Current Computer-Aided Drug DesignCurrent Computer-Aided Drug DesignCurrent Computer-Aided Drug Design1573-40991875-6697Bentham Science64410710.2174/1573409919666230607103721ChemistryResearch ArticleResearch on the Regulatory Mechanism of Ginseng on the Tumor Microenvironment of Colorectal Cancer based on Network Pharmacology and Bioinformatics ValidationWangTianchenginfo@benthamscience.netZhangWeijieinfo@benthamscience.netFangCancaninfo@benthamscience.netWangNaninfo@benthamscience.netZhuangYueinfo@benthamscience.netGaoSonginfo@benthamscience.netSchool of lntegrated Traditional and Western Medicine, Anhui University of Traditional Chinese MedicineSchool of Chinese Medicine, Anhui University of Traditional Chinese MedicineSchool of Pharmacy, Anhui University of Traditional Chinese MedicineSchool of Pharmacy,, Anhui University of Traditional Chinese MedicineSchool of Acupuncture and Massage, Anhui University of Traditional Chinese MedicineSchool of Chinese Medicine, Anhui University of Chinese Medicine0105202420548650007012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://rjeid.com/1573-4099/article/view/644107

Background:A network pharmacology study on the biological action of ginseng in the treatment of colorectal cancer (CRC) by regulating the tumor microenvironment (TME).

Objective:To investigate the potential mechanism of action of ginseng in the treatment of CRC by regulating TME.

Methods:This research employed network pharmacology, molecular docking techniques, and bioinformatics validation. Firstly, the active ingredients and the corresponding targets of ginseng were retrieved using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), the Traditional Chinese Medicine Integrated Database (TCMID), and the Traditional Chinese Medicine Database@Taiwan (TCM Database@Taiwan). Secondly, the targets related to CRC were retrieved using Genecards, Therapeutic Target Database (TTD), and Online Mendelian Inheritance in Man (OMIM). Tertiary, the targets related to TME were derived from screening the GeneCards and National Center for Biotechnology Information (NCBI)-Gene. Then the common targets of ginseng, CRC, and TME were obtained by Venn diagram. Afterward, the Protein-protein interaction (PPI) network was constructed in the STRING 11.5 database, intersecting targets identified by PPI analysis were introduced into Cytoscape 3.8.2 software cytoHubba plugin, and the final determination of core targets was based on degree value. The OmicShare Tools platform was used to analyze the Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the core targets. Autodock and PyMOL were used for molecular docking verification and visual data analysis of docking results. Finally, we verified the core targets by Gene Expression Profiling Interactive Analysis (GEPIA) and Human Protein Atlas (HPA) databases in bioinformatics.

Results:A total of 22 active ingredients and 202 targets were identified to be closely related to the TME of CRC. PPI network mapping identified SRC, STAT3, PIK3R1, HSP90AA1, and AKT1 as possible core targets. Go enrichment analysis showed that it was mainly involved in T cell co-stimulation, lymphocyte co-stimulation, growth hormone response, protein input, and other biological processes; KEGG pathway analysis found 123 related signal pathways, including EGFR tyrosine kinase inhibitor resistance, chemokine signaling pathway, VEGF signaling pathway, ErbB signaling pathway, PD-L1 expression and PD-1 checkpoint pathway in cancer, etc. The molecular docking results showed that the main chemical components of ginseng have a stable binding activity to the core targets. The results of the GEPIA database showed that the mRNA levels of PIK3R1 were significantly lowly expressed and HSP90AA1 was significantly highly expressed in CRC tissues. Analysis of the relationship between core target mRNA levels and the pathological stage of CRC showed that the levels of SRC changed significantly with the pathological stage. The HPA database results showed that the expression levels of SRC were increased in CRC tissues, while the expression of STAT3, PIK3R1, HSP90AA1, and AKT1 were decreased in CRC tissues.

Conclusion:Ginseng may act on SRC, STAT3, PIK3R1, HSP90AA1, and AKT1 to regulate T cell costimulation, lymphocyte costimulation, growth hormone response, protein input as a molecular mechanism regulating TME for CRC. It reflects the multi-target and multi-pathway role of ginseng in modulating TME for CRC, which provides new ideas to further reveal its pharmacological basis, mechanism of action and new drug design and development.

