Traditional Chinese medicine (TCM) has unique advantages in alleviating gastric cancer (GC), and Jinlingzi Powder is a common drug used in TCM treatment. However, the potential mechanism for its treatment of GC is unclear. The purpose of this study is to integrate transcriptomics, network pharmacology and molecular docking to investigate the active components and targets of Jinlingzi Powder's intervention in GC and related pathways, in order to provide a basis for further revealing its mechanism of action and developing Jinlingzi Powder. We obtained the potential targets of Jinlingzi Powder and GC-related genes from public database. Then we identified and visualized Potential targets and signaling pathways through bioinformatics analysis, including protein-protein interaction (PPI), Gene Ontology (GO) functional enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Subsequently, molecular docking was performed to further validate these findings. Resultly, the results showed that potential targets including IL6, PTGS2, MMP9, HMOX1, MYC, CHRM3, TOP2A, CA2, and KCNMA1 were the therapeutic targets of Jinlingzi Powder for gastric cancer. The functional enrichment analysis indicate that through synergistically regulating some biological pathway, such as inflammatory response, cellular response to tumor necrosis factor, AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, TNF signaling pathway, MicroRNAs in cancer, Pathways in cancer, etc. , which have therapeutic effects on gastric cancer. In addition, the molecular docking results showed that the compounds had good binding activity to the action target in vivo. In Conclusion, this study comprehensively describes the potential targets and molecular mechanisms of Jinlingzi Powder for the treatment of gastric cancer. It also provides promising avenues for revealing the treatment of diseases by TCM through scientific basis and therapeutic mechanisms.

Liyao Chen, Yiqiang Liu, Ying Wu, Cuixian Wu, Yan Qin, Peng Wu. Prediction of the Mechanism of Jinlingzi Powder in the Intervention of Gastric Cancer Based on Transcriptomics and Network Pharmacology. Frontiers in Medical Science Research (2023) Vol. 5, Issue 10: 49-62. https://doi.org/10.25236/FMSR.2023.051008.

[1] Smyth EC, Nilsson M, Grabsch HI, et al. Gastric cancer. Lancet. 2020 Aug 29; 396(10251): 635-648. 

[2] Lazăr DC, Avram MF, Romoșan I, et al. Prognostic significance of tumor immune microenvironment and immunotherapy: Novel insights and future perspectives in gastric cancer. World J Gastroenterol. 2018 Aug 28; 24(32): 3583-3616. 

[3] Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov; 68(6): 394-424. 

[4] Pilleron S, Sarfati D, Janssen-Heijnen M, et al. Global cancer incidence in older adults, 2012 and 2035: A population-based study. Int J Cancer. 2019 Jan 1; 144(1): 49-58. 

[5] Charalampakis N, Economopoulou P, Kotsantis I, et al. Medical management of gastric cancer: a 2017 update. Cancer Med. 2018 Jan; 7(1): 123-133. 

[6] Wu CE, Xue WW, Zhuang YW, et al. A clinical study on the efficacy of Yiqi Huayu Jiedu decoction for reducing the risk of postoperative recurrence and metastasis of gastric cancer: Protocol for a multicenter, randomized, double-blind, placebo-controlled trial. Medicine (Baltimore). 2020 Nov 25; 99(48): e23417. 

[7] Zhao L, Zhao AG, Zhao G, et al. Survival benefit of traditional chinese herbal medicine (a herbal formula for invigorating spleen) in gastric cancer patients with peritoneal metastasis. Evid Based Complement Alternat Med. 2014; 2014: 625493. 

[8] Machlowska J, Baj J, Sitarz M, et al. Gastric Cancer: Epidemiology, Risk Factors, Classification, Genomic Characteristics and Treatment Strategies. Int J Mol Sci. 2020 Jun 4; 21(11): 4012. 

[9] Yang L, Li H, Yang M, et al. Exploration in the Mechanism of Kaempferol for the Treatment of Gastric Cancer Based on Network Pharmacology. Biomed Res Int. 2020 Oct 21; 2020: 5891016. 

[10] Dai S, Wang H, Wang M, et al. Comparative transcriptomics and network pharmacology analysis to identify the potential mechanism of celastrol against osteoarthritis. Clin Rheumatol. 2021 Oct; 40(10): 4259-4268. 

[11] Chen S, Jiang H, Cao Y, et al. Drug target identification using network analysis: Taking active components in Sini decoction as an example. Sci Rep. 2016 Apr 20; 6: 24245. 

[12] Berger SI, Iyengar R. Network analyses in systems pharmacology. Bioinformatics. 2009 Oct 1; 25(19): 2466-2472.

