; 183: 119-31.
[http://dx.doi.org/10.1016/j.ijbiomac.2021.04.139] [PMID: 33905802]
[27]
Lin L, Cheng K, Xie Z, et al. Purification and characterization a polysaccharide from Hedyotis diffusa and its apoptosis inducing activity toward human lung cancer cell line A549. Int J Biol Macromol 2019; 122: 64-71.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.10.077] [PMID: 30342944]
[28]
Huang L, Xu H, Wu T, Li G. Hedyotis diffusa Willd. Suppresses Hepatocellular Carcinoma via Downregulating AKT/mTOR Pathways. Evid Based Complement Alternat Med 2021; 2021: 1-9.
[http://dx.doi.org/10.1155/2021/5210152] [PMID: 34527062]
[29]
Shao J, Gong G, Trombetta L. An evidence-based perspective of hedyotis diffusa or oldenlandia diffusa (spreading hedyotis) for cancer patients. In: Cho WCS, Ed. Evid-Based Anticancer Mater Medica. Dordrecht: Springer 2011; pp. 179-92.
[http://dx.doi.org/10.1007/978-94-007-0526-5_9]
[30]
Sun G, Wei L, Feng J, Lin J, Peng J. Inhibitory effects of Hedyotis diffusa Willd. on colorectal cancer stem cells. Oncol Lett 2016; 11(6): 3875-81.
[http://dx.doi.org/10.3892/ol.2016.4431] [PMID: 27313710]
[31]
Yeh YC, Chen HY, Yang SH, et al. Hedyotis diffusa combined with scutellaria barbata are the core treatment of chinese herbal medicine used for breast cancer patients: A Population-based study. Evid Based Complement Alternat Med 2014; 2014: 1-9.
[http://dx.doi.org/10.1155/2014/202378] [PMID: 24734104]
[32]
Xu HY, Zhang YQ, Liu ZM, et al. ETCM: An encyclopaedia of traditional Chinese medicine. Nucleic Acids Res 2019; 47(D1): D976-82.
[http://dx.doi.org/10.1093/nar/gky987] [PMID: 30365030]
[33]
Li S, Zhang B. Traditional Chinese medicine network pharmacology: Theory, methodology and application. Chin J Nat Med 2013; 11(2): 110-20.
[http://dx.doi.org/10.1016/S1875-5364(13)60037-0] [PMID: 23787177]
[34]
Zhang R, Zhu X, Bai H, Ning K. Network pharmacology databases for traditional chinese medicine: Review and assessment. Front Pharmacol 2019; 10: 123.
[http://dx.doi.org/10.3389/fphar.2019.00123] [PMID: 30846939]
[35]
Liu W, Li L, Ye H, Tu W. [Weighted gene co-expression network analysis in biomedicine research]. Chin J Biotechnol 2017; 33(11): 1791-801.
[http://dx.doi.org/10.13345/j.cjb.170006] [PMID: 29202516]
[36]
Zhang B, Horvath S. A general framework for weighted gene co-expression network analysis. Stat Appl Genet Mol Biol 2005; 4: 17.
[http://dx.doi.org/10.2202/1544-6115.1128]
[37]
Langfelder P, Horvath S. WGCNA: An R package for weighted correlation network analysis. BMC Bioinformatics 2008; 9(1): 559.
[http://dx.doi.org/10.1186/1471-2105-9-559] [PMID: 19114008]
[38]
Li A, Horvath S. Network neighborhood analysis with the multi-node topological overlap measure. Bioinformatics 2007; 23(2): 222-31.
[http://dx.doi.org/10.1093/bioinformatics/btl581] [PMID: 17110366]
[39]
Ru J, Li P, Wang J, et al. TCMSP: A database of systems pharmacology for drug discovery from herbal medicines. J Cheminform 2014; 6(1): 13.
[http://dx.doi.org/10.1186/1758-2946-6-13] [PMID: 24735618]
[40]
Xue R, Fang Z, Zhang M, Yi Z, Wen C, Shi T. TCMID: traditional Chinese medicine integrative database for herb molecular mechanism analysis. Nucleic Acids Res 2012; 41(D1): D1089-95.
[http://dx.doi.org/10.1093/nar/gks1100] [PMID: 23203875]
[41]
Nickel J, Gohlke BO, Erehman J, et al. SuperPred: update on drug classification and target prediction. Nucleic Acids Res 2014; 42(W1): W26-31.
[http://dx.doi.org/10.1093/nar/gku477] [PMID: 24878925]
[42]
Shannon P, Markiel A, Ozier O, et al. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res 2003; 13(11): 2498-504.
[http://dx.doi.org/10.1101/gr.1239303] [PMID: 14597658]
[43]
Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021: Customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res 2021; 49(D1): D605-12.