Ginsengcolorectal cancertumor microenvironmentnetwork pharmacologymolecular dockingregulatory mechanismbioinformatics validation.Pickhardt, P.J.; Kim, D.H.; Pooler, B.D.; Hinshaw, J.L.; Barlow, D.; Jensen, D.; Reichelderfer, M.; Cash, B.D. Assessment of volumetric growth rates of small colorectal polyps with CT colonography: a longitudinal study of natural history. Lancet Oncol., 2013, 14(8), 711-720. doi: 10.1016/S1470-2045(13)70216-X PMID: 23746988Sundling, K.E.; Zhang, R.; Matkowskyj, K.A. Pathologic features of primary colon, rectal, and anal malignancies. Cancer Treat. Res., 2016, 168, 309-330. doi: 10.1007/978-3-319-34244-3_15 PMID: 29206380Siegel, R.L.; Miller, K.D.; Fedewa, S.A.; Ahnen, D.J.; Meester, R.G.S.; Barzi, A.; Jemal, A. Colorectal cancer statistics, 2017. CA Cancer J. Clin., 2017, 67(3), 177-193. doi: 10.3322/caac.21395 PMID: 28248415Gulbake, A.; Jain, A.; Jain, A.; Jain, A.; Jain, S.K. Insight to drug delivery aspects for colorectal cancer. World J. Gastroenterol., 2016, 22(2), 582-599. doi: 10.3748/wjg.v22.i2.582 PMID: 26811609Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: the next generation. Cell, 2011, 144(5), 646-674. doi: 10.1016/j.cell.2011.02.013 PMID: 21376230Huang, S. Discussion on medicinal uses of ginseng, American ginseng and Panax notoginseng. Zhongguo Zhongyiyao Xiandai Yuancheng Jiaoyu, 2011, 9(15), 73-74.Gao, J.; Yu, S. Research progress in chemical constituents and pharmacological action of renshenGinseng). Zhongguo Xiandai Zhongyao, 2021, 27(01), 127-137.Liu, Y.; Xiao, W.; Xiao, P.; Xu, L.; He, C.; Peng, Y.; Liu, H. Adaptogens and tonics of traditional chinese medicine. Zhongguo Xiandai Zhongyao, 2015, 17(01), 1-5.Wang, L. Discussion on the application of ginseng in exogenous diseases. J. Tradit. Chin. Med., 2015, 56(22), 1965-1967.Wang, Z.Y.; Wang, X.; Zhang, D.Y.; Hu, Y.J.; Li, S. Traditional Chinese medicine network pharmacology: development in new era under guidance of network pharmacology evaluation method guidance. Zhongguo Zhongyao Zazhi, 2022, 47(1), 7-17. doi: 10.19540/j.cnki.cjcmm.20210914.702 PMID: 35178906Ru, J.; Li, P.; Wang, J.; Zhou, W.; Li, B.; Huang, C.; Li, P.; Guo, Z.; Tao, W.; Yang, Y.; Xu, X.; Li, Y.; Wang, Y.; Yang, L. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J. Cheminform., 2014, 6(1), 13. doi: 10.1186/1758-2946-6-13 PMID: 24735618Huang, L.; Xie, D.; Yu, Y.; Liu, H.; Shi, Y.; Shi, T.; Wen, C. TCMID 2.0: a comprehensive resource for TCM. Nucleic Acids Res., 2018, 46(D1), D1117-D1120. doi: 10.1093/nar/gkx1028 PMID: 29106634Sanderson, K. Databases aim to bridge the East-West divide of drug discovery. Nat. Med., 2011, 17(12), 1531. doi: 10.1038/nm1211-1531a PMID: 22146440Liu, H.; Cao, M.; Jin, Y.; Jia, B.; Wang, L.; Dong, M.; Han, L.; Abankwah, J.; Liu, J.; Zhou, T.; Chen, B.; Wang, Y.; Bian, Y. Network pharmacology and experimental validation to elucidate the pharmacological mechanisms of Bushen Huashi decoction against kidney stones. Front. Endocrinol., 2023, 14, 1031895. doi: 10.3389/fendo.2023.1031895 PMID: 36864834Zhang, X.; Li, S.; Peng, L.; Wang, Z.; Zeng, R.; Ren, W.; Deng, K. Exploring yang-warming mechanism of aconite based