[13] Liu Z, Ma H, Lai Z. Revealing the potential mechanism of Astragalus membranaceus improving prognosis of hepatocellular carcinoma by combining transcriptomics and network pharmacology. BMC Complement Med Ther. 2021 Oct 18; 21(1): 263. 

[14] Zheng Ya, Wang Bolong, Zou Shengqin. Network pharmacological analysis of the mechanism of action of Jinlingzi San [J]. New Drugs in Chinese Medicine and Clinical Pharmacology, 2019, 30(10): 1211-1221. 

[15] Dai Yi, Ai Tianbi. Research progress on anticancer active components of Toosendan Fructus and Rhizoma Corydalis [J]. Journal of Shantou University (Natural Science Edition), 2018,33(01):57-62.

[16] Li L, Zhu Z, Zhao Y, et al. FN1, SPARC, and SERPINE1 are highly expressed and significantly related to a poor prognosis of gastric adenocarcinoma revealed by microarray and bioinformatics. Sci Rep. 2019 May 24; 9(1): 7827. 

[17] Han L, Han Y. Network Pharmacology-Based Study on the Active Component and Mechanism of the Anti-Gastric-Cancer Effect of Herba Sarcandrae. J Healthc Eng. 2021 Nov 19; 2021: 3001131. 

[18] Huang Y, Lin J, Yi W, et al. Research on the Potential Mechanism of Gentiopicroside Against Gastric Cancer Based on Network Pharmacology. Drug Des Devel Ther. 2020 Nov 23; 14: 5109-5118. 

[19] Nacher JC, Schwartz JM. A global view of drug-therapy interactions. BMC Pharmacol. 2008 Mar 4; 8: 5. 

[20] Haghi A, Azimi H, Rahimi R. A Comprehensive Review on Pharmacotherapeutics of Three Phytochemicals, Curcumin, Quercetin, and Allicin, in the Treatment of Gastric Cancer. J Gastrointest Cancer. 2017 Dec; 48(4): 314-320. 

[21] Wangchuk P, Sastraruji T, Taweechotipatr M, et al. Anti-inflammatory, Anti-bacterial and Anti-acetylcholinesterase Activities of two Isoquinoline Alkaloids-Scoulerine and Cheilanthifoline. Nat Prod Commun. 2016 Dec; 11(12): 1801-1804. 

[22] Huang SP, Wu MS, Wang HP, et al. Correlation between serum levels of interleukin-6 and vascular endothelial growth factor in gastric carcinoma. J Gastroenterol Hepatol. 2002 Nov;17(11):1165-1169. 

[23] Qu Y, Yang X, Li J, et al. Network Pharmacology and Molecular Docking Study of Zhishi-Baizhu Herb Pair in the Treatment of Gastric Cancer. Evid Based Complement Alternat Med. 2021 Dec 2; 2021: 2311486. 

[24] Tang Jiaqi, Hu Nan, Wang Huiyu, et al. Expression and clinical significance of IL-6, STT3A and PD-L1 in gastric cancer tissues [J]. Journal of Clinical Oncology, 2021, 26(07): 590-595. 

[25] Sun WH, Sun YL, Fang RN, et al. Expression of cyclooxygenase-2 and matrix metalloproteinase-9 in gastric carcinoma and its correlation with angiogenesis. Jpn J Clin Oncol. 2005 Dec; 35(12):707-713. 

[26] Amano H, Hayashi I, Endo H, et al. Host prostaglandin E(2)-EP3 signaling regulates tumor-associated angiogenesis and tumor growth. J Exp Med. 2003 Jan 20; 197(2): 221-32. 

[27] Ahmadi M, Emery DC, Morgan DJ. Prevention of both direct and cross-priming of antitumor CD8+ T-cell responses following overproduction of prostaglandin E2 by tumor cells in vivo. Cancer Res. 2008 Sep 15; 68(18): 7520-7529. 

[28] He H, Xia HH, Wang JD, et al. Inhibition of human telomerase reverse transcriptase by nonsteroidal antiinflammatory drugs in colon carcinoma. Cancer. 2006 Mar 15;106(6):1243-1249.

[29] Shin Vivian Y, Wu William K K, Chu Kent-Man, et al. Nicotine induces cyclooxygenase-2 and vascular endothelial growth factor receptor-2 in association with tumor-associated invasion and angiogenesis in gastric cancer. Mol Cancer Res. 2005 Nov; 3(11): 607-615. 

