BIOINFORMATICS APPROACH ON ACTION AND MECHANISM OF BROMELAIN IN HEPATOCELLULAR CARCINOMA
DOI:
https://doi.org/10.22159/ajpcr.2021.v14i9.42661Keywords:
Bromelain, Hepatocellular carcinoma, Protein-protein interaction-network, KEGG, p53, β-cateninAbstract
Objective: The objective of the study was to understand biomolecular interactions of Bromelain and its networking with p53 and β-catenin by a computational method of analysis in Hepatocellular carcinoma (HCC) condition.
Methodology: The protein interaction partners for p53 and β-catenin involved in the progression of HCC were collected from National Center for Biotechnology Information. We collected data points and standardized the data points for our data analysis from the public database. We used Cytoscape 3.8.2 version plug-in for constructing a Protein-Protein interaction network. We constructed a pathway network using Biorender.com.
Results: The protein interactions concerning p53 and β-catenin are identified and a network is constructed. A total of 18 and 34 nodes were identified which are involved in down-regulation and up-regulation of β-catenin and a total of 30 and 27 nodes for homosapiens are identified which are involved in the downregulation and upregulation of the p53 gene. We identified different pathways which trigger and impact the p53 and Wnt/β- catenin signaling pathways as potential target sites for Bromelain to arrest the progression of cancer
Conclusion: In conclusion, our in silico studies anti-cancer activity of Bromelain in HCC relating its effect on apoptosis, cell differentiation, mesenchymal transition, p53 signaling, and Wnt/β-catenin signaling pathways.
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References
Li Z, Xu J, Cui H, Song J, Chen J, Wei J. Bioinformatics analysis of key biomarkers and potential molecular mechanisms in hepatocellular carcinoma induced by hepatitis B virus. Medicine 2020;99:e20302.
Sushma SM, Narsaiah B. Molecular insights into Bromelain application in industry and health care. Biosci Biotechnol Res Commun 2021;13:36-46.
Available from: https://www.ncbi.nlm.nih.gov/pmc/?term=p53+and+ beta+catenin+in+hcc. [Last accessed on 2021 Mar 03].
Available from: https://www.biorender.com. [Last accessed on 2021 Mar 07].
Available from: https://www.genome.jp/kegg-bin/show_ pathway?hsa05225. [Last accessed on 2021 Mar 05].
Sushma SM, Narsaiah B. Cytotoxic effect of bromelain on HepG2 hepatocellular carcinoma cell line. Appl Biochem Biotechnol 2021;193:1873-97.
Tang W, Lv B, Yang B, Chen Y, Yuan F, Ma L, et al. TREM2 acts as a tumor suppressor in hepatocellular carcinoma by targeting the PI3K/ Akt/β-catenin pathway. Oncogenesis 2019;8:9.
Han J, Xie C, Pei T, Wang J, Lan Y, Huang K, et al. Deregulated AJAP1/β-catenin/ZEB1 signaling promotes hepatocellular carcinoma carcinogenesis and metastasis. Cell Death Dis 2017;8:e2736.
Zhao J, Wang Y, Han M, Lu H, Chen X, Liu S, et al. P7TP3 inhibits tumor development, migration, invasion and adhesion of liver cancer through the Wnt/β-catenin signaling pathway. Cancer Sci 2020;111:994-1007.
Zhu P, Liang H, Huang X, Zeng Q, Liu Y, Lv J, et al. Circular RNA Hsa_circ_0004018 inhibits Wnt/β-catenin signaling pathway by targeting microRNA-626/DKK3 in hepatocellular carcinoma. Onco Targets Ther 2020;13:9351-64.
Lei C, Wang Q, Tang N, Wang K. GSTZ1-1 downregulates Wnt/β- catenin signalling in hepatocellular carcinoma cells. FEBS Open Bio 2020;10:6-17.
Yuan K, Xie K, Lan T, Xu L, Chen X, et al. TXNDC12 promotes EMT and metastasis of hepatocellular carcinoma cells via activation of β-catenin. Cell Death Differ 2020;27:1355-68.
Wu N, Zhao J, Yuan Y, Lu C, Zhu W, Jiang Q. NOP7 interacts with β-catenin and activates β-catenin/TCF signaling in hepatocellular carcinoma cells. Onco Targets Ther 2018;11:6369-76.