[http://dx.doi.org/10.1093/nar/gkaa1074] [PMID: 33237311]
[44]
Wu T, Hu E, Xu S, et al. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation 2021; 2(3): 100141.
[http://dx.doi.org/10.1016/j.xinn.2021.100141] [PMID: 34557778]
[45]
Harris MA, Clark J, Ireland A, et al. The Gene Ontology (GO) database and informatics resource. Nucleic Acids Res 2004; 32(90001): 258D-61.
[http://dx.doi.org/10.1093/nar/gkh036] [PMID: 14681407]
[46]
Kanehisa M, Goto S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res 2000; 28(1): 27-30.
[http://dx.doi.org/10.1093/nar/28.1.27]
[47]
Gao YQ, Xu LB, Zhang YY, He LL, Shu ZH, Pan XC. Exploring the nursing effect of application Albizia bark on autism in children based on network pharmacology and molecular docking. Eur Rev Med Pharmacol Sci 2022; 26(22): 8539-50.
[http://dx.doi.org/10.26355/eurrev_202211_30390] [PMID: 36459035]
[48]
Pradeepkiran J, Reddy P. Structure based design and molecular docking studies for phosphorylated tau inhibitors in alzheimer’s disease. Cells 2019; 8(3): 260.
[http://dx.doi.org/10.3390/cells8030260] [PMID: 30893872]
[49]
Morgan E, Soerjomataram I, Rumgay H, et al. The global landscape of esophageal squamous cell carcinoma and esophageal adenocarcinoma incidence and mortality in 2020 and projections to 2040: New estimates from GLOBOCAN 2020. Gastroenterology 2022; 163(3): 649-658.e2.
[http://dx.doi.org/10.1053/j.gastro.2022.05.054] [PMID: 35671803]
[50]
Li Z, Feiyue Z, Gaofeng L. Traditional Chinese medicine and lung cancer-From theory to practice. Biomed Pharmacother 2021; 137: 111381.
[http://dx.doi.org/10.1016/j.biopha.2021.111381] [PMID: 33601147]
[51]
Xiang Y, Guo Z, Zhu P, Chen J, Huang Y. Traditional Chinese medicine as a cancer treatment: Modern perspectives of ancient but advanced science. Cancer Med 2019; 8(5): 1958-75.
[http://dx.doi.org/10.1002/cam4.2108] [PMID: 30945475]
[52]
Wu Z, Yin B, You F. Molecular mechanism of anti-colorectal cancer effect of hedyotis diffusa willd and its extracts. Front Pharmacol 2022; 13: 820474.
[http://dx.doi.org/10.3389/fphar.2022.820474] [PMID: 35721163]
[53]
Tang S, Liao K, Shi Y, Tang T, Cui B, Huang Z. Bioinformatics analysis of potential Key lncRNA-miRNA-mRNA molecules as prognostic markers and important ceRNA axes in gastric cancer. Am J Cancer Res 2022; 12(5): 2397-418.
[http://dx.doi.org/10.2156-6976/ajcr0138865] [PMID: 35693096]
[54]
Yao H, Li C, Tan X. An age stratified analysis of the biomarkers in patients with colorectal cancer. Sci Rep 2021; 11(1): 22464.
[http://dx.doi.org/10.1038/s41598-021-01850-x] [PMID: 34789836]
[55]
Li L, Liu X, Wen Y, Liu P, Sun T. Identification of prognostic markers of DNA damage and oxidative stress in diagnosing papillary renal cell carcinoma based on high-throughput bioinformatics screening. J Oncol 2023; 2023: 1-13.
[http://dx.doi.org/10.1155/2023/4640563] [PMID: 36785669]
[56]
Zhang Q, Lv L, Ma P, Zhang Y, Deng J, Zhang Y. Identification of an autophagy-related pair signature for predicting prognoses and immune activity in pancreatic adenocarcinoma. Front Immunol 2021; 12: 743938.
[http://dx.doi.org/10.3389/fimmu.2021.743938] [PMID: 34956177]
[57]
Zeng JH, Xiong DD, Pang YY, et al. Identification of molecular targets for esophageal carcinoma diagnosis using miRNA-seq and RNA-seq data from The Cancer Genome Atlas: A study of 187 cases. Oncotarget 2017; 8(22): 35681-99.
[http://dx.doi.org/10.18632/oncotarget.16051] [PMID: 28415685]
[58]
Chang C, Saltzman A, Yeh S, et al. Androgen receptor: An overview. Crit Rev Eukaryot Gene Expr 1995; 5(2): 97-125.
[http://dx.doi.org/10.1615/CritRevEukarGeneExpr.v5.i2.10] [PMID: 8845584]
[59]
Awan AK, Iftikhar SY, Morris TM, et al. Androgen receptors may act in a paracrine manner to regulate oesophageal adenocarcinoma growth. Eur J Surg Oncol 2007; 33(5): 561-8.