on network pharmacology. Journal of Beijing University of Traditional Chinese Medicine., 2019, 42(02), 143-148.Kim, S.; Chen, J.; Cheng, T.; Gindulyte, A.; He, J.; He, S.; Li, Q.; Shoemaker, B.A.; Thiessen, P.A.; Yu, B.; Zaslavsky, L.; Zhang, J.; Bolton, E.E. PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Res., 2021, 49(D1), D1388-D1395. doi: 10.1093/nar/gkaa971 PMID: 33151290Daina, A.; Michielin, O.; Zoete, V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res., 2019, 47(W1), W357-W364. doi: 10.1093/nar/gkz382 PMID: 31106366Zhao, Y.; Ma, C.; Qiu, Q.; Huang, X.; Qiaolongbatu, X.; Qu, H.; Wu, J.; Fan, G.; Wu, Z. Exploring the components and mechanisms of Shen-qi-wang-mo granule in the treatment of retinal vein occlusion by UPLC-Triple TOF MS/MS and network pharmacology. Sci. Rep., 2023, 13(1), 5330. doi: 10.1038/s41598-023-32472-0 PMID: 37005436Bateman, A.; Martin, M-J.; Orchard, S.; Magrane, M.; Agivetova, R.; Ahmad, S.; Alpi, E.; Bowler-Barnett, E.H.; Britto, R.; Bursteinas, B.; Bye-A-Jee, H.; Coetzee, R.; Cukura, A.; Da Silva, A.; Denny, P.; Dogan, T.; Ebenezer, T.G.; Fan, J.; Castro, L.G.; Garmiri, P.; Georghiou, G.; Gonzales, L.; Hatton-Ellis, E.; Hussein, A.; Ignatchenko, A.; Insana, G.; Ishtiaq, R.; Jokinen, P.; Joshi, V.; Jyothi, D.; Lock, A.; Lopez, R.; Luciani, A.; Luo, J.; Lussi, Y.; MacDougall, A.; Madeira, F.; Mahmoudy, M.; Menchi, M.; Mishra, A.; Moulang, K.; Nightingale, A.; Oliveira, C.S.; Pundir, S.; Qi, G.; Raj, S.; Rice, D.; Lopez, M.R.; Saidi, R.; Sampson, J.; Sawford, T.; Speretta, E.; Turner, E.; Tyagi, N.; Vasudev, P.; Volynkin, V.; Warner, K.; Watkins, X.; Zaru, R.; Zellner, H.; Bridge, A.; Poux, S.; Redaschi, N.; Aimo, L.; Argoud-Puy, G.; Auchincloss, A.; Axelsen, K.; Bansal, P.; Baratin, D.; Blatter, M-C.; Bolleman, J.; Boutet, E.; Breuza, L.; Casals-Casas, C.; de Castro, E.; Echioukh, K.C.; Coudert, E.; Cuche, B.; Doche, M.; Dornevil, D.; Estreicher, A.; Famiglietti, M.L.; Feuermann, M.; Gasteiger, E.; Gehant, S.; Gerritsen, V.; Gos, A.; Gruaz-Gumowski, N.; Hinz, U.; Hulo, C.; Hyka-Nouspikel, N.; Jungo, F.; Keller, G.; Kerhornou, A.; Lara, V.; Le Mercier, P.; Lieberherr, D.; Lombardot, T.; Martin, X.; Masson, P.; Morgat, A.; Neto, T.B.; Paesano, S.; Pedruzzi, I.; Pilbout, S.; Pourcel, L.; Pozzato, M.; Pruess, M.; Rivoire, C.; Sigrist, C.; Sonesson, K.; Stutz, A.; Sundaram, S.; Tognolli, M.; Verbregue, L.; Wu, C.H.; Arighi, C.N.; Arminski, L.; Chen, C.; Chen, Y.; Garavelli, J.S.; Huang, H.; Laiho, K.; McGarvey, P.; Natale, D.A.; Ross, K.; Vinayaka, C.R.; Wang, Q.; Wang, Y.; Yeh, L-S.; Zhang, J.; Ruch, P.; Teodoro, D. UniProt: the universal protein knowledgebase in 2021. Nucleic Acids Res., 2021, 49(D1), D480-D489. doi: 10.1093/nar/gkaa1100 PMID: 33237286Zhou, Y.; Zhang, Y.; Lian, X.; Li, F.; Wang, C.; Zhu, F.; Qiu, Y.; Chen, Y. Therapeutic target database update 2022: facilitating drug discovery with enriched comparative data of targeted agents. Nucleic Acids Res., 2022, 50(D1), D1398-D1407. doi: 10.1093/nar/gkab953 PMID: 34718717Amberger, J.S.; Bocchini, C.A.; Schiettecatte, F.; Scott, A.F.; Hamosh, A. OMIM.org: Online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders. Nucleic