[30] Casado M, Mollá B, Roy R, et al. Protection against Fas-induced liver apoptosis in transgenic mice expressing cyclooxygenase 2 in hepatocytes. Hepatology. 2007 Mar; 45(3): 631-638. 

[31] Enders GA. Cyclooxygenase-2 overexpression abrogates the antiproliferative effects of TGF-beta. Br J Cancer. 2007 Nov 19; 97(10): 1388-1392. 

[32] Torii A, Kodera Y, Ito M, et al. Matrix metalloproteinase 9 in mucosally invasive gastric cancer. Gastric Cancer. 1998 Mar; 1(2): 142-145. 

[33] Ren QG, Yang SL, Li PD, et al. Low heme oxygenase-1 expression promotes gastric cancer cell apoptosis, inhibits proliferation and invasion, and correlates with increased overall survival in gastric cancer patients. Oncol Rep. 2017 Nov; 38(5): 2852-2858. 

[34] Duffy MJ, O'Grady S, Tang M, Crown J. MYC as a target for cancer treatment. Cancer Treat Rev. 2021 Mar; 94: 102154. 

[35] Liu M, Yao B, Gui T, et al. PRMT5-dependent transcriptional repression of c-Myc target genes promotes gastric cancer progression. Theranostics. 2020 Mar 15; 10(10): 4437-4452. 

[36] Semenov I, Brenner R. Voltage effects on muscarinic acetylcholine receptor-mediated contractions of airway smooth muscle. Physiol Rep. 2018 Sep; 6(17): e13856. 

[37] Sorokin M, Poddubskaya E, Baranova M, et al. RNA sequencing profiles and diagnostic signatures linked with response to ramucirumab in gastric cancer. Cold Spring Harb Mol Case Stud. 2020 Apr 1; 6(2): a004945. 

[38] Wang Y. Transcriptional Regulatory Network Analysis for Gastric Cancer Based on mRNA Microarray. Pathol Oncol Res. 2017 Oct; 23(4): 785-791. 

[39] Cui Y, Pu R, Ye J, et al. LncRNA FAM230B Promotes Gastric Cancer Growth and Metastasis by Regulating the miR-27a-5p/TOP2A Axis. Dig Dis Sci. 2021 Aug; 66(8): 2637-2650. 

[40] Kivela AJ, Parkkila S, Saarnio J, et al. Expression of von Hippel-Lindau tumor suppressor and tumor-associated carbonic anhydrases IX and XII in normal and neoplastic colorectal mucosa. World J Gastroenterol. 2005 May 7; 11(17): 2616-2625. 

[41] Ma G, Liu H, Hua Q, et al. KCNMA1 cooperating with PTK2 is a novel tumor suppressor in gastric cancer and is associated with disease outcome. Mol Cancer. 2017 Feb 23; 16(1): 46. 

[42] Singh N, Baby D, Rajguru JP, et al. Inflammation and cancer. Ann Afr Med. 2019 Jul-Sep; 18(3): 121-126. 

[43] Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002 Dec 19-26; 420(6917): 860-867. 

[44] Balkwill F. Tumour necrosis factor and cancer. Nat Rev Cancer. 2009 May; 9(5): 361-371. 

[45] Kuniyasu H, Oue N, Wakikawa A, et al. Expression of receptors for advanced glycation end-products (RAGE) is closely associated with the invasive and metastatic activity of gastric cancer. J Pathol. 2002 Feb; 196(2): 163-170. 

[46] Abe R, Yamagishi S. AGE-RAGE system and carcinogenesis. Curr Pharm Des. 2008; 14(10): 940-945. 

[47] Zhou Q, Wu X, Wang X, et al. The reciprocal interaction between tumor cells and activated fibroblasts mediated by TNF-α/IL-33/ST2L signaling promotes gastric cancer metastasis. Oncogene. 2020 Feb; 39(7): 1414-1428. 

[48] Ju X, Zhang H, Zhou Z, et al. Tumor-associated macrophages induce PD-L1 expression in gastric cancer cells through IL-6 and TNF-ɑ signaling. Exp Cell Res. 2020 Nov 15; 396(2): 112315. 

[49] Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004 Jan 23; 116(2): 281-297. 

[50] Ghafouri-Fard S, Vafaee R, Shoorei H, Taheri M. MicroRNAs in gastric cancer: Biomarkers and therapeutic targets. Gene. 2020 Oct 5; 757: 144937. 

[51] Li F, Wu T, Xu Y, et al. A comprehensive overview of oncogenic pathways in human cancer. Brief Bioinform. 2020 May 21; 21(3): 957-969.