[http://dx.doi.org/10.1016/j.ejso.2006.12.001] [PMID: 17254742]
[60]
Benyamina A, Kebir O, Blecha L, Reynaud M, Krebs MO. CNR1 gene polymorphisms in addictive disorders: A systematic review and a meta-analysis. Addict Biol 2011; 16(1): 1-6.
[http://dx.doi.org/10.1111/j.1369-1600.2009.00198.x] [PMID: 20192949]
[61]
Gouvêa ES, Santos Filho AF, Ota VK, Mrad V, Gadelha A, Bressan RA. The role of the CNR1 gene in schizophrenia: A systematic review including unpublished data. Braz J Psychiatry 2017; 39(2): 160-71.
[http://dx.doi.org/10.1590/1516-4446-2016-1969]
[62]
Bedoya F, Meneu JC, Macías MI, et al. Mutation in CNR1 gene and VEGF expression in esophageal cancer. Tumori 2009; 95(1): 68-75.
[http://dx.doi.org/10.1177/030089160909500112] [PMID: 19366059]
[63]
Barbon A, Barlati S. Genomic organization, proposed alternative splicing mechanisms, and RNA editing structure of GRIK1. Cytogenet Genome Res 2000; 88(3-4): 236-9.
[http://dx.doi.org/10.1159/000015558] [PMID: 10828597]
[64]
Ren Z, Liu J, Yao L, Li J, Qi Z, Li B. Glutamate receptor ionotropic, kainate 1 serves as a novel tumor suppressor of colorectal carcinoma and predicts clinical prognosis. Exp Ther Med 2020; 20(6): 1.
[http://dx.doi.org/10.3892/etm.2020.9296] [PMID: 33093905]
[65]
Tournier C, Hess P, Yang DD, et al. Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 2000; 288(5467): 870-4.
[http://dx.doi.org/10.1126/science.288.5467.870] [PMID: 10797012]
[66]
Tang L, Zhu S, Peng W, Yin X, Tan C, Yang Y. Epigenetic identification of mitogen-activated protein kinase 10 as a functional tumor suppressor and clinical significance for hepatocellular carcinoma. PeerJ 2021; 9: e10810.
[http://dx.doi.org/10.7717/peerj.10810] [PMID: 33604188]
[67]
Sun R, Xiang T, Tang J, et al. 19q13 KRAB zinc-finger protein ZNF471 activates MAPK10/JNK3 signaling but is frequently silenced by promoter CpG methylation in esophageal cancer. Theranostics 2020; 10(5): 2243-59.
[http://dx.doi.org/10.7150/thno.35861] [PMID: 32089740]
[68]
Fei Z, Xie R, Chen Z, et al. Establishment of a novel risk score system of immune genes associated with prognosis in esophageal carcinoma. Front Oncol 2021; 11: 625271.
[http://dx.doi.org/10.3389/fonc.2021.625271] [PMID: 33859939]
[69]
Wu H, Huang M, Lu M, et al. Regulation of microtubule-associated protein tau (MAPT) by miR-34c-5p determines the chemosensitivity of gastric cancer to paclitaxel. Cancer Chemother Pharmacol 2013; 71(5): 1159-71.
[http://dx.doi.org/10.1007/s00280-013-2108-y] [PMID: 23423488]
[70]
Ye J, Zhang Z, Sun L, Fang Y, Xu X, Zhou G. miR-186 regulates chemo-sensitivity to paclitaxel via targeting MAPT in non-small cell lung cancer (NSCLC). Mol Biosyst 2016; 12(11): 3417-24.
[http://dx.doi.org/10.1039/C6MB00576D] [PMID: 27714074]
[71]
Sekino Y, Han X, Babasaki T, et al. Microtubule-associated protein tau (MAPT) promotes bicalutamide resistance and is associated with survival in prostate cancer. Urol Oncol 2020; 38(10): 795.e1-8.
[http://dx.doi.org/10.1016/j.urolonc.2020.04.032] [PMID: 32430253]
[72]
Mohammed H, Russell IA, Stark R, et al. Progesterone receptor modulates ERα action in breast cancer. Nature 2015; 523(7560): 313-7.
[http://dx.doi.org/10.1038/nature14583] [PMID: 26153859]
[73]
Xie SH, Lagergren J. The male predominance in esophageal adenocarcinoma. Clin Gastroenterol Hepatol 2016; 14(3): 338-347.e1.
[http://dx.doi.org/10.1016/j.cgh.2015.10.005] [PMID: 26484704]
[74]
Cizkova M, Vacher S, Meseure D, et al. PIK3R1 underexpression is an independent prognostic marker in breast cancer. BMC Cancer 2013; 13(1): 545.
[http://dx.doi.org/10.1186/1471-2407-13-545] [PMID: 24229379]

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