Acids Res., 2015, 43(D1), D789-D798. doi: 10.1093/nar/gku1205 PMID: 25428349Stelzer, G.; Rosen, N.; Plaschkes, I.; Zimmerman, S.; Twik, M.; Fishilevich, S.; Stein, TI.; Nudel, R.; Lieder, I.; Mazor, Y.; Kaplan, S.; Dahary, D.; Warshawsky, D.; Guan-Golan, Y.; Kohn, A.; Rappaport, N.; Safran, M.; Lancet, D. The genecards suite: From gene data mining to disease genome sequence analyses. Curr Protoc Bioinform, 2016, 54, 1.30.1-1.30.33. doi: 10.1002/cpbi.5Xiang, C.P.; Zhou, R.; Zhang, J.J.; Yang, H.J. Study on network pharmacological mechanism of "treating different diseases with same method" of Notoginseng Radix et Rhizoma in treating diabetic nephropathy, diabetic encephalopathy and diabetic cardiomyopathy. Zhongguo Zhongyao Zazhi, 2021, 46(10), 2424-2433. doi: 10.19540/j.cnki.cjcmm.20210128.401 PMID: 34047086Liang, L.; Zhu, J.; Chen, G.; Qin, X.; Chen, J. Prognostic values for the mRNA expression of the ADAMTS family of genes in gastric cancer. J. Oncol., 2020, 2020, 1-24. doi: 10.1155/2020/9431560 PMID: 32884571Shannon, P.; Markiel, A.; Ozier, O.; Baliga, N.S.; Wang, J.T.; Ramage, D.; Amin, N.; Schwikowski, B.; Ideker, T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res., 2003, 13(11), 2498-2504. doi: 10.1101/gr.1239303 PMID: 14597658Szklarczyk, D.; Gable, A.L.; Nastou, K.C.; Lyon, D.; Kirsch, R.; Pyysalo, S.; Doncheva, N.T.; Legeay, M.; Fang, T.; Bork, P.; Jensen, L.J.; von Mering, C. 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-D612. doi: 10.1093/nar/gkaa1074 PMID: 33237311Lin, F.; Zhang, G.; Yang, X.; Wang, M.; Wang, R.; Wan, M.; Wang, J.; Wu, B.; Yan, T.; Jia, Y. A network pharmacology approach and experimental validation to investigate the anticancer mechanism and potential active targets of ethanol extract of Wei-Tong-Xin against colorectal cancer through induction of apoptosis via PI3K/AKT signaling pathway. J. Ethnopharmacol., 2023, 303, 115933. doi: 10.1016/j.jep.2022.115933 PMID: 36403742Taowen, P.; Shuyuan, F.; Xiaoli, S.; Annan, W.; Feng, Q.; Yizhong, Z.; Jing, L.; Bin, L.; Kun, L.; Yunpeng, D. Study on the action mechanism of the peptide compounds of Wuguchong on diabetic ulcers, based on UHPLC-Q-TOF-MS, network pharmacology and experimental validation. J. Ethnopharmacol., 2022, 288, 114974. doi: 10.1016/j.jep.2022.114974 PMID: 35033625Sterling, T.; Irwin, J.J. ZINC 15 – Ligand discovery for everyone. J. Chem. Inf. Model., 2015, 55(11), 2324-2337. doi: 10.1021/acs.jcim.5b00559 PMID: 26479676Velankar, S.; Burley, S.K.; Kurisu, G.; Hoch, J.C.; Markley, J.L. The protein data bank archive, Methods Mol Biol., 2021, 2305, 3-21. doi: 10.1007/978-1-0716-1406-8_1Seeliger, D.; de Groot, B.L. Ligand docking and binding site analysis with PyMOL and Autodock/Vina. J. Comput. Aided Mol. Des., 2010, 24(5), 417-422. doi: 10.1007/s10822-010-9352-6 PMID: 20401516Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461. doi: 10.1002/jcc.21334 PMID: 19499576Sheng-Ju, W.; Qian-Qian, L.; Hua-Juan, J.; Yan-Fen, C.; Yu-Hang, Y.; Yao, H.E.; Jin-Ming, Z.; Jin, P. Active components and mechanism of Taohong Siwu Decoction in treatment of primary dysmenorrhea based on network pharmacology and