Fan X, Ma X, Cui L, Dang S, Qu J, Zhang J, et al. CARF activates beta-catenin/TCF signaling in the hepatocellular carcinoma. Oncotarget 2016;7:80404-14.
Liu F, Wu X, Jiang X, Qian Y, Gao J. Prolonged inhibition of class I PI3K promotes liver cancer stem cell expansion by augmenting SGK3/ GSK-3β/β-catenin signaling. J Exp Clin Cancer Res 2018;37:122.
Lin X, Zuo S, Luo R, Li Y, Yu G, Zou Y, et al. HBX-induced miR- 5188 impairs FOXO1 to stimulate β-catenin nuclear translocation and promotes tumor stemness in hepatocellular carcinoma. Theranostics 2019;9:7583-98.
Zhu M, Gong Z, Wu Q, Su Q, Yang T, Yu R, et al. Homoharringtonine suppresses tumor proliferation and migration by regulating EphB4- mediated β-catenin loss in hepatocellular carcinoma. Cell Death Dis 2020;11:632.
Huang WJ, Tian XP, Bi SX, Zhang SR, He TS, Song LY, et al. The β-catenin/TCF-4-LINC01278-miR-1258-Smad2/3 axis promotes hepatocellular carcinoma metastasis. Oncogene 2020;39:4538-50.
Lin X, Li AM, Li YH, Luo RC, Zou YJ, Liu YY, et al. Silencing MYH9 blocks HBx-induced GSK3β ubiquitination and degradation to inhibit tumor stemness in hepatocellular carcinoma. Signal Transduct Target Ther 2020;5:13.
Cai Z, Qian ZY, Jiang H, Ma N, Li Z, Liu LY, et al. hPCL3s promotes hepatocellular carcinoma metastasis by activating β-catenin signaling. Cancer Res 2018;78:2536-49.
Lin Z, He R, Luo H, Lu C, Ning Z, Wu Y, et al. Integrin-β5, a miR- 185-targeted gene, promotes hepatocellular carcinoma tumorigenesis by regulating β-catenin stability. J Exp Clin Cancer Res 2018;37:17.
Lang YD, Chen HY, Ho CM, Shih JH, Hsu EC, Shen R, et al. PSPC1-interchanged interactions with PTK6 and β-catenin synergize oncogenic subcellular translocations and tumor progression. Nat Commun 2019;10:5716.
Chen J, Rajasekaran M, Xia H, Zhang X, Kong SN, Sekar K, et al. The microtubule-associated protein PRC1 promotes early recurrence of hepatocellular carcinoma in association with the Wnt/β-catenin signalling pathway. Gut 2016;65:1522-34.
Wen J, Xiong K, Aili A, Wang H, Zhu Y, Yu Z, et al. PEX5, a novel target of microRNA-31-5p, increases radioresistance in hepatocellular carcinoma by activating Wnt/β-catenin signaling and homologous recombination. Theranostics 2020;10:5322-40.
Lei T, Zhu X, Zhu K, Jia F, Li S. EGR1-induced upregulation of lncRNA FOXD2-AS1 promotes the progression of hepatocellular carcinoma via epigenetically silencing DKK1 and activating Wnt/β-catenin signaling pathway. Cancer Biol Ther 2019;20:1007-16.
Cao MQ, You AB, Zhu XD, Zhang W, Zhang YY, Zhang SZ, et al. miR- 182-5p promotes hepatocellular carcinoma progression by repressing FOXO3a. J Hematol Oncol 2018;11:12.
Guan L, Li T, Ai N, Wang W, He B, Bai Y, et al. MEIS2C and MEIS2D promote tumor progression via Wnt/β-catenin and hippo/YAP signaling in hepatocellular carcinoma. J Exp Clin Cancer Res 2019;38:417.
Fu X, Zhu X, Qin F, Zhang Y, Lin J, Ding Y, et al. Linc00210 drives Wnt/β-catenin signaling activation and liver tumor progression through CTNNBIP1-dependent manner. Mol Cancer 2018;17:73.
Zhang GC, Yu XN, Sun JL, Xiong J, Yang YJ, Jiang XM, et al. UBE2M promotes cell proliferation via the β-catenin/cyclin D1 signaling in hepatocellular carcinoma. Aging (Albany NY) 2020;12:2373-92.