molecular docking technology. Zhongguo Zhongyao Zazhi, 2020, 45(22), 5373-5382. doi: 10.19540/j.cnki.cjcmm.20200723.401 PMID: 33350196Tang, Z.; Li, C.; Kang, B.; Gao, G.; Li, C.; Zhang, Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res., 2017, 45(W1), W98-W102. doi: 10.1093/nar/gkx247 PMID: 28407145Digre, A.; Lindskog, C. The human protein atlas—spatial localization of the human proteome in health and disease. Protein Sci., 2021, 30(1), 218-233. doi: 10.1002/pro.3987 PMID: 33146890Gao, F.; Pei, Y.; Ren, Y.; Chen, Z.; Lu, J.; Zhang, Y. Possible mechanisms by which Polygonati rhizoma opposes atherosclerosis based on network pharmacology and molecular docking analyses. Yao Xue Xue Bao, 2022, 55(11), 2642-2650.Imran, M.; Salehi, B.; Sharifi-Rad, J.; Aslam Gondal, T.; Saeed, F.; Imran, A.; Shahbaz, M.; Tsouh Fokou, P.V.; Umair Arshad, M.; Khan, H.; Guerreiro, S.G.; Martins, N.; Estevinho, L.M. Kaempferol: A key emphasis to its anticancer potential. Molecules, 2019, 24(12), 2277. doi: 10.3390/molecules24122277 PMID: 31248102Alam, W.; Khan, H.; Shah, M.A.; Cauli, O.; Saso, L. Kaempferol as a dietary anti-inflammatory agent: current therapeutic standing. Molecules, 2020, 25(18), 4073. doi: 10.3390/molecules25184073 PMID: 32906577Sun, H.; Ye, Y.; Pan, Y. Immunological-adjuvant saponins from the Roots ofPanax notoginseng. Chem. Biodivers., 2005, 2(4), 510-515. doi: 10.1002/cbdv.200590032 PMID: 17192000Deng, X.; Zhao, J.; Qu, L.; Duan, Z.; Fu, R.; Zhu, C.; Fan, D. Ginsenoside Rh4 suppresses aerobic glycolysis and the expression of PD-L1 via targeting AKT in esophageal cancer. Biochem. Pharmacol., 2020, 178, 114038. doi: 10.1016/j.bcp.2020.114038 PMID: 32422139Jin, W. Regulation of Src family kinases during colorectal cancer development and its clinical implications. Cancers, 2020, 12(5), 1339. doi: 10.3390/cancers12051339 PMID: 32456226Chen, X.; Chen, J.; Feng, W.; Huang, W.; Wang, G.; Sun, M.; Luo, X.; Wang, Y.; Nie, Y.; Fan, D.; Wu, K.; Xia, L. FGF19-mediated ELF4 overexpression promotes colorectal cancer metastasis through transactivating FGFR4 and SRC. Theranostics, 2023, 13(4), 1401-1418. doi: 10.7150/thno.82269 PMID: 36923538Guan, L.; Liu, Z.; Wang, H.; Lai, M. JAK/STAT3 signaling pathway and its inhibitors in tumor therapy. Chung Kuo Yao Hsueh Tsa Chih, 2018, 53(23), 1973-1977.Wang, X.; Crowe, P.J.; Goldstein, D.; Yang, J.L. STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers. Int. J. Oncol., 2012, 41(4), 1181-1191. doi: 10.3892/ijo.2012.1568 PMID: 22842992Han, S.; Kim, H.; Lee, M.Y.; Lee, J.; Ahn, K.S.; Ha, I.J.; Lee, S.G. Anti-cancer effects of a new herbal medicine PSY by inhibiting the STAT3 signaling pathway in colorectal cancer cells and its phytochemical analysis. Int. J. Mol. Sci., 2022, 23(23), 14826. doi: 10.3390/ijms232314826 PMID: 36499154Ai, X.; Xiang, L.; Huang, Z.; Zhou, S.; Zhang, S.; Zhang, T.; Jiang, T. Overexpression of PIK3R1 promotes hepatocellular carcinoma progression. Biol. Res., 2018, 51(1), 52. doi: 10.1186/s40659-018-0202-7 PMID: 30497511Lou, T.; Zhang, L.; Jin, Z.; Miao, C.; Wang, J.; Ke, K. miR-455-5p enhances 5-fluorouracil sensitivity in colorectal cancer cells by targeting PIK3R1 and DEPDC1. Open Med. (Wars.), 2022, 17(1), 847-856. doi: 10.1515/med-2022-0474 PMID: 35582195Zagouri, F.; Sergentanis, T.N.; Provatopoulou, X.; Kalogera, E.; Chrysikos, D.; Lymperi, M.; Papadimitriou, C.A.; Zografos, E.; Bletsa, G.; Kalles, V.S.; Zografos, G.C.; Gounaris, A. Serum levels of HSP90 in the continuum of breast ductal and lobular lesions. In Vivo, 2011, 25(4), 669-672. PMID: 21709012Wu, J.; Liu, T.; Rios, Z.; Mei, Q.; Lin, X.; Cao, S. Heat shock proteins and cancer. Trends Pharmacol. Sci., 2017, 38(3), 226-256. doi: 10.1016/j.tips.2016.11.009 PMID: 28012700Zhang, M.; Peng, Y.; Yang, Z.; Zhang, H.; Xu, C.; Liu, L.; Zhao, Q.; Wu, J.; Wang, H.; Liu, J. DAB2IP down-regulates HSP90AA1 to inhibit the malignant biological behaviors of colorectal cancer. BMC Cancer, 2022, 22(1), 561. doi: 10.1186/s12885-022-09596-z PMID: 35590292Agarwal, A.; Das, K.; Lerner, N.; Sathe, S.; Cicek, M.; Casey, G.; Sizemore, N. The AKT/IκB kinase pathway promotes angiogenic/metastatic gene expression in colorectal cancer by activating nuclear factor-κB and β-catenin. Oncogene, 2005, 24(6), 1021-1031. doi: 10.1038/sj.onc.1208296 PMID: 15592509Sahlberg, S.H.; Mortensen, A.C.; Haglöf, J.; Engskog, M.K.R.; Arvidsson, T.; Pettersson, C.; Glimelius, B.; Stenerlöw, B.; Nestor, M. Different functions of AKT1 and AKT2 in molecular pathways, cell migration and metabolism in colon cancer cells. Int. J. Oncol., 2017, 50(1), 5-14. doi: 10.3892/ijo.2016.3771 PMID: 27878243Pal, S.; Kozono, D.; Yang, X.; Fendler, W.; Fitts, W.; Ni, J.; Alberta, J.A.; Zhao, J.; Liu, K.X.; Bian, J.; Truffaux, N.; Weiss, W.A.; Resnick, A.C.; Bandopadhayay, P.; Ligon, K.L.; DuBois, S.G.; Mueller, S.; Chowdhury, D.; Haas-Kogan, D.A. Dual HDAC and PI3K inhibition abrogates NFκB- and FOXM1-Mediated DNA damage response to radiosensitize pediatric high-grade gliomas. Cancer Res., 2018, 78(14), 4007-4021. doi: 10.1158/0008-5472.CAN-17-3691 PMID: 29760046Baptistella, A.R.; Landemberger, M.C.; Dias, M.V.S.; Giudice, F.S.; Rodrigues, B.R.; da Silva, P.P.C.E.; Cassinela, E.K.; Lacerda, T.C.; Marchi, F.A.; Leme, A.F.P.; Begnami, M.D.; Aguiar, S., Jr; Martins, V.R. Rab5C enhances resistance to ionizing radiation in rectal cancer. J. Mol. Med., 2019, 97(6), 855-869. doi: 10.1007/s00109-019-01760-6 PMID: 30968159Xing, K.; Chen, Y.; Li, Q.; Li, X.; Wang, X.; Cai, Y.; Wu, W.; Luo, Q. Regulatory effect of YAP protein on the expression of TGF-α and EGFR in HPV infected human cervical cancer cells. Acta Universitatis Medicinalis Anhui., 2020, 55(11), 1735-1740.Alsahafi, E.N.; Thavaraj, S.; Sarvestani, N.; Novoplansky, O.; Elkabets, M.; Ayaz, B.; Tavassoli, M.; Legends, M.F. EGFR overexpression increases radiotherapy response in HPV-positive head and neck cancer through inhibition of DNA damage repair and HPV E6 downregulation. Cancer Lett., 2021, 498, 80-97. doi: 10.1016/j.canlet.2020.10.035 PMID: 33137407Singh, P.; Jain, S.L.; Sakhuja, P.; Agarwal, A. Expression of VEGF-A, HER2/neu, and KRAS in gall bladder carcinoma and their correlation with clinico-pathological parameters. Indian J. Pathol. Microbiol., 2021, 64(4), 687-692. doi: 10.4103/IJPM.IJPM_248_20 PMID: 34673587