Zhuang L, Wang X, Wang Z, Ma X, Han B, Zou H, et al. MicroRNA- 23b functions as an oncogene and activates AKT/GSK3β/β-catenin signaling by targeting ST7L in hepatocellular carcinoma. Cell Death Dis 2017;8:e2804.
Wu H, Ng R, Chen X, Steer CJ, Song G. MicroRNA-21 is a potential link between non-alcoholic fatty liver disease and hepatocellular carcinoma via modulation of the HBP1-p53-Srebp1c pathway. Gut 2016;65:1850-60.
Zhu RX, Cheng AS, Chan HL, Yang DY, Seto WK. Growth arrest-specific gene 2 suppresses hepatocarcinogenesis by intervention of cell cycle and p53-dependent apoptosis. World J Gastroenterol 2019;25:4715-26.
Qi W, Gao C, Zhang L, Gao Z, Sui J, Han C, et al. A p53-responsive microRNA, functions as a tumor suppressor in hepatocellular carcinoma by targeting FOXP4. Am J Cancer Res 2019;9:2665-78.
Cao H, Chen X, Wang Z, Wang L, Xia Q, Zhang W. The role of MDM2-p53 axis dysfunction in the hepatocellular carcinoma transformation. Cell Death Discov 2020;6:53.
Cioca A, Cimpean A, Ceausu R, Fit AM, Zaharie T, Al-Hajjar N, et al. Crosstalk between EGFR and p53 in hepatocellular carcinoma. Asian Pac J Cancer Prev 2014;15:8069-73.
Ye Y, Wang G, Wang G, Zhuang J, He S, Song Y, et al. The oncogenic role of tribbles 1 in hepatocellular carcinoma is mediated by a feedback loop involving microRNA-23a and p53. Front Physiol 2017;8:789.
Wu JH, Guo JP, Shi J, Wang H, Li LL, Guo B, et al. CMA down-regulates p53 expression through degradation of HMGB1 protein to inhibit irradiation-triggered apoptosis in hepatocellular carcinoma. World J Gastroenterol 2017;23:2308-17.
Zhao J, Wozniak A, Adams A, Cox J, Vittal A, Voss J, et al. SIRT7 regulates hepatocellular carcinoma response to therapy by altering the p53-dependent cell death pathway. J Exp Clin Cancer Res 2019;38:252.
Ma Z, Guo D, Wang Q, Liu P, Xiao Y, Wu P, et al. Lgr5-mediated p53 repression through PDCD5 leads to doxorubicin resistance in hepatocellular carcinoma. Theranostics 2019;9:2967-83.
Zhu L, Dai L, Yang N, Liu M, Ma S, Li C, et al. Transcription factorIRX5 promotes hepatocellular carcinoma proliferation and inhibits apoptosis by regulating the p53 signalling pathway. Cell Biochem Funct 2020;38:621-9.
Chang TC, Wei PL, Makondi PT, Chen WT, Huang CY, Chang YJ. Bromelain inhibits the ability of colorectal cancer cells to proliferate via activation of ROS production and autophagy. PLoS One 2019;14:e0210274.
Mohamad NE, Abu N, Yeap SK, Alitheen NB. Bromelain enhances the anti-tumor effects of cisplatin on 4T1 breast tumor model in vivo. Integr Cancer Ther 2019;18:1534735419880258.
Park S, Oh J, Kim M, Jin EJ. Bromelain effectively suppresses Kras-mutant colorectal cancer by stimulating ferroptosis. Anim Cells Syst (Seoul) 2018;22:334-40.
Kalra N, Bhui K, Roy P, Srivastava S, George J, Prasad S, et al. Regulation of p53, nuclear factor kappaB and cyclooxygenase-2 expression by bromelain through targeting mitogen-activated protein kinase pathway in mouse skin. Toxicol Appl Pharmacol 2008;226:30-7.
Amini A, Ehteda A, Moghaddam SM, Akhter J, Pillai K, Morris DL. Cytotoxic effects of bromelain in human gastrointestinal carcinoma cell lines (MKN45, KATO-III, HT29-5F12, and HT29-5M21). Onco Targets Ther 2013;6:403-9.
Kumar SS, Anjali T. In silico design and molecular docking studies of some 1, 2-benzisoxazole derivatives for their analgesic and anti-inflammatory activity. Int J Curr Pharm Res 2017;9:133-6.
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Copyright (c) 2021 Sushma S Murthy, T. Bala Narsaiah
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